Christophe Gaudin

Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease : the STRADIVARIUS randomized controlled trial

CONTEXT Abdominal obesity is associated with metabolic abnormalities and increased risk of atherosclerotic cardiovascular disease. However, no obesity management strategy has demonstrated the ability to slow progression of coronary disease. OBJECTIVE To determine whether weight loss and metabolic effects of the selective cannabinoid type 1 receptor antagonist rimonabant reduces progression of coronary disease in patients with abdominal obesity and the metabolic syndrome. DESIGN, SETTING, AND PATIENTS Randomized, double-blinded, placebo-controlled, 2-group, parallel-group trial (enrollment December 2004-December 2005) comparing rimonabant with placebo in 839 patients at 112 centers in North America, Europe, and Australia. INTERVENTIONS Patients received dietary counseling, were randomized to receive rimonabant (20 mg daily) or matching placebo, and underwent coronary intravascular ultrasonography at baseline (n = 839) and study completion (n = 676). MAIN OUTCOME MEASURES The primary efficacy parameter was change in percent atheroma volume (PAV); the secondary efficacy parameter was change in normalized total atheroma volume (TAV). RESULTS In the rimonabant vs placebo groups, PAV (95% confidence interval [CI]) increased 0.25% (-0.04% to 0.54%) vs 0.51% (0.22% to 0.80%) (P = .22), respectively, and TAV decreased 2.2 mm3 (-4.09 to -0.24) vs an increase of 0.88 mm3 (-1.03 to 2.79) (P = .03). In the rimonabant vs placebo groups, imputing results based on baseline characteristics for patients not completing the trial, PAV increased 0.25% (-0.04% to 0.55%) vs 0.57% (0.29% to 0.84%) (P = .13), and TAV decreased 1.95 mm3 (-3.8 to -0.10) vs an increase of 1.19 mm3 (-0.73 to 3.12) (P = .02). Rimonabant-treated patients had a larger reduction in body weight (4.3 kg [-5.1 to -3.5] vs 0.5 kg [-1.3 to 0.3]) and greater decrease in waist circumference (4.5 cm [-5.4 to -3.7] vs 1.0 cm [-1.9 to -0.2]) (P < .001 for both comparisons). In the rimonabant vs placebo groups, high-density lipoprotein cholesterol levels increased 5.8 mg/dL (4.9 to 6.8) (22.4%) vs 1.8 mg/dL (0.9 to 2.7) (6.9%) (P < .001), and median triglyceride levels decreased 24.8 mg/dL (-35.4 to -17.3) (20.5%) vs 8.9 mg/dL (-14.2 to -1.8) (6.2%) (P < .001). Rimonabant-treated patients had greater decreases in high-sensitivity C-reactive protein (1.3 mg/dL [-1.7 to -1.2] [50.3%] vs 0.9 mg/dL [-1.4 to -0.5] [30.9%]) and less increase in glycated hemoglobin levels (0.11% [0.02% to 0.20%] vs 0.40% [0.31% to 0.49%]) (P < .001 for both comparisons). Psychiatric adverse effects were more common in the rimonabant group (43.4% vs 28.4%, P < .001). CONCLUSIONS After 18 months of treatment, the study failed to show an effect for rimonabant on disease progression for the primary end point (PAV) but showed a favorable effect on the secondary end point (TAV). Determining whether rimonabant is useful in management of coronary disease will require additional imaging and outcomes trials, which are currently under way. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00124332.

Analysis of Stroke in ATHENA: A Placebo-Controlled, Double-Blind, Parallel-Arm Trial to Assess the Efficacy of Dronedarone 400 mg BID for the Prevention of Cardiovascular Hospitalization or Death From Any Cause in Patients With Atrial Fibrillation/Atrial Flutter

