ORCID Profile
0000-0002-5358-8552
Current Organisations
Flinders Medical Centre
,
South Australian Health and Medical Research Institute
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Publisher: Wiley
Date: 08-1998
DOI: 10.1111/J.1445-5994.1998.TB02108.X
Abstract: Direct anti-thrombin inhibitors such as hirudin have theoretical advantages over heparin. Two large studies in acute coronary syndromes were designed to test the thrombin hypothesis by demonstrating improved outcomes in hirudin treated patients. TIMI 9 assessed the effect of hirudin in patients with ST elevation receiving thrombolytic therapy. GUSTO 2 assessed the full spectrum of acute coronary syndromes of ST elevation and non-ST elevation. Over 15,000 patients were entered into the studies and no major benefit was demonstrated for hirudin. This may, however, relate to endpoints measured and the timing of the anti-thrombin.
Publisher: Wiley
Date: 14-11-2011
Publisher: Massachusetts Medical Society
Date: 24-03-2005
DOI: 10.1056/NEJMOA050522
Publisher: AMPCo
Date: 11-2010
Publisher: Wiley
Date: 10-1998
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-10-1996
Abstract: Background Elderly patients with acute myocardial infarction have much to gain from reperfusion with thrombolytic therapy but are also at increased risk of adverse events. We examined outcomes according to age of patients receiving thrombolysis in an international trial. Methods and Results Patients were randomized to streptokinase plus subcutaneous heparin, streptokinase plus intravenous heparin, accelerated tissue plasminogen activator (TPA) plus intravenous heparin, or streptokinase and TPA plus intravenous heparin. Clinical outcomes at 30 days (death, stroke, and nonfatal, disabling stroke) and 1-year mortality were summarized descriptively for patients aged (n=24 708), 65 to 74 (n=11 201), 75 to 85 (n=4625), and years (n=412) and assessed as continuous functions of age. Older patients had a higher-risk profile with regard to baseline clinical and angiographic characteristics. Mortality at 30 days increased markedly with age (3.0%, 9.5%, 19.6%, and 30.3% in the four groups, respectively), as did stroke, cardiogenic shock, bleeding, and reinfarction. Combined death or disabling stroke occurred less often with accelerated TPA in all but the oldest patients, who showed a weak trend toward a lower incidence with streptokinase plus subcutaneous heparin: odds ratio 1.13 95% confidence interval 0.6, 2.1. Similarly, accelerated TPA treatment resulted in lower 1-year mortality in all but the oldest patients (47% TPA versus 40.3% streptokinase). Conclusions Lower mortality and greater net clinical benefit were seen with accelerated TPA in patients aged ≤85 years. Because data are limited for patients aged years, the relative superiority of a given thrombolytic regimen cannot be determined. The interactions of stroke and mortality with newer thrombolytic strategies must be examined explicitly in older patients.
Publisher: Wiley
Date: 10-1989
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.JACC.2009.01.046
Abstract: We assessed the incremental value of baseline Q waves over time from symptom onset as a marker of clinical outcome in ST-segment elevation myocardial infarction (STEMI). Time from symptom onset is a central focus in STEMI patients. The presence of Q waves on the baseline electrocardiogram (ECG) has been suggested to be of incremental value to time from symptom onset in evaluating clinical outcomes. We evaluated baseline Q waves and ST-segment resolution 30 min after primary percutaneous intervention (PCI) ECGs in 4,530 STEMI patients without prior infarction. Additionally, peak biomarkers 90-day mortality and the composite of death, congestive heart failure (CHF), or cardiogenic shock were assessed. Fifty-six percent of patients had baseline Q waves: they were older, more frequently male and diabetic, and had a more advanced Killip class. Patients with baseline Q waves had greater mortality and a higher composite rate of death, CHF, and shock versus patients without baseline Q waves at 90 days (5.3% vs. 2.1% and 12.1% vs. 4.8%, respectively, both p < 0.001). Complete ST-segment resolution was highest, whereas 90-day mortality and the composite outcome were lowest among those randomized < or =3 h without baseline Q waves. After multivariable adjustment, baseline Q-wave but not time from symptom onset was significantly associated with a 78% relative increase in the hazard of 90-day mortality and a 90% relative increase in the hazard of death, shock, and CHF. Baseline Q waves in STEMI patients treated with primary PCI provide an independent prognostic marker of clinical outcome. These data might be useful in designing future clinical trials as well as in evaluating patients for triage and potential transfer for planned primary PCI. (Pexelizumab in Conjunction With Angioplasty in Acute Myocardial Infarction [APEX-AMI] NCT00091637).
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.JACC.2019.07.015
Abstract: Patients with acute coronary syndrome (ACS) and history of coronary artery bypass grafting (CABG) are at high risk for recurrent cardiovascular events and death. This study sought to determine the clinical benefit of adding alirocumab to statins in ACS patients with prior CABG in a pre-specified analysis of ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). Patients (n = 18,924) 1 to 12 months post-ACS with elevated atherogenic lipoprotein levels despite high-intensity statin therapy were randomized to alirocumab or placebo subcutaneously every 2 weeks. Median follow-up was 2.8 years. The primary composite endpoint of major adverse cardiovascular events (MACE) comprised coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint. Patients were categorized by CABG status: no CABG (n = 16,896) index CABG after qualifying ACS, but before randomization (n = 1,025) or CABG before the qualifying ACS (n = 1,003). In each CABG category, hazard ratios (95% confidence intervals) for MACE (no CABG 0.86 [0.78 to 0.95], index CABG 0.85 [0.54 to 1.35], prior CABG 0.77 [0.61 to 0.98]) and death (0.88 [0.75 to 1.03], 0.85 [0.46 to 1.59], 0.67 [0.44 to 1.01], respectively) were consistent with the overall trial results (0.85 [0.78 to 0.93] and 0.85 [0.73 to 0.98], respectively). Absolute risk reductions (95% confidence intervals) differed across CABG categories for MACE (no CABG 1.3% [0.5% to 2.2%], index CABG 0.9% [-2.3% to 4.0%], prior CABG 6.4% [0.9% to 12.0%]) and for death (0.4% [-0.1% to 1.0%], 0.5% [-1.9% to 2.9%], and 3.6% [0.0% to 7.2%]). Among patients with recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy, alirocumab was associated with large absolute reductions in MACE and death in those with CABG preceding the ACS event. (ODYSSEY OUTCOMES: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab NCT01663402).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-10-2000
DOI: 10.1161/01.CIR.102.15.1761
Abstract: Background —New recombinant plasminogen activators have been developed to simulate the fibrinolytic action of the physiological serine protease tissue plasminogen activator (alteplase, t-PA), and have prolonged half-life features permitting bolus administration. One such activator, reteplase (r-PA), was compared with t-PA in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-III Trial. Methods and Results —At 1-year follow-up, survival status was ascertained in 97.4% of the 15 059 patients enrolled in the GUSTO-III trial. At 1 year, the mortality rate for the t-PA–assigned group was 11.06%, and for r-PA it was 11.20% ( P =0.77). The absolute mortality difference of 0.14% has 95% CIs of −1.21% to 0.93%. There were no significant differences in outcome by intention-to-treat for the 2 different plasminogen activators in the prespecified groups (age, infarct location, time-to-treatment). The absolute difference in mortality rates between t-PA and r-PA progressively narrowed over the predetermined observation times after random assignment it was 0.31% at 24 hours, 0.26% at 7 days, 0.23% at 30 days, and 0.14% at 1 year. Of note, mortality rate in the trial between 30 days and 1 year in 13 883 patients was 4.02% and did not differ between the treatment groups. However, this mortality rate was substantially greater than in GUSTO-I, in which mortality rate for t-PA versus streptokinase between 30 days and 1-year was 2.97% (heart rate 1.36, 95% CI 1.23, 1.50, P .001). Conclusions —The r-PA and t-PA strategies yielded similar survival outcomes after 30 days in this trial. The increase in mortality rate during extended follow-up compared with previous trials may reflect higher-risk patients and highlights the need for improved secondary prevention strategies.
Publisher: Elsevier BV
Date: 2001
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-03-1995
Abstract: Background Despite remarkable advances in the treatment of acute myocardial infarction, substantial early patient mortality remains. Appropriate choices among alternative therapies and the use of clinical resources depend on an estimate of the patient’s risk. In idual patients reflect a combination of clinical features that influence prognosis, and these factors must be appropriately weighted to produce an accurate assessment of risk. Prior studies to define prognosis either were performed before widespread use of thrombolysis or were limited in s le size or spectrum of data. Using the large population of the GUSTO-I trial, we performed a comprehensive analysis of relations between baseline clinical data and 30-day mortality and developed a multivariable statistical model for risk assessment in candidates for thrombolytic therapy. Methods and Results For the 41 021 patients enrolled in GUSTO-I, a randomized trial of four thrombolytic strategies, relations between clinical descriptors routinely collected at initial presentation, and death within 30 days (which occurred in 7% of the population) were examined with both univariable and multivariable analyses. Variables studied included demographics, history and risk factors, presenting characteristics, and treatment assignment. Risk modeling was performed with logistic multiple regression and validated with bootstrapping techniques. Multivariable analysis identified age as the most significant factor influencing 30-day mortality, with rates of 1.1% in the youngest decile ( years) and 20.5% in patients (adjusted χ 2 =717, P .0001). Other factors most significantly associated with increased mortality were lower systolic blood pressure (χ 2 =550, P .0001), higher Killip class (χ 2 =350, P .0001), elevated heart rate (χ 2 =275, P .0001), and anterior infarction (χ 2 =143, P .0001). Together, these five characteristics contained 90% of the prognostic information in the baseline clinical data. Other significant though less important factors included previous myocardial infarction, height, time to treatment, diabetes, weight, smoking status, type of thrombolytic, previous bypass surgery, hypertension, and prior cerebrovascular disease. Combining prognostic variables through logistic regression, we produced a validated model that stratified patient risk and accurately estimated the likelihood of death. Conclusions The clinical determinants of mortality in patients treated with thrombolytic therapy within 6 hours of symptom onset are multifactorial and the relations complex. Although a few variables contain most of the prognostic information, many others contribute additional independent prognostic information. Through consideration of multiple characteristics, including age, medical history, physiological significance of the infarction, and medical treatment, the prognosis of an in idual patient can be accurately estimated.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.JCIN.2009.08.016
Abstract: Our purpose was to evaluate long-term mortality and identify factors associated with 1-year mortality in patients who underwent elective percutaneous coronary intervention (PCI). While long-term outcomes in PCI patients have been reported previously, limited data are currently available regarding the comparative long-term outcomes in PCI patients who receive enoxaparin versus intravenous unfractionated heparin (UFH). We conducted a follow-up analysis of clinical outcomes at 1 year in patients enrolled in the STEEPLE (SafeTy and Efficacy of Enoxaparin in Percutaneous coronary intervention patients, an internationaL randomized Evaluation) trial of 3,528 patients undergoing elective PCI. Patients were randomized to receive either intravenous 0.50-mg/kg or 0.75-mg/kg enoxaparin or intravenous UFH during elective PCI procedures. All-cause mortality at 1 year after index PCI was the main outcome measure. Mortality rates were 1.4%, 2.0%, and 1.5% from 1 month to 1 year, and 2.3%, 2.2%, and 1.9% from randomization to 1 year, after index PCI in patients receiving 0.50 mg/kg enoxaparin, 0.75 mg/kg enoxaparin, and UFH, respectively. Multivariate analysis identified nonfatal myocardial infarction and/or urgent target vessel revascularization up to 30 days after index PCI (hazard ratio: 3.5, 95% confidence interval: 1.7 to 7.3 p < 0.001), and major bleeding within 48 h (hazard ratio: 3.0, 95% confidence interval: 1.1 to 8.5 p = 0.04) as the strongest independent risk factors for 1-year mortality. The 1-year mortality rates were low and comparable between patients receiving enoxaparin and UFH during elective PCI. Periprocedural ischemic or bleeding events were the strongest independent predictors of 1-year mortality. (The STEEPLE Trial NCT00077844).
Publisher: Oxford University Press (OUP)
Date: 25-03-2013
Abstract: The TRA·CER trial compared vorapaxar, a novel platelet protease-activated receptor (PAR)-1 antagonist, with placebo in 12 944 patients with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS). In this analysis, we explored the effect of vorapaxar on myocardial infarction (MI). A blinded, independent central endpoint adjudication committee prospectively defined and classified MI according to the universal MI definition, including peak cardiac marker value (creatine kinase-MB [CK-MB] and/or troponin). Because the trial failed to meet its primary endpoint, these analyses are considered exploratory. During a median follow-up of 502 days, 1580 MIs occurred in 1319 patients. The majority (n = 1025, 64.9%) were type 1 (spontaneous) MI, followed by type 4a [percutaneous coronary intervention (PCI)-related] MI (n = 352 22.3%). Compared with placebo, vorapaxar reduced the hazard of a first MI of any type by 12% [hazard ratio (HR), 0.88 95% confidence interval (CI), 0.79-0.98 P = 0.021] and the hazard of total number of MIs (first and subsequent) by 14% (HR, 0.86 95% CI, 0.77-0.97 P = 0.014), an effect that was sustained over time. Vorapaxar reduced type 1 MI by 17% (HR, 0.83 95% CI, 0.73-0.95 P = 0.007). Type 4a MIs were not significantly reduced by vorapaxar (HR, 0.90 95% CI, 0.73-1.12 P = 0.35). Vorapaxar effect was consistent across MI sizes defined by peak cardiac marker elevations and across key clinical subgroups however, in patients not treated with thienopyridine at baseline (HR, 0.65 95% CI, 0.46-0.92) compared with patients who received thienopyridine (HR, 0.91 95% CI, 0.81-1.02), there was a trend towards a higher effect (Pint = 0.077). The PAR-1 antagonist vorapaxar was associated with a reduction of MI, including total number of infarctions. This reduction was sustained over time and was mostly evident in type 1 MI, the most common type of MI observed.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.CLINTHERA.2013.07.429
Abstract: Dual antiplatelet therapy is a guideline mandated for patients with acute coronary syndromes (ACS). Despite its use, thrombotic events continue to occur both early and late. Platelet function testing has been used to define the in vitro effects of new antiplatelet agents, and it has been suggested that it be used to choose therapy. The role of platelet function testing, particularly with newer antiplatelet agents, remains unclear. We review the rationale for platelet function testing and its application in monitoring patients on antiplatelet therapy. We also review recent clinical trials of newer antiplatelet agents. On the basis of this review, we reach conclusions on the current role of antiplatelet function testing in monitoring modern antiplatelet therapy and the role of the new antiplatelet agents in the treatment of ACS. We reviewed recent publications on platelet function testing and clinical trials of newer antiplatelet therapies compared with clopidogrel. Platelet function testing is complex, but there is now a bedside test, VerifyNow. High platelet reactivity has been associated with worse cardiovascular outcomes in patients undergoing percutaneous coronary intervention. Recent clinical trials have not found any advantage in outcomes in patients who have their therapy adjusted by monitoring their platelet function. Newer agents, prasugrel, ticagrelor, and cangrelor, produce more rapid, complete, less variable effects on platelet function than clopidogrel. Prasugrel was found to improve outcomes compared with clopidogrel in patients with ACS undergoing percutaneous intervention. Ticagrelor is beneficial in all patients with ACS and reduces cardiovascular mortality compared with clopidogrel. Cangrelor improves outcomes in patients undergoing stenting. Recent studies to assess the role of platelet function monitoring of the effects of clopidogrel and modifying treatments have not been successful. Recent clinical trials have indicated that newer antiplatelet agents have advantages over clopidogrel in the treatment of ACS. Platelet function testing gives us a guide to the timing, efficacy, and variability of therapy and can correlate with poor patient outcomes however, the use of antiplatelet function testing to tailor therapy does not seem appropriate.
Publisher: Elsevier BV
Date: 11-1998
DOI: 10.1016/S0002-8703(98)70133-4
Abstract: The safety and efficacy of bedside monitors of activated partial thromboplastin time (aPTT) have not been examined in a large population receiving intravenous heparin after thrombolytic treatment for acute myocardial infarction. We compared outcomes among patients monitored with these devices versus standard monitoring methods. Investigators chose the bedside device (n = 1713 patients) or their standard method (n = 26,162) for all aPTT measurements at their sites. Clinical outcomes at 30 days, 1-year mortality rate, and aPTT levels at 6, 12, and 24 hours were compared. Bedside-monitored patients had significantly less moderate/severe bleeding (10% vs 12%, P < .01), fewer transfusions (7% vs 11%, P < .001), and a smaller decrease in hematocrit (5.5% vs 6.7%, P < .001) but significantly more recurrent ischemia (22% vs 20%, P = .01). Fewer bedside-monitored patients had subtherapeutic aPTT levels at 12 and 24 hours. Among patients with subtherapeutic levels at 6 and 12 hours, more bedside-monitored patients had therapeutic levels when next monitored. After adjustment for baseline differences, no significant difference in mortality rate was observed in bedside-monitored patients at 30 days (4.3% vs 4.8%, P = .27) and at 1 year (7.1% vs 7.7%, P = .38). The groups had similar rates of reinfarction, shock, heart failure, and stroke. This prospective substudy supports the use of bedside monitoring of heparin anticoagulation after thrombolysis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2011
DOI: 10.1161/CIRCOUTCOMES.110.945311
Abstract: Prior studies demonstrate a direct relationship between treatment delays to primary percutaneous intervention and mortality in patients with ST-segment elevation myocardial infarction (STEMI). This analysis compared the relationship of symptom onset-to-balloon time and door-to-balloon time on mortality in patients with STEMI. We analyzed different treatment delays (symptom onset-to-balloon time, door-to-balloon time) and mortality in 5745 STEMI patients. Baseline characteristics, flow grade, 90-day mortality, and clinical outcomes were compared in patients stratified by treatment delay. Multivariable logistic regression modeling was performed to assess the independent and relative effect of each treatment delay on 90-day mortality. Female sex, increased age, and worse thrombolysis in myocardial infarction flow grade were significantly associated with longer symptom onset-to-balloon times and door-to-balloon times. Longer symptom onset-to-balloon time was significantly associated with worse 90-day mortality (3.7%, 4.2%, and 6.5% for time delays hours, 3 to 5 hours, and hours, respectively, P .0001). Similarly, longer door-to-balloon times were significantly associated with worse 90-day mortality (3.2%, 4.0%, 4.6%, and 5.3% for delays minutes, 60 to 90 minutes, 90 to 120 minutes, and ≥120 minutes respectively, P .0001). In a multivariate model of 90-day mortality, door-to-balloon time (χ 2 6.0, P .014), and symptom onset-to-hospital arrival (χ 2 9.8, P .007) remained independent determinants. Both symptom onset-to-balloon time and hospital door-to-balloon time are strongly associated with 90-day mortality following STEMI. URL: www.clinicaltrials.gov . Unique identifier: NCT00091637.
Publisher: American Medical Association (AMA)
Date: 19-04-2016
Abstract: p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes in myocardial infarction (MI). Pilot data in a phase 2 trial in non-ST elevation MI indicated that the p38 MAPK inhibitor losmapimod attenuates inflammation and may improve outcomes. To evaluate the efficacy and safety of losmapimod on cardiovascular outcomes in patients hospitalized with an acute myocardial infarction. LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries from June 3, 2014, until December 8, 2015. Part A consisted of a leading cohort (n = 3503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22,000 patients). Patients were considered potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk. Patients were randomized to either twice-daily losmapimod (7.5 mg n = 1738) or matching placebo (n = 1765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks. The primary end point was the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12. In part A, among the 3503 patients randomized (median age, 66 years 1036 [29.6%] were women), 99.1% had complete ascertainment for the primary outcome. The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with losmapimod (8.1% hazard ratio, 1.16 95% CI, 0.91-1.47 P = .24). The on-treatment rates of serious adverse events were 16.0% with losmapimod and 14.2% with placebo. Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population. clinicaltrials.gov Identifier: NCT02145468.
Publisher: Elsevier BV
Date: 03-1989
DOI: 10.1016/0735-1097(89)90225-8
Abstract: Ultrasound tissue characterization, the evaluation of certain physical properties of a tissue based on its acoustic properties, is an evolving application in echocardiography. The ability to identify acutely and chronically injured tissue has been demonstrated in a number of animal studies, but data in humans are limited. The present study tested the hypothesis that quantitative echocardiographic texture analysis, a method of evaluating the spatial pattern of echoes in echocardiographic images, would differentiate amyloid and hypertrophic cardiomyopathy from normal myocardium. Routine clinical echocardiographic data were obtained on 34 subjects at the Mayo Clinic (10 normal subjects, 10 patients with amyloid heart disease, 8 patients with hypertrophic cardiomyopathy and 6 patients with left ventricular hypertrophy due to hypertension). Standard videotape recordings of these echocardiograms were analyzed at the University of Iowa. Echocardiographic data were digitized with use of a calibrated, 256 gray level digitization system. Quantitative texture analysis was performed on data from the ventricular septum and posterior left ventricular wall in end-diastolic and end-systolic, short-axis and long-axis echocardiographic images. The gray level run length texture variables were able to discriminate hypertrophic cardiomyopathy and amyloid heart disease from normal myocardium and from each other (p less than 0.0083 for comparisons of the quantitative texture features of amyloid versus hypertrophic cardiomyopathy versus normal by multivariate analysis of variance). The texture of the myocardium in hypertensive left ventricular hypertrophy not associated with amyloid or hypertrophic cardiomyopathy was in general not significantly different from that of normal myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Wiley
Date: 23-12-2015
DOI: 10.1002/CCD.26335
Abstract: We evaluated outcomes associated with transradial vs. transfemoral approaches and vorapaxar in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) in the TRACER trial. Vorapaxar reduces ischemic events but increases the risk of major bleeding. We compared 30-day and 2-year major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization) and noncoronary artery bypass graft (CABG)-related bleedings in 2,192 transradial and 4,880 transfemoral patients undergoing PCI after adjusting for confounding variables, including propensity for transradial access. Overall, 30-day GUSTO moderate/severe and non-CABG TIMI major/minor bleeding occurred less frequently in transradial (0.9% vs. 2.0%, P = 0.001) vs. transfemoral (1.1% vs. 2.5%, P = 0.005) patients. A similar reduction was seen at 2 years (3.3% vs. 4.7%, P = 0.008 3.3% vs. 4.9%, P < 0.001, respectively). Transradial was associated with an increased risk of ischemic events at 30 days (OR 1.38, 95% CI 1.11-1.72 P = 0.004), driven primarily by increased periprocedural myocardial infarctions. At 2 years, rates of MACE were comparable (HR 1.14, 95% CI 0.98-1.33 P = 0.096). Although bleeding rates were higher with vorapaxar in transfemoral vs. transradial patients, there was no significant treatment interaction. Also, the access site did not modulate the association between vorapaxar and MACE. Transradial access was associated with lower bleeding rates and similar long-term ischemic outcomes, suggesting transradial access is safer than transfemoral access among ACS patients receiving potent antiplatelet therapies. Because of the nonrandomized allocation of arterial access, these results should be considered exploratory. © 2015 Wiley Periodicals, Inc.
