Meta-analyses have shown that lowering blood pressure significantly decreases the risk of major cardiovascular events.1,2 This reduction in risk occurs across all age groups and is observed for every major individual event (heart attack, stroke, heart failure, and coronary heart disease).
In one large meta-analysis of blood pressure treatment regimens, for every 5 mm Hg reduction in systolic blood pressure, there was a 9.1% reduction in risk of major cardiovascular events amongst individuals above 65 years old with hypertension and an 11.9% reduction amongst individuals below 65 years old with hypertension.2
There have been several randomized controlled trials using chlorthalidone that evaluated the effect of treatment on outcomes such as heart disease, stroke, cardiovascular mortality, and all-cause mortality.3-5 The Multiple Risk Factors Intervention Trials (MRFIT) trial was one trial that included chlorthalidone.3 This trial enrolled 12,866 high-risk men aged 35-57, 62% (n=8,012) of whom were hypertensive at baseline. The subjects were randomly assigned to either a special intervention (SI) or usual care (UC). The SI group underwent lifestyle counseling, and stepped-care treatment for hypertension. The SI initially included a choice of hydrochlorothiazide 100 mg or chlorthalidone 50 mg daily as the first antihypertensive treatment. However, after five years, the investigators observed a mortality benefit amongst those prescribed chlorthalidone compared with those given hydrochlorothiazide, so the protocol was altered to include only chlorthalidone. After 10.5 years of follow up, mortality rates amongst hypertensive men were lower in the SI group than in the UC group by 15% (p=0.19) for coronary heart disease and by 11% (p=0.13) for all causes. The outcomes for SI compared with UC during the 3.8 post trial years (March 1982 through December 1985) were more significant than during the preceding six to eight years (through February 1982). Amongst those with diastolic blood pressure ≥100 mm Hg, with 10.5 years of follow-up, death rates were lower for SI than for UC by 36% (p = 0.07) for coronary heart disease and 50% (p=0.0001) for all causes.
The Systolic Hypertension in the Elderly Program (SHEP) trial was a randomized controlled trial in patients over 60 years of age with systolic hypertension.4 Patients were randomly assigned to either treatment with stepped antihypertensive care beginning with chlorthalidone (starting at a dose of 12.5 mg/day, with atenolol added on as a second step), or placebo. The primary outcome was fatal and non-fatal stroke. The five-year cumulative total stroke rate was 5.2 per 100 participants for active treatment and 8.2 per 100 participants for placebo. The relative risk by proportional hazards regression analysis was 0.64 (P=.0003). The incidence of total stroke was reduced by 36% in the treatment arm, with a five-year absolute benefit of 30 events per 1000 participants. Major cardiovascular events were also reduced in the treatment group, with a five-year absolute benefit of 55 events per 1000 participants.
In the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) trial, the primary outcome (fatal coronary heart disease or nonfatal myocardial infarction) did not differ significantly between the three trial arms (chlorthalidone, amlodipine, and lisinopril) with a six-year rate of approximately 11.5% per 100 persons.5 Compared with chlorthalidone (six-year rate, 11.5%), the relative risk for amlodipine was 0.98 (95% CI, 0.90-1.07; six-year rate, 11.3%) and 0.99 (95% CI, 0.91-1.08; six-year rate, 11.4%) for lisinopril. Similarly, all cause mortality did not differ between groups with a six-year rate of approximately 17%. The chlorthalidone group had a significantly lower six-year rate of heart failure than the amlodipine group (10.2% vs. 7.7%; RR, 1.38; 95% CI, 1.25-1.52). Compared to lisinopril, chlorthalidone also had a significantly lower rate of combined cardiovascular disease outcomes (33.3% vs. 30.9%; RR, 1.10; 95% CI, 1.05-1.16), stroke (6.3% vs. 5.6%; RR, 1.15; 95% CI, 1.02-1.30); and heart failure (8.7% vs. 7.7%; RR, 1.19; 95% CI, 1.07-1.31).
Finally, chlorthalidone was the recommended diuretic used in the Systolic Blood Pressure Intervention Trial (SPRINT).6 In this study, subjects randomized to the intensive blood pressure arm (SBP <120 mmHg) had a significantly lower rate of the primary composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes than the standard treatment arm (SBP <140 mm Hg) (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% CI, 0.64 to 0.89; p<0.001). All-cause mortality was also significantly lower in the intensive treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; p=0.003).
- Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665.
- Blood Pressure Lowering Treatment Trialists C, Turnbull F, Neal B, et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ. May 17 2008;336(7653):1121-1123.
- Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor Intervention Trial. Circulation. Nov 1990;82(5):1616-1628.
- Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA. Jun 1991;265(24):3255-3264.
- Officers A, Coordinators for the ACRGTA, Lipid-Lowering Treatment to Prevent Heart Attack T. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. Dec 18 2002;288(23):2981-2997.
- Group SR, Wright JT, Jr., Williamson JD, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. Nov 26 2015;373(22):2103-2116.