Pharmacy & Therapeutics - May 2008 - (Page 297) Meeting Highlights: American College of Cardiology medication (i.e., ezetimibe) before exhausting the options with statins, the strongest recommendation we can make on this panel is, ‘Turn back to statins, especially those with favorable outcomes data.’ ” Outcomes data from another trial—IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVEIT)—comparing Vytorin with simvastatin alone among 18,000 patients recovering from acute coronary syndromes are expected in 2012. In a newsroom interview, Dr. Nissen recommended that in the future, when approval of a drug is based on surrogate endpoint trials (as was the case with ezetimibe), such approval should be contingent upon the immediate launch of an outcomes trial. DUAAL: Amlodipine and Atorvastatin (Caduet) or more of the patients (5.8% with amlodipine; 0.0% with atorvastatin; and 10.6% with the combination). The complementary mechanisms of atorvastatin and amlodipine may be advantageous in the management of patients with CAD and TMI, Dr. Deanfield concluded. He pointed out that within 18 weeks, statin use virtually eliminated any evidence of ischemia during patients’ normal daily activities. “What we found, very unexpectedly, was that the statin was as effective an antianginal and anti-ischemic drug as the traditional medications we use for treating angina and ischemia.” Niacin and Laropiprant (Cordaptive) • Michael J. Koren, MD, Jacksonville Center for Clinical Research, Jacksonville, Fla. Interest in lipid-lowering agents other than those from the statin class was piqued by the ENHANCE findings suggesting that the way in which LDL-C is lowered might be important. Side effects from those agents, however, have been a major impediment to their uptake and a major factor behind the widespread prescribing of ezetimibe as an alternative to highdose statins. With niacin, its favorable effects on LDL-C and HDL-C levels are confounded by the flushing that occurs in 90% of patients, Dr. Koren said. Laropiprant, a potent, highly selective prostaglandin D2 subtype 1 (DP1)-receptor antagonist that has been shown to significantly reduce niacin-induced flushing, is added to extended-release (ER) niacin in Merck’s Cordaptive. Dr. Koren presented data from a multinational, double-blind, randomized, parallel-group study of 1,455 dyslipidemic patients who were treated for 16 weeks with ER niacin (Niaspan, Abbott). The study involved multistep titration to 2 g with aspirin plus nonsteroidal anti-inflammatory drugs (NSAIDs) to mitigate flushing or a forced titration of a 1-g fixed dose of ER niacin/ 20 mg laropiprant for four weeks, advanced to 2 g ER niacin/ 40 mg laropiprant for 12 weeks. The primary endpoint was the number of days per week during which patients experienced moderate-to-severe or extreme flushing (according to the Global Flushing Severity Scale) during the treatment period. Of those patients in the ER niacin/laropiprant group, 47% had no moderate-to-extreme flushing episodes, compared with 22% in the ER niacin group (P < 0.001). Twenty-eight percent of patients had between zero and 0.5 or more episodes per week with ER niacin/laropiprant, compared with 34% who received ER niacin (Niaspan). Safety profiles were similar for both groups. Discontinuation rates for flushing were 7.4% with ER niacin/laropiprant and 12.4% for ER niacin, Dr. Koren reported. In an interview, he stated: “The take-home message is that the number of severe flushes in the Cordaptive group was about one per month, as compared with one per week with ER niacin.” The trial’s regimen should allow more patients to reach and maintain a 2-g dose of niacin, he added. On April 28, 2008, the FDA issued a “not approvable” letter to Merck regarding its Cordaptive application. Merck has announced that it is providing additional information to the FDA. • John Deanfield, MD, Professor of Cardiology, University College, London, United Kingdom Interest in results from the DoUble-blind Atorvastatin AmLodipine (DUAAL) study was also heightened by ENHANCE’s suggestion of pleiotropic statin effects. DUAAL findings point to statin benefits in endothelial function that translate into reductions in transient myocardial ischemia (TMI), according to Dr. Deanfield. In CAD patients with stable angina, TMI is associated with increased morbidity and mortality and may reflect disturbed arterial biology. The calcium antagonist amlodipine besylate (Norvasc, Pfizer) can have potent antianginal effects, and statins have a favorable effect on vascular function. Dr. Deanfield also said that the combination of amlodipine and atorvastatin (Caduet, Pfizer) demonstrated synergistically favorable effects on the endothelium and, in an antihypertensive regimen, reduced the number of cardiovascular events. The objective of DUAAL was to evaluate the anti-ischemic and antianginal effects of atorvastatin 10 → 80 mg (Lipitor, Pfizer) and amlodipine 5 → 10 mg, separately and in combination. The randomized, double-blind, parallel-group multinational trial included a two-week run-in phase and 24 weeks of active therapy with a dose titration at the sixth week. DUAAL included 311 patients with stable angina, a history of coronary artery disease, and three TMI episodes and/or 15 minutes of ischemia during 48-hour Holter monitoring. Investigators assessed changes in TMI by Holter monitoring, exercise ischemia, and inflammatory biomarkers at 26 weeks. Holter-recorded median TMI episodes decreased in a similar fashion from baseline values in all three groups at week 26 as follows: –5.0 at baseline, –0.5 with amlodipine, 0.0 with atorvastatin, and –1.0 with the combination (P < 0.001). Patient diaries showed significant decreases in angina episodes (from five attacks per week to about one attack per week) and nitroglycerin use (from about three attacks per week to 0.75 attacks per week), as well, in all groups. Levels of hs-CRP increased in the amlodipine patients and fell significantly in the atorvastatin group when compared with baseline values and when compared with amlodipine. Peripheral edema was the only adverse drug event, occurring in 2% Vol. 33 No. 5 • May 2008 • P&T® 297
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