The positive side of negative news (AHA Scientific Sessions 2005)

Developments from this meeting underscored the importance of getting to the bottom of clinical questions.

By Peggy Peck, amednews correspondent — Posted Dec. 19, 2005

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In recent years, scientific meetings and professional journals have been pilloried for emphasizing the positive while giving short shrift to the negative, but the American Heart Assn. turned that notion on its head at its 2005 Scientific Sessions held Nov. 13-16 in Dallas.

From the first plenary to the final late-breaking abstracts session, the news was negative and the truth unvarnished, as again and again trials reported null or marginal results.

Timothy Gardner, MD, a thoracic surgeon and AHA program committee chair, said the newfound willingness to prominently report negative findings is an important feature of scientific meetings. In the past, many "negative trials never made it to the light of day, which left clinicians and patients without [this] knowledge. I think it is important to report when a treatment has failed."

On balance, most studies that were reported at late-breaking clinical trials sessions had null results, but three offered dramatic illustrations of this point: PREVENT IV, IDEAL, and FIELD. The first two were also published in the Journal of the American Medical Association, while the third was published online in The Lancet.

No benefit to gene therapy

PREVENT IV, Project of Ex-vivo Vein Graft Engineering via Transfection, investigated a promising experimental compound, edifoligide, and a novel procedure, pretreatment of saphenous veins before grafting.

The drug was touted as a genetic "decoy" designed to attract E2F, a transcription factor that triggers neointimal hyperplasia. The decoy action would, researchers thought, block the natural activity of E2F, which, if effective, would reduce neointimal hyperplasia.

To test this idea, the drug or a saline placebo was infused into the veins of patients before surgery.

In this double-blind, placebo-controlled trial of 3,014 patients undergoing primary coronary-artery bypass graft surgery with at least two saphenous vein grafts, the per-patient graft failure rate was 45% among those randomized to edifoligide and 46% among those randomized to the placebo arm.

Moreover, when the grafts were assessed with angiography, 29% of the veins pretreated with edifoligide and 30% of the veins in the placebo arm had narrowed by 75% within 12 to 18 months of treatment.

The real value of the study, said lead investigator John Alexander, MD, an assistant professor of cardiology at Duke University Medical Center in North Carolina, is the information about graft failure rates. Saphenous grafts are routinely used for treatment of peripheral arterial disease as well as for CABG procedures. "So it is important to know that almost 30% of these grafts fail within a year."

Dr. Gardner concurred, noting that the results confirm that use of saphenous veins should be limited, while "arterial grafts should be used when available."

PREVENT IV is also a cautionary tale about the danger of hyping early results. In this case, phase I and II results were so promising that the Food and Drug Administration had fast-tracked the drug, but the PREVENT IV results may have now permanently derailed it.

Is lower really better?

The Incremental Decrease in Clinical Endpoints through Aggressive Lipid Lowering trial -- IDEAL -- offered a surprising finding that an aggressive lipid-lowering strategy with a high dose of atorvastatin (Lipitor) did not offer a significant benefit over standard treatment with 20 mg of simvastatin (Zocor).

Patients randomized to 80 mg of atorvastatin had an 11% relative reduction in major coronary events versus patients randomized to simvastatin. Of interest, patients in the high- dose atorvastatin arm did lower LDL to an average of 81 mg/dL, while those in the simvastatin arm achieved an average LDL of 104 mg/dL. However, the lower LDL did not translate into significant differences in either cardiovascular or all-cause mortality.

Business news services quickly reported the finding as a "win" for simvastatin. Still, the cardiologists here tended to downplay this study's results, perhaps taking their cues from its lead author, Terje R. Pederson, MD, PhD, professor of medicine at Ulleval University Hospital and director of the Center for Preventative Medicine in Oslo, Norway.

At a news conference, Dr. Pederson explained that a number of studies have reported a significant benefit for aggressive lipid-lowering. Balanced against that preponderance of evidence, he maintained that this lack of a statistically significant difference wasn't likely to have "a dramatic impact." Moreover, atorvastatin did reduce "the whole burden of cardiovascular disease substantially and significantly. That is likely to count more than a 'p' value."

