American College of Cardiology: 56th Annual Scientific Session focuses on emerging clinical trial data, continuing research

Key Points

This year's program was notable for the numerous late-breaking clinical trials that failed to achieve their primary end points, including MERLIN, COURAGE, RADIANCE 1 and 2, ILLUSTRATE, and METEOR, which are described in this article. The lack of effective cardiovascular drugs in late-phase clinical trials is concerning, said outgoing ACC president Steven E. Nissen, MD, MACC, chief of cardiovascular medicine at the Cleveland Clinic, Cleveland, Ohio. Increasingly, these drugs are being evaluated with imaging studies to gauge their potential usefulness before investigators progress to large morbidity and mortality trials, a trend that will probably increase, he said.

Following are summaries of each of these trials, presented with the key end points and, when possible, their implications for clinical practice. The data from some of these trials have since been published in primary research journals; all citations available at press time are included within each summary.

Ranolazine demonstrates reductions in arrhythmia but fails to meet primary end point

Ranolazine does not reduce the risk of cardiovascular events in patients with non-ST-elevation acute coronary syndromes (ACS) but is safe for long-term administration and may have a potential antiarrhythmic effect, according to the results of the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes (MERLIN) trial.

Ranolazine was approved in 2006 as a second-line therapy in patients who continue to experience angina despite treatment with other antianginal medications. The long-term safety of ranolazine was uncertain because the agent was associated with slight prolongation of the QT interval. However, experimental data have demonstrated possible suppression of pro-arrhythmic markers, said lead investigator David A. Morrow, MD, MPH, associate physician, division of cardiovascular medicine, Brigham and Women's Hospital, Boston, Mass.

The MERLIN trial included 6,560 patients with non-ST-elevation ACS who had clinical indicators of a moderate-to-high risk of recurrent ischemic events. The patients were randomized to receive ranolazine or placebo for approximately 12 months in addition to their regular medical therapy (96% were taking aspirin, 90% were taking an antithrombin, 90% were taking beta-blockers, 82% were taking statins, 79% were taking angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs], and 30% were taking oral nitrates). Ranolazine was initiated intravenously (200 mg over 1 hour followed by an 80-mg/h infusion for ≤96 hours) and followed by its oral extended-release formulation (1,000 mg twice daily).

In addition, the risk of clinically significant arrhythmias identified by Holter monitoring was reduced by a significant 11% (P<.001) in the patients assigned to ranolazine.

The data from MERLIN offer reassurance that ranolazine is safe for long-term administration: the agent may even be antiarrhythmic. These results could serve as the basis for approval of ranolazine as a first-line agent for the treatment of angina, Dr Morrow said.

"The significant reduction in recurrent ischemia provides evidence for efficacy as an antianginal agent in a broader population than ever studied before with ranolazine," Dr Morrow said, adding that these results warrant further investigation of the antiarrhythmic effects of the drug.

COURAGE

PCI plus medical therapy versus medical therapy alone yields equal clinical outcomes in patients with CAD

The use of medical therapy alone is as efficacious as percutaneous intervention (PCI) plus medical therapy as an initial strategy in preventing death or major cardiovascular events in patients with stable coronary artery disease (CAD) and myocardial ischemia, according to William E. Boden, MD, lead investigator of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial.

The main advantage of the initial PCI strategy is relief of angina, but even in this regard, medical therapy alone performed better than expected, and at 5 years was virtually indistinguishable from PCI plus medical therapy, Dr Boden said.

The COURAGE trial included 2,287 patients with stable CAD, ≥70% stenosis in ≥1 proximal coronary artery, and objective evidence of myocardial ischemia on an electrocardiogram (or ≥80% stenosis and angina without provocative testing).

"The criteria were chosen to ensure a high-risk population," said Dr Boden, professor of medicine and public health at the University of Buffalo, NY. "We wanted to give angioplasty the best possible opportunity to show benefit."

Medical therapy included antiplatelet therapy, beta-blockers, statins, ACE inhibitors, smoking cessation, and diet and exercise. All patients received aggressive therapy to lower low-density lipoprotein (LDL) cholesterol levels to a target of <85 mg/dL, aspirin 81 to 325 mg/d or clopidogrel 75 mg/d, and medical anti-ischemic therapy. A total of 1,149 patients underwent PCI in addition to medical therapy, and 1,138 patients were treated exclusively with medical therapy.

At 5 years, 70% of all patients had attained an LDL cholesterol level of <85 mg/dL, 65% had achieved the systolic blood pressure (SBP) target of <130 mmHg, 94% had achieved the diastolic blood pressure (DBP) target of <85 mmHg, and 45% of patients with diabetes had achieved a glycated hemoglobin level of ≤7.0%.

An additional revascularization was performed in 21.1% of the patients randomized to PCI plus medical therapy compared with 32.6% of patients randomized to medical therapy alone (P<.001) (Table 2).

