Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial

Context  Ranolazine is a novel antianginal agent that reduces ischemia in patients with chronic angina but has not been studied in patients with acute coronary syndromes (ACS). Objective  To determine the efficacy and safety of ranolazine during long-term treatment of patients with non–ST-elevation ACS. Design, Setting, and Patients  A randomized, double-blind, placebo-controlled, multinational clinical trial of 6560 patients within 48 hours of ischemic symptoms who were treated with ranolazine (initiated intravenously and followed by oral ranolazine extended-release 1000 mg twice daily, n = 3279) or matching placebo (n = 3281), and followed up for a median of 348 days in the Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial between October 8, 2004, and February 14, 2007. Main Outcome Measures  The primary efficacy end point was a composite of cardiovascular death, myocardial infarction (MI), or recurrent ischemia through the end of study. The major safety end points were death from any cause and symptomatic documented arrhythmia. Results  The primary end point occurred in 696 patients (21.8%) in the ranolazine group and 753 patients (23.5%) in the placebo group (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.83-1.02; P = .11). The major secondary end point (cardiovascular death, MI, or severe recurrent ischemia) occurred in 602 patients (18.7%) in the ranolazine group and 625 (19.2%) in the placebo group (HR, 0.96; 95% CI, 0.86-1.08; P = .50). Cardiovascular death or MI occurred in 338 patients (10.4%) allocated to ranolazine and 343 patients (10.5%) allocated to placebo (HR, 0.99; 95% CI, 0.85-1.15; P = .87). Recurrent ischemia was reduced in the ranolazine group (430 [13.9%]) compared with the placebo group (494 [16.1%]; HR, 0.87; 95% CI, 0.76-0.99; P = .03). QTc prolongation requiring a reduction in the dose of intravenous drug occurred in 31 patients (0.9%) receiving ranolazine compared with 10 patients (0.3%) receiving placebo. Symptomatic documented arrhythmias did not differ between the ranolazine (99 [3.0%]) and placebo (102 [3.1%]) groups (P = .84). No difference in total mortality was observed with ranolazine compared with placebo (172 vs 175; HR, 0.99; 95% CI, 0.80-1.22; P = .91). Conclusions  The addition of ranolazine to standard treatment for ACS was not effective in reducing major cardiovascular events. Ranolazine did not adversely affect the risk of all-cause death or symptomatic documented arrhythmia. Our findings provide support for the safety and efficacy of ranolazine as antianginal therapy. Trial Registration  clinicaltrials.gov Identifier: NCT00099788      

Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial

Context  Although low levels of high-density lipoprotein cholesterol (HDL-C) increase risk for coronary disease, no data exist regarding potential benefits of administration of HDL-C or an HDL mimetic. ApoA-I Milano is a variant of apolipoprotein A-I identified in individuals in rural Italy who exhibit very low levels of HDL. Infusion of recombinant ApoA-I Milano–phospholipid complexes produces rapid regression of atherosclerosis in animal models. Objective  We assessed the effect of intravenous recombinant ApoA-I Milano/phospholipid complexes (ETC-216) on atheroma burden in patients with acute coronary syndromes (ACS). Design  The study was a double-blind, randomized, placebo-controlled multicenter pilot trial comparing the effect of ETC-216 or placebo on coronary atheroma burden measured by intravascular ultrasound (IVUS). Setting  Ten community and tertiary care hospitals in the United States. Patients  Between November 2001 and March 2003, 123 patients aged 38 to 82 years consented, 57 were randomly assigned, and 47 completed the protocol. Interventions  In a ratio of 1:2:2, patients received 5 weekly infusions of placebo or ETC-216 at 15 mg/kg or 45 mg/kg. Intravascular ultrasound was performed within 2 weeks following ACS and repeated after 5 weekly treatments. Main Outcome Measures  The primary efficacy parameter was the change in percent atheroma volume (follow-up minus baseline) in the combined ETC-216 cohort. Prespecified secondary efficacy measures included the change in total atheroma volume and average maximal atheroma thickness. Results  The mean (SD) percent atheroma volume decreased by -1.06% (3.17%) in the combined ETC-216 group (median, -0.81%; 95% confidence interval [CI], -1.53% to -0.34%; P = .02 compared with baseline). In the placebo group, mean (SD) percent atheroma volume increased by 0.14% (3.09%; median, 0.03%; 95% CI, -1.11% to 1.43%; P = .97 compared with baseline). The absolute reduction in atheroma volume in the combined treatment groups was -14.1 mm³ or a 4.2% decrease from baseline (P<.001). Conclusions  A recombinant ApoA-I Milano/phospholipid complex (ETC-216) administered intravenously for 5 doses at weekly intervals produced significant regression of coronary atherosclerosis as measured by IVUS. Although promising, these results require confirmation in larger clinical trials with morbidity and mortality end points.      

