Coverage from the American College of Cardiology meeting, March 24-27, 2007

Newest antianginal is safe over the long term; reduces arrhythmias

Ranolazine, the newest antianginal agent approved in the United States, 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 results from a study known as MERLIN (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes).

Prior to MERLIN, the long-term safety of ranolazine had been uncertain because it was associated with slight prolongation of the QT interval, said its lead investigator David A. Morrow, MD, MPH. For this reason, ranolazine was approved in 2006 as second-line therapy in patients who continue to experience angina despite treatment with other antianginal medications.

In MERLIN, 6560 patients with non-ST-elevation ACS and clinical indicators of moderate-to-high risk of recurrent ischemic events were randomized to ranolazine or placebo for approximately 12 months, with both groups receiving standard medical therapy. Ranolazine was initiated intravenously in the hospital followed by its oral extended-release formulation (1000 mg twice daily).

The entire cohort was well treated, with 96% on aspirin, 90% on an antithrombin, 90% on β blockers, 82% on statins, 79% on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and 30% on oral nitrates.

The primary end point—a composite of cardiovascular death, myocardial infarction, or recurrent ischemia—occurred in 21.8% of patients randomized to ranolazine and 23.5% randomized to placebo, a statistically nonsignificant 8% relative difference in favor of ranolazine.

P

P

P

Ranolazine was associated with certain benefits, however, including significant reductions in the incidence of recurrent ischemia (13% reduction; = .03), worsening angina (23% reduction; = .023), and the need for antianginal therapy (19% reduction; = .006), compared with placebo.

P

Also, the risk of clinically significant arrhythmias on Holter monitoring was reduced by 11% (< .001) in the patients assigned to ranolazine.

The new data offer reassurance that ranolazine is safe for long-term administration and may even be antiarrhythmic, said Dr Morrow, associate physician in the division of cardiovascular medicine at Brigham and Women's Hospital, Boston.

"The significant reduction in recurrent ischemia provides evidence for efficacy as an antianginal agent in a broader population than ever studied before with ranolazine," he said. "The significant antiarrhythmic effects of ranolazine suggested by a significant reduction in arrhythmias warrant additional investigation."

The results from MERLIN could serve as the basis for approval of ranolazine as a first-line agent for the treatment of angina, he added.

PCI can be safely deferred in stable CAD patients with ischemia

Optimal medical therapy alone is an acceptable initial strategy for patients with stable coronary artery disease (CAD) and myocardial ischemia, said William E. Boden, MD. In a trial known as COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation), medical therapy titrated to reach aggressive targets in low-density lipoprotein (LDL) cholesterol, blood pressure, and, if diabetic, hemoglobin A1c (HbA_1c) was as effective as percutaneous intervention (PCI) plus optimal medical therapy as an initial strategy in preventing death or major cardiovascular events in such patients.

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

In COURAGE, 2287 patients with stable CAD, a stenosis of at least 70% in at least 1 proximal coronary artery, and objective evidence of myocardial ischemia on an electrocardiogram (or a stenosis of at least 80% and angina without provocative testing) were randomized to 1 of the 2 treatment strategies.

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

All patients received aggressive therapy to lower LDL cholesterol levels to a target of less than 85 mg/dL, aspirin (81-325 mg/day), or clopidogrel (75 mg/day), and medical anti-ischemic therapy. One-half underwent PCI in addition to medical therapy, and one-half were treated exclusively with medical therapy.

At 5 years, 70% of the subjects had attained an LDL cholesterol level of less than 85 mg/dL, 65% achieved the systolic blood pressure target of less than 130 mm Hg, 94% achieved the diastolic blood pressure target of less than 85 mm Hg, and 45% of those with diabetes achieved an HbA_1c level of 7.0% or less.

P

P

After a median follow-up of 4.6 years, 18.5% of those assigned to medical therapy alone and 19.0% assigned to PCI plus medical therapy had an event, a statistically nonsignificant difference (= .62). The incidence of the combined end point of death, myocardial infarction (MI), or stroke was 19.5% in the patients randomized to optimal medical therapy alone and 20.0% in those randomized to PCI/optimal medical therapy, again nonsignificant. There was a nonsignificant trend toward fewer MIs in the patients treated with medicine only vs PCI/medicines (12.3% vs 13.2%, = .33).