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.JCIN.2018.02.006
Abstract: In 13,038 patients with non-ST-segment elevation acute coronary syndrome undergoing index percutaneous coronary intervention (PCI) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) and TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trials, the relationship between PCI-related myocardial infarction (MI) and 1-year mortality was assessed. The definition of PCI-related MI is controversial. The third universal definition of PCI-related MI requires cardiac troponin >5 times the 99th percentile of the normal reference limit from a stable or falling baseline and PCI-related clinical or angiographic complications. The definition from the Society for Cardiovascular Angiography and Interventions (SCAI) requires creatine kinase-MB elevation >10 times the upper limit of normal (or 5 times if new electrocardiographic Q waves are present). Implications of these definitions on prognosis, prevalence, and implementation are not established. In our cohort of patients undergoing PCI, PCI-related MIs were classified using the third universal type 4a MI definition and SCAI criteria. In the subgroup of patients included in the angiographic core laboratory (ACL) substudy of EARLY ACS (n = 1,401) local investigator- versus ACL-reported angiographic complications were compared. Altogether, 2.0% of patients met third universal definition of PCI-related MI criteria, and 1.2% met SCAI criteria. One-year mortality was 3.3% with the third universal definition (hazard ratio: 1.96 95% confidence interval: 1.24 to 3.10) and 5.3% with SCAI criteria (hazard ratio: 2.79 95% confidence interval: 1.69 to 4.58 p < 0.001). Agreement between ACL and local investigators in detecting angiographic complications during PCI was overall moderate (κ = 0.53). The third universal definition of MI and the SCAI definition were both associated with significant risk for mortality at 1 year. Suboptimal concordance was observed between ACL and local investigators in identifying patients with PCI complications detected on angiography. (Trial to Assess the Effects of Vorapaxar [SCH 530348 MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRA·CER] [Study P04736] NCT00527943 EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome [Study P03684AM2] NCT00089895).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-12-2018
Abstract: Vorapaxar, a protease‐activated receptor‐1 antagonist, is approved for secondary prevention of cardiovascular events but is associated with increased intracranial hemorrhage. TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) was a trial of vorapaxar versus placebo among patients with acute coronary syndrome. Strokes were adjudicated by a central events committee. Of 12 944 patients, 199 (1.5%) had ≥1 stroke during the study period (median follow‐up, 477 days). Four patients had a single stroke of unknown type 195 patients had ≥1 stroke classified as hemorrhagic or nonhemorrhagic (165 nonhemorrhagic, 28 hemorrhagic, and 2 both). Strokes occurred in 96 of 6473 patients (1.5%) assigned vorapaxar and 103 of 6471 patients (1.6%) assigned placebo. Kaplan‐Meier incidence of stroke for vorapaxar versus placebo was higher for hemorrhagic stroke (0.45% versus 0.14% [hazard ratio, 2.74 95% confidence interval, 1.22–6.15]), lower but not significantly different for nonhemorrhagic stroke (1.53% versus 1.98% at 2 years [hazard ratio, 0.79 95% confidence interval, 0.58–1.07]), and similar for stroke overall (1.93% versus 2.13% at 2 years [hazard ratio, 0.94 95% confidence interval, 0.71–1.24]). Stroke occurred in % of patients. Vorapaxar‐assigned patients had increased hemorrhagic stroke but a nonsignificant trend toward lower nonhemorrhagic stroke. Overall stroke frequency was similar with vorapaxar versus placebo.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-01-2014
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.IJCARD.2013.10.062
Abstract: A substantial portion of patients with atrial fibrillation (AF) also have coronary artery disease (CAD) and are at risk for coronary events. Warfarin is known to reduce these events, but increase the risk of bleeding. We assessed the effects of apixaban compared with warfarin in AF patients with and without prior CAD. In ARISTOTLE, 18,201 patients with AF were randomized to apixaban or warfarin. History of CAD was defined as documented CAD, prior myocardial infarction, and/or history of coronary revascularization. We analyzed baseline characteristics and clinical outcomes of patients with and without prior CAD and compared outcomes by randomized treatment using Cox models. A total of 6639 (36.5%) patients had prior CAD. These patients were more often male, more likely to have prior stroke, diabetes, and hypertension, and more often received aspirin at baseline (42.2% vs. 24.5%). The effects of apixaban were similar among patients with and without prior CAD on reducing stroke or systemic embolism and death from any cause (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.71-1.27, P for interaction=0.12 HR 0.96, 95% CI 0.81-1.13, P for interaction=0.28). Rates of myocardial infarction were numerically lower with apixaban than warfarin among patients with and without prior CAD. The effect of apixaban on reducing major bleeding and intracranial hemorrhage was consistent in patients with and without CAD. In patients with AF, apixaban more often prevented stroke or systemic embolism and death and caused less bleeding than warfarin, regardless of the presence of prior CAD. Given the common occurrence of AF and CAD and the higher rates of cardiovascular events and death, our results indicate that apixaban may be a better treatment option than warfarin for these high-risk patients.
Publisher: AMPCo
Date: 05-1995
Publisher: Oxford University Press (OUP)
Date: 13-03-2014
Abstract: This study characterized a medically managed population in a non-ST-segment elevation acute coronary syndrome (NSTEACS) cohort and evaluated prognosis and outcomes of vorapaxar vs. placebo. In the TRACER study, 12,944 NSTEACS patients were treated with standard care and vorapaxar (a novel platelet protease-activated receptor-1 antagonist) or placebo. Of those, 4194 patients (32.4%) did not undergo revascularization during index hospitalization, and 8750 (67.6%) underwent percutaneous coronary intervention or coronary artery bypass grafting. Patients managed medically were heterogeneous with different risk profiles, including 1137 (27.1%) who did not undergo coronary angiography. Patients who underwent angiography but were selected for medical management included those without evidence of significant coronary artery disease (CAD), with prior CAD but no new significant lesions, and with significant lesions who were not treated with revascularization. Cardiovascular event rates were highest among those without angiography and lowest in the group with angiography but without CAD. In the medically managed cohort, 2-year primary outcome (cardiovascular death, myocardial infarction, stroke, recurrent ischaemia with rehospitalization, urgent coronary revascularization) event rates were 16.3% with vorapaxar and 17.0% with placebo (HR 0.99, 95% CI 0.83-1.17), with no interaction between drug and management strategy (p=0.75). Key secondary endpoint (cardiovascular death, myocardial infarction, stroke) rates were 13.4% with vorapaxar and 14.9% with placebo (HR 0.89, 95% CI 0.74-1.07), with no interaction (p=0.58). Vorapaxar increased GUSTO moderate/severe bleeding numerically in medically managed patients (adjusted HR 1.46, 95% CI 0.99-2.15). NSTEACS patients who were initially medically managed had a higher risk-factor burden, and one-third had normal coronary arteries. Outcome in the medically managed cohort was significantly related to degree of CAD, highlighting the importance of coronary angiography. Efficacy and safety of vorapaxar appeared consistent with the overall trial results.
Publisher: Elsevier BV
Date: 08-2011
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.AHJ.2015.02.012
Abstract: p38 mitogen-activated protein kinase (MAPK) mediates cytokine production and lification of the inflammatory cascade. Through inhibition of p38 MAPK, losmapimod appears to attenuate the inflammatory response in the vascular wall and thus may help stabilize plaques. The LATITUDE-TIMI 60 trial is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study planned to be conducted in a 3-stage design. Overall, the trial is designed to include 25,500 patients hospitalized with non-ST-elevation or ST-elevation myocardial infarction (MI) randomized to oral losmapimod (7.5 mg twice daily) versus matching placebo. Part A consists of a leading cohort (n = 3,500) that will provide an initial assessment of safety and exploratory efficacy before progressing to part B. Part B (n = ~22,000) of the study is event driven and will provide the primary assessment of efficacy. An independent safety review will be conducted after 3,500 patients in part B1 to determine whether a more focused schedule of clinic visits and laboratory assessments can be implemented (part B2). All patients are to be treated with study drug until week 12 and followed up until week 24. The primary end point is the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization. The key secondary end point is the composite of cardiovascular death or MI. The trial is designed to provide ≥90% power for the primary end point. The LATITUDE-TIMI 60 trial will determine the efficacy and safety of short-term p38 MAPK inhibition with losmapimod in acute MI. The trial design adopts a stepwise approach to decision making and collection of data.
Publisher: Elsevier BV
Date: 12-2001
DOI: 10.1016/S0140-6736(01)06887-8
Abstract: The combination of fibrinolytic therapy and heparin for acute myocardial infarction fails to achieve reperfusion in 40-70% of patients, and early reocclusion occurs in a substantial number. We did a randomised, open-label trial to compare the thrombin-specific anticoagulant, bivalirudin, with heparin in patients undergoing fibrinolysis with streptokinase for acute myocardial infarction. 17073 patients with acute ST-elevation myocardial infarction were randomly assigned an intravenous bolus and 48-h infusion of either bivalirudin (n=8516) or heparin (n=8557), together with a standard 1.5 million unit dose of streptokinase given directly after the antithrombotic bolus. The primary endpoint was 30-day mortality. Secondary endpoints included reinfarction within 96 h and bleeding. Strokes and reinfarctions were adjudicated by independent committees who were unaware of treatment allocation. Analysis was by intention to treat. By 30 days, 919 patients (10.8%) in the bivalirudin group and 931 (10.9%) in the heparin group had died (odds ratio 0.99 [95% CI 0.90-1.09], p=0.85). The mortality rates adjusted for baseline risk factors were 10.5% for bivalirudin and 10.9% for heparin (0.96 [0.86-1.07], p=0.46). There were significantly fewer reinfarctions within 96 h in the bivalirudin group than in the heparin group (0.70 [0.56-0.87], p=0.001). Severe bleeding occurred in 58 patients (0.7%) in the bivalirudin group versus 40 patients (0.5%) in the heparin group (p=0.07), and intracerebral bleeding occurred in 47 (0.6%) versus 32 (0.4%), respectively (p=0.09). The rates of moderate and mild bleeding were significantly higher in the bivalirudin group than the heparin group (1.32 [1.00-1.74], p=0.05 and 1.47 [1.34-1.62], p<0.0001 respectively). Transfusions were given to 118 patients (1.4%) in the bivalirudin group versus 95 patients (1.1%) in the heparin group (1.25 [0.95-1.64], p=0.11). Bivalirudin did not reduce mortality compared with unfractionated heparin, but did reduce the rate of adjudicated reinfarction within 96 h by 30%. Small absolute increases were seen in mild and moderate bleeding in patients given bivalirudin. Bivalirudin is a new anticoagulant treatment option in patients with acute myocardial infarction treated with streptokinase.
Publisher: Elsevier BV
Date: 09-1997
Publisher: SAGE Publications
Date: 10-1986
DOI: 10.1177/016173468600800401
Abstract: In this study we tested the efficacy of quantitative texture analysis in the identification of acute myocardial ischemia using an ultrasound data acquisition system that digitizes and stores echocardiographic data in polar format. In nine closed-chest dogs, data were acquired before and after coronary occlusion using a 2.4 MHz echocardiographic system. Regions of interest were analyzed at end-diastole and end-systole from the ischemic area and normal area at the same depth of field. Ultrasound data were evaluated using previously reported quantitative gray level texture measures. After occlusion, texture changes indicative of ischemia were found in systolic images. The directional component of the data analysis was important analysis in the azimuthal direction was more accurate than in the axial direction. Six texture measures exhibited significant changes in the ischemic region from control to occlusion when analyzing data in the azimuthal direction. One false positive result occurred (significant texture change in the normal region from control to occlusion) in the azimuthal direction. Several false positive alterations in the normal regions from control to occlusion were found when the texture was evaluated in the axial direction. For accurate assessment of ischemic changes, preocclusion image data were required. We conclude that quantitative echocardiographic texture analysis using polar format data can identify subtle changes in myocardial texture such as that due to acute ischemia, using data acquired through the Chest Wall.
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.JCIN.2010.06.017
Abstract: The aim of this study was to evaluate outcomes of patients with moderate- and high-risk acute coronary syndromes (ACS) and multivessel coronary artery disease managed with percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG). There is uncertainty about the preferred revascularization strategy for high-risk patients with multivessel disease. Among 13,819 moderate- and high-risk ACS patients enrolled in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, 5,627 had multivessel disease (including left anterior descending artery involvement) and were managed by PCI (n = 4,412) or CABG (n = 1,215). Propensity score matching was applied to adjust for differences in baseline clinical and angiographic characteristics, yielding a total of 1,056 patients (528 managed by PCI, and 528 managed by CABG). Propensity-matched patients undergoing CABG had higher 1-month rates of stroke (1.1% vs. 0.0%, p = 0.03) and myocardial infarction (13.3% vs. 8.8%, p = 0.03), received more blood transfusions (40.3% vs. 6.3%, p < 0.0001) and more frequently developed acute renal injury (31.7% vs. 14.2%, p < 0.0001), whereas PCI was associated with higher rates of unplanned revascularization at both 1 month and at 1 year (0.8% vs. 5.2%, p < 0.0001 and 3.8% vs. 16.5%, p < 0.0001, respectively). There were no significant differences between the CABG and PCI groups in 1-month or 1-year mortality (2.5% vs. 2.1%, p = 0.69 and 4.4% vs. 5.7%, p = 0.58, respectively). In this propensity-matched comparison from the ACUITY trial, moderate- and high-risk patients with ACS and multivessel disease treated with PCI rather than CABG had lower rates of peri-procedural stroke, myocardial infarction, major bleeding, and renal injury, with comparable 1-month and 1-year rates of mortality, but more frequently developed recurrent ischemia requiring repeat revascularization procedures during follow-up. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes [ACS] NCT00093158).
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.AHJ.2014.09.002
Abstract: Protease-activated receptor 1 antagonism with vorapaxar represents a novel strategy for platelet inhibition. In TRACER, vorapaxar was compared with placebo plus standard of care among 12,944 patients with non-ST-segment elevation acute coronary syndromes. We anticipated that most patients would have received clopidogrel as part of standard care. We investigated the modification of vorapaxar's effect associated with clopidogrel use over time. The marginal structural model method was used to estimate causal modification of vorapaxar effect by use of clopidogrel over time. The primary outcomes were the composite of cardiovascular death, myocardial infarction, or stroke and Global Use of Strategies to Open Occluded Coronary Arteries moderate or severe bleeding. The event accrual period excluded the time during which clopidogrel was clinically warranted. Among 12,887 patients who received study medication, 11,117 (86.3%) received clopidogrel before randomization, of whom 38.5% stopped later in the trial (median time to stoppage 200 days with placebo interquartile range [IQR] 14-367) (186 days with vorapaxar IQR 17-366). In total, 1,770 (13.7%) patients were not on clopidogrel at randomization, of whom 47.8% started afterward (median time to start 2 days IQR 2-4). During the period of event accrual, vorapaxar was associated with a 26% reduction in the composite of cardiovascular death, myocardial infarction, or stroke when used with clopidogrel (hazard ratio [HR] 0.74 95% CI 0.60-0.91) and a 24% reduction when used without clopidogrel (HR 0.76 95% CI 0.56-1.02) (interaction P = .89). The hazard of Global Use of Strategies to Open Occluded Coronary Arteries bleeding with vorapaxar was not significantly different without clopidogrel (HR 1.33 95% CI 0.81-2.20) or with clopidogrel (HR 1.09 95% CI 0.76-1.56) (interaction P = .53). We observed no interaction between vorapaxar and clopidogrel after non-ST-segment elevation acute coronary syndromes on efficacy or safety outcomes, supporting a complementary role of protease-activated receptor 1 and P2Y12 antagonism.
Publisher: Oxford University Press (OUP)
Date: 27-05-2017
Abstract: To study the relation between visit-to-visit variability of blood pressure (BP) and cardiovascular risk in patients with stable coronary heart disease. In 15 828 patients from the STABILITY trial (darapladib vs. placebo in patients with established coronary heart disease), BP variability was assessed by the standard deviation (SD) of systolic BP, the SD of diastolic BP, maximum BP, and minimum BP, from 5 measurements (baseline and months 1, 3, 6, and 12) during the first year after randomisation. Mean (SD) average BP during the first year of study was 131.0 (13.7) mmHg over 78.3 (8.3) mmHg. Mean (SD) of the visit-to-visit SD was 9.8 (4.8) mmHg for systolic and 6.3 (3.0) mmHg for diastolic BP. During the subsequent median follow-up of 2.6 years, 1010 patients met the primary endpoint, a composite of time to cardiovascular death, myocardial infarction, or stroke. In Cox regression models adjusted for average BP during first year of study, baseline vascular disease, treatment, renal function and cardiovascular risk factors, the primary endpoint was associated with SD of systolic BP (hazard ratio for highest vs. lowest tertile, 1.30, 95% CI 1.10-1.53, P = 0.007), and with SD of diastolic BP (hazard ratio for highest vs. lowest tertile, 1.38, 95% CI 1.18-1.62, P < 0.001). Peaks and troughs in BP were also independently associated with adverse events. In patients with stable coronary heart disease, higher visit-to-visit variabilities of both systolic and diastolic BP are strong predictors of increased risk of cardiovascular events, independently of mean BP.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-08-2013
DOI: 10.1161/CIRCULATIONAHA.113.002303
Abstract: Dual antiplatelet therapy in older versus younger patients with acute coronary syndromes is understudied. Low-dose prasugrel (5 mg/d) is recommended for younger, lower-body-weight patients and elderly patients with acute coronary syndromes to mitigate the bleeding risk of standard-dose prasugrel (10 mg/d). A total of 9326 medically managed patients with acute coronary syndromes from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial ( years of age, n=7243 ≥75 years of age, n=2083) were randomized to prasugrel (10 mg/d 5 mg/d for those ≥75 or years of age and kg in weight) or clopidogrel (75 mg/d) plus aspirin for ≤30 months. A total of 515 participants ≥75 years of age (25% of total elderly population) had serial platelet reactivity unit measurements in a platelet-function substudy. Cumulative risks of the primary end point (cardiovascular death/myocardial infarction/stroke) and Thrombolysis in Myocardial Infarction (TIMI) major bleeding increased progressively with age and were ≥2-fold higher in older participants. Among those ≥75 years of age, TIMI major bleeding (4.1% versus 3.4% hazard ratio, 1.09 95% confidence interval, 0.57–2.08) and the primary end point rates were similar with reduced-dose prasugrel and clopidogrel. Despite a correlation between lower 30-day on-treatment platelet reactivity unit values and lower weight only in the prasugrel group, there was a nonsignificant treatment-by-weight interaction for platelet reactivity unit values among participants ≥75 years of age in the platelet-function substudy ( P =0.06). No differences in weight were seen in all participants ≥75 years of age with versus without TIMI major/minor bleeding in both treatment groups. Older age is associated with substantially increased long-term cardiovascular risk and bleeding among patients with medically managed acute coronary syndromes, with no differences in ischemic or bleeding outcomes with reduced-dose prasugrel compared with clopidogrel in elderly patients. No significant interactions among weight, pharmacodynamic response, and bleeding risk were observed between reduced-dose prasugrel and clopidogrel in elderly patients. URL: t2/home . Unique identifier: NCT0069999.
Publisher: Wiley
Date: 04-2006
Publisher: Informa UK Limited
Date: 04-01-2018
DOI: 10.1080/03007995.2017.1418175
Abstract: There remain substantial gaps in implementation of evidence-based care in patients with acute coronary syndromes (ACS) in Australia, which contribute to high recurrent event rates. Improved translation of evidence into effective action is a key health-care priority. We engaged cardiovascular experts from across Australia to develop straightforward, easily actionable recommendations on key medications to use following ACS. An eight-person steering committee (SC) reviewed the published evidence and developed an initial set of statements to be developed into consensus recommendations using a modified Delphi technique. A panel of 21 expert cardiologists in the ACS field (including the SC) voted on their level of agreement with the statements using a 6 point Likert scale. Statements that did not reach consensus (≥80% agreement) were reviewed by the SC, modified as appropriate based on input from the panel and circulated for re-voting. Twenty-eight statements were developed by the SC across six classes of medication: low-density lipoprotein (LDL) cholesterol lowering agents, aspirin, dual antiplatelet therapy, renin-angiotensin-aldosterone system inhibitors, beta blockers and "other". Twenty-six recommendations were endorsed by the voting panel two statements did not reach consensus. Despite the extensive evidence base and detailed guidelines outlining best practice post ACS, there remain considerable gaps in translating these into everyday care. We used an internationally recognized technique to develop practical consensus recommendations on medical treatment following ACS. These simple, up-to-date recommendations aim to improve evidence-based medication use and thereby reduce the risk of future cardiovascular events for Australian patients with ACS.
Publisher: Massachusetts Medical Society
Date: 26-08-1999
Publisher: Wiley
Date: 25-01-2013
DOI: 10.1111/ECHO.12136
Abstract: Recently it has been demonstrated that high resolution transthoracic echocardiography (HRTTE) is able to detect differences in the wall thickness of the left anterior descending coronary artery (LAD) between patients with coronary artery disease (CAD) and normal volunteers. We sought to validate this technique, develop a normal range of values and demonstrate the test-retest variability of each measurement. Two hundred forty-two volunteer participants had a HRTTE study to measure their LAD wall thickness, luminal, and external diameters. Thirty of these subjects had these measurements taken on 3 separate occasions by 2 different echosonographers. All subjects were free of clinical CAD, hypertension, hyperlipidemia, and diabetes mellitus. The average anterior wall thickness was 1.1 ± 0.2 mm posterior wall thickness was 1.1 ± 0.2 mm, luminal diameter 2.2 ± 0.6 mm, and external elastic membrane (EEM) diameter 4.5 ± 0.9 mm. The bias of the measurements within the same operator for LAD wall thickness, luminal diameter, and EEM was 0.042, -0.06, and -0.077 mm, respectively. The bias of the measurements between 2 different operators for LAD wall thickness, luminal diameter, and EEM was 0.082, -0.077, and -0.027 mm, respectively. In conclusion, HRTTE measurement of the LAD vessel is reproducible within and between operators in normal volunteers. This technique therefore warrants further study as a potential screening modality for subclinical coronary atherosclerosis.
Publisher: Elsevier BV
Date: 05-2015
Publisher: AMPCo
Date: 02-2014
DOI: 10.5694/MJA13.10645
Abstract: To evaluate the impact of the regionalised Integrated Cardiovascular Clinical Network (ICCNet) on 30-day mortality among patients with myocardial infarction (MI) in an Australian rural setting. An integrated cardiac support network incorporating standardised risk stratification, point-of-care troponin testing and cardiologist-supported decision making was progressively implemented in non-metropolitan areas of South Australia from 2001 to 2008. Hospital administrative data and statewide death records from 1 July 2001 to 30 June 2010 were used to evaluate outcomes for patients diagnosed with MI in rural and metropolitan hospitals. Risk-adjusted 30-day mortality. 29 623 independent contiguous episodes of MI were identified. The mean predicted 30-day mortality was lower among rural patients compared with metropolitan patients, while actual mortality rates were higher (30-day mortality: rural, 705/5630 [12.52%] v metropolitan, 2140/23 993 [8.92%] adjusted odds ratio [OR], 1.46 95% CI, 1.33-1.60 P< 0.001). After adjustment for temporal improvement in MI outcome, availability of immediate cardiac support was associated with a 22% relative odds reduction in 30-day mortality (OR, 0.78 95% CI, 0.65-0.93 P= 0.007). A strong association between network support and transfer of patients to metropolitan hospitals was observed (before ICCNet, 1102/2419 [45.56%] v after ICCNet, 2100/3211 [65.4%] P< 0.001), with lower mortality observed among transferred patients. Cardiologist-supported remote risk stratification, management and facilitated access to tertiary hospital-based early invasive management are associated with an improvement in 30-day mortality for patients who initially present to rural hospitals and are diagnosed with MI. These interventions closed the gap in mortality between rural and metropolitan patients in South Australia.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-11-1995
DOI: 10.1161/01.CIR.92.10.2811
Abstract: Background Stroke is the most feared complication of thrombolysis for acute myocardial infarction because of the resulting mortality and disability. We analyzed the incidence, timing, and outcomes of stroke in an international trial. Methods and Results Patients were randomly assigned to one of four thrombolytic strategies. Neurological events were confirmed clinically and anatomically and were adjudicated by a blinded committee. Stroke survivors, categorized by residual deficit and disability, assessed their quality of life with a time trade-off technique. Multivariable regression identified patient characteristics associated with intracranial hemorrhage. Overall, 1.4% of the patients had a stroke (93% anatomic documentation). The risk ranged from 1.19% with streptokinase/subcutaneous heparin therapy to 1.64% with combination thrombolytic therapy ( P =.007). Primary intracranial hemorrhage rates ranged from 0.46% with streptokinase/subcutaneous heparin to 0.88% with combination therapy ( P .001). Of all strokes, 41% were fatal, 31% were disabling, and 24% were nondisabling, with no significant treatment-related differences. Stroke subtype affected prognosis: 60% of patients with primary intracranial hemorrhage died and 25% were disabled versus 17% dead and 40% disabled with nonhemorrhagic infarctions. Patients with moderate or severe residual deficits showed significantly decreased quality of life. Advanced age, lower weight, prior cerebrovascular disease or hypertension, systolic and diastolic blood pressures, randomization to tissue plasminogen activator, and an interaction between age and hypertension were significant predictors of intracranial hemorrhage. Conclusions Stroke remains a rare but catastrophic complication of thrombolysis. Additional studies should assess the net clinical benefit of thrombolysis in high-risk subgroups, particularly the elderly and patients with prior cerebrovascular events.
