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Stents, cholesterol and heart drugs dominate cardiology conference talks

From the May ACP Hospitalist, copyright © 2007 by the American College of Physicians.

By Jessica Berthold

The appropriate use of stents, the efficacy of cholesterol drugs and the safety of heart failure medication were hot topics at the American College of Cardiology's (ACC) 56th Annual Scientific Session, held in New Orleans in March. An unusual number of failed trials were unveiled at the conference.

"We've seen more negative studies than ever at this meeting, but some do provide hope," said E. Murat Tuzcu, FACP, chairman of the Scientific Session program committee and director of the Intravascular Ultrasound Laboratory at the Cleveland Clinic.

The COURAGE trial generated the biggest buzz in the hallways. The heavily reported study found that patients with stable coronary artery disease were no less likely to die or experience serious cardiac events if they underwent percutaneous intervention in addition to optimal medical therapy than patients receiving medical therapy alone. Stents did provide faster and better relief from angina at first, but after five years the relief was equal to that of medication. The study was published in the March 29 New England Journal of Medicine.

"We've seen more negative studies than ever at this meeting, but some do provide hope." —E. Murat Tuzcu, FACP

Opinions were mixed on whether COURAGE would actually change the way cardiologists practice. In a conference highlights session, Anthony N. DeMaria, MD, editor of the Journal of the American College of Cardiology, said it would reduce the total number of angioplasties, while Robert A. Harrington, MD, a member of the Scientific Session program committee and director of cardiovascular clinical trials at the Clinical Research Institute of Duke University School of Medicine in Durham, N.C., said he thought it would serve mostly to enhance conversations between doctors and patients about treatment options. "I don't think [the trial] is saying to do one over the other," Dr. Harrington said.

The study doesn't undervalue PCI for patients with acute myocardial infarction, but shows PCI "has very little value to offer" those with stable coronary artery disease, said Salim Yusuf, MD, director of cardiology at McMaster University, Hamilton, Ontario, during a panel discussion. Still, Dr. Yusuf expressed doubt that many of his colleagues would actually alter how they practice, given that angioplasties are a $15 billion to $20 billion industry. "We're going to have a hell of a time putting the genie back in the bottle," he said.

Meanwhile, the ILLUSTRATE trial was one of several that found that raising HDL cholesterol levels didn't reduce the risk of coronary atherosclerosis. In the study, unveiled at the conference and reported widely, researchers tested whether adding the HDL-raising drug torcetrapib to atorvastatin therapy to lower LDL cholesterol levels would result in improved results over statin therapy alone.

Torcetrapib was effective in raising HDL cholesterol levels significantly, but after 24 months, those who received the combination therapy saw no statistical change in plaque volume compared with the atorvastatin-only group. As well, blood pressure averaged 4.6 mm Hg higher for the combination therapy group, according to data published in the March 29 New England Journal of Medicine.

Lead study author Steve E. Nissen, MD, immediate past president of the ACC and chairman of the department of cardiovascular medicine at the Cleveland Clinic in Cleveland, said the results were "discouraging," but he continues to believe that other drugs in the cholesterol ester transfer protein (CETP) inhibition class could work and that research should proceed. "The failure of this study doesn't rule out the possibility that a [different] drug could work … but the bar to prove it has gotten higher," Dr. Nissen said.

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Evaluating safety

A handful of studies found that drugs whose safety had previously been called into question were, in fact, safe to use, though not necessarily effective.

FUSION II

The FUSION II study found that nesiritide (Natrecor) doesn't reduce death or cardiorenal hospitalization when added to standard treatment for outpatients with stage D heart failure, nor does it cause excess harm.

The double-blind trial randomly assigned 920 outpatients with chronic decompensated heart failure to nesiritide, 2 mcg/kg bolus and 0.01 mcg/kg per minute, for 4 to 6 hours or matching placebo once or twice weekly for 12 weeks, with a 4-week taper and 8-week follow-up. All patients received standard heart failure therapy.

While past studies have found that nesiritide increased death and renal dysfunction among patients with acute decompensated heart failure, this study found no difference in all-cause death or cardiovascular or cardiorenal hospitalization between the groups (36.7% in the nesiritide group vs. 36.8% in the placebo group). Safety outcomes were also similar, though there were more drug-related adverse events in the nesiritide group (42%) than in the placebo group (27.5%). Practitioners should stick to current guidelines for using the drug until more research is done, said lead study author Clyde W. Yancy, FACP, of Baylor University Medical Center at Dallas.

MERLIN TIMI-36

Addressing concerns that the new angina drug ranolazine appeared to be related to small EKG changes, the MERLIN TIMI-36 trial found the medication safe for use in patients with acute and chronic angina, though it didn't reduce cardiovascular death or myocardial infarction.