PCI did demonstrate an initial advantage in relieving angina, but this advantage declined over time until it virtually disappeared by the study's conclusion. "Within 1 year, close to 60% of the medically treated patients were angina-free, with no between-group difference in angina-free status at 5 years," Dr Boden said. Seventy-four percent of the patients in the PCI plus medical therapy group and 72% of patients in the medical therapy alone group did not experience angina (P=.35).

The results of the COURAGE trial support existing guidelines from the American Heart Association (AHA) and the ACC, which advise that PCI can be safely deferred in patients with stable CAD, even in those with extensive multivessel involvement and inducible ischemia.

"There was an implicit belief that PCI would reduce the chance of having an MI and dying," Dr Boden said. "We found that patients were at no more and no less of a risk of having an event or dying if you defer stenting."

Dr Boden said that treating patients to targets for BP, lipids, and blood glucose is important for stabilizing a systemic disease that takes decades to manifest. "We may be stabilizing plaques that are about to rupture," he stated.

Although the medical therapy required to attain treatment goals equal to those of the COURAGE trial may be considered aggressive, the study has broad applications worldwide for patients with symptomatic disease, Dr Boden said.

An economic and quality-of-life analysis of a subset of 2,287 patients enrolled in the COURAGE trial demonstrated that a PCI strategy as a first choice relative to optimal medical therapy had an incremental cost-effectiveness ratio of $217,000 per quality-adjusted life-year gained, said William Weintraub, MD, chief of cardiology and director of the Christiana Center for Outcomes Research, Newark, Del.

At times during the study, optimal medical therapy was a dominant strategy, offering better outcomes at a lower cost, Dr Weintraub said. The results of the COURAGE trial have since been published in the New England Journal of Medicine (2007 [Epub ahead of print]).

ACUITY

Bivalirudin as efficacious as combination therapy for ACS

Treating patients with ACS with bivalirudin alone is associated with similar rates of ischemic adverse events and 50% fewer episodes of major bleeding compared with treatment with heparin plus glycoprotein IIb/IIIa inhibitors (GPI) or with bivalirudin plus GPI, according to the results of the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial.

"Our findings are important because they demonstrate that in high-risk patients with ACS, bivalirudin, the simplest and least expensive regimen, results in the overall best clinical outcomes, said lead author Gregg W. Stone, MD, director of cardiovascular research and education, Columbia University Medical Center, New York, NY.

The ACUITY trial included 13,819 moderate-to-high risk patients with ACS from 450 centers in 17 countries. Upon arrival at the emergency department and before cardiac catheterization, the patients were randomized to standard therapy with unfractionated heparin or to enoxaparin plus GPI (n=4,605), bivalirudin plus GPI (n=4,604), or bivalirudin alone (n=4,612). Selective GPI use was permitted in the bivalirudin-only group based on physician discretion (<10% of patients).

The median patient age was 63 years; abnormal baseline cardiac markers were present in 59% of patients, and 35% of patients had dynamic ST-segment changes. After catheterization, 56% of patients were managed with PCI, 11% with coronary artery bypass grafting (CABG), and 33% with medication or other noninvasive treatment.

A total of 524 deaths occurred during the 1-year follow-up (4.4% of patients treated with heparin plus GPI, 4.2% of patients treated with bivalirudin plus GPI, and 3.8% of patients treated with bivalirudin alone). Although fewer deaths occurred in the bivalirudin-alone treatment group than in the other treatment groups, the difference was not significant, and bivalirudin is not inferior to the other treatments in terms of mortality, Dr Stone said.

A major bleeding episode or MI during the first 30 days of the study were highly significant predictors of 1-year mortality. After adjusting for other variables, the HR was 2.89 for a major bleeding episode during the first 30 days and 2.47 for MI (P<.0001 for both) for all treatment groups.

There was a trend (P=.10) towards increased ischemia among patients treated with bivalirudin alone: 7.1% exper-ienced an MI within 1 year compared with 6.2% of patients treated with heparin plus GPI and 6.4% of patients treated with bivalirudin plus GPI. Dr Stone said the increased mortality due to MI was associated only with death occurring in the first week after an MI. "A patient surviving for at least 8 days after an MI was not more likely to die during the remainder of follow-up than patients not having an MI," he said.

"While heart attacks tend to happen in the hospital, we found the risk of death associated with major bleeding continues long-term. This makes major bleeding an even more powerful predictor of death than having a heart attack," Dr Stone said. Overall, 3.4% of patients without an MI or major bleeding at 30 days died at 1 year versus 8.6% of patients with an MI, 12.5% of patients with a major bleeding episode, and 28.9% of patients with both an MI and major bleeding during the first 30 days.

There were no significant differences among treatment groups in terms of unplanned revascularization procedures after 1 year of follow-up. The rates of in-stent thrombosis were similar and occurred in 2.3% of patients in the heparin plus GPI group, 2.4% of patients in the bivalirudin plus GPI group, and 1.9% of patients in the bivalirudin-alone group. There were no differences in the incidence of re-thrombosis between patients receiving drug-eluting or bare metal stents.