The HCTZ dosage used in the ACCOMPLISH trial (12.5–25 mg/day) was lower than were dosages used in placebo-controlled studies that established the antihypertensive benefits of HCTZ, Dr. Cushman noted. Also, if the combined end points of death from cardiovascular causes, nonfatal MI or stroke, resuscitation after sudden cardiac arrest, hospitalization for angina, and coronary revascularization were reconfigured to exclude the angina and revascularization outcomes, there would have been no significant difference between groups in the primary combined outcome, he said.
One could interpret the ACCOMPLISH results to suggest that HCTZ doses of 25 mg/day or less are not as effective in preventing cardiovascular events as are full doses of amlodipine monotherapy or doses of diuretics used in previous trials, suggested Dr. Cushman, who has been a consultant, adviser, or lecturer for Novartis.
Dr. Louis Kuritzky suggested that results might have been different had ACCOMPLISH used the more potent diuretic chlorthalidone instead of HCTZ. In addition, it's unclear whether the results of the trial are generalizable, because the ACCOMPLISH cohort was older and more likely to have diabetes, dyslipidemia, and left ventricular hypertrophy than was the hypertensive population as a whole, said Dr. Kuritzky of the University of Florida, Gainesville.
He has been a consultant or speaker for Novartis and other drug companies but has no association with the company that markets chlorthalidone.
The ACCOMPLISH investigators chose HCTZ because it's the dominant diuretic used for hypertension. Choosing a different diuretic to combine with an ACE inhibitor would not provide the mechanistic synergy of a combined ACE inhibitor and calcium channel blocker that provides an antiatherosclerotic effect, Dr. Jamerson and his associates noted.
“It really does matter what agent you use,” he said.
The findings have “huge implications” for millions taking BP medication, Dr. Kenneth Jamerson said. Courtesy UM Photo Services, Martin Vloet
Ambulatory Monitoring Supports ACCOMPLISH Results
The initial analysis of ACCOMPLISH results reported mean systolic blood pressures of 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-HCTZ group using measurements taken predominantly in clinics.
The new analysis by Dr. Jamerson and associates studied 24-hour ambulatory blood pressure monitoring results in a subgroup of 573 patients, to provide a more accurate look at treatment effects on blood pressure.
After 2 years, the treatment groups did not differ significantly in 24-hour mean, daytime, or nighttime blood pressure levels. More than 80% in both groups achieved 24-hour blood pressure control (a mean systolic pressure less than 135 mm Hg over 24 hours). Rates of escape from control, morning surge in blood pressure, or dipping status did not differ significantly between groups, he reported.
Comparing the 288 patients on benazepril-amlodipine and 185 on benazepril-HCTZ, mean systolic pressures in clinic were 129.7 vs. 130.3 mm Hg and mean 24-hour measurements were 123.9 vs. 122.3 mm Hg, respectively. Mean daytime systolic pressures were 125.9 mm Hg vs. 124.1 mm Hg, and nighttime pressures were 118.1 vs. 116.9 mm Hg, respectively.
The proportion with a.m. dipping of systolic pressure comprised 29% of the benazepril-amlodipine group and 32% of the benazepril-HCTZ group, and 24-hour blood pressure control was achieved in 81% and 85%, respectively. Ten percent and 12% of the respective groups had any hourly mean systolic pressure above 160 mm Hg. Nighttime hypertension was seen in 19% on benazepril-amlodipine and 17% on benazepril-HCTZ. An a.m. surge (defined as greater than a 55- mm Hg rise between 6 and 10 a.m. compared with the lowest nighttime hourly mean) occurred in 3% and 4%, respectively.
The benazepril-amlodipine dosing was 20/5 mg once daily for 1 month, then 40/5 mg, followed by 40/10 mg if needed to achieve blood pressure goals. The benazepril-HCTZ group started with 20/12.5 mg once daily for 1 month, then 40/12.5 mg, followed by 40/25 mg if needed.