Background— Many patients with atrial fibrillation are at high risk for stroke and require antithrombotic therapy. Antiarrhythmic drugs have not previously been shown to reduce the risk of stroke in atrial fibrillation. The effect of dronedarone, a new multichannel-blocking antiarrhythmic drug, on stroke has been evaluated in a randomized, double-blind clinical trial, ATHENA (A placebo-controlled, double-blind, parallel-arm Trial to assess the efficacy of dronedarone 400 mg BID for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter). Methods and Results— Patients with persistent or paroxysmal atrial fibrillation and at least 1 risk factor for cardiovascular hospitalization were randomized to receive dronedarone (400 mg BID) or double-blind matching placebo and followed up for a minimum of 1 year to a common termination at 30 months. All strokes that occurred during the study were included in the present post hoc analysis. There were 4628 patients randomized to placebo or dronedarone. The baseline risk factors for stroke were well balanced between the 2 groups, and the baseline mean CHADS2 score was 2. The baseline use of either oral anticoagulant therapy or antiplatelet agent alone was 60%. Dronedarone reduced the risk of stroke from 1.8% per year to 1.2% per year (hazard ratio 0.66, 95% confidence interval 0.46 to 0.96, P=0.027). The effect of dronedarone was similar whether or not patients were receiving oral anticoagulant therapy, and there was a significantly greater effect of dronedarone in patients with higher CHADS2 scores. Conclusions— In this post hoc analysis, a reduction in stroke was observed in patients with atrial fibrillation who were receiving usual care, which included antithrombotic therapy and heart rate control, who were randomized to dronedarone. Further studies to investigate the effect of dronedarone and other antiarrhythmic agents on stroke are indicated.

Rimonabant for prevention of cardiovascular events (CRESCENDO) : a randomised, multicentre, placebo-controlled trial.

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.

Dronedarone in patients with congestive heart failure: insights from ATHENA

Aims Dronedarone is a new multichannel blocking antiarrhythmic drug for treatment of atrial fibrillation (AF). In patients with recently decompensated congestive heart failure (CHF) and depressed LV function, the drug was associated with excess mortality compared with a placebo group. The present study aimed to analyse in detail the effects of dronedarone on mortality and morbidity in AF patients CHF. Methods and results We performed a post hoc analysis of ATHENA, a large placebo-controlled outcome trial in 4628 patients with paroxysmal or persistent AF, to evaluate the relationship between clinical outcomes and dronedarone therapy in patients with stable CHF. The primary outcome was time to first cardiovascular (CV) hospitalization or death. There were 209 patients with NYHA class II/III CHF and a left ventricular ejection fraction ≤0.40 at baseline (114 placebo, 95 dronedarone patients). A primary outcome event occurred in 59/114 placebo patients compared with 42/95 dronedarone patients [hazard ratio (HR) 0.78, 95% CI = 0.52–1.16]. Twenty of 114 placebo patients and 12/95 dronedarone patients died during the study (HR 0.71, 95% CI = 0.34–1.44). Fifty-four placebo and 42 dronedarone patients were hospitalized for an intermittent episode of NYHA class IV CHF (HR = 0.78, 95% CI = 0.52–1.17). Conclusion In this post-hoc analysis of ATHENA patients with AF and stable CHF, dronedarone did not increase mortality and showed a reduction of CV hospitalization or death similar to the overall population. However, in the light of the ANtiarrhythmic trial with DROnedarone in Moderate to severe CHF Evaluating morbidity DecreAse study, dronedarone should be contraindicated in patients with NYHA class IV or unstable NYHA classes II and III CHF.

Rhythm- and Rate-Controlling Effects of Dronedarone in Patients With Atrial Fibrillation (from the ATHENA Trial)

