Hydrochlorothiazide and atenolol combination antihypertensive therapy: effects of drug initiation order

Abstract

For combination antihypertensive therapy with thiazide diuretics and beta-blockers, the effect of the order of initiation of the drugs on the outcome has not been tested. Patients with uncomplicated hypertension were randomized to receive either hydrochlorothiazide (HCTZ) or atenolol monotherapy, followed by addition of the alternative drug. Blood pressure (BP) responses were evaluated by race and order of drug initiation. A total of 368 participants received combination therapy. Among the participants, blacks showed a greater BP-lowering effect than whites did with HCTZ monotherapy (-13.0/-7.4 mm Hg vs. -8.0/-4.2 mm Hg, P < 0.001) but a smaller BP-lowering effect than did whites with atenolol monotherapy (-1.1/-2.9 mm Hg vs. -9.9/-9.2 mm Hg, P < 0.0001). These differences were not evident during combination therapy. However, both groups showed greater response to HCTZ + atenolol than to atenolol + HCTZ (-19.1/-14.2 mm Hg vs. -15.6/-11.3 mm Hg, P < 0.0001). Despite optimal dosing of HCTZ + atenolol, only two-thirds of the participants achieved BP control. In HCTZ/atenolol combination antihypertensive therapy, the order in which the drugs are initiated affects total BP lowering during the first 4-6 months of therapy.

Figure 1

Progression of participants through the study protocol. ^#Dose of first drug not increased: hydrochlorothiazide (HCTZ) dose was held due to blood pressure (BP) <120/70 mm Hg at visit, but BP was above this cutoff on follow-up, so atenolol was added or atenolol dose was held due to heart rate <55 bpm, another dose-limiting side effect, or BP <120/70 mm Hg, but because BP was above this cutoff on follow-up, HCTZ was added.

Figure 2

Adjusted home-recorded systolic blood pressure (SBP) and diastolic blood pressure (DBP) responses to atenolol, HCTZ, and the combination of the two drugs (adjusted for baseline BP, family history of high blood pressure, strategy arm, and final doses of HCTZ and atenolol). “ATEN arm” indicates those randomized to atenolol monotherapy (with addition of HCTZ); “HCTZ arm” indicates those randomized to HCTZ (with addition of atenolol). ATEN, atenolol; HCTZ, hydrochlorothiazide.

Figure 3

Blood pressure (BP) reduction in relation to treatment and race (adjusted for age, gender, baseline BP, adherence, treatment strategy, and final doses of HCTZ and atenolol). **P < 0.01, ***P < 0.0001 by race. ATEN, atenolol; DBP, diastolic blood pressure; HCTZ, hydrochlorothiazide; SBP, systolic blood pressure.

Figure 4

Plasma renin activity (PRA) in relation to race and treatment strategy. Baseline indicates the baseline values for the two randomized groups. “ATEN arm” indicates those randomized to atenolol monotherapy (with addition of HCTZ), “HCTZ arm” indicates those randomized to HCTZ (with addition of atenolol). **P < 0.01, ***P < 0.0001 for comparison between blacks and whites. ATEN, atenolol; HCTZ, hydrochlorothiazide.