Pilot study to evaluate a water displacement technique to compare effects of diuretics and ACE inhibitors to alleviate lower extremity edema due to dihydropyridine calcium antagonists

Abstract

Combination therapy is required in many patients to achieve goal blood pressure (BP). Calcium antagonists are highly effective antihypertensive drugs in a broad range of demographic groups. Yet, higher doses are associated with an increased frequency of lower extremity edema. The purpose of our open label, single-center clinical trial was to evaluate the use of concomitant pharmacologic therapies to attenuate the lower extremity edema associated with dihydropyridine calcium antagonists therapy using a water displacement technique. Forty-seven patients received 5 mg/day of oral amlodipine for a period of 6 weeks after a 4-week wash-out off of all antihypertensive medications to establish baseline BP. They were then randomized to receive either an additional 5 mg of amlodipine, 25 mg of hydrochlorothiazide (HCTZ), or 20 mg of benazepril for an additional 6 weeks. Blood pressure determinations and water displacement measurements were obtained at the end of the 4-week placebo wash-out period, after 6 weeks of 5 mg/day of oral amlodipine therapy, and after an additional 6 weeks of 5 mg of amlodipine and randomized drug therapy. Adjusted BP reductions (based on pretreatment BP) were -6.8/-3.8 mm Hg for the 10-mg amlodipine group, -9.9/-8.2 mm Hg for the amlodipine (5 mg)/HCTZ (25 mg) group, and -26.2/-16.4 mm Hg for the amlodipine (5 mg)/benazepril (20 mg) group (P < .0167, group 3 v group 1 diastolic BP, which was statistically significant by the improved Bonferroni method). Seventeen of the 47 patients developed at least a 10% increase in lower extremity edema water displacement in response to 5 mg/day of oral amlodipine therapy (36.2%). Adding 5 mg of amlodipine to a baseline of 5 mg of amlodipine resulted in no net change in lower extremity edema (+58.0 mL,+ 0.6% change, n=5). Adding 25 mg of HCTZ reduced lower extremity edema by a mean of 136.3 mL (-11.1% change, n=4). Benazepril reduced water displacement by 204.4 mL (-14.3% change, n=8). Our pilot study indicates that adding an angiotensin converting enzyme inhibitor to a dihydropyridine calcium channel blocker is the most effective way to not only reduce systolic and diastolic BP but also attenuate lower extremity edema. Due to the inherent daily variability of lower extremity edema, power calculations indicate many patients (n=702, 356 in each group) would be needed to compare the antiedema efficacy of the angiotensin converting enzyme inhibitor and the thiazide diuretic.