Percutaneous Coronary Intervention in Patients Receiving Enoxaparin or Unfractionated Heparin After Fibrinolytic Therapy for ST-Segment Elevation Myocardial Infarction in the ExTRACT-TIMI 25 Trial C. ...Michael Gibson, Sabina A. Murphy, Gilles Montalescot, David A. Morrow, Diego Ardissino, Marc Cohen, Dietrich C. Gulba, Oscar H. Kracoff, Basil S. Lewis, Nathan Roguin, Elliott M. Antman, Eugene Braunwald, for the ExTRACT-TIMI 25 Investigators We sought to evaluate whether enoxaparin (ENOX) is superior to unfractionated heparin as adjunctive therapy for patients with ST-segment elevation myocardial infarction (STEMI) who receive fibrinolytic therapy and subsequently undergo percutaneous coronary intervention (PCI) by analyzing data from the EXTRACT–TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute MI Treatment) trial. Among patients treated with fibrinolytic therapy for STEMI who underwent subsequent PCI, ENOX administration was associated with a reduced risk of death or recurrent MI without difference in the risk of major bleeding. Administration of ENOX provided a seamless transition to the cardiac catheterization laboratory without the need for an additional antithrombin.
Background 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. Methods 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. Results 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; Pinteraction = .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; Pinteraction = .46) prior CABG. Conclusions 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.
Background 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. Methods 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. Results 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. Conclusions 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.
Background Major bleeding in acute coronary syndromes (ACS) is associated with an increased risk of subsequent mortality and recurrent ischemic events. Observational data and small randomized trials ...suggest that radial instead of femoral access for coronary angiography/intervention results in fewer bleeding complications, with preserved and possibly improved efficacy. Radial access versus femoral access has yet to be formally evaluated in a randomized trial adequately powered for the comparison of clinically important outcomes. Objectives The aim of this study is to evaluate the efficacy and safety of radial versus femoral access for coronary angiography/intervention in patients with ACS managed with an invasive strategy. Design This was a multicenter international randomized trial with blinded assessment of outcomes. 7021 patients with ACS (with or without ST elevation) have been randomized to either radial or femoral access for coronary angiography/intervention. The primary outcome is the composite of death, myocardial infarction, stroke, or non–coronary artery bypass graft-related major bleeding up to day 30. The key secondary outcomes are (1) death, myocardial infarction, or stroke up to day 30 and (2) non–coronary artery bypass graft-related major bleeding up to day 30. Percutaneous coronary intervention (PCI) success rates will also be compared between the two access sites. Conclusions The RIVAL trial will help define the optimal access site for coronary angiography/intervention in patients with ACS.
Summary Background In the ARISTOTLE trial, the rate of stroke or systemic embolism was reduced by apixaban compared with warfarin in patients with atrial fibrillation (AF). Patients with AF and ...previous stroke or transient ischaemic attack (TIA) have a high risk of stroke. We therefore aimed to assess the efficacy and safety of apixaban compared with warfarin in prespecified subgroups of patients with and without previous stroke or TIA. Methods Between Dec 19, 2006, and April 2, 2010, patients were enrolled in the ARISTOTLE trial at 1034 clinical sites in 39 countries. 18 201 patients with AF or atrial flutter were randomly assigned to receive apixaban 5 mg twice daily or warfarin (target international normalised ratio 2·0–3·0). The median duration of follow-up was 1·8 years (IQR 1·4–2·3). The primary efficacy outcome was stroke or systemic embolism, analysed by intention to treat. The primary safety outcome was major bleeding in the on-treatment population. All participants, investigators, and sponsors were masked to treatment assignments. In this subgroup analysis, we estimated event rates and used Cox models to compare outcomes in patients with and without previous stroke or TIA. The ARISTOTLE trial is registered with ClinicalTrials.gov , number NTC00412984. Findings Of the trial population, 3436 (19%) had a previous stroke or TIA. In the subgroup of patients with previous stroke or TIA, the rate of stroke or systemic embolism was 2·46 per 100 patient-years of follow-up in the apixaban group and 3·24 in the warfarin group (hazard ratio HR 0·76, 95% CI 0·56 to 1·03); in the subgroup of patients without previous stroke or TIA, the rate of stroke or systemic embolism was 1·01 per 100 patient-years of follow-up with apixaban and 1·23 with warfarin (HR 0·82, 95% CI 0·65 to 1·03; p for interaction=0·71). The absolute reduction in the rate of stroke and systemic embolism with apixaban versus warfarin was 0·77 per 100 patient-years of follow-up (95% CI −0·08 to 1·63) in patients with and 0·22 (−0·03 to 0·47) in those without previous stroke or TIA. The difference in major bleeding with apixaban compared with warfarin was 1·07 per 100 patient-years (95% CI 0·09–2·04) in patients with and 0·93 (0·54–1·32) in those without previous stroke or TIA. Interpretation The effects of apixaban versus warfarin were consistent in patients with AF with and without previous stroke or TIA. Owing to the higher risk of these outcomes in patients with previous stroke or TIA, the absolute benefits of apixaban might be greater in this population. Funding Bristol-Myers Squibb and Pfizer.