Publisher: Oxford University Press (OUP)
Date: 14-10-2020
DOI: 10.1093/EURHEARTJ/EHAA649
Abstract: Lipoprotein(a) concentration is associated with first cardiovascular events in clinical trials. It is unknown if this relationship holds for total (first and subsequent) events. In the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab reduced lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), and cardiovascular events compared with placebo. This post hoc analysis determined whether baseline levels and alirocumab-induced changes in lipoprotein(a) and LDL-C [corrected for lipoprotein(a) cholesterol] independently predicted total cardiovascular events. Cardiovascular events included cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina or heart failure, ischaemia-driven coronary revascularization, peripheral artery disease events, and venous thromboembolism. Proportional hazards models estimated relationships between baseline lipoprotein(a) and total cardiovascular events in the placebo group, effects of alirocumab treatment on total cardiovascular events by baseline lipoprotein(a), and relationships between lipoprotein(a) reduction with alirocumab and subsequent risk of total cardiovascular events. Baseline lipoprotein(a) predicted total cardiovascular events with placebo, while higher baseline lipoprotein(a) levels were associated with greater reduction in total cardiovascular events with alirocumab (hazard ratio P trend = 0.045). Alirocumab-induced reductions in lipoprotein(a) (median −5.0 [−13.6, 0] mg/dL) and corrected LDL-C (median −51.3 [−67.1, −34.0] mg/dL) independently predicted lower risk of total cardiovascular events. Each 5-mg/dL reduction in lipoprotein(a) predicted a 2.5% relative reduction in cardiovascular events. Baseline lipoprotein(a) predicted the risk of total cardiovascular events and risk reduction by alirocumab. Lipoprotein(a) lowering contributed independently to cardiovascular event reduction, supporting the concept of lipoprotein(a) as a treatment target after ACS.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-1989
DOI: 10.1097/00004872-198908000-00002
Abstract: This study tested the hypothesis that a sphygmomanometer cuff bladder long enough to encircle the arm in most adults ('obese cuff') would provide a more accurate and precise estimate of intra-arterial pressure than the usual 'standard' cuff bladder. In 53 patients undergoing diagnostic coronary angiography (35 males, 18 females, aged 36-79 years), indirect blood pressure, measured in the left arm with a random-zero sphygmomanometer, was compared with simultaneously measured femoral intra-arterial pressure. Duplicate indirect measurements were made with each of two cuffs containing bladders measuring 39 x 15 cm ('obese') and 23 x 12 cm ('standard'). The obese cuff bladder encircled 80% or more of the arm circumference in all subjects, whereas the standard cuff bladder met this requirement in only 19% of the subjects. For both systolic and diastolic pressure there was marked interin idual variability in the differences between indirect and direct measurements with both cuffs. With the obese cuff there was no systematic error in the diastolic blood pressure measurement. The standard cuff consistently overestimated diastolic pressure by 7.7 +/- 8.3 mmHg (mean +/- s.d.). For both cuffs, the difference between indirect and direct diastolic pressure increased with arm size (P less than 0.05). Both cuffs underestimated systolic blood pressure, the obese cuff by 15.5 +/- 11.7 mmHg and the standard cuff by 7.6 +/- 12.1 mmHg. These systolic blood pressure underestimates were greater at higher blood pressures (P less than 0.01) and with smaller arms (P less than 0.05). Age was not related to measurement error with either cuff.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-08-2014
Abstract: Clinical trials traditionally use time‐to‐first‐event analysis embedded within the composite endpoint of cardiovascular death ( CVD ), myocardial infarction ( MI ), or stroke. However, many patients have event, and this approach may not reflect overall experience. We addressed this by analyzing all cardiovascular events in TRACER. TRACER randomized 12 944 patients with non‐ ST ‐segment elevation acute coronary syndromes to placebo or to protease‐activated receptor 1 antagonist vorapaxar with a median follow‐up of 502 days (interquartile range, 349 to 667). Analysis of vorapaxar's effect on recurrent CVD , MI , or stroke was prespecified using the Wei, Lin, and Weissfeld approach. Vorapaxar did not reduce the first occurrence of the primary endpoint of CVD , MI , stroke, revascularization, or rehospitalization for recurrent ischemia, but reduced the secondary composite endpoint of CVD , MI , or stroke (14.7% vorapaxar vs. 16.4% placebo hazard ratio [ HR], 0.89 95% confidence interval [ CI], 0.81 to 0.98 P =0.02 number needed to treat [ NNT ], 81). Recurrent secondary events occurred in 2.7% of patients. Vorapaxar reduced overall occurrences of ischemic events, first and subsequent ( HR, 0.88 95% CI, 0.80 to 0.98 P =0.02 NNT, 51). Also, there was a trend indicating that vorapaxar reduced the expanded endpoint, including revascularization and rehospitalization for recurrent ischemia ( HR, 0.92 95% CI, 0.84 to 1.01 P =0.09). Vorapaxar increased overall occurrences of moderate and severe Global Use of Strategies to Open Occluded Coronary Arteries bleeding ( HR, 1.42 95% CI, 1.21 to 1.66 P .001) and Thrombolysis in Myocardial Infarction clinically significant bleeding ( HR, 1.550 95% CI, 1.403 to 1.713 P .001). Vorapaxar reduced overall occurrences of ischemic events, but increased bleeding. These exploratory findings broaden our understanding of vorapaxar's potential and expand our understanding of the value of capturing recurrent events. URL: ClinicalTrials.gov. Unique identifier: NCT00527943.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.AHJ.2017.10.007
Abstract: Type 2 myocardial infarction (MI) is characterized by an imbalance between myocardial blood supply and demand, leading to myocardial ischemia without coronary plaque rupture, but its diagnosis is challenging. In the TRACER trial, patients with non-ST-segment elevation acute coronary syndromes were included. We aimed to describe provoking factors, cardiac biomarker profiles, treatment patterns, and clinical outcomes of patients with type 2 MIs. MI events during trial follow-up were adjudicated by an independent clinical events classification committee (CEC) and were classified according to the Third Universal Definition of MI. Using available source documents retrieved as part of the CEC process, we performed a retrospective chart abstraction to collect details on the type 2 MIs. Cox regression models were used to explore the association between MI type (type 1 or type 2) and cardiovascular death. Overall, 10.3% (n=1327) of TRACER participants had a total of 1579 adjudicated MIs during a median follow-up of 502 days (25th and 75th percentiles [IQR] 349-667). Of all MIs, 5.2% (n=82) were CEC-adjudicated type 2 MIs, occurring in 76 patients. The incidence of type 2 MI was higher in the first month following randomization, after which the distribution became more scattered. The most frequent potential provoking factors for type 2 MIs were tachyarrhythmias (38.2%), anemia/bleeding (21.1%), hypotension/shock (14.5%), and hypertensive emergencies (11.8%). Overall, 36.3% had a troponin increase >10× the upper limit of normal. Coronary angiography was performed in 22.4% (n=17) of patients during hospitalizations due to type 2 MIs. The hazard of cardiovascular death was numerically higher following type 2 MI (vs. no MI, adj. HR 11.82, 95% CI 5.71-24.46 P<.0001) than that of type 1 MI (vs. no MI, adj. HR 8.90, 95% CI 6.93-11.43 P<.0001). Type 2 MIs were more prevalent in the first month after ACS, were characterized by the presence of triggers and infrequent use of an invasive strategy, and were associated with a high risk of death. Further efforts are needed to better define the role and implications of type 2 MI in both clinical practice and research.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-05-2011
DOI: 10.1161/CIRCULATIONAHA.110.000786
Abstract: Atopaxar (E5555) is a reversible protease-activated receptor-1 thrombin receptor antagonist that interferes with platelet signaling. The primary objective of the Lessons From Antagonizing the Cellular Effects of Thrombin–Acute Coronary Syndromes (LANCELOT—ACS) trial was to evaluate the safety and tolerability of atopaxar in patients with ACS. Six hundred and three subjects were randomized within 72 hours of non–ST-elevation ACS to 1 of 3 doses of atopaxar (400-mg loading dose followed by 50, 100, or 200 mg daily) or matching placebo. The incidence of Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) major or minor bleeding did not differ significantly between the combined atopaxar and placebo groups (3.08% versus 2.17%, respectively P =0.63), and there was no dose-related trend ( P =0.80). The incidence of CURE major bleeding was numerically higher in the atopaxar group compared with the placebo group (1.8% versus 0% P =0.12). The incidence of cardiovascular death, myocardial infarction, stroke, or recurrent ischemia was similar between the atopaxar and placebo arms (8.03% versus 7.75% P =0.93). The incidence of CV death, MI, or stroke was 5.63% in the placebo group and 3.25% in the combined atopaxar group ( P =0.20). Dose-dependent trends for efficacy were not seen. Atopaxar significantly reduced ischemia on continuous ECG monitoring (Holter) at 48 hours compared with placebo (relative risk, 0.67 P =0.02). Transient dose-dependent transaminase elevation and relative QTc prolongation were observed with the highest doses of atopaxar. In patients after ACS, atopaxar significantly reduced early ischemia on Holter monitoring without a significant increase in major or minor bleeding. Larger trials are required to fully establish the efficacy and safety of atopaxar. URL: www.ClinicalTrials.gov . Unique identifier: NCT00548587.
Publisher: Oxford University Press (OUP)
Date: 13-07-2012
Publisher: BMJ
Date: 03-1990
DOI: 10.1136/HRT.63.3.195
Abstract: The accuracy and reproducibility of indirect measurement of cardiac output at rest by the carbon dioxide rebreathing (indirect Fick) method with an automated respiratory analysis system (Gould 9000IV) were compared with simultaneous measurements made in duplicate by dye dilution and thermodilution in 25 patients having cardiac catheterisation studies. Measurements of cardiac output by the carbon dioxide rebreathing method were not significantly different from those obtained with dye dilution (mean difference -0.3 l/min, SD 0.76, 95% confidence interval -0.7 to 0.1). Thermodilution significantly over-estimated cardiac output by a mean of 2.2 l/min or 39% (SD 1.5, 95% confidence interval 1.6 to 2.8) compared with the carbon dioxide rebreathing method and significantly overestimated cardiac output by 1.9 l/min or 31% (SD 1.2, 95% confidence interval 1.2 to 2.5) compared with dye dilution. The reproducibility of measurements of cardiac output in in idual patients was satisfactory with the dye dilution method but was poor with carbon dioxide rebreathing and thermodilution. Indirect measurement of resting cardiac output by the Gould 9000IV automated carbon dioxide rebreathing method is more accurate but the variability inherent with this method requires that multiple measurements be taken for each determination. Measurement of cardiac output by the thermodilution method by a commercially available cardiac output computer was not satisfactory because not only was there considerable variability between repeat measurements but the method also consistently overestimated cardiac output compared with the dye dilution method.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2015
Abstract: Perioperative antiplatelet agents potentially increase bleeding after non– ST ‐segment elevation ( NSTE ) acute coronary syndromes ( ACS ). The protease‐activated receptor 1 antagonist vorapaxar reduced cardiovascular events and was associated with increased bleeding versus placebo in NSTE ACS , but its efficacy and safety in noncardiac surgery ( NCS ) remain unknown. We aimed to evaluate ischemic, bleeding, and long‐term outcomes of vorapaxar in NCS after NSTE ACS . In the TRACER trial, 2202 (17.0%) patients underwent major or minor NCS after NSTE ACS over 1.5 years (median) continuing study treatment perioperatively was recommended. The primary ischemic end point for this analysis was cardiovascular death, myocardial infarction, stent thrombosis, or urgent revascularization within 30 days of NCS . Safety outcomes included 30‐day NCS bleeding and GUSTO moderate/severe bleeding. Overall, 1171 vorapaxar and 1031 placebo patients underwent NCS . Preoperative aspirin and thienopyridine use was 96.8% versus 97.7% ( P =0.235) and 89.1% versus 86.1% ( P =0.036) for vorapaxar versus placebo, respectively. Within 30 days of NCS , no differences were observed in the primary ischemic end point between vorapaxar and placebo groups (3.4% versus 3.9% adjusted odds ratio 0.81, 95% CI 0.50 to 1.33, P =0.41). Similarly, no differences in NCS bleeding (3.9% versus 3.4% adjusted odds ratio 1.41, 95% CI 0.87 to 2.31, P =0.17) or GUSTO moderate/severe bleeding (4.2% versus 3.7% adjusted odds ratio 1.15, 95% CI , 0.72 to 1.83, P =0.55) were observed. In a 30‐day landmarked analysis, NCS patients had a higher long‐term risk of the ischemic end point (adjusted hazard ratio 1.62, 95% CI 1.33 to 1.97, P .001) and GUSTO moderate/severe bleeding (adjusted hazard ratio 5.63, 95% CI 3.98 to 7.97, P .001) versus patients who did not undergo NCS , independent of study treatment. NCS after NSTE ACS is common and associated with more ischemic outcomes and bleeding. Vorapaxar after NSTE ACS was not associated with increased perioperative ischemic or bleeding events in patients undergoing NCS .
Publisher: Wiley
Date: 08-1998
DOI: 10.1111/J.1445-5994.1998.TB02109.X
Abstract: Unlike unfractionated heparin, direct thrombin inhibitors such as hirudin and Hirulog inhibit clot-bound as well as fluid-phase thrombin, escape neutralisation by platelet secretion products, do not require monitoring, and are unassociated with immune thrombocytopenia. They have been shown to have modest advantages over heparin when given after thrombolytic therapy, reducing reinfarction by 14%. In the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO 2b) trial, patients treated with streptokinase and adjunctive hirudin had a reduction in death or myocardial infarction of 40% at 30 days (8.6% with hirudin versus 14.4% with heparin, p = 0.004). In the Hirulog Early Reperfusion/Occlusion (HERO 1) trial, 48% of patients who received Hirulog as adjunctive therapy with streptokinase had Thrombolysis in Myocardial Infarction (TIMI) trial grade 3 flow in the infarct-related artery, compared with 35% of patients who received heparin with streptokinase (p < 0.05). The HERO 2 study, involving 17,000 patients, will test the hypothesis that Hirulog and aspirin given before streptokinase will reduce mortality compared with aspirin plus heparin. Early administration of direct thrombin inhibitors may potentially improve the outcome of patients treated with thrombolytic therapy.
Publisher: BMJ
Date: 02-1999
DOI: 10.1136/HRT.81.2.128
Publisher: Elsevier BV
Date: 11-1995
DOI: 10.1016/0735-1097(95)00299-5
Abstract: Our purpose was to evaluate the relation between smoking and the outcomes of patients receiving thrombolysis for acute myocardial infarction. A paradoxic beneficial effect has been observed in smokers with a myocardial infarction. We analyzed outcomes and baseline characteristics of 11,975 nonsmokers, 11,117 ex-smokers and 17,507 current smokers in a multinational trial of thrombolysis for acute myocardial infarction. Patients were randomized to one of four thrombolytic protocols. An angiographic substudy in 2,431 patients evaluated reperfusion, reocclusion and ventricular function. Effects of smoking were evaluated by logistic regression analysis after adjustment for age and gender. A mortality model evaluated the simultaneous effect of baseline characteristics on the prognostic importance of smoking. These processes were performed with data from both the main trial and the angiographic substudy then angiographic factors (coronary anatomy, patency and ejection fraction) were added to the model. Smokers were significantly younger by a mean of 11 years) and had less comorbidity or severe coronary artery disease than nonsmokers. Nonsmokers had significantly higher hospital and 30-day mortality rates (9.9% and 10.3%, respectively) than smokers (3.7% vs. 4%, respectively, both p < 0.001) and more in-hospital complications. The unadjusted odds ratio for 30-day mortality in nonsmokers was 3.36 (95% confidence interval [CI] 2.08 to 5.41), 1.21 (95% CI 0.71 to 2.08) after adjustment for age and gender and 1.08 (95% CI 0.59 to 1.96) after adjustment for all clinical baseline characteristics. Smokers receiving thrombolysis for acute myocardial infarction presented 11 years earlier than nonsmokers, which generally accounted for their better outcome. When other differences in clinical and angiographic baseline factors and therapeutic responses were evaluated, no significant difference in mortality was seen between smokers and nonsmokers.
Publisher: Wiley
Date: 10-2018
DOI: 10.1002/CLC.23043
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.JCIN.2008.03.019
Abstract: We sought to characterize the utilization and impact of a conservative medical management strategy for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) and significant coronary artery disease on early angiography. Practice guidelines recommend an early invasive management strategy for NSTE ACS, but revascularization procedures may not always be performed after early angiography, even when significant coronary artery disease is present. We evaluated 8,225 intermediate- to high-risk NSTE ACS patients with at least 1 coronary lesion >50% stenosis on early angiography from the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) trial (2001 to 2003), comparing patients treated with conservative medical management with those who underwent in-hospital percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) within 7 days of randomization. A total of 2,633 patients (32%) were medically managed, 4,294 (52%) underwent PCI, and 1,298 (16%) underwent CABG. The strongest independent predictors of conservative medical management versus any intervention were prior CABG, lower body weight, lack of a reinfarction between randomization and catheterization, and 3-vessel disease. With conservative medical management, the cumulative risk of 1-year mortality after discharge increased rapidly during the first 90 days and thereafter remained higher at 7.7% compared with that seen in patients treated with PCI (3.6%) or CABG (6.2%). One-third of patients with NSTE ACS and significant coronary disease on early angiography were managed without in-hospital revascularization in the SYNERGY trial, and these patients had an increased risk of late mortality. These findings highlight the need for novel treatment approaches for NSTE ACS patients who are not candidates for revascularization. (SYNERGY trial NCT00043784).
Publisher: American Medical Association (AMA)
Date: 08-10-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-1986
Abstract: Patients with heart failure have increased vascular resistance and evidence for increased neurohumoral drive. High levels of circulating norepinephrine are found in patients with heart failure, but it is not known whether they reflect increased sympathetic neural activity or result from altered synthesis, release, or metabolism of norepinephrine. We used microneurography (peroneal nerve) to directly record sympathetic nerve activity to muscle (mSNA) and also measured plasma norepinephrine levels in patients with heart failure and in normal control subjects. Our goal was to determine whether sympathetic nerve activity is increased in patients with heart failure and whether plasma norepinephrine levels correlate with levels of mSNA in heart failure. Resting muscle sympathetic nerve activity in 16 patients with moderate to severe heart failure (54 +/- 5 bursts/min, mean +/- SE) was significantly higher (p less than .01) than the levels of activity in either nine age-matched normal control subjects (25 +/- 4 bursts/min) or 19 "young" normal control subjects (24 +/- 2 bursts/min). We found a significant correlation between plasma norepinephrine levels and mSNA (r = .73, p less than .05). Neither mSNA nor plasma norepinephrine levels correlated with total systemic vascular resistance, cardiac index, left ventricular ejection fraction, or heart rate. However, both mSNA and plasma norepinephrine levels showed significant positive correlations (p less than .05) with left ventricular filling pressures (r = .80, mSNA vs filling pressures r = .82, norepinephrine levels vs filling pressures) and mean right atrial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Elsevier BV
Date: 2006
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.AHJ.2016.04.013
Abstract: Albuminuria is associated with cardiovascular (CV) outcomes. We evaluated albuminuria, alone and in combination with estimated glomerular filtration rate (eGFR), as a predictor of mortality and CV morbidity in 12,944 patients with non-ST-segment elevation acute coronary syndromes. Baseline serum creatinine and urinary dipsticks were obtained, with albuminuria stratified into no/trace albuminuria, microalbuminuria (≥30 but <300 mg/dL), or macroalbuminuria (≥300 mg/dL). Kaplan-Meier rates and proportional Cox hazards models of CV death, overall mortality, CV death or myocardial infarction (MI), and bleeding were calculated. Incidence of acute kidney injury, identified by adverse event reporting and creatinine increase (absolute ≥0.3 mg/dL or relative ≥50%), was descriptively reported. Both dipstick albuminuria and creatinine values were available in 9473 patients (73.2%). More patients with macroalbuminuria, versus no/trace albuminuria, had diabetes (66% vs 27%) or hypertension (86% vs 68%). Rates for CV death and overall mortality per strata were 3.1% and 4.8% (no/trace albuminuria) 5.8% and 9.0% (microalbuminuria) and 7.7% and 12.6% (macroalbuminuria) at 2 years of follow-up. Corresponding rates for CV death or MI were 12.2%, 16.9%, and 23.5%, respectively. Observed acute kidney injury rates were 0.6%, 1.2%, and 2.9% (n = 79), respectively. Adjusted HRs for macroalbuminuria on CV mortality were 1.65 (95% CI 1.15-2.37), and after adjustment with eGFR, 1.37 (95% CI 0.93-2.01). Corresponding HRs for overall mortality were 1.82 (95% CI 1.37-2.42) and 1.47 (95% CI 1.08-1.98). High-risk patients with non-ST-segment elevation acute coronary syndromes and albuminuria have increased morbidity and increased overall mortality independent of eGFR.
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.AHJ.2013.06.019
Abstract: Patients with prior coronary artery bypass graft surgery (CABG) who present with an acute coronary syndrome have a high risk for recurrent events. Whether intensive antiplatelet therapy with ticagrelor might be beneficial compared with clopidogrel is unknown. In this substudy of the PLATO trial, we studied the effects of randomized treatment dependent on history of CABG. Patients participating in PLATO were classified according to whether they had undergone prior CABG. The trial's primary and secondary end points were compared using Cox proportional hazards regression. Of the 18,613 study patients, 1,133 (6.1%) had prior CABG. Prior-CABG patients had more high-risk characteristics at study entry and a 2-fold increase in clinical events during follow-up, but less major bleeding. The primary end point (composite of cardiovascular death, myocardial infarction, and stroke) was reduced to a similar extent by ticagrelor among patients with (19.6% vs 21.4% adjusted hazard ratio [HR], 0.91 [0.67, 1.24]) and without (9.2% vs 11.0% adjusted HR, 0.86 [0.77, 0.96] P(interaction) = .73) prior CABG. Major bleeding was similar with ticagrelor versus clopidogrel among patients with (8.1% vs 8.7% adjusted HR, 0.89 [0.55, 1.47]) and without (11.8% vs 11.4% HR, 1.08 [0.98, 1.20] P(interaction) = .46) prior CABG. Prior-CABG patients presenting with acute coronary syndrome are a high-risk cohort for death and recurrent cardiovascular events but have a lower risk for major bleeding. Similar to the results in no-prior-CABG patients, ticagrelor was associated with a reduction in ischemic events without an increase in major bleeding.
Publisher: Oxford University Press (OUP)
Date: 05-05-2014
Abstract: Delcasertib is a selective inhibitor of delta-protein kinase C (delta-PKC), which reduced infarct size during ischaemia/reperfusion in animal models and diminished myocardial necrosis and improved reperfusion in a pilot study during primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI). A multicentre, double-blind trial was performed in patients presenting within 6 h and undergoing primary PCI for anterior (the primary analysis cohort, n = 1010 patients) or inferior (an exploratory cohort, capped at 166 patients) STEMI. Patients with anterior STEMI were randomized to placebo or one of three doses of delcasertib (50, 150, or 450 mg/h) by intravenous infusion initiated before PCI and continued for ∼2.5 h. There were no differences between treatment groups in the primary efficacy endpoint of infarct size measured by creatine kinase MB fraction area under the curve (AUC) (median 5156, 5043, 4419, and 5253 ng h/mL in the placebo, delcasertib 50, 150, and 450 mg/mL groups, respectively) in the anterior STEMI cohort. No treatment-related differences were seen in secondary endpoints of infarct size, electrocardiographic ST-segment recovery AUC or time to stable ST recovery, or left ventricular ejection fraction at 3 months. No differences in rates of adjudicated clinical endpoints (death, heart failure, or serious ventricular arrhythmias) were observed. Selective inhibition of delta-PKC with intravenous infusion of delcasertib during PCI for acute STEMI in a population of patients treated according to contemporary standard of care did not reduce biomarkers of myocardial injury.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-09-2010
DOI: 10.1161/CIRCULATIONAHA.109.933796
Abstract: Background— Reduced renal function is associated with a poorer prognosis and increased bleeding risk in patients with acute coronary syndromes and may therefore alter the risk-benefit ratio with antiplatelet therapies. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor compared with clopidogrel reduced the primary composite end point of cardiovascular death, myocardial infarction, and stroke at 12 months but with similar major bleeding rates. Methods and Results— Central laboratory serum creatinine levels were available in 15 202 (81.9%) acute coronary syndrome patients at baseline, and creatinine clearance, estimated by the Cockcroft Gault equation, was calculated. In patients with chronic kidney disease (creatinine clearance mL/min n=3237), ticagrelor versus clopidogrel significantly reduced the primary end point to 17.3% from 22.0% (hazard ratio [HR], 0.77 95% confidence interval [CI], 0.65 to 0.90) with an absolute risk reduction greater than that of patients with normal renal function (n=11 965): 7.9% versus 8.9% (HR, 0.90 95% CI, 0.79 to 1.02). In patients with chronic kidney disease, ticagrelor reduced total mortality (10.0% versus 14.0% HR, 0.72 95% CI, 0.58 to 0.89). Major bleeding rates, fatal bleedings, and non–coronary bypass–related major bleedings were not significantly different between the 2 randomized groups (15.1% versus 14.3% HR, 1.07 95% CI, 0.88 to 1.30 0.34% versus 0.77% HR, 0.48 95% CI, 0.15 to 1.54 and 8.5% versus 7.3% HR, 1.28 95% CI, 0.97 to 1.68). The interactions between creatinine clearance and randomized treatment on any of the outcome variables were nonsignificant. Conclusions— In acute coronary syndrome patients with chronic kidney disease, ticagrelor compared with clopidogrel significantly reduces ischemic end points and mortality without a significant increase in major bleeding but with numerically more non–procedure-related bleeding. Clinical Trial Registration— URL:www.clinicatrials.gov. Unique identifier: NCT00391872.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-06-2016
Abstract: We evaluated lipoprotein‐associated phospholipase A 2 (Lp‐ PLA 2 ) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp‐ PLA 2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. Plasma Lp‐ PLA 2 activity was determined at baseline (n=14 500) at 1 month (n=13 709) serially (n=100) at 3, 6, and 18 months and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp‐ PLA 2 activity levels and outcomes. At baseline, the median Lp‐ PLA 2 level was 172.4 μmol/min per liter (interquartile range 143.1–204.2 μmol/min per liter). Comparing the highest and lowest Lp‐ PLA 2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23–1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29–2.93) for hospitalization for heart failure, 1.42 (1.07–1.89) for cardiovascular death, and 1.37 (1.03–1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp‐ PLA 2 activity. There were no associations between on‐treatment Lp‐ PLA 2 activity or changes of Lp‐ PLA 2 activity and outcomes, and there were no significant interactions between baseline and on‐treatment Lp‐ PLA 2 activity or changes in Lp‐ PLA 2 activity levels and the effects of darapladib on outcomes. Although high Lp‐ PLA 2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp‐ PLA 2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp‐ PLA 2 activity. URL : www.clinicaltrials.gov . Unique identifier: NCT 00799903.