Dronedarone is a multi-channel-blocking drug for the treatment of patients with atrial fibrillation (AF) or atrial flutter (AFL) with rate- and rhythm-controlling properties. A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg b.i.d. for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients With Atrial Fibrillation/Atrial Flutter (ATHENA) demonstrated that dronedarone reduced the risk for first cardiovascular hospitalization or death from any cause. The aim of this post hoc analysis was to evaluate the rhythm- and rate-controlling properties of dronedarone in the ATHENA trial. Patients were randomized to dronedarone 400 mg twice daily (n = 2,301) or placebo (n = 2,327). Electrocardiographic tracings were classified for AF or AFL or sinus rhythm. Patients with AF or AFL on every postbaseline electrocardiogram were classified as having permanent AF or AFL. All electrical cardioversions were documented. The use of rate-controlling medications was equally distributed in the 2 treatment groups. The median time to first AF or AFL recurrence of patients in sinus rhythm at baseline was 498 days in placebo patients and 737 days in dronedarone patients (hazard ratio 0.749, 95% confidence interval 0.681 to 0.824, p <0.001). In the dronedarone group, 339 patients (15%) had ≥1 electrical cardioversion, compared to 481 (21%) in the placebo group (hazard ratio 0.684, 95% confidence interval 0.596 to 0.786, p <0.001). The likelihood of permanent AF or AFL was lower with dronedarone (178 patients [7.6%]) compared to placebo (295 patients [12.8%]) (p <0.001). At the time of first AF or AFL recurrence, the mean heart rates were 85.3 and 95.5 beats/min in the dronedarone and placebo groups, respectively (p <0.001). In conclusion, dronedarone demonstrated both rhythm- and rate-controlling properties in ATHENA. These effects are likely to contribute to the reduction of important clinical outcomes observed in this trial.

Anticoagulation With Otamixaban and Ischemic Events in Non–ST-Segment Elevation Acute Coronary Syndromes: The TAO Randomized Clinical Trial

IMPORTANCE The optimal anticoagulant for patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) managed with an invasive strategy remains controversial. OBJECTIVE To compare the clinical efficacy and safety of otamixaban, a novel intravenous direct factor Xa inhibitor, with that of unfractionated heparin plus downstream eptifibatide in patients with NSTE-ACS undergoing a planned early invasive strategy. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, active-controlled superiority trial that enrolled 13,229 patients with NSTE-ACS and a planned early invasive strategy, at 568 active sites in 55 countries and conducted between April 2010 and February 2013. A planned interim analysis was conducted for otamixaban dose selection. INTERVENTIONS Eligible participants were randomized to otamixaban (bolus and infusion, at 1 of 2 doses) or unfractionated heparin plus, at the time of percutaneous coronary intervention, eptifibatide. The otamixaban dose selected at interim analysis was an intravenous bolus of 0.080 mg/kg followed by an infusion of 0.140 mg/kg per hour. MAIN OUTCOMES AND MEASURES The primary efficacy outcome was the composite of all-cause death or new myocardial infarction through day 7. RESULTS Rates of the primary efficacy outcome were 5.5% (279 of 5105 patients) randomized to receive otamixaban and 5.7% (310 of 5466 patients) randomized to receive unfractionated heparin plus eptifibatide (adjusted relative risk, 0.99 [95% CI, 0.85-1.16]; P = .93). There were no differences for the secondary end points, including procedural thrombotic complications. The primary safety outcome of Thrombosis in Myocardial Infarction major or minor bleeding through day 7 was increased by otamixaban (3.1% vs 1.5%; relative risk, 2.13 [95% CI, 1.63-2.78]; P < .001). Results were consistent across prespecified subgroups. CONCLUSIONS AND RELEVANCE Otamixaban did not reduce the rate of ischemic events relative to unfractionated heparin plus eptifibatide but did increase bleeding. These findings do not support the use of otamixaban for patients with NSTE-ACS undergoing planned early percutaneous coronary intervention. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01076764.

Impact of dronedarone on hospitalization burden in patients with atrial fibrillation: results from the ATHENA study

Aims Cardiovascular (CV) hospitalization is a predictor of CV mortality and has a negative impact on patients’ quality of life. The primary endpoint of A placebo-controlled, double-blind, parallel-arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENTs with Atrial fibrillation/atrial flutter (ATHENA), a composite of first CV hospitalization or death from any cause, was significantly reduced by dronedarone. This post hoc analysis evaluated the secondary endpoint of CV hospitalization and the clinical benefit of dronedarone on the number and duration of CV hospitalizations in patients with atrial fibrillation (AF). Methods and results ATHENA was a double-blind, parallel group study in 4628 patients with a history of paroxysmal/persistent AF and additional risk factors, treated with placebo or dronedarone. Dronedarone treatment significantly reduced the risk of first CV hospitalization (P < 0.0001 vs. placebo), while the risk of first non-CV hospitalization was similar in both groups (P = 0.77). About half of the CV hospitalizations were AF-related, with a median duration of hospital stay of four nights. The risk of any hospitalization for AF [hazard ratio (95% confidence interval) 0.626 (0.546−0.719)] and duration of hospital stay were significantly reduced by dronedarone (P < 0.0001 vs. placebo). Dronedarone treatment reduced total hospitalizations for acute coronary syndrome (P = 0.0105) and the time between the first AF/atrial flutter recurrence and CV hospitalization/death (P = 0.0048). Hospitalization burden was significantly reduced across all levels of care (P < 0.05). Cumulative incidence data indicated that the effects of dronedarone persisted for at least 24 months. Conclusion Dronedarone reduced the risk for CV hospitalization and the total hospitalization burden in this patient group. The trial is registered under ClinicalTrials.gov #NCT 00174785.

