By Michael Crawford, MD, Editor

SYNOPSIS: A large randomized trial of fixed-dose antihypertensive treatment in patients at intermediate risk of cardiovascular events with systolic blood pressure < 160 mmHg showed no difference in outcomes vs. placebo.

SOURCE: Lonn EM, Bosch J, López-Jaramillo P, et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2009-2020.

The role of antihypertensive therapy in intermediate-risk patients, defined as 1%/year risk of major cardiovascular (CV) events, with systolic blood pressure (SBP) < 160 mmHg, is unclear. Thus, the Heart Outcome Prevention Evaluation (HOPE)-3 trial was conceived. In 228 centers in 21 countries, men 55 years of age with at least one CV risk factor or women 60 years of age with two risk factors were randomized to candesartan 16 mg plus hydrochlorothiazide 12.5 mg a day or placebo. Excluded were patients with known CV disease, symptomatic hypotension, or moderate to advanced renal dysfunction. There also was a rosuvastatin 10 mg vs. placebo arm to the trial that was reported in this same journal issue. The primary efficacy outcomes were CV death, myocardial infarction, or stroke, and the composite of these events plus resuscitated cardiac arrest, heart failure, or revascularization. There were several secondary outcomes and safety outcomes. More than 6,000 patients were randomized to each arm, and the median follow-up was 5.6 years. In the whole population, mean BP was 138/82 mmHg. It decreased in both groups, but to a larger degree in the active treatment group (mean difference -6/3 mmHg). There was no significant difference in either the first or the second primary outcomes (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.79-1.10; P = 0.4, and HR, 0.95; CI, 0.81-1.11; P = 0.5). However, in the prespecified subgroup with SBP > 144 mmHg (upper one-third of population), mean 154, who were in the active treatment group, there were significantly fewer primary events (first primary endpoint HR, 0.73; CI, 0.56-0.94, and second HR, 0.76; CI, 0.60-0.96). In the subgroups of the population with baseline SBP < 143 mmHg, there was no significant difference in outcomes between active treatment and placebo. Symptomatic hypotension, dizziness, or lightheadedness was more common in the active treatment group (3.4% vs. 2.0%; P < 0.001), but syncope, renal dysfunction, or abnormal potassium levels were not. The authors concluded that fixed-dose dual antihypertensive therapy in subjects at intermediate risk for CV disease did not lower the rate of major CV events, despite lowering mean SBP 6 mmHg to an average of 128 mmHg.

COMMENTARY

The subjects enrolled in this trial were at increased risk for CV events (about 10% over 10 years) and worthy of treatment consideration. In fact, the rosuvastatin arm of the study showed a significant reduction in CV events. This study population differed from SPRINT in several ways, but most importantly only 3% had evidence of mild renal dysfunction as compared to 60% in SPRINT. Clearly, these were lower-risk patients. This conclusion is supported by the primary outcome incidence in the two studies — 2.2% for SPRINT and 0.8% for HOPE. Also, SPRINT used more extensive and complicated treatment regimens and observed more adverse events. Neither study included many diabetics (excluded in SPRINT, and 6% in HOPE). In addition, the baseline mean SBP in SPRINT was higher (155 vs. 138 mmHg) and the mean reduction in SBP was more in SPRINT (11 mmHg vs. 6 mmHg). So one could argue that less aggressive therapy in HOPE eliminated the potential benefit of treatment. However, other studies of hypertension treatment have shown that even a 5 mmHg average reduction with therapy can produce significant benefits. Perhaps the baseline SBP is the issue. In the subgroup analysis of HOPE, the upper one-third of SBP patients (> 143 mmHg, mean 154 mmHg) showed a significant decrease in the coprimary outcomes. This mean SBP is similar to that in SPRINT (154 vs. 155 mmHg). Since the lower two-thirds of baseline SBP subjects in HOPE (SBP
< 143 mmHg) did not exhibit a benefit from SBP-lowering therapy, the HOPE results contradict the lower is better hypothesis and support the J curve concept. The HOPE results support treatment for SBP > 140 mmHg, but not lower values in patients with low to moderate CV risk. Thus, it may be that treatment targets depend on CV risk and baseline blood pressure, and that universal SBP targets for all are not the correct approach. Based on HOPE, SPRINT, and other studies, one could conclude that SBP > 160 mmHg should be treated, but in low-risk patients, perhaps < 150 mmHg is adequate; in intermediate-risk patients, < 140 mmHg; and in high-risk patients, < 130 mmHg. This type of approach is similar to our current approach to cholesterol management.