Pharmacy & Therapeutics - May 2008 - (Page 296) MEETING HIGHLIGHTS American College of Cardiology 57th Scientific Sessions, 2008 Reuben B. David The peak-interest clinical trials at the American College of Cardiology (ACC) Scientific Sessions, which took place from March 29 to April 2, 2008, are generally ushered into the high-profile Late-Breaking Clinical Trials sessions. This year, the ENHANCE trial (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) was precluded from the “Late-Breakers” because a peek at the unexpectedly disappointing data had already been afforded in January. Amid pre-meeting publicity about allegedly inappropriate data delays (and a Congressional hearing delving into them), the ACC created a special plenary session “Showcase” presentation of the data with a review panel for comment. The ENHANCE findings intensified interest in both non–lipid-lowering benefits of statins and non-statins for lipid lowering. This 57th ACC conference hosted a record 29,000 attendees in Chicago, Illinois. ENHANCE, a Scientific Showcase Presentation, Sets the Statin Stage ENHANCE: Ezetimibe/Simvastatin (Vytorin) versus Simvastatin (Zocor) Alone • John Kastelein, MD, PhD, Professor of Medicine and Chairman, Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands • Steven Nissen, MD, Chairman, Department of Clinical Cardiology, Cleveland Clinic, Cleveland, Ohio • Michael Davidson, MD, Professor of Medicine, Rush University Medical Center, Chicago, Ill. • Harlan M. Krumholz, MD, Professor of Internal Medicine, Yale University, New Haven, Conn. Dr. Kastelein, ENHANCE lead investigator, reported that among 720 patients with familial hypercholesterolemia who were receiving a combination of ezetimibe 10 mg (Zetia) plus simvastatin 80 mg (Vytorin, Merck/Schering-Plough) or 80 mg of simvastatin (Zocor) alone, low-density lipoprotein-cholesterol (LDL-C) levels declined by an incremental reduction of 16.5% (P < 0.01) with Vytorin versus simvastatin (simvastatin, 318 mg/dL at baseline, 193 mg/dL at 24 months; Vytorin, 319 mg/dL at baseline, 141 mg/dL at 24 months). Other cholesterol changes favored Vytorin to a significant degree as well (Table 1). High-sensitivity C-reactive protein (hs-CRP) levels also fell (by an incremental reduction of 26%) with Vytorin. Despite the drop in LDL-C levels, the primary endpoint— the change in carotid intima media thickness—was essentially the same in both groups (0.0111 mm with simvastatin alone and 0.0058 mm with Vytorin; P = 0.29). Possible explanations, according to Dr. Kastelein, were that the measurement technique had not been accurate enough, that ezetimibe had no favorable vascular effects, and that patients had already received effective pharmacotherapy at enrollment. Dr. Nissen, former ACC President, projected a slide with the The author is a medical writer living in New York, New York. heading “Corporate Misconduct” at a Society for Vascular Biology and Medicine symposium the previous day. Among the bulleted items, he discussed (1) delays in reporting the data (18 months from the study’s end to the first release of the data), (2) changes in methodology after data review and an attempt to change the primary endpoint, and (3) a denial of data access to investigators because of suspected unfavorable findings. At a Merck/Schering-Plough press briefing following the Showcase presentation, Dr. Davidson called the evidence in support of the benefits of LDL-C lowering “overwhelming” and said that the most likely explanation for the lack of a benefit on carotid artery intima thickness was that it was impossible to see an effect because “the population was so well treated even before the study started.” At the same briefing, Dr. Kastelein stated emphatically that all data had remained blinded until December 2007. Problems with reading the 40,000 B-mode ultrasonography images, he explained, had contributed strongly to the delay in presenting the data. In addition, he had recused himself from some discussions associated with these difficulties, he said later in an interview. Dr. Krumholz spoke for the Showcase Panel following the ENHANCE presentation. He said that ENHANCE suggests that the way in which LDL-C levels are lowered might matter. He concluded: “For clinicians who may have employed this Table 1 Changes from Baseline after Therapy With Zocor versus Vytorin Ezetimibe/ Simvastatin simvastatin 80 mg 10/80 mg P Value Total cholesterol, % LDL-cholesterol, % Triglycerides (median), % –31.9 –39.1 –23.2 –45.3 –55.6 –29.8 <0.01 <0.01 <0.01 296 P&T® • May 2008 • Vol. 33 No. 5
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