Publisher: Elsevier BV
Date: 04-2002
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-05-2020
Abstract: A proposed cause of dyspnea induced by ticagrelor is an increase in adenosine blood levels. Because caffeine is an adenosine antagonist, it can potentially improve drug tolerability with regard to dyspnea. Furthermore, association between caffeine and cardiovascular events is of clinical interest. This prespecified analysis used data from the PEGASUS TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54) trial, which randomized 21 162 patients with prior myocardial infarction to ticagrelor 60 mg or 90 mg or matching placebo (twice daily). Baseline caffeine intake in cups per week was prospectively collected for 9694 patients. Outcomes of interest included dyspnea, major adverse cardiovascular events (ie, the composite of cardiovascular death, myocardial infarction, or stroke), and arrhythmias. Dyspnea analyses considered the pooled ticagrelor group, whereas cardiovascular outcome analyses included patients from the 3 randomized arms. After adjustment, caffeine intake, compared with no intake, was not associated with lower rates of dyspnea in patients taking ticagrelor (adjusted hazard ratio (HR), 0.91 95% CI , 0.76–1.10 P =0.34). There was no excess risk with caffeine for major adverse cardiovascular events (adjusted HR, 0.78 95% CI, 0.63–0.98 P =0.031), sudden cardiac death (adjusted HR, 0.98 95% CI, 0.57–1.70 P =0.95), or atrial fibrillation (adjusted odds ratio, 1.07 95% CI, 0.56–2.04 P =0.84). In patients taking ticagrelor for secondary prevention after myocardial infarction, caffeine intake at baseline was not associated with lower rates of dyspnea compared with no intake. Otherwise, caffeine appeared to be safe in this population, with no apparent increase in atherothrombotic events or clinically significant arrhythmias. URL : www.clinicaltrials.gov Unique identifier: NCT 01225562.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Oxford University Press (OUP)
Date: 11-2004
DOI: 10.1016/J.EHJ.2004.08.006
Abstract: We analysed the contemporary incidence, outcomes, and predictors of heart failure (HF) and/or left ventricular systolic dysfunction (LVSD) before discharge in patients with acute myocardial infarction (MI). The baseline presence of HF or LVSD, or its development during hospitalisation, increases short- and long-term risk after MI, yet its incidence, predictors, and outcomes have not been well described in a large, international, general MI population. The VALIANT registry included 5573 consecutive MI patients at 84 hospitals in nine countries from 1999 to 2001. A multivariable logistic survival model was constructed using baseline variables to determine the adjusted mortality risk for those with in-hospital HF and/or LVSD. Baseline variables were also tested for associations with in-hospital HF and/or LVSD. Of the 5566 patients analysed, 42% had HF and/or LVSD during hospitalisation. Their in-hospital mortality rate was 13.0% compared with 2.3% for those without HF and/or without LVSD. After adjustment for other baseline risk factors, in-hospital HF and/or LVSD carried a hazard ratio for in-hospital mortality of 4.12 (95% confidence interval: 3.08-5.56). Patients with HF and/or LVSD also had disproportionately higher rates of other cardiovascular events. HF and/or LVSD is common in the general contemporary MI population and precedes 80.3% of all in-hospital deaths after MI. Survivors of early MI-associated HF and/or LVSD have more complications, longer hospitalisations, and are more likely to die during hospitalisation. Although baseline variables can identify MI patients at highest risk for HF and/or LVSD, such patients are less likely to receive indicated procedures and medical therapies.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.JACC.2016.02.056
Abstract: The Bleeding Academic Research Consortium (BARC) scale has been proposed to standardize bleeding endpoint definitions and reporting in cardiovascular trials. Validation in large cohorts of patients is needed. This study sought to investigate the relationship between BARC-classified bleeding and mortality and compared its prognostic value against 2 validated bleeding scales: TIMI (Thrombolysis In Myocardial Infarction) and GUSTO (Global Use of Strategies to Open Occluded Arteries). We analyzed bleeding in 12,944 patients with acute coronary syndromes without ST-segment elevation, with or without early invasive strategy. The main outcome measure was all-cause death. During follow-up (median: 502 days), noncoronary artery bypass graft (CABG) bleeding occurred in 1,998 (15.4%) patients according to BARC (grades 2, 3, or 5), 484 (3.7%) patients according to TIMI minor/major, and 514 (4.0%) patients according to GUSTO moderate/severe criteria. CABG-related bleeding (BARC 4) occurred in 155 (1.2%) patients. Patients with BARC (2, 3, or 4) bleeding had a significant increase in risk of death versus patients without bleeding (BARC 0 or 1) the hazard was highest in the 30 days after bleeding (hazard ratio: 7.35 95% confidence interval: 5.59 to 9.68 p < 0.0001) and remained significant up to 1 year. The hazard of mortality increased progressively with non-CABG BARC grades. BARC 4 bleeds were significantly associated with mortality within 30 days (hazard ratio: 10.05 95% confidence interval: 5.41 to 18.69 p < 0.0001), but not thereafter. Inclusion of BARC (2, 3, or 4) bleeding in the 1-year mortality model with baseline characteristics improved it to an extent comparable to TIMI minor/major and GUSTO moderate/severe bleeding. In patients with acute coronary syndromes without ST-segment elevation, bleeding assessed with the BARC scale was significantly associated with risk of subsequent death up to 1 year after the event and risk of mortality increased gradually with higher BARC grades. Our results support adoption of the BARC bleeding scale in ACS clinical trials. (Trial to Assess the Effects of Vorapaxar [SCH 530348 MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER] [Study P04736] NCT00527943).
Publisher: Elsevier BV
Date: 12-2002
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.AMJCARD.2018.06.052
Abstract: Patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) are sometimes treated with medical management alone rather than an invasive strategy. Among those medically managed without revascularization and discharged, a proportion will require revascularization later on, but little is known about this population. In TRILOGY ACS, 9,326 patients with NSTE ACS who were selected for medical management alone were randomized to treatment with prasugrel or clopidogrel and discharged without revascularization. Patient characteristics and ischemic and bleeding outcomes through 30 months were compared between patients who underwent downstream revascularization after the index hospitalization and those who did not. A total of 662 patients (7.1%) underwent later revascularization by percutaneous coronary intervention (73.1%), coronary artery bypass graft surgery (26.4%), or the two (0.5%). Median time to revascularization was 121 days (twenty-fifth, seventy-fifth percentiles: 41, 326). Revascularized patients were younger, more likely to be male, and had higher rates of hyperlipidemia, diabetes mellitus, prior myocardial infarction, and prior revascularization compared with those not revascularized. Europe and North America had the highest rates of revascularization. During the follow-up period, those who underwent revascularization had a higher rate of the composite outcome of cardiovascular death, myocardial infarction, or stroke occurring after revascularization compared with those not revascularized (hazard ratio [HR] 2.73 [95% confidence interval {CI} 2.21 to 3.38], p < 0.001) as well as a higher rate of each of the in idual outcomes. Major bleeding was also higher in those who underwent revascularization (GUSTO severe or life-threatening: HR 2.61 [95% CI 1.02 to 6.67], p = 0.045 TIMI major: HR 2.24 [95% CI 1.12 to 4.48], p = 0.022). There was no evidence that bleeding and ischemic outcomes varied by treatment with clopidogrel versus prasugrel. In conclusion, among patients initially medically managed after NSTE ACS, a small proportion later require revascularization and have a high rate of ischemic and major bleeding outcomes compared with those not requiring downstream revascularization.
Publisher: Wiley
Date: 08-1998
DOI: 10.1111/J.1445-5994.1998.TB02101.X
Abstract: The method of administration of alteplase has evolved since its introduction to clinical practice in the late 1980s. The initial dosage regimen of a graded administration of 100 mg was replaced by the front-loaded weight adjusted regimen, the efficacy of which was demonstrated in the GUSTO 1 trial. Double bolus administration was shown to achieve superior TIMI 3 patency of the infarct related artery in a small angiographic study, but the COBALT trial failed to show equivalence and indeed showed a slightly higher mortality and incidence of stroke, so cannot be recommended. Reteplase, a deletion mutant of alteplase, also showed superior efficacy in achieving coronary patency but no clinical superiority in outcomes in the 15,000 patient GUSTO 3 trial. The case of administration of reteplase, however, has some attraction as an alternative to alteplase. Trials of newer agents based on further modifications of alteplase are ongoing, but at present the front-loaded alteplase regimen remains the standard for clinical practice.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.JACC.2016.06.034
Abstract: Anticoagulation is often avoided in patients with atrial fibrillation who are at an increased risk of falling. This study assessed the relative efficacy and safety of edoxaban versus warfarin in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial in patients with atrial fibrillation judged to be at increased risk of falling. We performed a pre-specified analysis of the ENGAGE AF-TIMI 48, comparing patients with versus without increased risk of falling. Nine hundred patients (4.3%) were judged to be at increased risk of falling. These patients were older (median, 77 vs. 72 years p < 0.001), and had a higher prevalence of comorbidities including prior stroke/transient ischemic attack, diabetes, and coronary artery disease. After multivariable adjustment, patients at increased risk of falling experienced more bone fractures caused by falling (adjusted hazard ratio [HRadj]: 1.88 95% confidence interval [CI]: 1.49 to 2.38 p < 0.001), major bleeding (HRadj: 1.30 95% CI: 1.04 to 1.64 p = 0.023), life-threatening bleeding (HRadj: 1.67 95% CI: 1.11 to 2.50 p = 0.013), and all-cause death (HRadj: 1.45 95% CI: 1.23 to 1.70 p < 0.001), but not ischemic events including stroke/systemic embolic event (HRadj: 1.16 95% CI: 0.89 to 1.51 p = 0.27). No treatment interaction was observed between either dosing regimens of edoxaban and warfarin for the efficacy and safety outcomes. Treatment with edoxaban resulted in a greater absolute risk reduction in severe bleeding events and all-cause mortality compared with warfarin. Edoxaban is an attractive alternative to warfarin in patients at increased risk of falling, because it is associated with an even greater absolute reduction in severe bleeding events and mortality. (Effective aNticaoGulation with factor xA next Generation in Atrial Fibrillation [ENGAGE AF-TIMI 48] NCT00781391).
Publisher: AMPCo
Date: 05-2017
DOI: 10.5694/MJA16.01199
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.JACC.2016.03.524
Abstract: Peripheral artery disease (PAD) is associated with heightened ischemic and bleeding risk in patients with prior myocardial infarction (MI). This study evaluated the efficacy and safety of ticagrelor on major cardiovascular (CV) events and major adverse limb events in patients with PAD and a prior MI. PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) randomized 21,162 patients with prior MI (1 to 3 years) to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all on a background of low-dose aspirin. History of PAD was obtained at baseline. Occurrences of major adverse cardiovascular events (MACE) (defined as CV death, MI, or stroke) and major adverse limb events (MALE) (defined as acute limb ischemia or peripheral revascularization for ischemia) were recorded in follow-up. A total of 1,143 patients (5%) had known PAD. In the placebo arm, those with PAD (n = 404) had higher rates of MACE at 3 years than those without (n = 6,663 19.3% vs. 8.4% p < 0.001), which persisted after adjusting for baseline differences (adjusted hazard ratio: 1.60 95% confidence interval: 1.20 to 2.13 p = 0.0013), and higher rates of acute limb ischemia (1.0% vs. 0.1%) and peripheral revascularization procedures (9.15% vs. 0.46%). Whereas the relative risk reduction in MACE with ticagrelor was consistent, regardless of PAD, patients with PAD had a greater absolute risk reduction of 4.1% (number needed to treat: 25) due to their higher absolute risk. The absolute excess of TIMI major bleeding was 0.12% (number needed to harm: 834). The 60-mg dose had particularly favorable outcomes for CV and all-cause mortality. Ticagrelor (pooled doses) reduced the risk of MALE (hazard ratio: 0.65 95% confidence interval: 0.44 to 0.95 p = 0.026). Among stable patients with prior MI, those with concomitant PAD have heightened ischemic risk. In these patients, ticagrelor reduced MACE, with a large absolute risk reduction, and MALE. (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS-TIMI 54] NCT01225562).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-05-2011
DOI: 10.1161/CIRCULATIONAHA.110.001404
Abstract: Thrombin is a key mediator of platelet activation. Atopaxar is a reversible protease-activated receptor-1 antagonist that interferes with thrombin-mediated platelet effects. The phase II Lessons From Antagonizing the Cellular Effect of Thrombin–Coronary Artery Disease (LANCELOT–CAD) trial examined the safety and tolerability of prolonged therapy with atopaxar in subjects with CAD. Subjects with a qualifying history were randomized in a double-blind fashion to 3 dosing regimens of atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks and followed up for an additional 4 weeks. The key safety end points were bleeding according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Thrombolysis in Myocardial Infarction (TIMI) classifications. Secondary objectives included platelet aggregation and major adverse cardiac events. Seven hundred and twenty subjects were randomized. Overall bleeding rates tended to be higher with atopaxar compared with placebo by CURE criteria (placebo, 0.6% atopaxar, 3.9% relative risk, 6.82, P =0.03 50 mg, 3.9% 100 mg, 1.7% 200 mg, 5.9% P for trend=0.01) and TIMI criteria (placebo, 6.8% atopaxar, 10.3% relative risk, 1.52, P =0.17 50 mg, 9.9% 100 mg, 8.1% 200 mg, 12.9% P for trend=0.07). There was no difference in major bleeding. Major adverse cardiac events were numerically lower in the atopaxar subjects. All atopaxar regimens achieved high levels of platelet inhibition. A transient elevation in liver transaminases and dose-dependent QTc prolongation without apparent complications were observed in higher-dose atopaxar treatment groups. In this dose-ranging study of patients with CAD, treatment with atopaxar resulted in platelet inhibition, more minor bleeding, and numerically but not statistically fewer ischemic events. Larger-scale trials are needed to determine whether these patterns translate into clinically meaningful effects. URL: www.ClinicalTrials.gov . Unique identifier: NCT00312052.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Elsevier BV
Date: 02-1997
DOI: 10.1016/S0735-1097(96)00492-5
Abstract: This study sought to investigate the impact of surgical revascularization on outcome after myocardial infarction. Small variations in rates of coronary artery bypass graft surgery (CABG) were noted among thrombolytic regimens in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, prompting the question of whether survival differences were partly related to differences in CABG rates. Patients in the GUSTO trial were randomized to one of four thrombolytic strategies. Of 40,861 patients with complete data, 3,526 underwent surgical revascularization during their initial hospital admission. Thirty-day and 1-year mortality rates were estimated using Kaplan-Meier techniques, and the impact of CABG as a time-dependent covariate on death was evaluated using a Cox survival model, adjusting for baseline prognostic factors. The median time from study enrollment to CABG was 7 days across treatment groups. A 15% reduction in mortality for the tissue-type plasminogen activator (t-PA)-treated group was evident by the seventh day. Bypass surgery was a significant independent predictor of 30-day mortality (risk ratio 1.87) and a weaker predictor of 1-year mortality (risk ratio 1.21). Operative mortality was highest in patients with acute mitral regurgitation, ventricular septal defect or poor left ventricular function and in those undergoing CABG within the first 4 days of randomization. The survival benefit of accelerated t-PA was not related to surgical revascularization. Bypass surgery was associated with excess mortality in the first year, but the added short-term mortality associated with CABG may be balanced by anticipated long-term benefit in specific groups of patients.
Publisher: Elsevier BV
Date: 09-1985
DOI: 10.1016/S0735-1097(85)80131-5
Abstract: The purpose of this study was to determine if the difference in transthoracic impedance produced by different coupling agents affects the success of shocks for defibrillation. Three different coupling agents, Harco pads (Hewlett-Packard), Littman pads (3M) and Redux paste (Hewlett-Packard), were assessed in 10 anesthetized dogs in which ventricular fibrillation was induced by electrical stimulation of the right ventricle. Defibrillation was attempted 15 seconds later, using 50, 100 and 150 joules (selected energy). Actual delivered energy, current, impedance and the percent of the shocks that achieved defibrillation were determined for the three coupling agents. Redux paste gave significantly lower impedance and higher current than the two disposable performed coupling pads tested. Despite this, there were no significant differences in shock success among the three coupling agents. Thus, in this experimental model, over a three-fold energy range, disposable coupling pads were as effective as electrode paste for defibrillation despite the slightly higher impedance of the disposable pads.
Publisher: American Society for Clinical Investigation
Date: 04-1988
DOI: 10.1172/JCI113444
Publisher: Elsevier BV
Date: 08-2021
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.HLC.2019.04.014
Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAb) have progressed from showing marked low density lipoprotein cholesterol lowering in early phase trials through to reducing cardiovascular events in large clinical outcome trials. Recently in Australia, the indication for evolocumab has been expanded to include both heterozygous and homozygous familial hypercholesterolaemia under the Pharmaceutical Benefits Scheme (PBS). With prices remaining high currently their use in non-familial hypercholesterolaemia in Australia remains by private prescription only at this stage. This manuscript summarises the major outcomes trials of the PCSK9 mAbs and the secondary analyses that have assessed their benefits in high risk patient groups, and describes the consensus of authors on which patients would most likely benefit from PCSK9 mAb therapy.
Publisher: Massachusetts Medical Society
Date: 04-10-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-1987
Abstract: A 41-year-old man with a remote history of neck and mediastinal radiation was seen with severe paroxysms of hypertension, headache, and cutaneous flushing after bilateral carotid bypass surgery. Investigation revealed marked parallel fluctuations in blood pressure and heart rate and elevation of plasma norepinephrine to 1164 pg/ml during a paroxysm. We systematically evaluated his arterial and cardiopulmonary baroreceptor reflex function by assessing changes in heart rate, arterial pressure, and efferent muscle sympathetic nerve activity, which was measured directly by the microneurographic technique. Elevating resting arterial pressure from 130/88 to 164/100 mm Hg with phenylephrine or lowering it to 88/56 mm Hg with nitroprusside produced no reflex changes in heart rate or efferent sympathetic nerve activity. In contrast, decreases in cardiac filling pressures with lower body negative pressure produced a marked increase in sympathetic nerve activity. These findings indicate complete loss of the afferent limb of the arterial baroreceptor reflex but preservation of the cardiopulmonary baroreceptor reflex. They suggest that both carotid and aortic baroreceptors were impaired by the previous radiation and surgery. Despite the loss of arterial baroreceptor function, the patient did not have sustained hypertension. The paroxysms of hypertension appear to be due to spontaneous fluctuations in central sympathetic drive not buffered by arterial baroreceptors in a manner similar to that seen in sinoaortic-denervated animals.
Publisher: Elsevier BV
Date: 06-1996
DOI: 10.1016/0735-1097(96)00053-8
Abstract: This study sought to examine the relations among patient characteristics, time to thrombolysis and outcomes in the international GUSTO-I trial. Studies have shown better left ventricular function and decreased infarct size as well as increased survival with earlier thrombolysis, but the relative benefits of various thrombolytic agents with earlier administration are uncertain. We evaluated the relations of baseline characteristics to three prospectively defined time variables: symptom onset to treatment, symptom onset to hospital arrival (presentation delay) and hospital arrival to treatment (treatment delay). We also examined the relations of delays to clinical outcomes and to the relative 30-day mortality benefit with accelerated tissue-type plasminogen activator (t-PA) versus streptokinase. Female, elderly, diabetic and hypertensive patients had longer delays at all stages. Previous infarction or bypass surgery was an additional risk factor for treatment delay. Early thrombolysis was associated with lower overall mortality rate ( 4 h, 9.0%), but no additional relative benefit resulted from earlier treatment with accelerated t-PA versus streptokinase (p = 0.38). Longer presentation and treatment delays were both associated with increased mortality rate (presentation delay 4 h, 8.6% treatment delay 90 min, 8.1%). As time to treatment increased, the incidence of recurrent ischemia or reinfarction decreased, but the rates of shock, heart failure and stroke increased. Earlier treatment resulted in better outcomes, regardless of thrombolytic strategy. Elderly, female and diabetic patients were treated later, adding to their already substantial risk.
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.AHJ.2012.07.030
Abstract: The p38 mitogen-activated protein kinase (MAPK) is a nexus point in inflammation, sensing, and stimulating cytokine production and driving cell migration and death. In acute coronary syndromes, p38MAPK inhibition could stabilize ruptured atherosclerotic plaques, pacify active plaques, and improve microvascular function, thereby reducing infarct size and risk of subsequent cardiac events. The SOLSTICE trial is randomized, double-blind, placebo-controlled, parallel group, multicenter phase 2a study of 535 patients that evaluates the safety and efficacy of losmapimod (GW856553), a potent oral p38MAPK inhibitor, vs placebo in patients with non-ST-segment elevation myocardial infarction expected to undergo an invasive strategy. The coprimary end points are reduction in high-sensitivity C-reactive protein at 12 weeks and reduction in infarct size as assessed by troponin area under the curve at 72 hours. A key secondary end point is 72-hour and 12-week B-type natriuretic peptide levels as a measure of cardiac remodeling and ventricular strain. The primary safety assessments are serious and nonserious adverse events, results of liver function testing, and major adverse cardiac events. Cardiac magnetic resonance imaging (N = 117) and coronary flow reserve (N = 13) substudies will assess the effects of losmapimod on infarct size, myocardial function, and coronary vasoregulation. Information gained from the SOLSTICE trial will inform further testing of this agent in larger clinical trials.
Publisher: Springer Science and Business Media LLC
Date: 06-2012
DOI: 10.1007/S11239-012-0750-6
Abstract: Atopaxar is a reversible protease activated receptor (PAR)-1 thrombin receptor antagonist that interferes with platelet signaling. The effects of PAR-1 antagonists on biomarkers remain unknown. The primary objective was to assess the effects of atopaxar on biomarkers of inflammation and platelet activation. The LANCELOT-CAD trial randomized 720 subjects to atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks. Biomarkers were assessed at serial time points. A linear mixed model to account for repeated measures was used to evaluate the change in biomarker concentration from randomization across time to week 24. Least square means were determined from the linear mixed models. The concentration of sCD40L decreased on average over time by -553 (95 % CI -677, -429) ng/L in the combined atopaxar group versus -30.3 (-249 to 189) ng/L fall in the placebo arm (P < 0.001) and a dose-dependent trend was seen across treatment groups (P < 0.001 for trend). In contrast, Lp-PLA(2) mass rose on average over time by 12.6 (95 % CI 10.0, 15.3) ng/ml in the combined atopaxar group as compared with 2.6 (95 % CI -2.1, 7.3) ng/ml in the placebo arm (P < 0.001). Similarly, the concentration of IL-18 rose by 17.5 (95 % CI 12.4, 22.6) pg/ml in the atopaxar group versus a -1.2 (95 % CI -10.2, 7.8) pg/ml fall in the placebo group (P < 0.001). The effects of atopaxar on Lp-PLA(2) and IL-18 appeared to be dose-dependent (P < 0.001 for trend) and were observed in J-LANCELOT. Atopaxar did not have a significant effect on other inflammatory markers. In conclusion, atopaxar appeared to decrease sCD40L, but did not demonstrate an anti-inflammatory effect in patients with stable CAD. Although atopaxar increased the concentration of Lp-PLA(2) and IL-18, the clinical relevance of these findings remains unknown and warrants further investigation and validation.
