Does Low-Dose Diuretic Therapy Reduce Hypertension Risk?

Fixed combination low-dose chlorthalidone/amiloride has been linked to a reduction in both hypertension and left ventricular (LV) mass in patients with prehypertension, according to research published in the Journal of the American Heart Association.

Sandra Costa Fuchs, MD, PhD, from the Clinical Research Center at the Hospital de Clinicas de Porto Alegre and the Universidad Federal do Rio Grande do Sul in Brazil, and fellow researchers conducted a randomized, parallel, double-blind, placebo-controlled trial across 21 academic medical centers in Brazil to evaluate the safety and efficacy of low-dose diuretic therapy to prevent hypertension.

The PREVER-Prevention (Prevention of Hypertension in Patients with Prehypertension) trial (ClinicalTrials.gov identifier: NCT00970931) assessed data from eligible participants between 30 and 70 years of age who were not currently taking antihypertensive medication. Participants received either a combination pill (chlorthalidone 12.5 mg plus amiloride 2.5 mg [chlorthalidone/amiloride]) or a placebo.

Primary study outcome was incidence of hypertension among participants, with a hypertension diagnosis if 4 blood pressure measurements taken were ≥140 mm Hg or ≥90 mm Hg for systolic and diastolic blood pressures, respectively. Secondary outcomes included self-reported adverse events, development of or worsening microalbuminuria, change in LV mass, and fatal or nonfatal major cardiovascular disease events.

More than 1400 participants were initially enrolled in the 3-month “lifestyle intervention” phase of the study; 730 of those participants met PREVER-Prevention trial inclusion criteria. Trial participants were randomly assigned to either the chlorthalidone/amiloride group (n=372) or the placebo group (n=358), with similar baseline characteristics among both groups (50% women; mean age, 50.0±10.4 years; 55% white; mean systolic blood pressure, 127.9±7.3 mm Hg; mean diastolic blood pressure, 80.5±6.3 mm Hg). At 18 months, 312 participants from the chlorthalidone/amiloride group and 290 participants from the placebo group were evaluated. During the follow-up period, 60 and 68 participants in each group, respectively, discontinued their study participation.

Dr Fuchs and colleagues found that hypertension incidence was “significantly lower” among the chlorthalidone/amiloride group (hazard ratio [HR], 0.56; 95% CI, 0.38-0.82, P =.003); the cumulative hypertension incidence was also lower among this group (11.7% vs 19.5% in the placebo group; P =.004).

Systolic and diastolic blood pressures were significantly lower in the chlorthalidone/amiloride group throughout the course of follow-up, with “highly significant” differences in both blood pressure measures (P =.001 and .04, respectively). Pulse pressure was also greatly reduced in the chlorthalidone/amiloride group vs placebo (mean, 45.3 [95% CI, 44.6-46.1] vs mean, 46.3 [95% CI, 45.6-47.1]; P =.06).

Regarding secondary outcomes, participants in the chlorthalidone/amiloride group experienced a significant treatment-related decrease in LV mass, with the most statistically significant difference noted at 18 months (P =.02). At the trial’s conclusion, mean level of microalbuminuria was not significantly different between the 2 treatment groups (chlorthalidone/amiloride, 11.1±17.5 μg/24 h; vs placebo, 10.6±16.1 μg/24 h). In the chlorthalidone/amiloride group, 5.5% of patients developed diabetes compared with 3.3% in the placebo group (P =.18), and the incidence of new albuminuria was similar among both groups (7.7% vs 9.8%; P =.35, respectively).

“Our study documents the value of low-dose antihypertensive drug therapy for the prevention of hypertension,” the researchers wrote. “It also demonstrates a similar treatment-related hypertension-prevention benefit throughout the entire range of prehypertension [blood pressure] levels.”

They concluded, “In our study…we demonstrated that merely using a half dose of the first drug used in SPRINT [Systolic Blood Pressure Intervention Trial; ClinicalTrials.gov identifier: NCT01206062] (chlorthalidone) prevented the expected increase in [blood pressure] to hypertensive levels in a high proportion of patients studied.” 

Study Limitations

• Researchers were unable to enroll as many participants as planned because of resource limitations; however, the trial was “sufficiently large to allow for a satisfactory and highly significant test” of the presented hypothesis.
• Several secondary outcomes may have led to a chance difference in LV mass, as multiple hypotheses were tested.
• The study was unable to assess the effect of treatment on nighttime blood pressure and “white coat” or masked hypertension because of the absence of out-of-office blood pressure measurements. 

Reference

Fuchs SC, Poli-de-Figueiredo CE, Figueiredo JA, et al. Effectiveness of chlorthalidone plus amiloride for the prevention of hypertension: the PREVER-Prevention randomized clinical trial. J Am Heart Assoc. 2016;5(12):e004248. doi:10.1161/JAHA.116.004248