Summary Background Clopidogrel and aspirin are the most commonly used antiplatelet therapies for percutaneous coronary intervention (PCI). We assessed the effect of various clopidogrel and aspirin ...regimens in prevention of major cardiovascular events and stent thrombosis in patients undergoing PCI. Methods The CURRENT-OASIS 7 trial was undertaken in 597 centres in 39 countries. 25 086 individuals with acute coronary syndromes and intended early PCI were randomly assigned to double-dose (600 mg on day 1, 150 mg on days 2–7, then 75 mg daily) versus standard-dose (300 mg on day 1 then 75 mg daily) clopidogrel, and high-dose (300–325 mg daily) versus low-dose (75–100 mg daily) aspirin. Randomisation was done with a 24 h computerised central automated voice response system. The clopidogrel dose comparison was double-blind and the aspirin dose comparison was open label with blinded assessment of outcomes. This prespecified analysis is of the 17 263 individuals who underwent PCI. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Analyses were by intention to treat, adjusted for propensity to undergo PCI. This trial is registered with ClinicalTrials.gov , number NCT00335452. Findings 8560 patients were assigned to double-dose and 8703 to standard-dose clopidogrel (8558 and 8702 completed 30-day follow-up, respectively), and 8624 to high-dose and 8639 to low-dose aspirin (8622 and 8638 completed 30-day follow-up, respectively). Compared with the standard dose, double-dose clopidogrel reduced the rate of the primary outcome (330 events 3·9% vs 392 events 4·5%; adjusted hazard ratio 0·86, 95% CI 0·74–0·99, p=0·039) and definite stent thrombosis (58 0·7% vs 111 1·3%; 0·54 0·39–0·74, p=0·0001). High-dose and low-dose aspirin did not differ for the primary outcome (356 4·1% vs 366 4·2%; 0·98, 0·84–1·13, p=0·76). Major bleeding was more common with double-dose than with standard-dose clopidogrel (139 1·6% vs 99 1·1%; 1·41, 1·09–1·83, p=0·009) and did not differ between high-dose and low-dose aspirin (128 1·5% vs 110 1·3%; 1·18, 0·92–1·53, p=0·20). Interpretation In patients undergoing PCI for acute coronary syndromes, a 7-day double-dose clopidogrel regimen was associated with a reduction in cardiovascular events and stent thrombosis compared with the standard dose. Efficacy and safety did not differ between high-dose and low-dose aspirin. A double-dose clopidogrel regimen can be considered for all patients with acute coronary syndromes treated with an early invasive strategy and intended early PCI. Funding Sanofi-Aventis and Bristol-Myers Squibb.
Summary Background Blockade of the endocannabinoid receptor reduces obesity and improves metabolic abnormalities such as triglycerides, HDL cholesterol, and fasting blood glucose. We assessed whether ...rimonabant would improve major vascular event-free survival. Methods This double-blind, placebo-controlled trial was undertaken in 974 hospitals in 42 countries. 18 695 patients with previously manifest or increased risk of vascular disease were randomly assigned to receive either rimonabant 20 mg (n=9381) or matching placebo (n=9314). Randomisation was stratified by centre, implemented with an independent interactive voice response system, and all study personnel and participants were masked to group assignment. The primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke, as determined via central adjudication. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00263042. Findings At a mean follow-up of 13·8 months (95% CI 13·6–14·0), the trial was prematurely discontinued because of concerns by health regulatory authorities in three countries about suicide in individuals receiving rimonabant. All randomised participants were analysed. At the close of the trial (Nov 6, 2008), the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 364 (3·9%) patients assigned to rimonabant and 375 (4·0%) assigned to placebo (hazard ratio 0·97, 95% CI 0·84–1·12, p=0·68). With rimonabant, gastrointestinal (3038 33% vs 2084 22%), neuropsychiatric (3028 32% vs 1989 21%), and serious psychiatric side-effects (232 2·5% vs 120 1·3%) were significantly increased compared with placebo. Four patients in the rimonabant group and one in the placebo group committed suicide. Interpretation The premature termination of this trial has important lessons for drug development. A drug that was being marketed for weight loss, but being tested for improving cardiovascular outcomes, induced a level of serious neuropsychiatric effects that was deemed unacceptable by regulatory authorities, and both the drug and the trial were abruptly terminated. Funding Sanofi-Aventis.
