Pharmacy and Therapeutics - January 2008 - (Page 52) Meeting Highlights: American Heart Association, 2007 TRA–PCI: Thrombin Receptor Agonist and Percutaneous Coronary Intervention Moderators: • William B. Hillegass, MD, University of Alabama, Birmingham, Ala. • Christoph Bode, MD, University of Freiburg, Germany Presenter: Lisa K. Jennings, MD, University of Tennessee Health Science Center, Memphis, Tenn. Both Drs. Bode and Hillegass were moderators of a session that included an investigative thrombin receptor antagonist (TRA) known as SCH 530348 (Schering-Plough), presented by Dr. Jennings. What was noteworthy in this early-phase trial among patients undergoing non-urgent PCI was a reduction in ischemic events but no increase in bleeding risk. Dr. Jennings said that the potential advantage might be explained by a TRA– PCI substudy showing that the TRA affected only one of four inducers of IPA: • • • • a thrombin receptor agonist peptide (TRAP) adenosine diphosphate (ADP) collagen arachidonic acid SEACOAST I and II compared low-dose and high-dose combinations of extended-release niacin/simvastatin (1,000/20 mg or 2,000/20 mg in SEACOAST I and 1,000/40 mg or 2,000/40 mg in II) against simvastatin alone (20 mg in SEACOAST I; 80 mg in II). All patients in SEACOAST I had reached NCEP III Coronary Heart Disease risk-adjusted targets. Patients in SEACOAST II were at a higher risk and could have any LDL-C value. The primary endpoint of the double-blind, randomized trials was non–HDL-C values. Co-investigator Dr. Karas reported that after 24 weeks, among 314 patients in SEACOAST I, the combination significantly improved non–HDL-C values by about 25%, LDL-C by about 15%, and triglycerides by approximately 35%; HDL-C increased by nearly 25%. Most flushing episodes were mild or moderate in intensity. Overall discontinuations resulting from flushing were modest (7.5%) for the two combination arms. In SEACOAST II, with a total of 343 patients, among those receiving the higher-dose combination, more attained lipid target levels; 48.8% reached LDL, non-HDL, and triglyceride goals, compared with 18.7% for those receiving simvastatin 80 mg (P < 0.001). Sixty-one percent of patients receiving the combination achieved non–HDL-C goals, compared with 57.5% of those receiving simvastatin 80 mg (P = not significant). In that higher-dose group, 5% discontinued therapy because of flushing. Dr. Karas commented that flushing is not a side effect of niacin; it is an effect. Both Drs. Karas and Ballantyne did emphasize, however, the value of instructing patients to take aspirin a half-hour before their dose, preferably at bedtime. Dr. Ballantyne commented: “With good education and motivated patients, you can use this drug well and get better management of lipid disorders. Without spending the time on instruction, you may not see these numbers in practice. In our clinic, we take the extra time.” Moderator Hillegass commented, “It’s an early-stage, underpowered trial, but it’s very encouraging to think that [SCH 530348] might reduce ischemic events without this inexorable trade-off between bleeding events and ischemic events.” SEACOAST I and II: Niacin and Simvastatin Study authors: • Christie Ballantyne, MD, Baylor College of Medicine, Houston, Texas • Richard Karas, MD, Tufts New England Medical Center, Boston, Mass. In the SEACOAST study (Safety and Efficacy of A Combination Of niAcin ER and Simvastatin in paTients with dyslipidemia), more than half of patients who had not attained their lipid target levels following statin monotherapy achieved these target levels with a combination of niacin (Niaspan, Abbott/ Kos) and simvastatin (Zocor, Merck). In addition, the combination improved multiple clinically relevant lipid parameters among the high cardiovascular risk SEACOAST population, according to Dr. Ballantyne. Target levels, she noted, were high-density lipoprotein-cholesterol (HDL-C) of 40 mg/dL or more, triglycerides below 150 mg/dL, and National Cholesterol Education Program (NCEP) cardiovascular risk factor– adjusted goals for non–HDL-C and LDL-C. Dr. Ballantyne explained that although the number of patients with multiple lipid disorders, obesity, diabetes, and metabolic syndrome has been increasing, aggressive treatment with high-dose statins does not appear to adequately lower cardiovascular risk. He noted also that niacin reduces apo-lipoprotein B–containing particles (non–HDL-C) and is the most potent agent available for improving HDL-C levels. Couma-Gen: Warfarin Studies Presenter: Jeffrey Anderson, MD, Intermountain Healthcare and University of Utah, Salt Lake City, Utah Experts agree that pharmacogenetics (PG) will become a cornerstone of a personalized medicine that abolishes “onesize-fits-all” health care and ushers in an age of treatments tailor-made according to individual genotypes. The Couma-Gen Trial, which was conducted among 200 adults and was presented by Dr. Anderson, compared genotype-guided versus standard dosing with warfarin (Coumadin, Bristol-Myers Squibb) in patients starting oral anticoagulation therapy. Genotype variants, namely cytochrome P450 2C9 (CYP 2C9) and the VKORC1 haplotype (vitamin K epoxide reductase complex 1), plus a person’s age and weight, account for half of the 20-fold interindividual dose variability seen in more than two million patients receiving warfarin yearly. The impact of PG-guided warfarin dosing, however, has not been adequately tested in prospective trials, Dr. Anderson said. The Couma-Gen trial prospectively evaluated a PG-guided warfarin dosing algorithm to assess its impact on Inter national Normalized Ratio (INR)–based efficacy and safety endpoints. It was a prospective, blinded, randomized trial with standard- 52 P&T® • January 2008 • Vol. 33 No. 1
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