Pharmacy & Therapeutics- August 2008 - (Page 479) MEETING HIGHLIGHTS: American Society of Hypertension (140–159 mm Hg systolic BP and 90–99 mm Hg diastolic BP), Dr. Chrysant said that 81% of those receiving stepped titration of the receptor ARB-based regimen achieved BP below 140/90 mm Hg—the Joint National Commission’s (JNC 7) BP goal— and 60% achieved the stricter target of below 130/80 mm Hg. In the placebo arm, only 43% and 7%, respectively, achieved these goals. Dr. Kereiakes reported on 148 patients with stage 2 hypertension (systolic: 160 mm Hg and above; diastolic, 100 mm Hg and above). Mean differences from placebo were – 22.5 mm Hg systolic BP and –13.2 mm Hg diastolic BP. Overall, for patients receiving olmesartan-based therapy, treatment-related adverse events were not significantly increased. Commenting on all of these findings, Dr. Bakris said that olmesartan alone “is a very good starting choice for patients with stage I hypertension without diabetes.” He recommended initial monotherapy with a diuretic or calcium antagonist for stage I elderly or African-American patients. For those with stage 2 hypertension, he said, “I start with combination therapy on top of lifestyle modification.” when compared with placebo (P < 0.001). Seated office BP changes from baseline (systolic and diastolic, respectively), were similarly significant: placebo, –4.2 mm Hg and +1.6 mm Hg; DARA 200 mg, –16.9 mm Hg and –10.5 mm Hg; and DARA 500 mg, –17.3 mm Hg and –9.8 mm Hg. The pattern persisted, although it was attenuated, for mean nighttime ambulatory BP monitoring: placebo, –2.7 mm Hg (systolic) and –1.6 mm Hg (diastolic); DARA 200 mg, –10.7 mm Hg and –6.8 mm Hg; and DARA 500 mg, –14.3 mm Hg and –9.1 mm Hg (P = not significant). “These numbers are extremely impressive,” Dr. Neutel said, noting that the DARA reductions far surpassed what is expected for monotherapy treatment. Systolic BP reductions, from a baseline of –14.4 mm Hg during the final two hours of the dosing period for the 500-mg dose, Dr. Neutel said, “clearly demonstrate that this is a once-daily drug.” Adverse events were experienced by 27% of patients receiving the 500-mg dose and by 26.5% of patients receiving placebo. “They were no different from placebo despite the tremendous reductions in blood pressure,” he commented. Peripheral edema, considered a concern with endothelins, was reported in only one patient receiving the higher DARA dose. The other concern about endothelins has been liver abnormalities, and none were reported. The lack of adverse events usually associated with endothelin antagonists, Dr. Neutel speculated, is a result of the specificity of this agent for the endothelin A receptor. Dr. Neutel concluded, “What you see here is a new class of drug that effectively lowers systolic and diastolic BP in stage I and II hypertensive patients. The magnitude of the treatment effect appears greater than that of existing monotherapies.” I A Dual Receptor Antagonist (PS433540, DARA) • Joel M. Neutel, MD, Associate Professor of Medicine, University of California, Irvine An investigational antihypertensive agent that antagonizes two receptors appears to offer stronger BP reductions than existing monotherapies, according to results of a clinical trial presented by Dr. Neutel. The agent, PS433540 (Pharmacopeia, Inc.), is a dual angiotensin and endothelin receptor antagonist (DARA). Its half-life is about 15 hours, which makes it likely, he said, to be a once-daily agent. Both angiotensin II and endothelin are powerful vasoconstrictors thought to contribute to elevated BP. Dr. Neutel noted that DARA therapy has been safe and well tolerated in early trials and, at 250 mg, has provided ARBreceptor blockade similar to that of irbesartan (Avapro, Bristol-Myers Squibb/Sanofi-Synthelabo) at 300 mg. At 500 mg, blockade of both types of receptors is believed to be complete. Inclusion criteria for this first trial among hypertensive subjects were a mean (sitting) systolic BP of between 150 and 179 mm Hg and a diastolic BP below 110 mm Hg. For those participants qualifying, 24-hour ambulatory BP monitoring had to show a mean daytime systolic BP of 140 to 179 mm Hg and a diastolic BP of less than 110 mm Hg. Patients who met these criteria were then randomly assigned to receive DARA 200 mg or 500 mg daily or placebo. Ambulatory BP monitoring was conducted after four weeks of treatment. The primary endpoint was the change in mean systolic BP. Among 114 patients randomly assigned, 93 were evaluable. Their mean age was 59 years, and approximately 80% were Caucasian. Mean systolic BP was 160 mm Hg, and mean diastolic BP was 94 mm Hg. Changes from baseline for systolic and diastolic BP, respectively, were as follows: placebo, –0.40 mm Hg and +0.3 mm Hg (n = 25); DARA 200 mg, –12.20 mm Hg and –9.3 mm Hg (n = 35); and DARA 500 mg, –14.80 mm Hg and –10.1 mm Hg (n = 33). All DARA changes were significant COMING SOON TO P&T EDITORIAL: Eight Tech Trends David B. Nash, MD, MBA HEALTH CARE AND LAW: Vaccine Declinations Present New Challenges For Public Health Robert I. Field, JD, MPH, PhD DRUG FORECAST: Ixabepilone (Ixempra): A New Therapeutic Option For Locally Advanced or Metastatic Breast Cancer Nancy Egerton, PharmD, BCOP FEATURE ARTICLES: Medical Management of Parkinson’s Disease Marvin M. Goldenberg, PhD, RPh, MS Effect of Prescription Copay on Treatment Failure With Oral Antidiabetic Medications John Barron, PharmD, Peter Wahl, MLA, MS, Maxine Fisher, PhD, and Craig Plauschinat, MPH Vol. 33 No. 8 • August 2008 • P&T® 479
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