Central Pressure and Biomarker Responses to Renin Inhibition with Hydrochlorothiazide and Ramipril in Obese Hypertensives: The ATTAIN Study

Abstract

Background/aims: In obese, hypertensive subjects, the renin-angiotensin system (RAS) is enhanced and natriuresis impaired, suggesting a role for combination RAS blockade with diuretics. Data suggest that renin inhibition may attenuate diuretic-induced RAS activation and oxidative stress.

Methods: In this 8-week, double-blind study of 386 obese individuals (mean body mass index: 35.3) with stage 2 hypertension (mean age: 54.9 years; mean sitting systolic blood pressure, SBP: ≧160 but <200 mm Hg), we compared the efficacy of aliskiren + hydrochlorothiazide (HCTZ) in reducing blood pressure (BP), plasma renin activity (PRA), and a urinary marker of oxidative stress to ramipril. Subjects were randomized to aliskiren/HCTZ 150/12.5 mg or ramipril 5 mg for 1 week, and after the 1st week force titrated to aliskiren/HCTZ 300/25 mg or ramipril 10 mg for 7 weeks.

Results: After 8 weeks, aliskiren/HCTZ provided greater reductions in office BP than ramipril (-28.1/-10.1 vs. -16.6/-3.6 mm Hg, p < 0.0001) as well as 24-hour ambulatory and central pressure measures. Aliskiren/HCTZ also lowered PRA (-45 vs. +83%) and the urinary F2-isoprostane/creatinine ratio (-18 vs. +7%) to a greater extent than ramipril. Adverse events (AEs) were similar in the two groups (35.8% with aliskiren/HCTZ vs. 37.3% on ramipril reporting at least one AE).

Conclusions: Our findings suggest that the aliskiren/HCTZ combination reduced BP, PRA, and isoprostanes to a greater extent than did ramipril in obese patients with stage 2 hypertension.

Keywords: Aliskiren; Hydrochlorothiazide; Obesity; Plasma renin activity; Ramipril; Stage 2 hypertension.

Fig. 1

Study design.

Fig. 2

Patient flow diagram. In the aliskiren/HCTZ group, AEs (n = 6) were deep vein thrombosis, fatigue, hypoesthesia, palpitation, blurred vision, and dehydration/pollakiuria (n = 1, respectively). In the ramipril group, AEs (n = 3) were peripheral edema, increased blood creatinine phosphokinase and convulsion (n = 1/0.5%, respectively).

Fig. 3

Least square mean (LSM) changes versus baseline in msSBP (a) and msDBP (b) at the 8-week endpoint. ∗ p < 0.0001, ∗∗ p < 0.05, vs. ramipril. c Summary statistics for msSBP and msDBP throughout the double-blind period (ITT population). n is the number of ITT patients with both baseline and endpoint non-missing values (last-observation-carried-forward approach). Error bars denote SEM (from an analysis of covariance with baseline msSBP as a covariate and treatment at baseline as factors in the model).

Fig. 4

Least square mean (LSM) changes versus baseline (week 0) in ambulatory and central SBP (a) and DBP (b) at the 8-week endpoint compared to clinical BP. ∗ p < 0.001, ∗∗ p < 0.01, ∗∗∗ p < 0.05, vs. baseline.

Fig. 5

Hourly ambulatory 24-hour SBP and DBP at the 8-week endpoint.