Publisher: Wiley
Date: 10-1982
DOI: 10.1111/J.1445-5994.1982.TB03845.X
Abstract: The fabrication of nanocomposite films and fibers based on cellulose nanocrystals (P-tCNCs) and a thermoplastic polyurethane (PU) elastomer is reported. High-aspect-ratio P-tCNCs were isolated from tunicates using phosphoric acid hydrolysis, which is a process that affords nanocrystals displaying high thermal stability. Nanocomposites were produced by solvent casting (films) or melt-mixing in a twin-screw extruder and subsequent melt-spinning (fibers). The processing protocols were found to affect the orientation of both PU hard segments and the P-tCNCs within the PU matrix and therefore the mechanical properties. While the films were isotropic, both the polymer matrix and the P-tCNCs proved to be aligned along the fiber direction in the fibers, as shown using SAXS/WAXS, angle-dependent Raman spectroscopy, and birefringence analysis. Tensile tests reveal that fibers and films, at similar P-tCNC contents, display Young's moduli and strain-at-break that are within the same order of magnitude, but the stress-at-break was found to be ten-times higher for fibers, conferring them a superior toughness over films.
Publisher: Elsevier BV
Date: 2008
Publisher: Wiley
Date: 08-1986
DOI: 10.1113/JPHYSIOL.1986.SP016185
Abstract: Vasopressin facilitates the baroreflex control of the circulation. The peptide may act at several sites to augment the baroreflex. In this study we examined the effect of vasopressin on aortic baroreceptors in anaesthetized rabbits and on left ventricular mechanoreceptors in anaesthetized cats. Vasopressin (16 mu./kg. min) did not change resting nerve discharge in single fibres from aortic baroreceptors. Vasopressin (16 mu./kg. min) significantly enhanced the response of single aortic nerve fibre discharge to elevation in arterial pressure. The slope relating nerve activity to mean arterial pressure increased from 0.24 +/- 0.05 (mean +/- S.E. of mean) to 0.50 +/- 0.16 impulses/cardiac cycle. mmHg (P less than 0.05) in ten aortic medullated fibres and from 0.06 +/- 0.03 to 0.18 +/- 0.04 impulses/cardiac cycle. mmHg (P less than 0.05) in three non-medullated fibres. Vasopressin (16 mu./kg. min) did not change resting nerve discharge in single fibres from left ventricular mechanoreceptors. Vasopressin (16 mu./kg. min) significantly enhanced the response of single nerve fibre discharge from left ventricular mechanoreceptors in response to elevation of left ventricular end-diastolic pressure. The slope relating nerve activity to left ventricular end-diastolic pressure increased from 0.24 +/- 0.07 to 0.32 +/- 0.07 impulses/cardiac cycle. mmHg (P less than 0.05) in six medullated fibres and from 0.10 +/- 0.01 to 0.15 +/- 0.02 impulses/cardiac cycle. mmHg (P less than 0.05) in four non-medullated fibres. These data show that vasopressin sensitizes high and low pressure baroreceptors and suggest a mechanism by which vasopressin may facilitate the baroreflex control of the circulation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-1984
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.AHJ.2011.07.018
Abstract: Higher levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with a higher risk of cardiovascular events and may play a causal role in atherogenesis. Darapladib inhibits Lp-PLA(2) activity in plasma and in arterial plaques and may confer clinical benefit in preventing cardiovascular events. The SOLID-TIMI 52 trial is a randomized, double-blind, placebo-controlled, multicenter, event-driven trial. Approximately 13,000 subjects are being randomized to darapladib (160 mg enteric-coated tablet daily) or matching placebo within 30 days of hospitalization with an acute coronary syndrome. The primary end point is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points include major and total coronary events, in idual components of the primary end point, and all-cause mortality. The study will continue until approximately 1,500 primary end point events have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be approximately 3 years, with a total study duration of approximately 4.1 years. The SOLID-TIMI 52 trial will determine the clinical benefit of direct inhibition of Lp-PLA(2) activity with darapladib in patients after an acute coronary syndrome.
Publisher: Wiley
Date: 04-1992
DOI: 10.1111/J.1445-5994.1992.TB02791.X
Abstract: Streptokinase is the thrombolytic agent most commonly used for the treatment of acute myocardial infarction. We report eight patients who developed late uncommon adverse reactions to streptokinase probably due to immune complex disease. The clinical manifestations included vasculitic rashes, abnormal renal and liver function tests and a syndrome resembling adult respiratory distress syndrome. Major adverse events with streptokinase such as stroke, bleeding and other allergic reactions, have been previously documented but the morbidity related to delayed reactions has not been widely recognised. These reactions produced significant morbidity resulting in prolonged hospital stay and may need to be considered in the decision to use streptokinase.
Publisher: Informa UK Limited
Date: 20-08-2014
DOI: 10.1185/03007995.2014.949647
Abstract: Abstract The use of dual antiplatelet therapy has led to a substantial reduction in ischemic events post-acute coronary syndrome (ACS). Despite this, recurrent event rates remain high. Recent research has combined antiplatelet with anticoagulant therapy to reduce recurrent event rates further. Compared with standard medical therapy, rivaroxaban demonstrated improved efficacy outcomes and significantly reduced mortality after an ACS. Although clear benefits of novel oral anticoagulants post-ACS have been proven, concerns regarding bleeding are still a barrier to widespread use. This review explores key trials of dual antiplatelet therapy and examines the latest research in anticoagulation aiming to optimize clinical outcomes post-ACS.
Publisher: AMPCo
Date: 09-2007
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.JACC.2013.10.048
Abstract: This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG). Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients. Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method. Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55 95% CI: 0.36 to 0.83 p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3% HR: 1.36 95% CI: 0.92 to 2.02 p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%). In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3] NCT00527943).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1988
Abstract: To determine the effects of coronary angioplasty on coronary flow reserve (CFR), we studied 32 patients before and immediately after single-vessel coronary angioplasty and 31 patients evaluated late after angioplasty (7.5 +/- 1.2 months, mean +/- SEM). The geometry (percent area stenosis and minimal cross-sectional area) of each lesion was determined by quantitative coronary angiography (Brown/Dodge method) and the integrated optical density was measured by videodensitometry. CFR was measured with a No. 3F coronary Doppler catheter placed immediately proximal to the lesion and a maximally vasodilating dose of intracoronary papaverine. The translesional pressure gradient was obtained in all lesions before and immediately after angioplasty and in 18 of 31 vessels late after angioplasty. CFR immediately after angioplasty returned to normal levels (greater than 3.5 peak/resting velocity ratio) in 14 of 31 patients and was improved, although not normalized, in the remaining 17 patients. CFR immediately after dilation was not significantly correlated with any of the angiographic variables of arterial stenosis nor the resting pressure gradient. Moreover, the pressure gradient and absolute distal coronary pressure at peak hyperemia were not significantly different in vessels with normal and those with abnormal flow reserve immediately after dilation, suggesting that the residual stenosis did not significantly limit hyperemia. Late after angioplasty, however, a significant relationship emerged between CFR and all four indexes of residual arterial stenosis (percent area stenosis r = .70, p less than .01 minimum arterial cross-sectional area r = .70, p less than .01 integrated optical density r = .60, p less than .01 and translesional pressure gradient r = .77, p less than .01). Furthermore, in the absence of restenosis, CFR eventually normalized in all patients. These findings demonstrate that in one-half of patients there is a transient reduction in coronary flow reserve immediately after angioplasty. In the absence of restenosis, coronary flow reserve later normalizes. Consequently, measurements of coronary flow reserve immediately after angioplasty may not reflect the eventual success of the procedure in removing physiologic obstruction to coronary blood flow.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2016
DOI: 10.1161/CIRCINTERVENTIONS.115.003114
Abstract: Stent thrombosis (ST) is an important end point in cardiovascular clinical trials. Adjudication is traditionally based on clinical event committee (CEC) review of case report forms and source documentation rather than angiograms. However, the degree to which this method of adjudication is concordant with the review of independent angiographic core laboratories (ACLs) has not been studied. This report represents the first assessment of variability between local investigators (LIs), a CEC, and an ACL. Serial angiograms of 329 patients with acute coronary syndrome without ST-segment–elevation who underwent percutaneous coronary intervention at entry in the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Particpants With Acute Coronary Syndrome (TRACER) and who met criteria for possible ST subsequent to the index event were reviewed by an ACL. The ACL was blinded to the assessment by both LIs and the CEC regarding the presence or absence of ST. CEC adjudication was based on Academic Research Consortium definitions of ST, using case report form data and source documents, including catheterization laboratory reports. The ACL, CEC, and LIs agreed on the presence or absence of ST in 52.9% events ( κ =0.32 95% confidence interval, 0.26–0.39). The ACL and CEC agreed on 82.7% of events ( κ =0.57 95% confidence interval, 0.47–0.67) the ACL and LIs agreed on 61.1% of events ( κ =0.25 95% confidence interval, 0.16–0.34) and the CEC and LIs agreed on 62% of events ( κ =0.28 95% confidence interval, 0.21–0.36). ST reporting by an ACL, a CEC, and LIs is discordant. The assessment of ST is more often detected by direct review of angiograms by an ACL. URL: www.clinicaltrials.gov . Unique identifier: NCT00527943.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-08-2010
DOI: 10.1161/CIRCULATIONAHA.109.924068
Abstract: Background— Lead V 1 directly faces the right ventricle and may exhibit ST elevation during an acute inferior myocardial infarction when the right ventricle is also involved. Leads V 1 and V 3 indirectly face the posterolateral left ventricle, and ST depression (“mirror-image” ST elevation) in V 1 through V 3 may reflect concomitant posterolateral infarction. The prognostic significance of V 1 ST elevation during an acute inferior myocardial infarction may therefore be dependent on V 3 ST changes. Methods and Results— In 7967 patients with acute inferior myocardial infarction in the Hirulog and Early Reperfusion or Occlusion-2 (HERO-2) trial, V 1 ST levels were analyzed with adjustment for lead V 3 ST level for predicting 30-day mortality. V 1 ST elevation at baseline, analyzed as a continuous variable, was associated with higher mortality. Unadjusted, each 0.5-mm-step increase in ST level above the isoelectric level was associated with ≈25% increase in 30-day mortality this was true whether V 3 ST depression was present or not. The odds ratio for mortality was 1.21 (95% confidence interval, 1.07 to 1.37) after adjustment for inferolateral ST elevation and clinical factors and 1.24 (95% confidence interval, 1.09 to 1.40) if also adjusted for V 3 ST level. In contrast, lead V 1 ST depression was not associated with mortality after adjustment for V 3 ST level. V 1 ST elevation ≥1 mm, analyzed dichotomously in all patients, was associated with higher mortality. The odds ratio was 1.28 (95% confidence interval, 1.01 to 1.61) unadjusted, 1.51 (95% confidence interval, 1.19 to 1.92) adjusted for V 3 ST level, and 1.35 (95% confidence interval, 1.04 to 1.76) adjusted for ECG and clinical factors. Persistence of V 1 ST elevation ≥1 mm 60 minutes after fibrinolysis was associated with higher mortality (10.8% versus 5.5%, P =0.001). Conclusion— V 1 ST elevation identifies patients with acute inferior myocardial infarction who are at higher risk.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-10-1997
Abstract: Background Thrombolytic therapy improves survival after myocardial infarction through reperfusion of the infarct-related artery. Thrombin generated during thrombolytic administration may reduce the efficacy of thrombolysis. A direct thrombin inhibitor may improve early patency rates. Methods and Results Four hundred twelve patients presenting within 12 hours with ST-segment elevation were given aspirin and streptokinase and randomized in a double-blind manner to receive up to 60 hours of either heparin (5000 U bolus followed by 1000 to 1200 U/h), low-dose hirulog (0.125 mg/kg bolus followed by 0.25 mg · kg −1 · h −1 for 12 hours then 0.125 mg · kg −1 · h −1 ), or high-dose hirulog (0.25 mg/kg bolus followed by 0.5 mg · kg −1 · h −1 for 12 hours then 0.25 mg · kg −1 · h −1 ). The primary outcome was Thrombolysis In Myocardial Infarction trial (TIMI) grade 3 flow of the infarct-related artery at 90 to 120 minutes. TIMI 3 flow was 35% (95% CI, 28% to 44%) with heparin, 46% (95% CI, 38% to 55%) with low-dose hirulog, and 48% (95% CI, 40% to 57%) with high-dose hirulog (heparin versus hirulog, P =.023 heparin versus high-dose hirulog, P =.03). At 48 hours, reocclusion had occurred in 7% of heparin, 5% of low-dose hirulog, and 1% of high-dose hirulog patients ( P =NS). By 35 days, death, cardiogenic shock, or reinfarction had occurred in 25 heparin (17.9%), 19 low-dose hirulog (14%), and 17 high-dose hirulog patients (12.5%) ( P =NS). Two strokes occurred with heparin, none with low-dose hirulog, and two with high-dose hirulog. Major bleeding (40% from the groin site) occurred in 28% of heparin, 14% of low-dose hirulog, and 19% of high-dose hirulog patients (heparin versus low-dose hirulog, P .01). Conclusions Hirulog was more effective than heparin in producing early patency in patients treated with aspirin and streptokinase without increasing the risk of major bleeding. Direct thrombin inhibition may improve clinical outcome.
Publisher: Wiley
Date: 08-1998
DOI: 10.1111/J.1445-5994.1998.TB02106.X
Abstract: The patterns of revascularisation with percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) surgery in the GUSTO 1 trial patients in Australia are described. In comparison with rates documented in earlier trials of thrombolytic therapy in Australia, the rates of revascularisation post-thrombolysis increased by 50%, primarily due to a doubling in the rate of use of PTCA. However, the rates were low by international comparisons. There were marked variations in the rates of revascularisation between States, but no correlation with differences in mortality between States. The main predictors of post thrombolysis PTCA were prior angina, mild infarction and access to PTCA facilities.
Publisher: Massachusetts Medical Society
Date: 05-2014
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.IJCARD.2008.10.008
Abstract: Obese patients are at increased risk of acute coronary syndromes (ACS). We evaluated the prevalence of obesity in a large ACS population, as well as the relationship between body mass index (BMI) and the use of cardiac medications and procedures, clinical outcomes, and treatment effects between enoxaparin and unfractionated heparin (UFH). Using the database of the SYNERGY trial, we identified 9978 patients in 12 countries who were randomly assigned to receive enoxaparin or UFH. Patient weight at baseline and 30-day follow-up was recorded. BMI information was available on 9837 patients. BMI was analyzed in clinically meaningful categories ( or =35 kg/m(2)) and as a continuous variable. Thirty-two percent of patients were obese (BMI> or =30), with a greater proportion of patients with obesity from North America (36%) compared with other regions. Enoxaparin was dosed as 1 mg/kg regardless of body weight without maximum. The first dose of enoxaparin was underdosed in 15% of patients assigned enoxaparin, and obese patients were more likely to be underdosed than non-obese patients. Obese patients were younger, less often white, had more diabetes, hypertension, hyperlipidemia, family history of coronary artery disease, and congestive heart failure but fewer strokes, less peripheral vascular disease, and less often smoked. After adjustment, increased BMI was not an independent predictor of bleeding outcomes or 30-day death/myocardial infarction (MI), but increased BMI was predictive of lower 1-year mortality in the subgroup of patients with BMI at baseline below approximately 30 kg/m(2). No statistical interaction term was observed between obesity and randomized therapy for the outcomes of death/MI at 30 days and 6 months death at 30 days, 6 months, and 1 year and GUSTO or TIMI bleeding. Nearly one third of patients in SYNERGY were obese. Despite multiple comorbidities, obese patients had better unadjusted short- and long-term outcomes. After adjustment, higher BMI was not an independent predictor of in-hospital bleeding events or 30-day death/MI, but increased BMI was an independent predictor of 1-year mortality in patients with lower BMI but not in heavier patients. No interaction between the randomized treatment and obesity for efficacy and safety outcomes was observed across the range of BMI in this dataset. Standard dosing of enoxaparin should be used in patients without extreme obesity due to limited outcome data in these patients.
Publisher: Elsevier BV
Date: 11-2014
Publisher: American Physiological Society
Date: 07-1987
DOI: 10.1152/AJPHEART.1987.253.1.H1
Abstract: We measured the effect of vasopressin (8 mU X kg-1 X min-1) on reflex inhibition of renal sympathetic nerve activity induced by volume expansion in 13 sinoaortic-denervated anesthetized rabbits. Volume expansion increased left ventricular end-diastolic pressure (LVEDP) from 5.1 +/- 0.7 to 14.1 +/- 1.4 mmHg and decreased renal nerve activity (RNA) from 57.4 +/- 6.9 to 30.2 +/- 5.6 impulses/s. Infusion of vasopressin elevated LVEDP from 6.0 +/- 1.0 to 7.3 +/- 1.1 mmHg and decreased RNA from 61.8 +/- 7.2 to 47.1 +/- 6.3 impulses/s. Heart rate fell from 243 +/- 7 to 231 +/- 9 beats/min no other significant hemodynamic changes were seen. During the infusion of vasopressin, volume expansion increased LVEDP to 13.7 +/- 1.2 mmHg and decreased RNA to 17.0 +/- 4.2 impulses/s. The slopes relating the percent decrease in RNA to the rise in LVEDP were calculated from values of RNA recorded at several levels of LVEDP. The slope averaged -6.2 +/- 1.1%/mmHg before vasopressin and nearly doubled (-11.9 +/- 1.8%/mmHg) during vasopressin. Infusion of placebo (saline) instead of vasopressin did not alter the reflex inhibition of nerve activity. Bilateral vagotomy abolished the decrease in resting nerve activity that occurred during infusion of vasopressin as well as the reflex inhibition of RNA. These data demonstrate that vasopressin facilitates the reflex inhibition of renal sympathetic nerve activity associated with increases in LVEDP and mediated through vagal afferents.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-08-2017
Abstract: The major determinants and prognostic importance of self‐reported health in patients with stable coronary heart disease are uncertain. The STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial randomized 15 828 patients with stable coronary heart disease to treatment with darapladib or placebo. At baseline, 98% of participants completed a questionnaire that included the question, “Overall, how do you feel your general health is now?” Possible responses were excellent, very good, good, average , and poor . Adjudicated major adverse cardiac events, which included cardiovascular death, myocardial infarction, and stroke, were evaluated by Cox regression during 3.7 years of follow‐up for participants who reported excellent or very good health (n=2304), good health (n=6863), and average or poor health (n=6361), before and after adjusting for 38 covariates. Self‐reported health was most strongly associated with geographic region, depressive symptoms, and low physical activity ( P .0001 for all). Poor/average compared with very good/excellent self‐reported health was independently associated with major adverse cardiac events (hazard ratio [ HR ]: 2.30 [95% confidence interval ( CI ), 1.92–2.76] adjusted HR : 1.83 [95% CI , 1.51–2.22]), cardiovascular mortality ( HR : 4.36 [95% CI , 3.09–6.16] adjusted HR : 2.15 [95% CI , 1.45–3.19]), and myocardial infarction ( HR : 1.87 [95% CI , 1.46–2.39] adjusted HR : 1.68 [95% CI , 1.25–2.27] P .0002 for all). Self‐reported health is strongly associated with geographical region, mood, and physical activity. In a global coronary heart disease population, self‐reported health was independently associated with major cardiovascular events and mortality beyond what is measurable by established risk indicators. URL : www.ClinicalTrials.gov . Unique identifier: NCT 00799903.
Publisher: AMPCo
Date: 2007
Publisher: American College of Physicians
Date: 12-1996
DOI: 10.7326/0003-4819-125-11-199612010-00004
Abstract: Despite concern that hypertension increases the risk for intracranial hemorrhage during thrombolysis for acute myocardial infarction, the exact nature of the risk remains unclear. To assess the effects of previous hypertension and blood pressure at study entry on the outcomes of patients who had acute myocardial infarction and received thrombolysis. Randomized trial. 1081 hospitals in 15 countries. 41,021 patients who had myocardial infarction accompanied by ST-segment elevation and who presented to hospitals within 6 hours of symptom onset. One of four thrombolytic regimens. Mortality, stroke subtypes, and death plus disabling stroke in patients with previous hypertension and as functions of blood pressure at entry. Logistic regression analysis of relations among blood pressure at entry, baseline characteristics, and treatment effects. The incidence of total stroke and intracranial hemorrhage increased as systolic blood pressure at entry increased and was particularly high for systolic pressures of about 175 mm Hg or more (incidence of total stroke, 3.4% compared with 1.17% for pressures between 100 and 124 mm Hg). Patients who had systolic blood pressure of 175 mm Hg or more at entry and who received accelerated alteplase therapy had a lower rate of death within 30 days (4.3% compared with 7.8% P = 0.044) and a lower rate of death plus disabling stroke (4.9% compared with 8.9% P = 0.031) than patients treated with streptokinase, despite having higher rates of total and hemorrhagic stroke (incidence of hemorrhagic stroke, 2.3% compared with 1.5%). Assumptions based on previous trials and rates of stroke from the GUSTO-1 (Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries) trial suggest that in hypertensive patients with low risk for death from cardiac causes (no previous infarction, Killip class I), the risk-to-benefit ratio with thrombolysis is about unity, with about 13 lives saved per 1000 persons treated at the risk of about 13 intracranial hemorrhages. Patients with myocardial infarction and very elevated blood pressure who have thrombolysis and risk for stroke is higher in the former group. Future studies should assess 1) the risk-to-benefit ratio of thrombolysis in these patients, especially those at low risk for death from cardiac causes, and 2) whether decreasing elevated blood pressure before thrombolysis reduces the incidence of stroke without increasing mortality rates.
Publisher: Wiley
Date: 07-1979
DOI: 10.1111/J.1540-8159.1979.TB05222.X
Abstract: A permanent demand pacing generator was implanted in the right deltopectoral fossa with unipolar transvenous lead advanced to the right ventricle. Implant and subsequent pacing parameters were normal. Five days later an emergency DC cardioversion was performed with one paddle 2 inches from the generator. Cardioversion was followed by failure of QRS-sensing and, at immediate explant, rise in stimulation threshold. The pulse generator showed end-of-life characteristics. The patient died 4 days following replacement of the generator and lead. At autopsy, right ventricular infarction was found, presumably relating to current discharge along the lead. Pacemaker analysis showed damage to the protection zener diode and oscillator integrated circuit of the generator during cardioversion.
