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Failures become lessons learned in cardiology research

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

By Jessica Berthold

NEW ORLEANS—In medical research, as in life, failure is often as instructive as success. So it was at the American College of Cardiology's 56th Annual Scientific Session last month, where researchers reported on numerous trials that found no benefit to treatments ranging from stents to HDL cholesterol-raising drugs.

"There is possibly more to learn from a failed trial than a positive one," noted 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.

Indeed, the main study that grabbed headlines was COURAGE, which found that stable coronary artery disease patients were no less likely to die or experience serious cardiac events if they underwent percutaneous intervention in addition to optimal medical therapy than patients on medical therapy alone. Stents provided 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.

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 Dr. Harrington 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 certainly 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."

The ILLUSTRATE trial found that raising HDL cholesterol 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 would result in improved results over statin therapy alone.

Torcetrapib was effective in raising HDL cholesterol 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, said the results were "discouraging," but he continues to believe that other drugs in the 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.

A few of the many other trials that were presented at the conference included:

The RADIANCE I and II trials yielded similar results as ILLUSTRATE for patients with heterozygous familial hypercholesterolemia or mixed hyperlipidemia, finding that the addition of torcetrapib to atorvastatin raised patients' HDL cholesterol and lowered their LDL cholesterol, yet didn't cause regression of atherosclerosis as assessed by a combined measure of carotid arterial wall thickness. "It remains to be investigated whether this is a consequence of the molecule torcetrapib or whether the concept of CETP-inhibition is a flawed hypothesis," said lead author John J.P. Kastelstein, MD, PhD, of the Academic Medical Center of Amsterdam.

The ERASE trial found that the 111 patients who took 40 mg/kg CSL-111 (reconstituted HDL) saw no significant change in atheroma volume (-3.4%) compared with the 60 patients on placebo (-1.6%) after four weekly infusions. However, the CSL-111 group did show significant improvement in plaque characterization index on IVUS (-0.0097 vs. 0.0128 with placebo) and mean changes in coronary score on quantitative coronary angiography (-0.039 mm vs. -0.071 with placebo), according to results published in the March 26 Journal of the American Medical Association.

Given the small size of the trial, the results show promise, several experts said. "Four doses to regress a disease is asking a lot," Dr. Nissen said. "(The researchers) are to be commended for opening the door; now let's see if they can jump through it" with a follow-up trial, he added.

The ARISE study 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 14-365 days. While the drug didn't reduce patients' likelihood of experiencing a composite of major CV events (CV 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 CV death, cardiac arrest, MI or stroke by 19% (p=0.028), with 6.7% of succinobucol patients experiencing these vs. 8.2% of placebo. It also reduced new onset diabetes by 64% (1.6% on succinobucol became diabetic vs. 4.2% for placebo), mainly by improving glucose and HbA1c levels.

E. Murat Tuzcu, FACP, chairman of the Scientific Sessions program committee and director of the Intravascular Ultrasound Laboratory at the Cleveland Clinic, said ARISE offered "some hope" in the fight against atherosclerosis based on the secondary endpoints, 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.

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 randomized 920 chronic decompensated heart failure outpatients to nesiritide 2 mcg/kg bolus and 0.01 mcg/kg/min for 4-6 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 nesiritide increased death and renal dysfunction among acute decompensated heart failure patients, this study found no difference in all-cause death, CV or cardiorenal hospitalization between the groups (36.7% in nesiritide group vs. 36.8% in placebo). Safety outcomes were also similar, though there were more drug-related adverse events in the nesiritide group (42%) versus placebo (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.

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 randomized 1,797 patients with stage 1-2 diastolic hypertension to either 150 mg of aliskiren, 160 mg of valsartan, the combination of both, or placebo once daily for four weeks, followed by forced titration to double the dose for four weeks. At 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. Blood pressure control rate was 49.3% for the combination group compared to 37.4% for aliskiren alone, 33.8% for valsartan alone and 16.5% for 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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