Summary Background Variation in and irreversibility of platelet inhibition with clopidogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary ...syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopidogrel in such patients. Methods At randomisation, an invasive strategy was planned for 13 408 (72·0%) of 18 624 patients hospitalised for acute coronary syndromes (with or without ST elevation). In a double-blind, double-dummy study, patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300–600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6–12 months. All patients were given aspirin. The primary composite endpoint was cardiovascular death, myocardial infarction, or stroke. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00391872. Findings 6732 patients were assigned to ticagrelor and 6676 to clopidogrel. The primary composite endpoint occurred in fewer patients in the ticagrelor group than in the clopidogrel group (569 event rate at 360 days 9·0% vs 668 10·7%, hazard ratio 0·84, 95% CI 0·75–0·94; p=0·0025). There was no difference between clopidogrel and ticagrelor groups in the rates of total major bleeding (691 11·6% vs 689 11·5%, 0·99 0·89–1·10; p=0·8803) or severe bleeding, as defined according to the Global Use of Strategies To Open occluded coronary arteries, (198 3·2% vs 185 2·9%, 0·91 0·74–1·12; p=0·3785). Interpretation Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned. Funding AstraZeneca.
Abstract Background We aimed to determine the efficacy and safety of adding ezetimibe (Ez) to simvastatin (S) in a post-acute coronary syndrome (ACS) population in a prespecified on-treatment ...analysis. Methods We evaluated 17,706 post-ACS patients from the IMPROVE-IT trial who had low-density lipoprotein cholesterol (LDL-C) values between 50 and 125 mg/dL and who received Ez 10 mg/day with S 40 mg/day (Ez/S) or placebo with simvastatin 40 mg/day (P/S). The primary composite endpoint was cardiovascular death, myocardial infarction, unstable angina, coronary revascularization ≥30 days post randomization, or stroke. The on-treatment analysis included patients who received study drug for the duration of the trial or experienced a primary endpoint or non-cardiovascular death within 30 days of drug discontinuation. Results Mean LDL-C values at 1 year were 71 mg/dL for P/S and 54 mg/dL for Ez/S (absolute difference− 17 mg/dL = −24%; P < .001). The 7-year Kaplan–Meier estimate of the primary endpoint occurred in 32.4% in the P/S arm and 29.8% in the Ez/S arm (absolute difference 2.6%; HRadj 0.92 95% CI 0.87–0.98; P = .01). The absolute treatment effect favoring Ez/S was 30% greater than in the intention-to-treat analysis of IMPROVE-IT. Conclusions This analysis provides additional support for the efficacy and safety of adding Ez to S in this high-risk, post-ACS population.