The double-blind study involved 6,560 patients with acute coronary syndrome at 440 sites whose EKGs showed no ST-segment elevation. All were treated with standard-of-care medication; many had also had surgical procedures. The study group received 200 mg of ranolazine intravenously over one hour, followed by an infusion of 80 mg per hour for up to 96 hours. The group then took 1,000 mg of oral ranolazine twice daily for about 12 months. The control group underwent the same regimens with placebo.

Ranolazine didn't affect cardiovascular death, MI or recurrent ischemia combined (hazard ratio, 0.92; P= 0.11), but did significantly reduce recurrent ischemia alone; incidence was 13.9% with treatment and 16.1% with placebo (hazard ratio, 0.87; P= 0.03). As well, less clinically significant arrhythmia was seen on Holter monitoring in the ranolazine group than in the placebo group (73.7% vs. 83.1%, respectively; hazard ratio, 0.89; P<</i> 0.001).

The safety results of ranolazine are "reassuring," said lead study author David Morrow, MD, MPH, of Brigham and Women's Hospital at Harvard Medical School in Boston, adding that the potential anti-arrhythmic effects warranted additional investigation. Dr. Yusuf agreed on the latter point, but added that the trial shows the drug "has no role for routine management of ACS."

EVEREST

The EVEREST trial showed that tolvaptan, a vasopressin antagonist, didn't reduce death or hospitalizations in patients with acute decompensated heart failure, but did improve dyspnea and edema in the short term. Researchers randomly assigned 4,133 hospitalized patients at 359 centers to oral tolvaptan at 30 mg/day or placebo for a minimum of 60 days. Most received standard therapy as well. They were followed for a median of 9.9 months.

The composite of cardiovascular death or hospitalization for heart failure occurred in 871 patients in the tolvaptan group and 829 patients in the placebo group (42% vs. 40%, respectively; hazard ratio, 1.04; P= 0.55). Tolvaptan significantly improved day 1 patient-assessed dyspnea (74.3% in the tolvaptan group vs. 68% in the placebo group) and day 7 edema, with 73.8% of tolvaptan patients versus 70.5% of placebo patients seeing improvement in edema by at least two grades. The drug also lowered body weight compared with placebo, an effect that persisted after discharge. Results were published in the March 28 Journal of the American Medical Association.

"A novel therapy for [acute decompensated heart failure] has been identified that may potentially have an impact on clinical practice. However, use of tolvaptan must be carefully considered, as evidence of long-term benefit is lacking," Dr. Yancy wrote in an accompanying editorial. He also noted that "use of tolvaptan should not be extrapolated to patients who are dissimilar" from the trial participants.

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Other research

Two other studies offered glimmers of hope, some said, for treating patients for atherosclerosis and high blood pressure, respectively.

ARISE tested the pairing of succinobucol, a novel anti-oxidant/anti-inflammatory, with standard medical therapy for patients with unstable angina or MI in the previous 14 to 365 days. While the drug didn't reduce patients' likelihood of experiencing a composite of major cardiovascular events (cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, unstable angina or coronary revascularization) compared with placebo (17.2% vs. 17.3%), it did reduce the composite incidence of cardiovascular death, cardiac arrest, MI or stroke by 19% (P= 0.028); 6.7% of patients in the succinobucol group experienced these events versus 8.2% of those in the placebo group. The drug also reduced new-onset diabetes by 64% (1.6% of patients taking succinobucol became diabetic vs. 4.2% of patients taking placebo), mainly by improving glucose and hemoglobin A1c levels.

Dr. Tuzcu said ARISE offered "some hope" in the fight against atherosclerosis based on the secondary end points, while Dr. Harrington labeled the study "a big disappointment" that "on balance had no effect." Still, he added, there was enough ground to proceed with future research.

Another study found that combining new drug aliskiren, a direct renin inhibitor, with valsartan, an angiotensin-receptor blocker (ARB), lowered blood pressure in hypertensive patients more than using either medication alone.

The double-blind trial randomly assigned 1,797 patients with stage 1 to 2 diastolic hypertension to 150 mg of aliskiren, 160 mg of valsartan, a combination of both or placebo once daily for four weeks, followed by forced titration to double the dose for four weeks. At the study's end, patients who took the combination medicine lowered blood pressure up to an additional 4.5/3.2 mm Hg over those on either monotherapy regimen, and tolerability was retained. The blood pressure control rate was 49.3% for the combination group compared with 37.4% for those receiving aliskiren alone, 33.8% for those receiving valsartan alone and 16.5% for those receiving placebo.

While combining a diuretic with an ARB has a similar effect on blood pressure for some populations, aliskiren "gives the physician another choice" in treating patients for hypertension who may not tolerate or respond to diuretics, said Suzanne Oparil, MD, the study's lead author and director of the Vascular Biology and Hypertension Program in the Division of Cardiovascular Disease at the University of Alabama at Birmingham.

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ACP Hospitalist provides news and information for internists about the practice of medicine and reports on the policies, products and activities of ACP. All published material, which is covered by copyright, represents the views of the contributor and does not reflect the opinion of the American College of Physicians or any other institution unless clearly stated