Publisher: AMPCo
Date: 08-2016
DOI: 10.5694/MJA16.00368
Abstract: The modern care of suspected and confirmed acute coronary syndrome (ACS) is informed by an extensive and evolving evidence base. This clinical practice guideline focuses on key components of management associated with improved clinical outcomes for patients with chest pain or ACS. These are presented as recommendations that have been graded on both the strength of evidence and the likely absolute benefit versus harm. Additional considerations influencing the delivery of specific therapies and management strategies are presented as practice points. This guideline provides advice on the standardised assessment and management of patients with suspected ACS, including the implementation of clinical assessment pathways and subsequent functional and anatomical testing. It provides guidance on the: diagnosis and risk stratification of ACS provision of acute reperfusion therapy and immediate post-fibrinolysis care for patients with ST segment elevation myocardial infarction risk stratification informing the use of routine versus selective invasive management for patients with non-ST segment elevation ACS administration of antithrombotic therapies in the acute setting and considerations affecting their long term use and implementation of an in idualised secondary prevention plan that includes both pharmacotherapies and cardiac rehabilitation. Changes in management as a result of the guideline: This guideline has been designed to facilitate the systematic integration of the recommendations into a standardised approach to ACS care, while also allowing for contextual adaptation of the recommendations in response to the in idual's needs and preferences. The provision of ACS care should be subject to continuous monitoring, feedback and improvement of quality and patient outcomes.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.AMJCARD.2013.11.052
Abstract: Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial compared vorapaxar and placebo in 12,944 high-risk patients with non-ST-segment elevation acute coronary syndrome. We explored aspirin (ASA) use and its association with outcomes. Kaplan-Meier event rates were compared in groups defined by ASA dose (low, medium, and high). Landmark analyses with covariate adjustment were performed for 0 to 30, 31 to 180, and 181 to 365 days. Of 12,515 participants, 7,523, 1,049, and 3,943 participants were treated with low-, medium-, and high-dose ASA at baseline, respectively. Participants enrolled in North America versus elsewhere were more often treated with a high dose at baseline (66% vs 19%) and discharge (60% vs 3%). Unadjusted cardiovascular death, myocardial infarction, stroke, hospitalization for ischemia, or urgent revascularization event rates tended to be higher with higher baseline ASA (18.45% low, 19.13% medium, and 20.27% high p for trend = 0.15573). Unadjusted and adjusted hazard ratios (95% confidence intervals) for effect of vorapaxar on cardiovascular (unadjusted p for interaction = 0.065 adjusted p for interaction = 0.140) and bleeding (unadjusted p for interaction = 0.915 adjusted p for interaction = 0.954) outcomes were similar across groups. Landmark analyses showed similar safety and efficacy outcomes with vorapaxar and placebo by ASA dose at each time point except for 0 to 30 days, when vorapaxar tended to be worse for efficacy (hazard ratio 1.13, 95% confidence interval 0.89 to 1.44, p for interaction = 0.0157). In conclusion, most TRACER participants were treated with low-dose ASA, although a high dose was common in North America. High-dose participants tended to have higher rates of ischemic and bleeding outcomes. Although formal statistical testing did not reveal heterogeneity in vorapaxar's effect across dose subgroups, consistent trends support use of low-dose ASA with other antiplatelet therapies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-07-2016
DOI: 10.1161/CIRCULATIONAHA.115.019861
Abstract: Patients with stable ischemic heart disease and previous myocardial infarction (MI) vary in their risk for recurrent cardiovascular events. Atherothrombotic risk assessment may be useful to identify high-risk patients who have the greatest potential to benefit from more intensive secondary preventive therapy such as treatment with vorapaxar. We identified independent clinical indicators of atherothrombotic risk among 8598 stable, placebo-treated patients with a previous MI followed up for 2.5 years (median) in TRA 2°P-TIMI 50 [Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–TIMI 50]. The efficacy and safety of vorapaxar (SCH 530348 MK-5348) were assessed by baseline risk among patients with previous MI without prior stroke or transient ischemic attack for whom there is a clinical indication for vorapaxar. End points were cardiovascular death, MI, or ischemic stroke and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding. The 9 independent risk predictors were age, diabetes mellitus, hypertension, smoking, peripheral arterial disease, previous stroke, previous coronary bypass grafting, heart failure, and renal dysfunction. A simple integer-based scheme using these predictors showed a strong graded relationship with the rate of cardiovascular death/MI/ischemic stroke and the in idual components ( P for trend .001 for all). High-risk patients (≥3 risk indicators 20% of population) had a 3.2% absolute risk reduction in cardiovascular disease/MI/ischemic stroke with vorapaxar, and intermediate-risk patients (1–2 risk indicators 61%) had a 2.1% absolute risk reduction ( P .001 each), translating to a number needed to treat of 31 and 48. Bleeding increased across risk groups ( P for trend .01) however, net clinical outcome was increasingly favorable with vorapaxar across risk groups. Fatal bleeding or intracranial hemorrhage was 0.9% with both treatments in high-risk patients. Stratification of baseline atherothrombotic risk can assist with therapeutic decision making for vorapaxar use for secondary prevention after MI. URL: www.clinicaltrials.gov . Unique identifier: NCT00526474.
Publisher: Wiley
Date: 09-1986
Publisher: Elsevier BV
Date: 05-1997
Publisher: Elsevier BV
Date: 09-2001
Publisher: Wiley
Date: 12-1993
DOI: 10.1111/J.1445-5994.1993.TB04760.X
Abstract: The GUSTO II trial will investigate the role of antithrombin therapy in acute coronary syndromes, comparing standard doses of heparin with the specific antithrombin agent recombinant hirudin. The two drugs will be compared as primary therapy in patients with unstable angina or patients with myocardial infarction (MI) unsuitable for thrombolysis, and as post thrombolysis treatment in patients who fulfil standard criteria for thrombolysis therapy. A total of 12,000 patients will be studied in a global, multifactorial trial.
Publisher: Oxford University Press (OUP)
Date: 2017
DOI: 10.1373/CLINCHEM.2016.260570
Abstract: Higher growth differentiation factor 15 (GDF-15) concentrations are associated with cardiovascular (CV) and non-CV morbidity and mortality. However, information on associations between GDF-15 and the risk of specific CV and non-CV events in stable coronary heart disease (CHD) patients is limited. In 14 577 patients with stable CHD participating in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial (STABILITY), GDF-15 and other prognostic biomarkers (N-terminal pro–B-type natriuretic peptide, high-sensitivity troponin T, cystatin C, and high-sensitivity C-reactive protein) were measured. In adjusted Cox regression models, the associations between GDF-15 and the composite CV end point [CV death, myocardial infarction (MI), and stroke], as well as other CV and non-CV events, were assessed. The median concentration (interquartile range) of GDF-15 at baseline was 1253 (915–1827) ng/L. The hazard ratio for the composite end point for the highest compared to the lowest quartile of GDF-15 was 1.8 (95% CI, 1.5–2.2) for CV death, 2.63 (1.9–3.6) for sudden death, 3.06 (1.9–4.8) for heart failure (HF) death, 4.3 (1.3–14) for cancer death, 2.5 (1.3–4.7) for hospitalization for HF, 5.8 (3.2–10) for MI 1.4 (95% CI, 1.1–1.9) and for stroke, 1.8 (95% CI, 1.1–2.8). After adjustment for other prognostic biomarkers, GDF-15 remained significantly associated with all outcomes except for MI. In stable CHD, GDF-15 was independently associated with CV, non-CV, and cancer mortality, as well as with MI and stroke. When also adjusting for other prognostic biomarkers, the associations to all fatal and nonfatal events were maintained except for MI. Information on GDF-15, therefore, might be helpful when assessing the risk of adverse outcomes in patients with stable CHD. ClinicalTrials.gov Identifier: NCT00799903
Publisher: BMJ
Date: 04-1989
DOI: 10.1136/HRT.61.4.344
Abstract: The effect of a two minute cold pressor test on transmitral velocities measured by pulsed Doppler was studied in 11 healthy volunteers. Blood pressure increased significantly during cold immersion but peak atrial and peak early diastolic transmitral velocities and their ratio (A:E) were unchanged. There was no correlation between changes in Doppler variables and changes in calculated mean arterial blood pressure during the test. Heart rate changes were variable and not related to changes in blood pressure. In in idual people the change in pulse interval during cold immersion was significantly and inversely correlated with the change in the A:E ratio. The large acute increase in arterial pressure seen during the cold pressor test in normal volunteers had no consistent effect on the transmitral velocity profile although small changes in heart rate were associated with large changes in A:E ratio. The effect of small changes in heart rate may be of considerable importance in determining transmitral velocity profiles. Thus in clinical and experimental studies in which the heart rate is not controlled, Doppler data on transmitral flow should be interpreted with caution.
Publisher: Elsevier BV
Date: 1999
DOI: 10.1016/S0002-9149(98)00818-2
Abstract: The presenting electrocardiogram may contain information indicating the probability of successful reperfusion. The relation between 3 parameters in the presenting electrocardiogram (pathologic Q waves, T-wave inversion, and the slope of ST elevation) and Thrombolysis in Myocardial Infarction trial (TIMI) grade 3 flow in the infarct-related artery was assessed angiographically 90 minutes after beginning streptokinase in 362 patients. TIMI grade 3 flow was more common in patients without Q waves (55%) than in those with Q waves (35% p <0.001), and more common in patients without T-wave inversion (50%) than in those with T-wave inversion (30% p <0.002). There was no relation between the slope of the ST segment or the magnitude of its deviation and the achievement of TIMI grade 3 flow. Only 20% of the 59 patients with both Q waves and T-wave inversion had TIMI grade 3 flow, compared with 50% of the remaining patients (p <0.0001). Among patients treated within 3 hours, TIMI grade 3 flow was seen in 68% of those without versus 44% of those with Q waves (p <0.01), and in 62% of those without versus 43% of those with T-wave inversion (p = 0.06). Among patients treated after 3 hours, TIMI grade 3 flow was seen in 38% of those without versus 30% of those with Q waves (p = NS), and in 38% of those without versus 23% of those with T-wave inversion (p <0.05). On multivariate analysis, the absence of Q waves, the time from the onset of chest pain to treatment, and age were independent predictors of TIMI grade 3 flow. Pathologic Q waves in the presenting electrocardiogram provide valuable information as to the probability of achieving successful reperfusion following administration of streptokinase, and may be helpful for triage of patients to alternative reperfusion strategies, including percutaneous revascularization.
Publisher: Wiley
Date: 17-07-2019
DOI: 10.1002/CLC.23232
Publisher: AMPCo
Date: 11-2006
Publisher: Elsevier BV
Date: 2010
DOI: 10.1016/J.AHJ.2009.10.034
Abstract: Major bleeding significantly impacts outcomes in patients undergoing percutaneous coronary intervention (PCI). No uniform definitions exist for major and minor bleeding. Hematomas > or =5 cm at the femoral puncture site are considered major bleeding events in some trials and minor in others. Limited information is available on the incidence and clinical relevance of hematomas > or =5 cm in PCI patients. Data from the STEEPLE trial in patients undergoing elective PCI were used to assess the impact of hematomas > or =5 cm on ischemic outcomes (mortality, nonfatal myocardial infarction, or urgent target vessel revascularization) up to day 30 and all-cause 1-year mortality. Hematoma data were available for 3,342 of 3,528 patients in STEEPLE. Patients with (n = 103) and without (n = 3,239) hematomas > or =5 cm were evenly distributed across treatment groups. No differences were observed in 30-day ischemic outcomes between patients with and without hematomas (5.8% vs 5.9%, respectively P = .96). No transfusions were observed in patients with hematomas as compared with patients without hematomas (0% and 0.4%, respectively P = .52). A greater reduction in hemoglobin was observed (pre- vs post-PCI) in patients with hematomas as compared with patients without hematomas (-0.84 vs -0.35 g/L, P or =5 cm had no effect on 30-day ischemic events or 1-year mortality. Although there is no agreed classification for large hematomas, the lack of a relationship between hematomas > or =5 cm and clinical outcome after PCI justifies the classification of these hematomas as minor bleeds in STEEPLE.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2010
Publisher: Massachusetts Medical Society
Date: 24-01-2019
Publisher: Elsevier BV
Date: 1998
DOI: 10.1016/S0735-1097(97)00428-2
Abstract: We sought to assess the incidence and clinical relevance of examination data to recurrent ischemia within an international randomized trial. Ischemic symptoms commonly recur after thrombolysis for acute myocardial infarction. Patients (n = 40,848) were prospectively evaluated for recurrent angina and transient electrocardiographic (ECG) or hemodynamic changes. Five groups were developed: Group 1, patients with no signs or symptoms of recurrent ischemia Group 2, patients with angina only Group 3, patients with angina and ST segment changes Group 4, patients with angina and hemodynamic abnormalities and Group 5, patients with angina, ST segment changes and hemodynamic abnormalities. Baseline clinical and outcome variables were compared among the five groups. Group 1 comprised 32,717 patients, and Groups 2 to 5 comprised 20% of patients (4,488 in Group 2 3,021 in Group 3 337 in Group 4 and 285 in Group 5). Patients with recurrent ischemia were more often female, had more cardiovascular risk factors and less often received intravenous heparin. Significantly more extensive and more severe coronary disease, antianginal treatment, angioplasty and coronary bypass surgery were observed as a function of ischemic severity. The 30-day reinfarction rate was 1.6% in Group 1, 6.5% in Group 2, 21.7% in Group 3, 13.1% in Group 4 and 36.5% in Group 5 (p < 0.0001) in contrast, the 30-day mortality rate was significantly lower (p < 0.0001) in Groups 1, 2 and 3 (6.6%, 5.4% and 7.7%, respectively) than in Groups 4 and 5 (21.8% and 29.1%). Postinfarction angina greatly increases the risk of reinfarction, especially when accompanied by transient ECG changes. However, mortality is markedly increased only in the presence of concomitant hemodynamic abnormalities.
Publisher: Elsevier BV
Date: 09-2014
Publisher: Springer Science and Business Media LLC
Date: 1985
DOI: 10.1007/BF00583276
Abstract: Hibernation is an energy-conserving behavior in winter characterized by two phases: torpor and arousal. During torpor, markedly reduced metabolic activity results in inactivity and decreased body temperature. Arousal periods intersperse the torpor bouts and feature increased metabolism and euthermic body temperature. Alterations in physiological parameters, such as suppression of hemostasis, are thought to allow hibernators to survive periods of torpor and arousal without organ injury. While the state of torpor is potentially procoagulant, due to low blood flow, increased viscosity, immobility, hypoxia, and low body temperature, organ injury due to thromboembolism is absent. To investigate platelet dynamics during hibernation, we measured platelet count and function during and after natural torpor, pharmacologically induced torpor and forced hypothermia. Splenectomies were performed to unravel potential storage sites of platelets during torpor. Here we show that decreasing body temperature drives thrombocytopenia during torpor in hamster with maintained functionality of circulating platelets. Interestingly, hamster platelets during torpor do not express P-selectin, but expression is induced by treatment with ADP. Platelet count rapidly restores during arousal and rewarming. Platelet dynamics in hibernation are not affected by splenectomy before or during torpor. Reversible thrombocytopenia was also induced by forced hypothermia in both hibernating (hamster) and non-hibernating (rat and mouse) species without changing platelet function. Pharmacological torpor induced by injection of 5'-AMP in mice did not induce thrombocytopenia, possibly because 5'-AMP inhibits platelet function. The rapidness of changes in the numbers of circulating platelets, as well as marginal changes in immature platelet fractions upon arousal, strongly suggest that storage-and-release underlies the reversible thrombocytopenia during natural torpor. Possibly, margination of platelets, dependent on intrinsic platelet functionality, governs clearance of circulating platelets during torpor.
Publisher: Oxford University Press (OUP)
Date: 25-05-2010
Abstract: Controversy exists regarding the early use of glycoprotein IIb/IIIa inhibitors (GPIs) in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). The Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial provides a unique opportunity to examine early vs. late or non-use of GPIs in a large STEMI cohort treated with PCI. In the APEX-AMI trial, 3969 of 5707 patients received one of three GPIs at the operator's discretion (abciximab, eptifibatide, tirofiban). Of GPI-treated patients, the median time from symptom onset to GPI administration was 180 min (25th, 75th percentile: 130, 258) 1125 received the agent prior to arriving in the catheterization laboratory [pre-sheath GPI to sheath insertion: 37 min (16, 66)], whereas 2844 patients were treated after arrival in the catheterization laboratory [in-lab sheath insertion to GPI: 16 min (10, 27)]. The pre-sheath use of GPIs was associated with a significantly lower hazard of 90-day mortality [adjusted hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.48-0.95, P = 0.025] and of 90-day composite of death/CHF/shock (adjusted HR 0.81, 95% CI 0.65-1.00, P = 0.054). In-hospital severe and moderate bleeding was not related to the use of GPIs. This retrospective analysis from a large patient cohort with acute STEMI undergoing PCI suggests that pharmacological pre-treatment of PCI with GPIs, particularly abciximab, was associated with significantly lower occurrence of 90-day clinical outcomes and supports the pre-procedural administration of GPIs in this clinical setting.
Publisher: Oxford University Press (OUP)
Date: 13-11-2016
Publisher: AMPCo
Date: 02-2013
DOI: 10.5694/MJA12.11063
Abstract: To report the experience of implementing a 4-hour-rule program. A 3-2013 whole-of-hospital clinical service redesign program in a tertiary paediatric hospital in Western Australia, involving all patients presenting to the emergency department (ED) from 1 January 2009 to 31 December 2011. Percentage of patients admitted, discharged or transferred from the ED within 4 hours of arrival at triage, and percentage of patients discharged from inpatient wards before 10 am. The percentage of patients admitted, discharged or transferred within 4 hours of arrival at the ED increased from 87% in 2009 to 95% in 2011. Safety and quality measures, including the admission rate from the ED, unplanned reattendances at the ED within 48 hours of discharge, patient complaints and inhospital mortality, remained unchanged. The percentage of patients discharged from inpatient wards before 10 am increased from 18% in 2009 to 30% in 2011. The introduction of a 4-hour-rule program has resulted in improved timeliness of care for patients throughout the hospital, both in the ED and inpatient wards, with no adverse impact on the quality and safety of clinical care.
Publisher: American Medical Association (AMA)
Date: 04-2016
DOI: 10.1001/JAMACARDIO.2015.0359
Abstract: In the current therapeutic era, the risk for sudden cardiac death (SCD) after non-ST-segment elevation acute coronary syndrome (NSTE ACS) has not been characterized completely. To determine the cumulative incidence of SCD during long-term follow-up after NSTE ACS, to develop a risk model and risk score for SCD after NSTE ACS, and to assess the association between recurrent events after the initial ACS presentation and the risk for SCD. This pooled cohort analysis merged in idual data from 48 286 participants in 4 trials: the Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2), Study of Platelet Inhibition and Patient Outcomes (PLATO), Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER), and Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trials. The cumulative incidence of SCD and cardiovascular death was examined according to time after NSTE ACS. Using competing risk and Cox proportional hazards models, clinical factors at baseline and after the index event that were associated with SCD after NSTE ACS were identified. Baseline factors were used to develop a risk model. Data were analyzed from January 2, 2014, to December 11, 2015. Sudden cardiac death. Of the initial 48 286 patients, 37 555 patients were enrolled after NSTE ACS (67.4% men 32.6% women median [interquartile range] age, 65 [57-72] years). Among these, 2109 deaths occurred after a median follow-up of 12.1 months. Of 1640 cardiovascular deaths, 513 (31.3%) were SCD. At 6, 18, and 30 months, the cumulative incidence estimates of SCD were 0.79%, 1.65%, and 2.37%, respectively. Reduced left ventricular ejection fraction, older age, diabetes mellitus, lower estimated glomerular filtration rate, higher heart rate, prior myocardial infarction, peripheral artery disease, Asian race, male sex, and high Killip class were significantly associated with SCD. A model developed to calculate the risk for SCD in trials with systematic collection of left ventricular ejection fraction had a C index of 0.77. An integer-based score was developed from this model and yielded a calculated SCD probability ranging from 0.1% to 56.7% (C statistic, 0.75). In a multivariable model that included time-dependent clinical events occurring after the index hospitalization for ACS, SCD was associated with recurrent myocardial infarction (hazard ratio [HR], 2.95 95% CI, 2.29-3.80 P < .001) and any hospitalization (HR, 2.45 95% CI, 1.98-3.03 P < .001), whereas coronary revascularization had a negative relationship with SCD (HR, 0.75 95% CI, 0.58-0.98 P = .03). In the current therapeutic era, SCD accounts for about one-third of cardiovascular deaths after NSTE ACS. Risk stratification can be performed with good accuracy using commonly collected clinical variables. Clinical events occurring after the index hospitalization are underappreciated but important risk factors.
Publisher: Oxford University Press (OUP)
Date: 16-02-2016
Abstract: Thromboembolic risk stratification schemes and clinical guidelines for atrial fibrillation (AF) regard risk as independent of classification into paroxysmal (PAF) and non-paroxysmal atrial fibrillation (NPAF). The aim of the current study was to conduct a systematic review evaluating the impact of AF type on thromboembolism, bleeding, and mortality. PubMed was searched through 27 November 2014 for randomized controlled trials, cohort studies, and case series reporting prospectively collected clinical outcomes stratified by AF type. The incidence of thromboembolism, mortality, and bleeding was extracted. Atrial fibrillation clinical outcome data were extracted from 12 studies containing 99 996 patients. The unadjusted risk ratio (RR) for thromboembolism in NPAF vs. PAF was 1.355 (95% CI: 1.169-1.571, P < 0.001). In the study subset off oral anticoagulation, unadjusted RR was 1.689 (95% CI: 1.151-2.480, P = 0.007). The overall multivariable adjusted hazard ratio (HR) for thromboembolism was 1.384 (95% CI: 1.191-1.608, P < 0.001). The overall unadjusted RR for all-cause mortality was 1.462 (95% CI: 1.255-1.703, P < 0.001). Multivariable adjusted HR for all-cause mortality was 1.217 (95% CI: 1.085-1.365, P < 0.001). Rates of bleeding were similar, with unadjusted RR 1.00 (95% CI: 0.919-1.087, P = 0.994) and adjusted HR 1.025 (95% CI: 0.898-1.170, P = 0.715). Non-paroxysmal atrial fibrillation is associated with a highly significant increase in thromboembolism and death. These data suggest the need for new therapies to prevent AF progression and further studies to explore the integration of AF type into models of thromboembolic risk.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-1983
Abstract: We have assessed resting myocardial contractility and its baroreflex control in normotensive and hypertensive conscious rabbits. Hypertension was induced by bilateral cellophane wrapping of the kidneys with experiments performed 6 weeks later during the established phase of hypertension. The peak rate of change of left ventricular pressure (peak LV dP/dt) was used as the index of myocardial contractility. Baroreflex control of contractility and heart period (HP) was assessed by constructing stimulus response curves relating change in mean arterial pressure (MAP), induced by balloon occluders around the abdominal aorta and inferior vena cava, to change in peak LV dP/dt and HP. These stimulus response curves were obtained in normotensive rabbits with and without cardiac pacing, and in both normotensive and hypertensive animals after cardiac beta sympathetic blockade with propranolol, vagal blockade with methylscopolamine, and combined cardiac autonomic blockade with propranolol and scopolamine, as well as in rabbits with intact autonomic effectors. Resting MAP was significantly higher in the hypertensive rabbits (119 +/- 2 mm Hg) compared to normotensive controls (76 +/- 1 mm Hg). Resting peak LV dP/dt was also greater by 51% in the hypertensive animals (7054 +/- 287 mm Hg sec-1) compared to controls (4690 +/- 223 mm Hg sec-1). There was no significant difference in the resting heart period or resting left ventricular end diastolic pressure. Transient changes in MAP induced by occlusion of the aortic or venous balloons produced significant alterations in peak LV dP/dt in normotensive animals with and without pacing and in hypertensive control animals. In animals with cardiac sympathetic block, the range and slope or sensitivity of the stimulus response curves were not significantly changed but in animals with vagal blockade the sensitivity was reduced by 90% and the range at 30 mm Hg by 88%. After propranolol and methylscopolamine were administered together, the stimulus no longer evoked a response. These experiments demonstrate that myocardial contractility is under baroreflex control and suggest that this is mediated principally via parasympathetic nerves to the heart. There was no significant difference between the sensitivity of baroreflex control of myocardial contractility in the normotensive (-84 +/- 14 mm Hg sec-1 per mm Hg) and the hypertensive (-110 +/- 14 mm Hg sec-1 per mm Hg) rabbits, unlike the baroreflex control of heart period where sensitivity was markedly impaired in the hypertensive (sensitivity 3.8 +/- 0.8 msec/mm Hg) compared to the normotensive (6.9 +/- 1.0 msec/mm Hg) animals.
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.HRTHM.2006.11.021
Abstract: In survivors of myocardial infarction (MI), new left bundle branch block (LBBB) is associated with adverse outcomes, but its impact is not well described in post-MI patients with left ventricular (LV) systolic dysfunction and/or heart failure (HF). The aim of this study was to determine if new LBBB is an independent predictor of long-term fatal and nonfatal outcomes in high-risk survivors of MI by reviewing data from the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. In VALIANT, 14,703 patients with LV systolic dysfunction and/or HF were randomized to valsartan, captopril, or both a mean of 5 days after MI. Baseline ECG data were available from 14,259 patients. We assessed the predictive value of new LBBB for death and major cardiovascular outcomes after 3 years, adjusting for multiple baseline covariates including LV ejection fraction. At follow-up, patients with new LBBB (608 [4.2%]) compared with patients without new LBBB had more comorbidities and increased adjusted risk of death (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.2-1.6), cardiovascular death (HR 1.4, 95% CI 1.2-1.7), HF (HR 1.3, 95% CI 1.1-1.6), MI (HR 1.5, 95% CI 1.2-1.9), and the composite of death, HF, or MI (HR 1.4, 95% CI 1.2-1.6). In post-MI survivors with LV systolic dysfunction and/or HF, new LBBB was an independent predictor of all major adverse cardiovascular outcomes during long-term follow-up. This readily available ECG marker should be considered a major risk factor for long-term cardiovascular complications in high-risk patients after MI.
