ENHANCE trial published today

To coordinate with a special session at today’s American College of Cardiology meeting in Chicago, the official results of the ENHANCE trial were simultaneously published at 1 pm in a special edition of the New England Journal of Medicine. There were no surprises.

The authors, led by John J.P. Kastelein, M.D., Ph.D., at the Department of Vascular Medicine, Academic Medical Center, in Amsterdam, the Netherlands, concluded that the combined therapy of ezetimibe and simvastatin (Vytorin) did not result in a significant difference in changes in intima–media thickness (ultrasound measurement of the thickness of the walls of the carotid arteries, believed to reflect the amount of coronary artery disease), as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein:

Nor were there any clinically meaningful treatment-related changes in the patients’ vital signs or heart function, and adverse events between the groups were similar (34.2% and 29.5%, respectively). Reducing LDL-cholesterols is one of the cornerstones in current preventive treatments in cardiovascular disease, the authors noted. So, the reasons for the failure to observe clinical improvement after two years of this treatment, despite reductions in LDL-cholesterol, remains unknown. Treating surrogate measures, health indices, as we're continually learning, is not the same thing as addressing actual clinical health and outcomes.

The New England Journal of Medicine also published two editorials on this study, both discouraging use of Vytorin by physicians, as well as a paper led by pharmacist, Cynthia A. Jackevicius, Pharm.D., M.Sc. from the University Health Network. Dr. Jackevicius and colleagues compared the prescribing practices in the United States and Canada from 2002 through 2006 and found that by 2006, prescriptions for Vytorin drugs had grown to four times higher in the U.S. than in Canada, where direct consumer advertising is banned. “In 2007, more than $200 million was spent on direct-to-consumer advertising [by Merck and Schering Plough] for Vytorin alone, which probably had an effect on U.S. sales,” they wrote. Those sales have “eclipsed $5 billion.” While the meds increased overall healthcare costs, they wrote, the effect on clinical outcomes is uncertain.

Since JFS has covered the ENHANCE trial extensively, there’s no need to rehash it, but the discussions among cardiologists might be of interest. Dr. Richard Fogoros, M.D., former instructor of clinical cardiology at the University of Pittsburgh, said that patients currently taking Vytorin or Zetia shouldn't just stop their prescription medications without consulting their doctors, but “ought to discuss with their doctors whether the drugs were begun appropriately, in light of what now has been officially reported.”

Matthew Herper at Forbes has just written a comprehensive article based on more than a dozen cardiologists who reviewed the completed study for them. Among the doctors’ comments were:

Harlan Krumholtz, of Yale University, a member of an expert panel that discussed the drugs at the ACC meeting: "The burden of proof is on the companies to prove Zetia and Vytorin are safe and effective. They have not done that yet."

"The willingness of U.S. physicians to so rapidly adopt an unproven therapy is worrisome," says Paul Ridker, a cardiologist at the Brigham and Woman's Hospital in Boston. "The questions patients with high cholesterol should ask their physicians is simple: Will the drug you are giving me lower my risk of heart attack or stroke? If not, why are you prescribing it?"

The [arterial thicknesses] difference is so small as to be unimportant, says John Kastelein, the University of the Netherlands doctor who led the trial. "This is a zero trial," he says.

William Boden of the University of Buffalo says the idea that the arteries were thin does not explain away worries about Zetia's effectiveness against heart attack-causing atherosclerosis. "There's not a hint of things moving in the right direction," says Boden.

The full discussions in the Forbes article, “Vytorin Backlash,” are found here.