Design and rationale of the Treatment of Acute Coronary Syndromes with Otamixaban trial: A double-blind triple-dummy 2-stage randomized trial comparing otamixaban to unfractionated heparin and eptifibatide in non–ST-segment elevation acute coronary syndromes with a planned early invasive strategy

BACKGROUND Otamixaban is a synthetic intravenous direct factor Xa inhibitor, with rapid onset/offset, linear kinetics, and no significant renal elimination. A phase II trial in acute coronary syndromes (ACS) showed a marked reduction in the combined end point of death or myocardial infarction (MI) and similar bleeding rates with otamixaban at midrange doses, compared with unfractionated heparin (UFH) and eptifibatide. DESIGN The TAO trial is a phase III, randomized, double-blind, triple-dummy controlled trial testing the efficacy of otamixaban over UFH plus eptifibatide in patients with non-ST-segment elevation ACS to be treated with dual oral antiplatelet therapy and an invasive strategy. Approximately 13,220 patients in 55 countries will be randomized (1:1:1 ratio) to receive UFH plus downstream eptifibatide (started pre-percutaneous coronary intervention and continued per label) or otamixaban (0.08 mg/kg intravenous bolus at randomization then 0.100 or 0.140 mg/kg per hour intravenous infusion). An interim analysis was performed after ≥1,969 patients per arm completed 7 days of follow-up and the Data Monitoring Committee selected 1 otamixaban dose (blinded to investigators) to be carried forward using a prespecified algorithm. The primary efficacy outcome is the composite of all-cause mortality or new MI through day 7. The primary safety outcome is thrombolysis in MI major or minor bleeding through day 7. Secondary outcomes include all-cause mortality, recurrent ischemia/infarction resulting in prolonged/recurrent hospitalization, periprocedural angiographic complications, and pharmacokinetic data in 6,000 patients. CONCLUSIONS The TAO trial will assess the clinical efficacy and safety of otamixaban in non-ST-segment elevation ACS with planned invasive strategy.

Report of the European Society of Cardiology Cardiovascular Round Table regulatory workshop update of the evaluation of new agents for the treatment of acute coronary syndrome: Executive summary

Regulatory authorities interpret the results of randomized controlled trials according to published principles. The European Medicines Agency (EMA) is planning a revision of the 2000 and 2003 guidance documents on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (ACS) to achieve consistency with current knowledge in the field. This manuscript summarizes the key output from a collaborative workshop, organized by the Cardiovascular Round Table and the European Affairs Committee of the European Society of Cardiology, involving clinicians, academic researchers, trialists, European and US regulators, and pharmaceutical industry researchers. Specific questions in four key areas were selected as priorities for changes in regulatory guidance: patient selection, endpoints, methodologic issues and issues related to the research for novel agents. Patients with ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) should be studied separately for therapies aimed at the specific pathophysiology of either condition, particularly for treatment of the acute phase, but can be studied together for other treatments, especially long-term therapy. Unstable angina patients should be excluded from acute phase ACS trials. In general, cardiovascular death and reinfarction are recommended for primary efficacy endpoints; other endpoints may be considered if specifically relevant for the therapy under study. New agents or interventions should be tested against a background of evidence-based therapy with expanded follow-up for safety assessment. In conclusion, new guidance documents for randomized controlled trials in ACS should consider changes regarding patient and endpoint selection and definitions, and trial designs. Specific requirements for the evaluation of novel pharmacological therapies need further clarification.