Publisher: Wiley
Date: 04-1989
DOI: 10.1111/J.1440-1681.1989.TB01553.X
Abstract: 1. The accuracy of blood pressure measurement with the Takeda TM-2420 ambulatory blood pressure monitor and the TM-2020 data recorder have been assessed by comparison with simultaneous measurements taken using auscultation and direct femoral artery measurements. 2. Systolic blood pressure was underestimated by the TM-2420 by a mean of 10 mmHg (s.d. = 6, 95% confidence interval (CI) = -13 to -7) over the range of pressures measured by auscultation. It was underestimated by 23 mmHg (s.d. = 12, 95% CI = -28 to -18) compared with direct femoral artery measurements. 3. Diastolic pressure measurements were similar to those obtained by auscultation. When compared with direct femoral artery recordings, diastolic pressure was overestimated by about 5 mmHg (s.d. = 4, 95% CI = 3.4-6.6), which is consistent with indirect readings, taken with a 'standard' cuff (inflatable bladder 23 cm X 12 cm). 4. The TM-2420/2020 is thus suitable for ambulatory measurements of blood pressure when diastolic pressure is the criterion of interest.
Publisher: Wiley
Date: 13-04-2010
DOI: 10.1002/CCD.22340
Abstract: To explore clinical and bleeding outcomes in patients enrolled in the SYNERGY trial who had percutaneous coronary intervention (PCI) based on adherence to the dosing regimens of enoxaparin mandated by the protocol. In SYNERGY, 4,687 patients underwent PCI during index hospitalization. Patients in the subcutaneous (sc) enoxaparin group were to be given an 0.3 mg/kg IV bolus immediately before PCI if balloon inflation occurred > or = 8 hr after their last sc dose of enoxaparin. The incidence of the 1 degrees efficacy end point (death/myocardial infarction [MI] post PCI and through 30 days), and the rates of post-PCI in-hospital TIMI major and GUSTO severe bleeding were compared between patients randomized to unfractionated heparin (UFH) and those randomized to sc enoxaparin who did or did not receive a supplemental IV bolus of enoxaparin in accord with protocol-mandates. A total of 4,687 patients had PCI 2,323 were assigned sc enoxaparin and 1,332 received protocol-mandated IV enoxaparin bolus, while 215 enoxaparin patients received inappropriate IV therapy (either receiving IV enoxaparin before the 8-hr protocol time or not receiving the IV enoxaparin as directed after 8 hr). Death or MI occurring post PCI through 30-day follow-up tended to be lower in the enoxaparin patients who were treated according to protocol than in those who were not (12.3% vs. 14.4% adjusted P = 0.25), as was TIMI major bleeding (3.0% vs. 4.7%, adjusted P = 0.08). These exploratory analyses show that patients in SYNERGY who received the protocol-mandated supplemental IV bolus of 0.3 mg/kg enoxaparin before PCI performed 8-12 hr after their last sc enoxaparin dose tended to have improved outcomes compared with those who did not. Strategies to ensure adherence to dosing guidelines of enoxaparin during PCI should be considered.
Publisher: Massachusetts Medical Society
Date: 22-07-1999
Publisher: AMPCo
Date: 02-1991
DOI: 10.5694/J.1326-5377.1991.TB121019.X
Abstract: The efficacy of a series of 2-aryl/alkyl selenazolidine-4(R)-carboxylic acids (SCAs) in reducing NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]-induced lung adenomas in female A/J mice, a model for tobacco-related lung tumorigenesis, has been investigated. With selenazolidines in the diet for 1 month prior to carcinogen administration and during the subsequent 4 months of tumor development, 2-butylSCA, 2-cyclohexylSCA, 2-phenylSCA and 2-oxoSCA were chemopreventive, significantly reducing mean lung tumor numbers from the 10.9 of unsupplemented controls to 4.7, 5.3, 2.8 and 4.7, respectively. When selenazolidine supplementation began three days after carcinogen administration (i.e., post-initiation), 2-butylSCA, 2-cyclohexylSCA, and 2-oxoSCA were chemopreventive. In both regimens, selenocystine was also chemopreventive. In the post-initiation protocol, but with intervention at a precancerous stage (13 days), whole genome expression analysis of lung RNA identified six gene transcripts that weakly correlated with the efficacy of tumor reduction by the four selenocompounds at 4 months. None of these genes were among those identified to be influenced by chemopreventive selenium compounds in human lung cancer cell lines. When supplementation was for 1 month-prior until 3 days-after carcinogen administration, 2-butylSCA, and 2-phenylSCA were chemopreventive but selenocystine was ineffective. Both 2-butylSCA and 2-phenylSCA retained their chemopreventive activity (44% and 40% tumor number reduction, respectively), when the supplementation was shortened and restricted to a pre-initiation period (days -9 to -2). With supplementation spanning 2 days-prior until 3 days-after NNK, reductions in tumor numbers by 2-phenylSCA (26%) and 2-butylSCA (17%) did not achieve statistical significance. Thus, several 2-aryl/alkyl selenazolidines possess chemopreventive activity against NNK-induced lung tumors, and variously demonstrate pre-initiation and post-initiation efficacy.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-06-2013
DOI: 10.1161/CIRCULATIONAHA.112.142158
Abstract: In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR). The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an in idual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and in idual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53–1.00) and 0.88 (95% CI, 0.57–1.35) ( P interaction =0.078), for mortality were 0.91 (95% CI, 0.74–1.13) and 0.91 (95% CI, 0.71–1.16) ( P interaction =0.34), and for major bleeding were 0.50 (95% CI, 0.36–0.70) and 0.75 (95% CI, 0.58–0.97) ( P interaction =0.095), respectively. Similar results were seen for quartiles of in idual TTR. The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers’ and patients’ predicted quality of international normalized ratio control. URL: www.clinicaltrials.gov . Unique identifier: NCT00412984.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.AHJ.2016.05.012
Abstract: Antithrombotic therapy plays an important role in the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS) but is associated with bleeding risk. Advanced age may modify the relationship between efficacy and safety. Efficacy and safety of vorapaxar (a protease-activated receptor 1 antagonist) was analyzed across ages as a continuous and a categorical variable in the 12,944 patients with NSTE ACS enrolled in the TRACER trial. To evaluate the effect of age, Cox regression models were developed to estimate hazard ratios (HRs) with the adjustment of other baseline characteristics and randomized treatment for the primary efficacy composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization, and the primary safety composite of moderate or severe Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding. The median age of the population was 64years (25th, 75th percentiles = 58, 71). Also, 1,791 patients (13.8%) were ≤54years of age, 4,968 (38.4%) were between 55 and 64 years, 3,979 (30.7%) were between 65 and 74 years, and 2,206 (17.1%) were 75years or older. Older patients had higher rates of hypertension, renal insufficiency, and previous stroke and worse Killip class. The oldest age group (≥75years) had substantially higher 2-year rates of the composite ischemic end point and moderate or severe GUSTO bleeding compared with the youngest age group (≤54years). The relationships between treatment assignment (vorapaxar vs placebo) and efficacy outcomes did not vary by age. For the primary efficacy end point, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were as follows: 1.12 (0.88-1.43), 0.88 (0.76-1.02), 0.89 (0.76-1.04), and 0.88 (0.74-1.06), respectively (P value for interaction = .435). Similar to what was observed for efficacy outcomes, we did not observe any interaction between vorapaxar and age on bleeding outcomes. For the composite of moderate or severe bleeding according to the GUSTO classification, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were 1.73 (0.89-3.34), 1.39 (1.04-1.86), 1.10 (0.85-1.42), and 1.73 (1.29-2.33), respectively (P value for interaction = .574). Older patients had a greater risk for ischemic and bleeding events however, the efficacy and safety of vorapaxar in NSTE ACS were not significantly influenced by age.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.AHJ.2014.06.017
Abstract: In the TRACER trial, vorapaxar, a protease-activated receptor-1 antagonist, plus standard care in non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients did not significantly reduce the primary composite end point but reduced a key secondary end point and significantly increased bleeding. History of peripheral artery disease (PAD) was a risk-enrichment inclusion criterion. We investigated the efficacy and safety of vorapaxar in NSTE ACS patients with documented PAD. TRACER was a double-blind, randomized trial comparing vorapaxar with placebo in 12,944 patients with NSTE ACS. In total, 936 (7.2%) patients had a history of PAD. Ischemic events occurred more frequently among patients with PAD (25.3%) versus no PAD (12.2%, P < .001), and Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding was more common in PAD (9.1%) versus no PAD (5.0%, P = .004). Similar rates of the composite end point (cardiovascular death, myocardial infarction, or stroke) occurred in patients with PAD treated with vorapaxar and placebo (21.7% vs 24.8%, P interaction = .787). Patients with PAD treated with vorapaxar, when compared with placebo, also had a numerical reduction in peripheral revascularization procedures (8.1% vs 9.0%, P = .158) and a lower extremity utation rate (0.9% vs 1.5%, P = .107). Vorapaxar increased Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding similarly in patients with PAD (hazard ratio 1.47, 95% CI 0.89-2.45) and without (hazard ratio 1.48, 95% CI 1.22-1.79 P interaction = .921). Patients with NSTE ACS and PAD were at increased risk for ischemic events. Lower rates of ischemic end points, peripheral revascularization, and utation with vorapaxar did not reach statistical significance but warrant further investigation. Vorapaxar increased bleeding in both patients with and without PAD at a similar magnitude of risk.
Publisher: SAGE Publications
Date: 1985
DOI: 10.1177/016173468500700103
Abstract: Factors inherent to the ultrasound imaging system can influence quantitative ultrasound image texture and may produce changes that mask or mimic those due to alterations in tissue structure. In this study, we assessed the effect of the method of image data acquisition and analysis on the variations in quantitative texture measures that occurred solely due to the position of a region of interest (ROI) within the field of view. When ROI's, which varied in range and azimuth within the image of a tissue equivalent phantom (of uniform composition), were assessed by conventional analysis of scan-converted (rectangular coordinate) data, over 50 percent of all texture measures showed significant differences. Pseudo polar analysis reduced the number of texture measures showing regional variation by 80 percent (p 0.01) and true polar coordinate data analysis reduced the number by 74 percent (p 0.01). True polar analysis completely abolished differences in texture measures between ROI's separated in azimuth. Acquisition and analysis of tissue texture data using polar coordinates should allow a more definitive identification of abnormal tissue.
Publisher: Oxford University Press (OUP)
Date: 20-10-2013
Abstract: We assessed the effect of concomitant aspirin use on the efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation (AF). In ARISTOTLE, 18 201 patients were randomized to apixaban 5 mg twice daily or warfarin. Concomitant aspirin use was left to the discretion of the treating physician. In this predefined analysis, simple and marginal structured models were used to adjust for baseline and time-dependent confounders associated with aspirin use. Outcome measures included stroke or systemic embolism, ischaemic stroke, myocardial infarction, mortality, major bleeding, haemorrhagic stroke, major or clinically relevant non-major bleeding, and any bleeding. On Day 1, 4434 (24%) patients were taking aspirin. Irrespective of concomitant aspirin use, apixaban reduced stroke or systemic embolism [with aspirin: apixaban 1.12% vs. warfarin 1.91%, hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.39-0.85 vs. without aspirin: apixaban 1.11% vs. warfarin 1.32%, HR 0.84, 95% CI 0.66-1.07 P interaction = 0.10] and caused less major bleeding than warfarin (with aspirin: apixaban 3.10% vs. warfarin 3.92%, HR 0.77, 95% CI 0.60-0.99 vs. without aspirin: apixaban 1.82% vs. warfarin 2.78%, HR without aspirin 0.65, 95% CI 0.55-0.78 P interaction = 0.29). Similar results were seen in the subgroups of patients with and without arterial vascular disease. Apixaban had similar beneficial effects on stroke or systemic embolism and major bleeding compared with warfarin, irrespective of concomitant aspirin use.
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.AMJCARD.2014.05.054
Abstract: The therapeutic potential of vorapaxar in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention (PCI) is unknown. This prespecified analysis of a postrandomization subgroup evaluated the effects of vorapaxar compared with placebo among Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) participants undergoing PCI, focusing on the implanted stent type (drug-eluting stent [DES] vs bare-metal stent [BMS]). Among 12,944 recruited patients, 7,479 (57.8%) underwent PCI during index hospitalization, and 3,060 (40.9%) of those patients received exclusively BMS, whereas 4,015 (53.7%) received DES. The median (twenty-fifth, seventy-fifth percentiles) duration of thienopyridine therapy was 133 days (47, 246) with BMS and 221 days (88, 341) with DES. At 2 years among patients undergoing PCI, the primary (cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) and secondary (cardiovascular death, myocardial infarction, or stroke) end points did not differ between vorapaxar and placebo groups, which was consistent with the treatment effect observed in the overall study population (p value for interaction = 0.540). However, the treatment effect trended greater (p value for interaction = 0.069) and the risk for bleeding in patients taking vorapaxar versus placebo appeared attenuated in BMS-only recipients. After adjustment for confounders, the interaction was no longer significant (p value = 0.301). The covariate that mostly explained the stent-type-by-treatment interaction was the duration of clopidogrel therapy. In conclusion, among patients with PCI, the effect of vorapaxar is consistent with the overall TRACER results. Patients who received a BMS underwent shorter courses of clopidogrel therapy and displayed trends toward greater ischemic benefit from vorapaxar and lesser bleeding risk, compared with patients who received a DES.
Publisher: Elsevier BV
Date: 2008
Publisher: Wiley
Date: 08-1997
DOI: 10.1111/J.1445-5994.1997.TB02226.X
Abstract: Fibrinolytic therapy substantially reduces mortality from acute myocardial infarction. Patient selection is, however, important. The patient must present within 12 hours of the onset of ischaemic symptoms, have definite ECG changes of ST elevation or left bundle branch block and no contraindications. The major contraindications are those for risk of an intracerebral bleed, recent stroke, intracranial tumour or risk of a major systemic bleed. Age and hypertension are not contraindications but may modify the regimen used. Heparin is required with recombinant tissue plasminogen activator but is optional with streptokinase. The recent COBALT trial suggests that the accelerated weight related t-PA regimen given over 90 minutes is more satisfactory than double bolus t-PA. However, in patients under 75 years of age, the two regimens were equivalent. For patients suffering acute myocardial infarction, practitioners should now in idualise choice of therapy, rather than give the same cocktail to all patients. The choice of regimen will depend on the cardiac risk, the stroke risk, the bleeding risk and the cost.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-1989
Abstract: To determine if there would be a decrease in blood pressure after exercise in patients with borderline hypertension and if this decrease would be accompanied by a decrease in sympathetic nerve activity to muscle, we recorded multifiber postganglionic muscle sympathetic activity from the peroneal nerve at rest in nine men with borderline hypertension (age 25 +/- 1 years, mean +/- SEM) before and 60 minutes after 45 minutes of submaximal treadmill exercise. In addition, responses to a cold pressor test, handgrip, and the Valsalva maneuver were recorded before and after exercise. Four subjects were also studied before and after "sham" exercise. Sham exercise had no effect on blood pressure or sympathetic nerve activity whereas resting systolic blood pressure was lower after treadmill exercise in seven subjects (from 136 +/- 4 before to 123 +/- 2 mm Hg 60 minutes after exercise p less than 0.01). Sixty minutes after exercise, sympathetic nerve activity was lower in all seven subjects (from 19 +/- 2 to 11 +/- 2 bursts/min, p less than 0.015 or from 27 +/- 3 to 14 +/- 2 bursts/100 heartbeats, p less than 0.005) but was slightly increased in the two subjects without postexercise hypotension. Heart rate and pressor and sympathoneural responses to the cold pressor test, handgrip, and the Valsalva maneuver were not altered by prior exercise. When nitroprusside was infused in five subjects to produce a reduction in systolic blood pressure similar to that seen 60 minutes after exercise, this drug increased sympathetic discharge from 37 +/- 6 to 57 +/- 4 bursts/100 heartbeats (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Wiley
Date: 12-1993
Publisher: Oxford University Press (OUP)
Date: 19-08-2011
Abstract: ST-elevation in lead aVR is known to be associated with a worse prognosis in patients with acute ST elevation myocardial infarction (MI) but the significance of ST depression in lead aVR has been unclear. Infarction of the inferior apex of the left ventricle may not be appreciated on the standard 12-lead electrocardiogram (ECG) except by observing ST depression in lead aVR which is reciprocal to lead V(7). We therefore determined the prognostic value of the full spectrum of aVR ST changes in patients presenting with acute ST elevation MI. Lead aVR ST level was measured on randomization and 60 min ECGs in 15 315 patients with normal conduction from the HERO-2 trial. The outcome measure was 30-day mortality. aVR ST elevation ≥1 mm was associated with higher 30-day mortality for both inferior (22.5% for ≥1.5 mm and 13.2% for 1 mm) and anterior (23.5% for ≥1.5 mm and 11.5% for 1 mm) infarction. In contrast, deeper aVR ST depression (0, 0.5, 1, and ≥1.5 mm) was associated with higher mortality for anterior infarction (9.8, 13.2, 12.8, and 16.8%, respectively, trend P-value <0.0001) but not for inferior infarction. The resolution of aVR ST depression and ST elevation 60 min after fibrinolysis was associated with lower mortality. There is a U-shaped relationship between 30-day mortality and aVR ST level in patients presenting with anterior but not inferior ST elevation MI.
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.AHJ.2014.04.001
Abstract: Extensive coronary artery disease (CAD) is associated with higher risk. In this substudy of the PLATO trial, we examined the effects of randomized treatment on outcome events and safety in relation to the extent of CAD. Patients were classified according to presence of extensive CAD (defined as 3-vessel disease, left main disease, or prior coronary artery bypass graft surgery). The trial's primary and secondary end points were compared using Cox proportional hazards regression. Among 15,388 study patients for whom the extent of CAD was known, 4,646 (30%) had extensive CAD. Patients with extensive CAD had more high-risk characteristics and experienced more clinical events during follow-up. They were less likely to undergo percutaneous coronary intervention (58% vs 79%, P < .001) but more likely to undergo coronary artery bypass graft surgery (16% vs 2%, P < .001). Ticagrelor, compared with clopidogrel, reduced the composite of cardiovascular death, myocardial infarction, and stroke in patients with extensive CAD (14.9% vs 17.6%, hazard ratio [HR] 0.85 [0.73-0.98]) similar to its reduction in those without extensive CAD (6.8% vs 8.0%, HR 0.85 [0.74-0.98], Pinteraction = .99). Major bleeding was similar with ticagrelor vs clopidogrel among patients with (25.7% vs 25.5%, HR 1.02 [0.90-1.15]) and without (7.3% vs 6.4%, HR 1.14 [0.98-1.33], Pinteraction = .24) extensive CAD. Patients with extensive CAD have higher rates of recurrent cardiovascular events and bleeding. Ticagrelor reduced ischemic events to a similar extent both in patients with and without extensive CAD, with bleeding rates similar to clopidogrel.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.CLINTHERA.2013.06.015
Abstract: The PLATO (Platelet Inhibition and Patient Outcomes) randomized trial (NCT00391872) in patients with acute coronary syndromes (ACS) reported that ticagrelor (in addition to aspirin) reduced the rate of the composite end point of myocardial infarction (MI), stroke, or cardiovascular death compared with clopidogrel (in addition to aspirin) by 16% over 12 months (P < 0.001). No significant difference in the incidence of major bleeding was noted, but ticagrelor was associated with a higher rate of major bleeding not related to coronary artery bypass grafting. By extrapolating the key findings of PLATO, we sought to assess the cost-effectiveness of ticagrelor compared with clopidogrel in the management of ACS in a contemporary Australian setting. A Markov model with 4 health states (free from further ACS events, MI, stroke, and death) was developed to simulate the long-term costs and outcomes associated with ACS. Event risks were based on data derived directly from PLATO, and costs and utilities were drawn from published sources. A 10-year time horizon was simulated, and future costs and benefits were discounted at a 5% annual rate. However, treatment with ticagrelor and clopidogrel was only assumed for the first 12 months, with no benefits applied beyond drug cessation. Sensitivity analyses were undertaken based on variations to key data inputs. All costs for resource use applied in the analysis were based on published Australian prices (in 2010/2011 dollars [A$]). Over 10 years, the estimated quality-adjusted life-years lived per-patient were 5.74 and 5.68 for ticagrelor and clopidogrel, respectively. Net costs were A$19,132 for ticagrelor and A$18,428 for clopidogrel. These equated to an incremental cost-effectiveness ratio of A$9031 per quality-adjusted life-year gained for ticagrelor compared with clopidogrel. Sensitivity analyses indicated the result to be robust. When assessed from the perspective of the Australian health care system, ticagrelor is likely to be cost-effective compared with clopidogrel in preventing downstream morbidity and mortality associated with ACS.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-1986
Abstract: Information on the hemodynamic effects of vasopressin (AVP) in healthy humans is very limited despite its known importance in body fluid homeostasis and release in pathologic states such as hemorrhage and trauma. Although it is a potent vasoconstrictor in vitro, it does not cause the expected rise in arterial pressure when given systemically to animals with intact baroreflexes. It has been proposed that this is because AVP facilitates baroreflex control of the circulation. In this study, we assessed the effect of infusion of AVP on resting circulatory variables and on the baroreflex control of forearm vascular resistance and heart rate in healthy men. AVP in a dose of 0.4 ng/kg/min, which raised plasma level of AVP to 24 +/- 4 pg/ml, a value known to have a significant antidiuretic effect, had little hemodynamic effect, producing only mild bradycardia and a slight increase in central venous pressure. Reflex changes in heart rate during neck suction (-15 and -30 mm Hg) and neck pressure (+15 and +30 mm Hg) were not altered. Reflex responses to lower body negative pressure and to its release were also unchanged by this dose of AVP. In contrast, a higher dose of AVP (4 ng/kg/min), which raised plasma levels to 290 +/- 41 pg/ml, a concentration known to occur as a result of hemorrhagic hypotension and circulatory stresses, did cause hemodynamic changes. There was tachycardia (from 63 +/- 2 to 68 +/- 2 beats/min), a decrease in pulse pressure (from 62 +/- 2 to 53 +/- 2 mm Hg), an increase in central venous pressure (from 2.6 +/- 0.5 to 4.1 +/- 0.4 mm Hg), and surprisingly in view of the known vasoconstrictor effect of AVP, an increase in forearm flow (from 4.4 +/- 0.7 to 5.9 +/- 1.2 ml/min/100 ml tissue) and a decrease in forearm vascular resistance (from 24 +/- 4 to 18 +/- 3 U) there was no significant change in mean arterial pressure (from 83 +/- 2 to 83 +/- 3 mm Hg). Reflex changes in heart rate were unaltered. The maximal vasoconstrictor response in the forearm attained during lower body negative pressure was not influenced by AVP, but the reflex vasodilator response to the sudden release of lower body negative pressure was significantly augmented, vascular resistance falling to 23 +/- 4 U before and 13 +/- 2 U during AVP. The unanticipated findings in this study include the biphasic changes in heart rate with increasing doses of AVP, the absence of a pressor response, and the vasodilatation in forearm vessels.(ABSTRACT TRUNCATED AT 400 WORDS)
Publisher: Oxford University Press (OUP)
Date: 10-2002
Abstract: To determine the effects on homocysteine levels of two doses of folic acid compared to placebo, where the high dose is typical of that provided by pharmacological intervention and the low dose approximates that provided by dietary supplementation. The PACIFIC study was a double-blind, placebo-controlled, factorial randomized trial. Seven hundred and twenty-three in iduals with a history of myocardial infarction or unstable angina were recruited from 28 clinical cardiology centres in Australia and New Zealand and randomized to folic acid 2.0 mg daily, folic acid 0.2 mg daily or placebo. The primary outcome, homocysteine, was measured using a fluorescence polarization immunoassay. Compared to placebo, 2.0 mg folic acid reduced homo-cysteine by 1.8 micromol x 1(-1) [95% confidence interval (CI) 1.3-2.3] and 0.2 mg reduced homocysteine by 1.2 micromol x 1(-1) [95% CI 0.8-1.7). The higher dose reduced homocysteine significantly more than the lower dose (P=001). Both doses of folic acid reduced homocysteine, but the effects of the 2.0 mg dose were about one third greater than the 0.2 mg dose. Fortification of foods with folic acid should result in population-wide lower levels of homocysteine but high-dose pharmacological supplementation would produce greater reductions for high-risk in iduals.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-11-2015
DOI: 10.1161/CIRCULATIONAHA.114.015042
Abstract: Vorapaxar antagonizes protease-activated receptor 1, the primary receptor for thrombin on human platelets, and reduces recurrent thrombotic events in stable patients with a previous myocardial infarction (MI). We wished to determine whether the efficacy and safety of antiplatelet therapy with vorapaxar was modified by concurrent thienopyridine use. The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50 (TRA 2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in 26 449 patients with previous atherothrombosis. This prespecified analysis included 16 897 patients who qualified with a MI in the preceding 2 weeks to 12 months and was restricted to patients without a history of stroke or transient ischemic attack given its contraindication in that population. Randomization was stratified on the basis of planned thienopyridine use. Thienopyridine was planned at randomization in 12 410 (73%). Vorapaxar significantly reduced the composite of cardiovascular death, MI, and stroke in comparison with placebo regardless of planned thienopyridine therapy (planned thienopyridine, hazard ratio, 0.80, 0.70–0.91, P .001 no planned thienopyridine, hazard ratio, 0.75 0.60–0.94, P =0.011 P -interaction=0.67). Findings were similar when patients were stratified by actual thienopyridine use at baseline ( P -interaction=0.82) and through 18 months ( P -interaction=0.44). Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate or severe bleeding risk was increased with vorapaxar and was not significantly altered by planned thienopyridine (planned, hazard ratio, 1.50 1.18–1.89, P .001 no planned, hazard ratio, 1.90, 1.17–3.07, P =0.009 P -interaction=0.37) or actual thienopyridine use ( P -interaction=0.24). Vorapaxar reduced cardiovascular death, MI, or stroke in stable patients with a history of previous MI, whether treated concomitantly with a thienopyridine or not. The relative risk of moderate or severe bleeding was similarly increased irrespective of thienopyridine use. URL: www.clinicaltrials.gov . Unique identifier: NCT00526474.