Summary Background In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate ...whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA). Methods In ROCKET AF, patients with AF who were at increased risk of stroke were randomly assigned (1:1) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin (international normalised ratio 2·0–3·0). Patients and investigators were masked to treatment allocation. Between Dec 18, 2006, and June 17, 2009, 14 264 patients from 1178 centres in 45 countries were randomly assigned. The primary endpoint was the composite of stroke or non-CNS systemic embolism. In this substudy we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA. Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population. ROCKET AF is registered with ClinicalTrials.gov , number NCT00403767. Findings 7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2·79% rivaroxaban vs 2·96% warfarin; hazard ratio HR 0·94, 95% CI 0·77–1·16) and those without (1·44% vs 1·88%; 0·77, 0·58–1·01; interaction p=0·23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13·31% rivaroxaban vs 13·87% warfarin; HR 0·96, 95% CI 0·87–1·07) and those without (16·69% vs 15·19%; 1·10, 0·99–1·21; interaction p=0·08). Interpretation There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF. Funding Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare.
Summary Background Treatment with prasugrel and aspirin improves outcomes compared with clopidogrel and aspirin for patients with acute coronary syndrome who have had angiography and percutaneous ...coronary intervention; however, no clear benefit has been shown for patients managed first with drugs only. We assessed outcomes from the TRILOGY ACS trial based on whether or not patients had coronary angiography before treatment was chosen. Methods TRILOGY ACS ( ClinicalTrials.gov number NCT00699998 ) was a randomised controlled trial, done at more than 800 sites worldwide. Patients with non-ST-elevation acute coronary syndrome who were selected for management without revascularisation were randomly assigned to clopidogrel or prasugrel. The primary endpoint was cardiovascular death, myocardial infarction, or stroke at 30 months. In the present analysis we assessed differences in the primary endpoint by angiography status and whether the effects of treatment on the primary endpoint differed between patients who had angiography before enrolment and those who had not. Findings 7243 patients younger than 75 years were included in the TRILOGY ACS primary analysis. 3085 (43%) had angiography at baseline, 4158 (57%) had not. Fewer patients who had angiography reached the primary endpoint at 30 months compared with those who did not have angiography, according to Kaplan-Meier analysis (281/3085 12·8% vs 480/4158 16·5%, adjusted hazard ratio HR 0·63, 95% CI 0·53–0·75; p<0·0001). The proportion of patients who reached the primary endpoint was lower in the prasugrel group than in the clopidogrel group for those who had angiography (122/1524 10·7% vs 159/1561 14·9%, HR 0·77, 95% CI 0·61–0·98; p=0·032) but did not differ between groups in patients who did not have angiography (242/2096 16·3% vs 238/2062 16·7%, HR 1·01, 0·84–1·20; p=0·94; pinteraction =0·08). Overall, TIMI major bleeding and GUSTO severe bleeding were rare. Bleeding outcomes tended to be higher with prasugrel but did not differ significantly between treatment groups in either angiography cohort. Interpretation Among patients who had angiography who took prasugrel there were fewer cardiovascular deaths, myocardial infarctions, or strokes than in those who took clopidogrel. This result needs to be corroborated, but it is consistent with previous trials of more versus less intensive antiplatelet treatment. When angiography is done for acute coronary syndrome and anatomic coronary disease confirmed, the benefits and risks of intensive antiplatelet treatment exist whether the patient is treated with drugs or percutaneous coronary intervention. Funding Daiichi Sankyo, Eli Lilly.
Calcium antagonists are widely prescribed for angina pectoris but their effect on clinical outcome is controversial. We aimed to investigate the effect of the calcium antagonist nifedipine on ...long-term outcome in patients with stable angina pectoris.
We randomly assigned 3825 patients with treated stable symptomatic coronary disease to double-blind addition of nifedipine GITS (gastrointestinal therapeutic system) 60 mg once daily and 3840 to placebo. The primary endpoint was the combination of death, acute myocardial infarction, refractory angina, new overt heart failure, debilitating stroke, and peripheral revascularisation. Mean follow-up was 4·9 years (SD 1·1). Analysis was by intention to treat.
310 patients allocated nifedipine died (1.64 per 100 patient-years) compared with 291 people allocated placebo (1·53 per 100 patient-years; hazard ratio 1·07 95% CI 0·91–1·25, p=0·41). Primary endpoint rates were 4·60 per 100 patient-years for nifedipine and 4·75 per 100 patient-years for placebo (0·97 0·88–1·07, p=0·54). With nifedipine, rate of death and any cardiovascular event or procedure was 9·32 per 100 patient-years versus 10·50 per 100 patient-years for placebo (0·89 0·83–0·95, p=0·0012). The difference was mainly attributable to a reduction in the need for coronary angiography and interventions in patients assigned nifedipine, despite an increase in peripheral revascularisation. Nifedipine had no effect on the rate of myocardial infarction.
Addition of nifedipine GITS to conventional treatment of angina pectoris has no effect on major cardiovascular event-free survival. Nifedipine GITS is safe and reduces the need for coronary angiography and interventions.
Published online August 31, 2004
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