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
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.