P

An additional revascularization was performed in 21.1% of the group randomized to PCI/optimal medical therapy compared with a first revascularization in 32.6% of the group assigned to optimal medical therapy alone (< .001).

P

Percutaneous intervention did have 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," said Dr Boden, "with no between-group difference in angina-free status at 5 years." The rates of freedom from angina were 74% in the PCI group and 72% in the medical therapy alone group (= .35).

Although critics had pointed out that PCI is offered as a treatment to relieve angina, "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."

He said that treating patients to targets for blood pressure, 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 added.

Although such medical therapy to attain the treatment goals in COURAGE may be considered aggressive, "it is a very real-world study," said Dr Boden. "It applies broadly to patients with symptomatic disease worldwide."

Percutaneous intervention's role in stable CAD is now clear: as a strategy to relieve angina when medical therapy fails, said Salim Yusuf, MD, director of cardiology at McMaster University in Hamilton, Ontario, Canada. "We should call medical therapy 'aggressive management' and PCI 'palliative management,'" he said. "PCI has very little value to offer in the setting of stable CAD."

Algorithm for NSAID use in CVD patients starts with least risky agent

Cardiology Review

The guidelines detailed in the following item were also discussed in the April issue of .

Patients with cardiovascular disease (CVD) or risk factors for CVD who require pharmacologic therapy for relief of musculoskeletal symptoms should be started on the agent that poses the least thrombotic risk, said Elliott M. Antman, MD.

If a nonsteroidal anti-inflammatory drug (NSAID) is being considered in a cardiac patient, the degree of cyclooxy-genase (COX)-2 selectivity should serve as a guide to initial selection. Drugs with high COX-2 selectivity should be avoided initially. Be aware that COX-1 or COX-2 selectivity cannot be predicted based on the pharmacologic class of agents, as agents within a given class have varying degrees of COX-1 and COX-2 selectivity said Dr Antman, director of the Samuel A. Levine Cardiac Unit at Brigham and Women's Hospital in Boston.

When interpreting the relative risk of cardiovascular events between NSAIDs compared in clinical trials, consider how closely the comparator resembles the study drug in COX-2 selectivity, he said. For example, in the Multinational Etoricoxib and Diclofenac Arthritis Long-Term (MEDAL) study, etoricoxib was found noninferior to diclofenac in terms of their relative risk of thrombotic events. Although diclofenac has been called a "traditional" NSAID, both etoricoxib and diclofenac lie more on the COX-2 selective end of the spectrum of COX inhibition, so the finding was not unexpected, noted Dr Antman, and reveals more about diclofenac's risk of thrombotic events rather than etoricoxib's safety.

"Neither of these medications would be among the first choices for pain relief with regard to safety, especially in persons with or at risk of CVD," he said.

A study comparing a highly selective COX-2 inhibitor with an agent that possesses more COX-1 selectivity, such as naproxen, will most likely find larger differences in thrombotic risk.

Dr Antman offered some guiding principles for using an NSAID in a patient with heart disease.

• Use only if nonpharmacologic therapy fails.
• Use in the lowest-risk patients.
• Use the lowest-risk agents.
• Use the lowest dose needed to control symptoms.
• Use for the shortest duration needed.

The stepped-care approach starts with the least-risky agents. These would be acetaminophen, aspirin, tramodol, and narcotic analgesics (short-term only). Second-step agents are nonacetylated salicylates.

Third-, fourth-, and fifth-step agents "cross the danger zone and you should tiptoe very carefully," Dr Antman said. Third step would be non-COX-2-selective NSAIDS, such as naproxen. Fourth-step agents would be NSAIDs with some COX-2 selectivity, and last-resort drugs would be COX-2 selective agents, used only at recommended doses for the shortest period of time required to control symptoms.

Patients with a history of or at risk for gastrointestinal (GI) bleeding might be started on acetaminophen. Remember that high-dose acetaminophen is associated with hepatic toxicity, especially with excessive alcohol consumption. As an alternative, a proton pump inhibitor can be given to diminish the risk of recurrent GI bleeding in patients who require low-dose aspirin.