Effects of early treatment with statins on short-term clinical outcomes in acute coronary syndromes: a meta-analysis of randomized controlled trials

Context  The short-term effects of early treatment with statins in patients after the onset of acute coronary syndromes (ACS) for the outcomes of death, myocardial infarction (MI), and stroke are unclear. Objective  To evaluate relevant outcomes of patients from randomized controlled trials comparing early statin therapy with placebo or usual care at 1 and 4 months following ACS. Data Sources and Study Selection  Systematic search of electronic databases (MEDLINE, EMBASE, PASCAL, Cochrane Central Register) from their inception to August 2005, which was supplemented by contact with experts in the field. Two reviewers independently determined the eligibility of randomized controlled trials that compared treatment with statins with a control, were initiated within 14 days after onset of ACS, and had a minimal follow-up of 30 days. Trials with cerivastatin were only included in a sensitivity analysis. Data Extraction  Information on baseline characteristics of included trials and patients, reported methodological quality, lipid levels, and clinical outcome was independently extracted by 2 investigators. Investigators from each included trial contributed additional data if necessary. Data Synthesis  Twelve trials involving 13 024 patients with ACS were included in the meta-analysis. The risk ratios for the combined end point of death, MI, and stroke for patients treated with early statin therapy compared with control therapy were 0.93 (95% confidence interval [CI], 0.80-1.09; P = .39) at 1 month and 0.93 (95% CI, 0.81-1.07; P = .30) at 4 months following ACS. There were no statistically significant risk reductions from statins for total death, total MI, total stroke, cardiovascular death, fatal or nonfatal MI, or revascularization procedures (percutaneous coronary intervention or coronary artery bypass graft surgery). Sensitivity analyses with restriction to trials of high quality or with additional data from a large trial using cerivastatin indicated summary risk ratios even closer to 1. Conclusion  Based on available evidence, initiation of statin therapy within 14 days following onset of ACS does not reduce death, MI, or stroke up to 4 months.      

Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial.

CONTEXT: Tissue plasminogen activator is the only thrombolytic agent approved in the United States for treatment of acute ischemic stroke, and has limitations. Aptiganel hydrochloride is a novel and selective ligand for the ion-channel site of the N-methyl-D-aspartate receptor-channel complex and a promising neuroprotective agent in animal models of focal brain ischemia. OBJECTIVE: To determine whether aptiganel improves the clinical outcome for acute ischemic stroke patients. DESIGN: Nested phase 2/phase 3 randomized controlled trial conducted between July 1996 and September 1997. SETTING: One hundred fifty-six medical centers in the United States, Canada, Australia, South Africa, England, and Scotland. PARTICIPANTS: A total of 628 patients with hemispheric ischemic stroke (50.3% male; mean age, 71.5 years). INTERVENTIONS: Patients were randomly assigned within 6 hours of stroke to receive 1 of 3 treatment regimens: high-dose aptiganel (5-mg bolus followed by 0.75 mg/h for 12 hours; n = 214); low-dose aptiganel (3-mg bolus followed by 0.5 mg/h for 12 hours; n = 200); or placebo (n = 214). MAIN OUTCOME MEASURES: The primary efficacy end point was the Modified Rankin Scale score at 90 days after stroke onset. Secondary end points included mortality and change in National Institutes of Health (NIH) Stroke Scale score at 7 days after stroke. RESULTS: The trial was suspended by the sponsor and the independent data and safety monitoring board because of both a lack of efficacy and a potential imbalance in mortality. There was no improvement in outcome for either aptiganel (low-dose or high-dose) group compared with the placebo group at 90 days (median Modified Rankin Scale score for all 3 treatment groups = 3; P =.31). At 7 days, placebo-treated patients exhibited slightly greater neurological improvement on the NIH Stroke Scale than high-dose aptiganel patients (mean improvement for placebo group, -0.8 points vs for high-dose aptiganel, 0.9 points; P =.04). The mortality rate at 120 days in patients treated with high-dose aptiganel was higher than that in patients who received placebo (26.3% vs 19.2%; P =.06). Mortality in the low-dose aptiganel group was 22.5% (P =.39 vs placebo). CONCLUSIONS: Aptiganel was not efficacious in patients with acute ischemic stroke at either of the tested doses, and m ay be harmful. The larger proportion of patients with favorable outcomes and lower mortality rate in the placebo group suggest that glutamate blockade with aptiganel may have detrimental effects in an undifferentiated population of stroke patients.     

Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial

Context  Several lines of evidence have implied an association between Chlamydia pneumoniae infection and atherogenesis. Objective  To determine the effect of 12 weeks of antibiotic therapy on coronary heart disease events in patients with stable coronary artery disease and known C pneumoniae exposure. Design, Setting, and Participants  Randomized, placebo-controlled trial of 7747 adults with previous myocardial infarction that had occurred at least 6 weeks previously (median, 2.6 years) and a C pneumoniae IgG titer of 1:16 or more. Patients were recruited from 271 clinical practices in North America, Europe, Argentina, and India, from October 10, 1997, to July 22, 2001. Intervention  The patients received either azithromycin (600 mg/d for 3 days during week 1, then 600 mg/wk during weeks 2-12; n = 3879) or placebo (n = 3868). Main Outcome Measures  The primary event was the first occurrence of death from any cause, nonfatal reinfarction, coronary revascularization, or hospitalization for angina. Patients were followed up until 1038 events accrued. Results  After a median of 14 months of follow-up, there was no significant risk reduction in the likelihood of a primary event with azithromycin vs placebo (7% [95% confidence interval, -5% to 17%], P = .23). Analysis of hazard ratios suggested early benefits of azithromycin on the primary event and on death or reinfarction, but these decreased over time. There were no significant risk reductions for any of the components of the primary end point including death (8%), recurrent myocardial infarction (7%), revascularization procedures (5%), or hospitalizations for angina (-1%). Adverse events related to study drug were reported by 13.2% of those randomized to receive azithromycin, predominantly a result of diarrhea, compared with 4.6% randomized to receive placebo, and resulted in discontinuation of drug in 1.6% of those taking azithromycin and 0.4% taking placebo. Conclusion  Among stable patients with previous myocardial infarction and with evidence of C pneumoniae exposure, a 3-month course of azithromycin did not significantly reduce the clinical sequelae of coronary heart disease.      

Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial

Context  High-density lipoprotein (HDL) cholesterol is an inverse predictor of coronary atherosclerotic disease. Preliminary data have suggested that HDL infusions can induce atherosclerosis regression. Objective  To investigate the effects of reconstituted HDL on plaque burden as assessed by intravascular ultrasound (IVUS). Design and Setting  A randomized placebo-controlled trial was conducted at 17 centers in Canada. Intravascular ultrasound was performed to assess coronary atheroma at baseline and 2 to 3 weeks after the last study infusion. Patients  Between July 2005 and October 2006, 183 patients had a baseline IVUS examination and of those, 145 had evaluable serial IVUS examinations after 6 weeks. Intervention  Sixty patients were randomly assigned to receive 4 weekly infusions of placebo (saline), 111 to receive 40 mg/kg of reconstituted HDL (CSL-111); and 12 to receive 80 mg/kg of CSL-111. Main Outcome Measures  The primary efficacy parameter was the percentage change in atheroma volume. Nominal changes in plaque volume and plaque characterization index on IVUS and coronary score on quantitative coronary angiography were also prespecified end points. Results  The higher-dosage CSL-111 treatment group was discontinued early because of liver function test abnormalities. The percentage change in atheroma volume was –3.4% with CSL-111 and –1.6% for placebo (P = .48 between groups, P<.001 vs baseline for CSL-111). The nominal change in plaque volume was –5.3 mm³ with CSL-111 and –2.3 mm³ with placebo (P = .39 between groups, P<.001 vs baseline for CSL-111). The mean changes in plaque characterization index on IVUS (–0.0097 for CSL-111 and 0.0128 with placebo) and mean changes in coronary score (–0.039 mm for CSL-111 and –0.071 mm with placebo) on quantitative coronary angiography were significantly different between groups (P = .01 and P =.03, respectively). Administration of CSL-111 40 mg/kg was associated with mild, self-limiting transaminase elevation but was clinically well tolerated. Conclusions  Short-term infusions of reconstituted HDL resulted in no significant reductions in percentage change in atheroma volume or nominal change in plaque volume compared with placebo but did result in statistically significant improvement in the plaque characterization index and coronary score on quantitative coronary angiography. Elevation of HDL remains a valid target in vascular disease and further studies of HDL infusions, including trials with clinical end points, appear warranted. Trial Registration  clinicaltrials.gov Identifier: NCT00225719 Published online: March 26, 2007 (doi:10.1001/jama.297.15.jpc70004).      

Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial

Context  Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events. Clinical trials have generally failed to confirm benefits, possibly due to their relatively short duration. Objective  To evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular events. Design, Setting, and Patients  A randomized, double-blind, placebo-controlled international trial (the initial Heart Outcomes Prevention Evaluation [HOPE] trial conducted between December 21, 1993, and April 15, 1999) of patients at least 55 years old with vascular disease or diabetes mellitus was extended (HOPE–The Ongoing Outcomes [HOPE-TOO]) between April 16, 1999, and May 26, 2003. Of the initial 267 HOPE centers that had enrolled 9541 patients, 174 centers participated in the HOPE-TOO trial. Of 7030 patients enrolled at these centers, 916 were deceased at the beginning of the extension, 1382 refused participation, 3994 continued to take the study intervention, and 738 agreed to passive follow-up. Median duration of follow-up was 7.0 years. Intervention  Daily dose of natural source vitamin E (400 IU) or matching placebo. Main Outcome Measures  Primary outcomes included cancer incidence, cancer deaths, and major cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included heart failure, unstable angina, and revascularizations. Results  Among all HOPE patients, there were no significant differences in the primary analysis: for cancer incidence, there were 552 patients (11.6%) in the vitamin E group vs 586 (12.3%) in the placebo group (relative risk [RR], 0.94; 95% confidence interval [CI], 0.84-1.06; P = .30); for cancer deaths, 156 (3.3%) vs 178 (3.7%), respectively (RR, 0.88; 95% CI, 0.71-1.09; P = .24); and for major cardiovascular events, 1022 (21.5%) vs 985 (20.6%), respectively (RR, 1.04; 95% CI, 0.96-1.14; P = .34). Patients in the vitamin E group had a higher risk of heart failure (RR, 1.13; 95% CI, 1.01-1.26; P = .03) and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00-1.47; P = .045). Similarly, among patients enrolled at the centers participating in the HOPE-TOO trial, there were no differences in cancer incidence, cancer deaths, and major cardiovascular events, but higher rates of heart failure and hospitalizations for heart failure. Conclusion  In patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure.      

Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial

Context  The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease (CAD) and normal blood pressure remains uncertain. Objective  To compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD. Design, Setting, and Participants  Double-blind, randomized, multicenter, 24-month trial (enrollment April 1999-April 2002) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD (>20% stenosis by coronary angiography) and diastolic blood pressure <100 mm Hg. A substudy of 274 patients measured atherosclerosis progression by intravascular ultrasound (IVUS). Interventions  Patients were randomized to receive amlodipine, 10 mg; enalapril, 20 mg; or placebo. IVUS was performed at baseline and study completion. Main Outcome Measures  The primary efficacy parameter was incidence of cardiovascular events for amlodipine vs placebo. Other outcomes included comparisons of amlodipine vs enalapril and enalapril vs placebo. Events included cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina pectoris, hospitalization for congestive heart failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral vascular disease. The IVUS end point was change in percent atheroma volume. Results  Baseline blood pressure averaged 129/78 mm Hg for all patients; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups, respectively (P<.001 for both vs placebo). Cardiovascular events occurred in 151 (23.1%) placebo-treated patients, in 110 (16.6%) amlodipine-treated patients (hazard ratio [HR], 0.69; 95% CI, 0.54-0.88 [P = .003]), and in 136 (20.2%) enalapril-treated patients (HR, 0.85; 95% CI, 0.67-1.07 [P = .16]. Primary end point comparison for enalapril vs amlodipine was not significant (HR, 0.81; 95% CI, 0.63-1.04 [P = .10]). The IVUS substudy showed a trend toward less progression of atherosclerosis in the amlodipine group vs placebo (P = .12), with significantly less progression in the subgroup with systolic blood pressures greater than the mean (P = .02). Compared with baseline, IVUS showed progression in the placebo group (P<.001), a trend toward progression in the enalapril group (P = .08), and no progression in the amlodipine group (P = .31). For the amlodipine group, correlation between blood pressure reduction and progression was r = 0.19, P = .07. Conclusions  Administration of amlodipine to patients with CAD and normal blood pressure resulted in reduced adverse cardiovascular events. Directionally similar, but smaller and nonsignificant, treatment effects were observed with enalapril. For amlodipine, IVUS showed evidence of slowing of atherosclerosis progression.