Steven Nissen, MD, director of the cardiovascular coordinating center at the Cleveland Clinic Foundation, cautioned against interpreting the IDEAL results in a vacuum. "If you take all the evidence together from REVERSAL, PROVE IT, TNT, A to Z, and this new trial, the message is clear: lower is better," he said. Dr. Nissen was not involved in the IDEAL trial. "If you have a high-risk patient, what do you think is better: an LDL of 104 or an LDL of 81? I would still say 81."

But Raymond J. Gibbons, MD, a Mayo Clinic cardiologist and AHA president-elect, offered a different view, saying the study was powered to detect a difference of 21%, and "it did not do that."

However, high-dose atorvastatin did significantly reduce the rate of non-fatal myocardial infarction to 6% versus 7.2% in the simvastatin arm.

The study randomized 4,439 patients to high-dose Lipitor and 4,449 to standard-dose Zocor. The patients, who were recruited at 190 centers in northern Europe beginning in March 1999, were followed for a median of 4.8 years.

The Fenofibrate Intervention and Event Lowering in Diabetes -- FIELD -- trial dashed the hopes of those who thought fenofibrate (TriCor) would be a good alternative to statin therapy for people with type 2 diabetes.

Patients randomized to fenofibrate (200 mg daily) plus standard therapy had a slight increase in coronary heart disease mortality and a significant 24% decrease in non-fatal myocardial infarction, compared with placebo.

Taken together, fenofibrate was associated with an 11% decrease in the primary endpoint of nonfatal MI and CHD death.

"Based on these results, we cannot recommend substituting fenofibrate for statin therapy," said lead author Anthony Keech, MD, a professor of medicine at the University of Sydney in Australia.

In addition to these results, the Lancet published online a commentary by Helen Calhoun, MD, of the Conway Institute, University College in Dublin, Ireland. She wrote that "the results from this well-executed trial do not warrant a recommendation for increased fenofibrate use in patients with diabetes, nor do they provide convincing evidence of the benefit of fenofibrate therapy in patients already at target serum LDL cholesterol."

But Dr. Keech hastened to add that fenofibrate may "be a good addition to statin therapy since it does decrease non-fatal events."

Additionally, patients in the fenofibrate arm had "significantly less need for laser surgery, suggesting that this drug may reduce microvascular events such as diabetic retinopathy. Statins, which have a significant effect on macrovascular events, do not impact the microvasculature," Dr. Keech said.

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Conflicting data from stem cell therapy

Though negative results generally seemed to outweigh positive ones at the American Heart Assn.'s Scientific Sessions 2005, a pair of stem cell studies split the difference.

In a German placebo-controlled trial, post-myocardial infarction patients infused with stem-like cells from their own bone marrow improved global left ventricular function by 5.5% versus a 3% improvement in patients who received placebo infusions.

Moreover, patients who received the stem cell infusions five or more days after myocardial infarction improved function by 7% compared with 1.9% in the placebo group.

But when researchers from Norway injected autologous bone marrow cells into damaged myocardium, there was no benefit.

So does stem cell therapy work?

Yes, said Dr. Andreas M. Zeiher, a professor at J.W. Goethe-University in Frankfurt, Germany, and senior author of the Reinfusion of Enriched Progenitor Cells And Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial. The treatment is the first therapy "that has the potential to not only limit damage, but also regenerate heart function."

But Ketil Lunde, MD, a cardiology research fellow at the Rikshospitalet University Hospital in Oslo, Norway, disagreed. "Injection of mononuclear cells from the patient's own bone marrow into the infarct-related coronary artery a few days after acute myocardial infarction did not improve cardiac pump function or reduce infarct size during six months follow-up," said Dr. Lunde, who was the lead researcher of effects on left ventricular function by intracoronary injections of autologous mononuclear cells in acute anterior wall myocardial infarction, the ASTAMI randomized controlled trial.

Timothy Gardner, MD, chair of the AHA program committee and medical director at the Christiana Care Health Services Center for Heart and Vascular Health in Wilmington, Del., said it is too soon for simple answers. Some of the benefit reported by the REPAIR-AMI investigators might be explained by "the immune reaction to treatment, which might stimulate growth factors," he said.

REPAIR-AMI randomized 95 patients to the bone marrow cell treatment and 92 to placebo.

ASTAMI randomized 50 patients to bone marrow injections and 50 to a control group. Patients were followed for six months, and at the end of the trial there were no significant differences between the groups in ejection fraction, end diastolic volume or in infarct size, no matter which test was utilized in assessing the patients.