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.JACC.2019.10.057
Abstract: Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C). A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE). One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina. Baseline lipoprotein(a) levels (median: 21.2 mg/dl interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999 p = 0.0081). Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab NCT01663402).
Publisher: American Diabetes Association
Date: 15-03-2021
DOI: 10.2337/DC20-2842
Abstract: In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor. In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data. Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.02−1.06, P & 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85–1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment–baseline lipoprotein(a) interaction P = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03−1.12 P = 0.0002) for incident type 2 diabetes. In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.
Publisher: Wiley
Date: 12-1988
DOI: 10.1111/J.1440-1681.1988.TB01041.X
Abstract: 1. In order to examine the concentration of neuropeptide Y-like immunoreactivity (NPY-LI) and atrial natriuretic peptide (ANP) in the circulation in man, blood was s led from the iliac vein, the inferior vena cava, the superior vena cava, the pulmonary artery and the femoral artery in 13 patients undergoing cardiac catheterization. 2. Plasma NPY-LI levels were similar at all points s led and no arteriovenous differences were found. Plasma ANP concentration in the pulmonary artery was greater than in peripheral venous blood but there was a strong correlation between the two. 3. The concentration of NPY-LI and ANP in peripheral venous blood reflects central venous and arterial concentrations.
Publisher: Therapeutic Guidelines Limited
Date: 04-1996
Publisher: Informa Healthcare
Date: 29-06-2015
DOI: 10.1185/03007995.2015.1058247
Abstract: Ticagrelor is recommended in local and international guidelines as first-line therapy in combination with aspirin in patients presenting with acute coronary syndromes (ACS). The purpose of this article is to provide practical guidance regarding the use of ticagrelor in this setting. Ticagrelor, a direct-acting, reversible P2Y12 receptor antagonist, has a faster onset, and a more potent and predictable antiplatelet effect compared with clopidogrel. The authors recommend considering the use of ticagrelor in moderate-to-high risk ACS patients treated with an invasive approach and those managed non-invasively who have elevated troponin levels. Consistent with outcomes observed in the PLATO trial overall, ticagrelor was superior to clopidogrel treatment in patients with chronic kidney disease, a history of stroke or transient ischemic attack, the elderly, and patients requiring surgical revascularization. When switching from clopidogrel to ticagrelor, patients established on clopidogrel therapy can be switched directly without loading patients not loaded with clopidogrel and not taking maintenance dose clopidogrel for at least 5 days should first be loaded with ticagrelor. Guidelines recommend discontinuing ticagrelor 5 days before surgery if antiplatelet effects are not desired and recommencing therapy as soon as safe following surgery. Ticagrelor should be avoided in in iduals with a history of intracranial hemorrhage, moderate-to-severe hepatic impairment, high bleeding risk, within 24 hours of thrombolytic therapy, and in those treated with oral anticoagulants. Local, real-world experience suggests low bleeding rates with ticagrelor therapy. Dyspnoea is a common symptom in patients with ACS and is also a side-effect of ticagrelor therapy. Discontinuation of ticagrelor due to dyspnoea has been uncommon in clinical trials. However, local registry data suggest higher discontinuation rates (2-9%) related to dyspnoea in the real-world setting, indicating that clinicians may need to consider other potential causes of dyspnoea before discontinuing ticagrelor.
Publisher: American Medical Association (AMA)
Date: 13-03-1996
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.AHJ.2009.12.044
Abstract: Despite advances in therapy, global mortality due to acute myocardial infarction remains high. The international Hirulog and Early Reperfusion or Occlusion (HERO-2) trial of 17,073 patients with ST-segment elevation myocardial infarction provided the opportunity to explore international differences in outcomes. Patient characteristics, treatment, and outcomes were compared across 5 erse regions: Western countries, Latin America, Eastern Europe, Russia, and Asia. In addition, a representative s le of 1,743 screened patients was compared with enrolled patients. Larger percentages of eligible patients were randomized in Eastern Europe, Russia, and Asia than Western countries. These regions enrolled more patients with anterior myocardial infarction, Killip class III or IV, and late presentation (>4 hours). More patients aged >75 years were enrolled from Western countries. Overall risk levels were similar. Eastern Europe and Russia had lower rates than Western countries of coronary revascularization (2% vs 18%) and longer hospital stays (median 18 vs 7 days). Thirty-day mortality was lower in Western countries 6.7% versus 10.2% to 13.2% elsewhere, whereas reinfarction was more frequent (3.2% vs 1.5% to 3.0% each, P < .001). Regional mortality differences persisted after adjustment for baseline risk factors, treatments, or national health and economic statistics (each P < .001). The variation in mortality and other clinical outcomes across geographic regions was not adequately explained by risk factors, patterns of care, or national health statistics. Nevertheless, large international trials are a better way to assess potential new treatments across many countries than the alternative of separate smaller trials in each region.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2016
DOI: 10.1161/CIRCOUTCOMES.115.002488
Abstract: High-sensitivity troponin T (hs-TnT) assays promise greater discrimination of evolving myocardial infarction, but the impact of unguided implementation on the effectiveness of care is uncertain. We evaluated the impact of hs-TnT reporting on care and outcome among chest pain patients presenting to 5 emergency departments within a multicenter randomized trial. Patients were allocated to hs-TnT reporting (hs-report) or standard reporting (std-report Roche Elecys). The primary end point was death and new or recurrent acute coronary syndrome by 12 months. A total of 1937 patients without ST-segment elevation were enrolled between July 2011 and March 2013. The median age was 61 (interquartile range, 48–74) years, and 46.3% were women. During the index hospitalization, 1466 patients (75.7%) had maximal troponin ng/L within 24 hours. Randomization to hs-report format did not alter the admission rate (hs-report: 57.7% versus std-report: 58.0% P =0.069). There was no difference in angiography (hs-report: 11.9% versus std-report: 10.9% P =0.479). The hs-reporting did not reduce 12-month death or new/recurrent acute coronary syndrome in the overall population (hs-report: 9.7% versus std-report: 7.2% [hazard ratio, 0.83 (0.57–1.22) P =0.362]). However, among those with troponin levels ng/L, a modest reduction in the primary end point was observed (hs-report: 2.6% versus std-report: 4.4%, [hazard ratio, 0.58 95% confidence interval, 0.34–0.1.00 P =0.050). High-sensitivity troponin reporting alone is associated with only modest changes in practice. Clinical effectiveness in the adoption of high-sensitivity troponin may require close coupling with protocols that guide interpretation and care. URL: www.ANZCTR.org.au . Unique identifier: ACTRN12611000879965.
Publisher: Elsevier BV
Date: 09-2018
Publisher: Oxford University Press (OUP)
Date: 31-05-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-1991
Abstract: This study addressed the need for heparin administration to be continued for more than 24 hours after coronary thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). A total of 241 patients with acute myocardial infarction were treated with 100 mg rt-PA and a bolus of 5,000 units i.v. heparin followed by 1,000 units/hr i.v. heparin for 24 hours. At 24 hours, 202 patients were randomized to continue intravenous heparin therapy (n = 99) in full dosage or to discontinue heparin therapy and begin an oral antiplatelet regimen of aspirin (300 mg/day) and dipyridamole (300 mg/day) (n = 103). On prospective recording, there were no differences in the pattern of chest pain, reinfarction, or bleeding complications. Coronary angiography on cardiac catheterization at 7-10 days showed no differences in patency of the infarct-related artery. The proportion of patients with total occlusion (TIMI grade 0-1) of the infarct-related artery was 18.9% in the heparin group and 19.8% in the aspirin and dipyridamole group. In the patients with an incompletely occluded infarct-related artery, the lumen was reduced by 69 +/- 2% of normal in the heparin group and 67 +/- 2% in the aspirin and dipyridamole group. Left ventricular function assessed on cardiac catheterization and radionuclide study at day 2 and at 1 month showed no differences between the two groups. Left ventricular ejection fraction on radionuclide ventriculography at 1 month was 52.4 +/- 1.2% in the heparin group and 51.9 +/- 1.2% in the aspirin and dipyridamole group. We conclude that heparin therapy can be discontinued 24 hours after rt-PA therapy and replaced with an oral antiplatelet regimen without any adverse effects on chest pain, reinfarction, coronary patency, or left ventricular function.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1987
Abstract: Arginine vasopressin, a potent vasoconstrictor, does not raise arterial pressure in normal humans even at pathophysiological plasma levels. To examine whether the pressor effect of vasopressin in humans is buffered by baroreceptor reflex inhibition of sympathetic nerve activity, we recorded postganglionic muscle sympathetic nerve activity directly from the peroneal nerve in 12 normal men before, during, and after a 20-minute intravenous infusion of vasopressin, 4 ng/kg/min, that increased mean plasma concentrations from 6.2 +/- 0.6 to 320 +/- 68 (SE) pg/ml. During the first 5 minutes (n = 8), mean arterial pressure increased from 91 +/- 3 to 97 +/- 4 mm Hg (p less than 0.05) and integrated sympathetic nerve activity decreased from 271 +/- 45 to 156 +/- 33 units (p less than 0.05). At 15 minutes (n = 12), arterial pressure did not differ from control values whereas forearm vascular resistance fell (p less than 0.05) and central venous pressure and heart rate increased (p less than 0.05). Sympathetic nerve activity remained below control levels throughout the infusion (202 +/- 31 vs 254 +/- 40 units before infusion p less than 0.05). An effect of vasopressin on ganglionic transmission was excluded, since the sympathoexcitatory response to apnea was not attenuated during vasopressin. Thus, pathophysiologic levels of vasopressin in humans cause inhibition of muscle sympathetic nerve activity that is not due to a ganglionic blocking action. The sympathoinhibition may be caused in part by the modest increases in mean arterial and central venous pressures and attendant stimulation of arterial and cardiac baroreceptors. The reflex decrease in sympathetic nerve activity would be expected to buffer the direct vasoconstrictor effects of vasopressin.
Publisher: Canadian Science Publishing
Date: 08-1987
DOI: 10.1139/Y87-270
Abstract: Arginine vasopressin (AVP), a potent vasoconstrictor, does not raise arterial pressure in normal humans or neurally intact animals, even during infusions that achieve pathophysiological plasma concentrations. It has been proposed that this is because AVP facilitates the baroreflex control of the circulation. We performed a series of investigations to test this hypothesis, and to determine sites at which AVP might act to augment the baroreflex. In anesthetized rabbits, vasopressin (36 pmol∙kg −1 ∙min −1 ) increased discharge from both medullated and nonmedullated single fibres from aortic baroreceptor nerves during elevations in aortic arch pressure. Similarly, vasopressin (36 pmol∙kg −1 ∙min −1 ) increased the response of left ventricular mechanoreceptor single fibre discharge to elevations of left ventricular end-diastolic pressure. These observations suggest that sensitization of high and low pressure baroreceptors is one mechanism by which vasopressin may facilitate baroreflexes. In a further series of experiments in sinoaortic denervated anesthetized rabbits, vasopressin (18 pmol∙kg −1 ∙min −1 ) facilitated vagally mediated reflex inhibition of renal sympathetic nerve activity during volume expansion. In humans, AVP (0.37 pmol∙kg −1 ∙min −1 ) raised plasma AVP to an antidiuretic level (22 ± 4 fmol/mL), but did not change blood pressure or the baroreflex control of heart rate or forearm vascular resistance. A higher dose (3.7 pmol∙kg −1 ∙min −1 ) raised plasma levels to 268 ± 38 fmol/mL, decreased pulse pressure, increased central venous pressure (from 2.6 ± 0.5 to 4.1 ± 0.4 mmHg) (1 mmHg = 133.3 Pa) and suprisingly, in view of its direct vasoconstrictor effect, increased forearm blood flow by 30% and decreased forearm vascular resistance from 24 ± 4 to 18 ± 3 units (p 0.05) mean arterial pressure was unchanged. The reflex vasodilator response to the sudden release of lower body negative pressure was augmented by AVP, whereas reflex changes in heart rate were unaltered. To test the hypothesis that vasopressin caused this resting vasodilation through inhibition of sympathetic nerve activity, we recorded postganglionic efferent muscle sympathetic nerve activity directly from the peroneal nerve before, during, and after intravenous infusion of AVP, 3.7 pmol∙kg −1 ∙min −1 . Forearm vascular resistance again fell sympathetic nerve activity decreased abruptly on starting AVP, from 254 ± 40 to 163 ± 34 units (p 0.05), and remained below control throughout the infusion. This decrease did not appear to be due to a ganglionic action of AVP. The inhibition of sympathetic nerve activity probably resulted principally from mechanical stimulation of cardiac and arterial baroreceptors. However, since the marked reduction of nerve activity was not consistently associated with increases in arterial pressure or central venous pressure, we cannot exclude the possibility that vasopressin decreased sympathetic nerve activity in part by sensitizing baroreceptor afferents or by a central neural action. Sympathoinhibition would appear to be an important mechanism by which the potent pressor effects of AVP are countered in normal humans.
Publisher: Elsevier BV
Date: 05-1999
DOI: 10.1016/S0002-8703(99)70402-3
Abstract: Early meta-analyses suggested that prophylactic lidocaine use reduces ventricular fibrillation but increases mortality rates after acute myocardial infarction. We determined the frequency and effect on clinical outcomes with its use in the thrombolytic era. We studied 43,704 patients enrolled in GUSTO-I or GUSTO-IIb who had ST-segment elevation, underwent thrombolysis, and survived at least 1 hour after enrollment. Odds ratios (OR) and confidence intervals (CI) were calculated for the risk of asystole, atrioventricular block, ventricular fibrillation, and ventricular tachycardia during hospitalization for 24-hour, in-hospital, and 30-day mortality rates and for 24-hour and 30-day mortality rates after adjustment for baseline predictors of death. In GUSTO-I and GUSTO-IIb, 16% and 3.5% of patients, respectively, received prophylactic lidocaine. They had a lower risk of death at 24 hours (OR 0.81, 95% CI 0.67 to 0.97) and trends toward lower odds of in-hospital death (OR 0.90, 95% CI 0.81 to 1.01) and death at 30 days (OR 0.92, 95% CI 0.82 to 1. 02). After adjustment for baseline characteristics, however, the odds of death were similar with or without lidocaine (OR 0.90 and 0. 97, respectively). Outside the United States, lidocaine was associated with higher incidences of all serious arrhythmias, but in US patients it conferred a lower likelihood of ventricular fibrillation and no increase in asystole, atrioventricular block, or mortality rates. Prophylactic lidocaine use has decreased with the advent of thrombolysis, although its use may not be associated with increased mortality rates.
Publisher: Elsevier BV
Date: 08-2001
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.AHJ.2014.06.005
Abstract: The perceived risk of serious bleeding is an obstacle to the use of oral anticoagulation in East Asia. The efficacy and safety of apixaban in East Asian patients with atrial fibrillation are unknown. ARISTOTLE included 18,201 patients with nonvalvular atrial fibrillation randomized to apixaban 5mg twice daily or warfarin. The efficacy and safety of apixaban and warfarin among patients recruited from East Asia (n = 1,993) were compared with those recruited from outside East Asia (n = 16,208). Compared with warfarin, apixaban resulted in a consistent reduction in stroke or systemic embolism in East Asian (hazard ratio [HR] 0.74, 95% CI 0.50-1.10) and non-East Asian (HR 0.81, 95% CI 0.66-0.99) patients (interaction P = .70). Consistent benefits of apixaban over warfarin were also seen for major bleeding in East Asian (HR 0.53, 95% CI 0.35-0.80) and non-East Asian (HR 0.72, 95% CI 0.62-0.83) patients (interaction P = .17). There was a greater reduction in major or clinically relevant nonmajor bleeding with apixaban compared with warfarin in East Asian (HR 0.49, 95% CI 0.35-0.67) than in non-East Asian (HR 0.71, 95% CI 0.63-0.79) patients (interaction P = .03). Numerically higher rates of intracranial bleeding were seen in East Asian patients with warfarin but not with apixaban. Apixaban resulted in similar reductions in stroke or systemic embolism and major bleeding and greater reductions in major or clinically relevant nonmajor bleeding in patients from East Asia. Warfarin is associated with more intracranial bleeding, particularly in patients from East Asia.
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.HLC.2017.08.004
Abstract: Please note that on p.929 in 5.2.2.7, paragraph 3, the dose of dabigatran should read as BD rather than daily. We regret any inconvenience that this may have caused.
Publisher: Elsevier BV
Date: 2005
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-02-1999
Abstract: Background —Although 30-day survival is increased in patients with acute myocardial infarction complicated by cardiogenic shock who undergo coronary revascularization, the longer-term outcome in such patients and the duration of benefit from revascularization are unknown. Methods and Results —We analyzed 30-day survivors of acute myocardial infarction in the Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial and identified 36 333 who had not had cardiogenic shock (systolic blood pressure mm Hg for ≥1 hour, group 1) and 1321 patients who had shock (group 2). Group 2 patients were older and sicker. At 1 year, 97.4% of group 1 patients were alive versus 88.0% of group 2 ( P =0.0001). Among group 2 patients, 578 (44%) had undergone revascularization within 30 days (group 2A) and 728 (56%) had not (group 2B). Revascularization was not required by protocol but was selected by the attending physicians. At 1 year, 91.7% of group 2A patients were alive versus 85.3% of group 2B ( P =0.0003). With the use of multivariable logistic regression analysis to adjust for differences in baseline characteristics of shock patients alive at 30 days, revascularization within 30 days was independently associated with reduced 1-year mortality (odds ratio 0.6, [95% confidence interval 0.4, 0.9], P =0.007). Conclusions —Most patients (88%) with acute myocardial infarction complicated by cardiogenic shock who are alive at 30 days survived at least 1 year. Shock patients who underwent revascularization within 30 days had improved survival at 1 year compared with shock patients who did not receive revascularization, even after adjustment for differences in baseline characteristics between the 2 groups.
Publisher: AMPCo
Date: 09-2006
Publisher: Wiley
Date: 09-03-2012
DOI: 10.1111/J.1540-8175.2012.01667.X
Abstract: Statin therapy has been shown to reduce cardiovascular risk after myocardial infarction (MI). Using a novel technique of high-resolution transthoracic echocardiography (HRTTE), we sought to assess the statin-induced changes in left anterior descending coronary artery (LAD) wall thickness in previously statin naive patients over a 12-month period. Thirty subjects underwent HRTTE assessment of their LAD wall thickness predischarge post-MI (non-LAD territory) and at 3, 6, and 12 months. The LAD anterior and posterior wall thickness and vessel luminal diameter were measured. Blood lipid levels were also assessed at each study visit. All subjects were started on moderate lipid-lowering therapy (40 mg of atorvastatin or simvastatin). There was a sustained decrease in total cholesterol (-23%), triglycerides (-19%), and low-density lipoprotein (-41%) at the 3-month visit from the baseline, with no change in high-density lipoprotein level. Overall, there was no change in the LAD wall thickness and external or vessel lumen diameter over the 12-month period. Of those that demonstrated regression, the only predictor of percentage change in the LAD wall thickness was the baseline LAD wall thickness. Despite a favorable change in blood lipid profile, no overall change in the LAD wall thickness was detected over a 12-month period in subjects on moderate statin therapy using HRTTE. However, using case-based analysis, regression was able to be predicted by the baseline LAD wall thickness. HRTTE may be an instructive noninvasive modality to assess response to statin intervention.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-1990
DOI: 10.1097/00004872-199005000-00008
Abstract: Adrenaline facilitates the neural release of endogenous noradrenaline by stimulating prejunctional beta-receptors on adrenergic nerve endings. Recently, we demonstrated the functional significance of this action in the control of vascular resistance in young subjects with normal blood pressure. In the present study, we tested the hypothesis that the effects of adrenaline on neurogenic vasoconstriction are exaggerated in humans with borderline hypertension. Forearm blood flow was measured simultaneously in the experimental and contralateral arms of seven young men with borderline hypertension. We compared forearm vasoconstrictor responses to a reflex stimulus to noradrenaline release (lower-body negative pressure, LBNP) and to intra-arterial infusion of noradrenaline before and 30 min after brachial artery infusion of adrenaline (50 ng/min). These doses had no systemic effects. In the experimental arm, the vasoconstrictor response to LBNP was 65% greater 30 min after the adrenaline infusion (P = 0.075), whereas the response to intra-arterial noradrenaline decreased by 36% (P greater than 0.1). Forearm vascular responses to LBNP in the contralateral control arm that did not receive adrenaline were similar before and after the adrenaline infusion. The ratio of forearm vasoconstrictor responses (i.e. the increase in forearm vascular resistance) with LBNP to the forearm vasoconstrictor response to noradrenaline in the experimental arm was used as an index of neural release of the neurotransmitter noradrenaline. This ratio increased from 0.8 to 2.1 (P less than 0.05) after the adrenaline infusion. These facilitatory neural after-effects of adrenaline were similar in magnitude to our previous observation in young normotensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Oxford University Press (OUP)
Date: 20-09-2016
Abstract: Vorapaxar is effective in the prevention of secondary atherothrombotic events, although the efficacy/safety balance appears less favorable in the treatment of patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS). We hypothesized that patients with NSTE ACS already receiving thienopyridine prior to the ACS event may show differential efficacy/safety effects with vorapaxar vs. placebo added to their standard care. We studied 12,944 patients from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial with respect to thienopyridine use before admission for the index NSTE ACS event. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, rehospitalization for ischemia, and urgent revascularization. The key secondary endpoint was a composite of cardiovascular death, myocardial infarction, and stroke. Safety endpoints were bleeding complications. Only 1513 patients (11.7%) were receiving thienopyridine before admission for the index NSTE ACS event. In these patients, Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate/severe bleeding occurred in 5.7% treated with vorapaxar and 5.3% treated with a placebo (hazards ratio (HR) 1.10, 95% confidence interval (CI) 0.70-1.71) in thienopyridine-naïve patients, the rates were 5.7% and 4.1%, respectively (HR 1.32, 95% CI 1.11-1.57 P TRACER was largely conducted in thienopyridine-naïve patients with unknown tolerance to multiple antiplatelet treatments. Patients receiving thienopyridine before the index event may have had an attenuated increase in bleeding when adding vorapaxar, whereas concomitantly adding vorapaxar and thienopyridine in naïve patients may have uncovered a latent susceptibility to bleeding.
Publisher: Springer Science and Business Media LLC
Date: 11-07-2018
Location: Australia
No related grants have been discovered for Philip Aylward.