As previously described, a total of 12 705 patients were enrolled in HOPE-3 with a 2-by-2 factorial design. Patients were recruited from 228 centers in 21 countries and were followed-up for a median of 5.6 years. The first coprimary outcome was composite of death from CV causes, nonfatal myocardial infarction (MI), or nonfatal stroke with the second coprimary outcome including resuscitated cardiac arrest, heart failure, and revascularization.3

At baseline, the mean BP was 138.1/81.9 mm Hg, and the mean systolic BP (SBP) was 138.2 ± 14.7 mm Hg in the active treatment group and 137.9 ± 14.8 mm Hg in the placebo group. The decrease was 6.0/3.0 mm Hg greater in the treatment group vs the placebo group.3


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Candesartan (16 mg/d) plus hydrochlorothiazide (12.5 mg/d) was not associated with lower rates of major CV events compared with placebo. However, HOPE-3 researchers did observe significantly lower rates of the first and second coprimary outcomes in the upper third SBP group (patients with SBPs >143.5 mm Hg). In the middle and lower thirds, the effects were neutral such that there was a clear trend to benefit across baseline BP tertiles (P=.02 and P=.009 respectively for trend in the 2 outcomes).3

“The take-home message is, regardless of your risk, we should be treating BP above 140,” Dr Bakris said.

Blood Pressure vs Cholesterol

In an accompanying editorial published in the New England Journal of Medicine, William C. Cushman, MD and David C. Goff, Jr, MD, PhD pointed out that while the lipid-lowering therapy arm of the HOPE-3 trial resulted in a 24% CV event risk reduction, the antihypertensive therapy did not show benefits in the overall study population.4

“The observed difference between the active treatment group and the placebo group in the decrease in BP over the course of the trial (6.0/3.0 mm Hg) was small, and the 95% confidence interval for the estimated hazard ratio did not exclude the benefit one might expect (on the basis of the results from the meta-analysis) from this degree of BP lowering,” they wrote.4

In fact, Drs Cushman and Goff noted that neither BP lowering agent used in the HOPE-3 trial has demonstrated the ability to reduce CV event risk at such low doses. They argued the investigators should have considered using chlorthalidone instead of hydrochlorothiazide, or at least a higher dose of the latter.4

However, as Dr Bakris, pointed out, “The problem with that statement is that it only makes sense if you’re dealing with people with a higher risk of CVD, but the HOPE-3 investigators were not.”

“If you have a normotensive patient, it’s illogical to use a diuretic because the patient could then become hypotensive and you also run the risk of acute kidney injury,” Dr Bakris cautioned. “The patients in the SPRINT trial were already hypertensive [a SBP of 130 to 180 mm Hg with an increased risk of CV events] and being treated when they were enrolled, which is very different from HOPE-3.”  

In SPRINT, increased CV risk was defined by 1 or more of the following: “clinical or subclinical CVD other than stroke; chronic kidney disease, excluding polycystic kidney disease, with an estimated glomerular filtration rate of 20 to less than 60 ml per minute per 1.73m2 of body-surface area, calculated with the use of the 4-variable Modification of Diet in Renal Disease equation; a 10-year risk of CVD of 15% or greater on the basis of the Framingham risk score; or an age of 75 years or older.”1

“There is no proven benefit of use of any antihypertensive drugs in low risk patients with a BP <140,” Dr Bakris added.