Summary Background Vorapaxar inhibits platelet activation by antagonising thrombin-mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet ...drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial. Methods In TRA 2°P-TIMI 50—a randomised, placebo-controlled, parallel trial—we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2·5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2°P-TIMI 50 is registered at ClinicalTrials.gov ( NCT00526474 ). Findings 17 779 of 26 449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 to placebo). Median follow-up was 2·5 years (IQR 2·0–2·9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in the placebo group (3-year Kaplan-Meier estimates 8·1% vs 9·7%, HR 0·80, 95% CI 0·72–0·89; p<0·0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 3·4%, 3-year Kaplan-Meier estimate vs 151/8849 2·1%, 3-year Kaplan-Meier estimate, HR 1·61, 95% CI 1·31–1·97; p<0·0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0·6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0·4%, 3-year Kaplan-Meier estimate) with placebo (p=0·076). Other serious adverse events were equally distributed between groups. Interpretation For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding. Funding Merck.
We examined the extent of coronary artery disease (CAD) on 64-slice contrast-enhanced multidetector computed tomography in patients who underwent investigation of a chest pain syndrome who had a zero ...or low coronary calcium score (CS). In 668 consecutive patients with chest pain syndromes (39% with acute presentation, 61% with long-term presentation) who underwent cardiac multidetector computed tomography, we assessed prevalence and severity of coronary stenoses (≥1 coronary artery stenosis with ≥50% luminal narrowing) in 231 patients (54 ± 12 years of age, 45% women) with a 0 (n = 125) or low (n = 106) coronary CS. Obstructive (≥50% lesion) CAD was present in 27 of 231 patients, in 9 of 125 patients (7%) with a 0 CS, in 18 of 106 (17%) with a low CS (1 to 100), and in 14 of 90 patients (16%) with an acute presentation and 13 of 141 patients (9%) with a long-term presentation (p = NS). All patients in the 0 CS group had single-vessel disease, and 9 (50%) with low CS had multivessel disease, with left main involvement in 1. Of the 27 patients with obstructive CAD on multidetector computed tomography, invasive coronary angiography confirmed these findings in 21 of 23 patients (positive predictive value 91%), and 16 (76%) of them (6.9% of the 0 CS and low CS groups) underwent a myocardial revascularization procedure after invasive coronary angiographic concordance. In conclusion, despite the high known negative predictive value of CS for coronary events, a low and even 0 CS does not exclude clinically important obstructive CAD in patients undergoing investigation of an acute or long-term chest pain syndrome. Contrast-enhanced multidetector computed tomography should be the noninvasive computed tomographic test of choice when possible in these patients.
Abstract Background Cholesterol and blood pressure (BP) can be effectively and safely lowered with statin drugs and BP-lowering drugs, reducing major cardiovascular (CV) events by 20%-30% within 5 ...years in high-risk individuals. However, there are limited data in lower-risk populations. The H eart O utcomes P revention E valuation-3 (HOPE-3) trial is evaluating whether cholesterol lowering with a statin drug, BP lowering with low doses of 2 antihypertensive agents, and their combination safely reduce major CV events in individuals at intermediate risk who have had no previous vascular events and have average cholesterol and BP levels. Methods A total of 12,705 women 65 years or older and men 55 years or older with at least 1 CV risk factor, no known CV disease, and without any clear indication or contraindication to the study drugs were randomized to rosuvastatin 10 mg/d or placebo and to candesartan/hydrochlorothiazide 16/12.5 mg/d or placebo (2 × 2 factorial design) and will be followed for a mean of 5.8 years. The coprimary study outcomes are the composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke and the composite of CV death, nonfatal MI, nonfatal stroke, resuscitated cardiac arrest, heart failure, and arterial revascularization. Results Participants were recruited from 21 countries in North America, South America, Europe, Asia, and Australia. Mean age at randomization was 66 years and 46% were women. Conclusions The HOPE-3 trial will provide new information on cholesterol and BP lowering in intermediate-risk populations with average cholesterol and BP levels and is expected to inform approaches to primary prevention worldwide (HOPE-3 ClinicalTrials.gov NCT00468923 ).
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