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Research findings: ACTIVATE fails to scintillate; warfarin wins; help for smokers

What is good for mice is often not nearly as good in men, according to a trial investigating pactimibe, an acyl-Coenzyme A:cholesterol acyltransferase inhibitor. The findings were announced in November at the American Heart Assn. Scientific Sessions 2005.

"This drug worked in mice, even showing some reversal of atherosclerosis in some studies, but it didn't work in humans," said Steven E. Nissen, MD, medical director of the Cleveland Clinic Cardiovascular Coordinating Center in Ohio. He was the chief investigator of the ACAT Inhibition on the Progression of Coronary Atherosclerosis study.

Researchers expected the drug to prevent or reduce atherosclerosis, but intravascular ultrasound inspection of coronary arteries found that instead of reducing levels of plaque buildup in the arteries, it increased in the patients taking pactimibe.

Dr. Nissen said several other drugs in the class are under development, but he thinks that the companies working on those drugs should take a long, careful look at these results.

Meanwhile, another study detailed why an attempt to make it easier to keep patients with atrial fibrillation properly anticoagulated also failed. In fact, the use of clopidogrel (Plavix) plus aspirin, a standard approach for certain other conditions, proved to be far inferior to warfarin.

The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events study was halted early by the Data Monitoring and Safety Board at the first interim analysis when it showed there was a 47% increase in events among those in the clopidogrel plus aspirin group.

Also presented at the meeting was a study regarding an investigational smoking cessation drug that targets the main nicotine receptor in the brain and could offer short-term benefit to smokers motivated to quit.

In a randomized trial that compared varenicline to bupropion (Zyban) and placebo, 44% of smokers taking varenicline were smoke-free at 12 weeks versus 30% of smokers taking bupropion and 17.7% of those in the placebo arm. But the benefit might not be durable. After 12 months, only one in five smokers treated with varenicline, which is being developed by Pfizer, were still smoke-free.

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Treatment tips

Here are some treatment tips from the meeting:

Protein drives down blood pressure. OmniHeart researchers found that adding protein to a restricted-calorie diet can lower blood pressure.

"Our [diet intervention] study provides evidence that substituting carbohydrates with protein -- about half of that protein from plant sources -- or with unsaturated fat mostly in the form of monounsaturated fat can lower blood pressure, improve cholesterol levels and reduce heart disease risk," said Lawrence Appel, MD, MPH, of Johns Hopkins School of Medicine in Baltimore.

After three months of three different sequentially administered diets fed to 164 adults, OmniHeart investigators found the entire group's systolic blood pressure had dropped by an average 9.5 mm Hg on the diet emphasizing proteins. On the diet emphasizing higher fats, there was a 9.3 mm Hg drop, and on the carbohydrate-rich diet, there was an 8.2 mm Hg drop.

Pioglitazone reduces second MI risk. Diabetics who have had a heart attack in the previous six months may reduce the risk of a second myocardial infarction by adding pioglitazone (Actos) to standard therapy for glucose and lipid control. That was the major finding from a prespecified subset analysis of data from 2,445 patients enrolled in the Prospective Pioglitazone Clinical Trial in Macrovascular Events. Therapy was associated with a 28% reduction in risk of recurrent MI, said Dr. Erland Erdmann of the University of Koeln in Germany. Pioglitazone also was associated with a 37% relative reduction in the risk of acute coronary syndrome.

The main study results included a suggestion that pioglitazone increased heart failure risk. In this subset analysis, 63 of the 1,215 patients in the placebo group and 92 of the 1,230 patients in the pioglitazone arm were hospitalized for treatment of congestive heart failure. "When we looked at mortality, in the control group exactly one-third of the congestive heart failure patients died, but in the pioglitazone group 22 of the 92 patients died," Dr. Erdmann said. "That was less than one-fourth."

Pioglitazone is known to promote edema by directly stimulating sodium reabsorption in the kidney. Dr. Erdmann said the likely explanation is that patients on the pioglitazone arm were "misdiagnosed with congestive heart failure. They really had edema." There was no excess heart failure mortality in the pioglitazone arm.

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External links

More information about lectures, presentations and other developments at the American Heart Assn. 2005 Scientific Sessions (link)

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