Antihypertensives not linked to decreased cardiovascular events: The HOPE-3 trial

1. The treatment group receiving a combination of candesartan and hydrochlorothiazide demonstrated significant decreases in systolic and diastolic blood pressure compared to the placebo group.

2. There was no significant difference between the treatment and placebo group in terms of a composite measure of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Previous epidemiologic research suggests that there is a graded increase in cardiovascular risk above blood pressures as low as 115mmHg. Prior studies have clearly established the benefits of antihypertensive therapy in patients with systolic blood pressure (sBP) above 160mmHg and an absence of vascular or renal disease, diabetes, or hypertension with end-organ dysfunction. However, less is known about the efficacy of antihypertensive therapy in patients with intermediate risk of cardiovascular disease and sBP under 160mmHg.

The Heart Outcomes Prevention Evaluation (HOPE-3) trial sought to answer this question among 12,705 participants at intermediate risk who did not have cardiovascular disease. These participants were randomized to receive either fixed-dose combination of candesartan and hydrochlorothiazide or placebo. Over a median follow-up of 5.6 years, there were significant and enduring decreases in both sBP and diastolic blood pressure (dBP) in the treatment group compared with placebo. There were no significant differences in terms of primary outcomes (the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke and the composite of these events plus resuscitated cardiac arrest, heart failure, or revascularization).

HOPE-3 adds considerably to the literature regarding antihypertensive use in reducing cardiovascular risk, contradicting the “lower is better” hypothesis. However, the greatest challenge facing practitioners remains synthesizing these findings alongside myriad other studies with conflicting results.

Click to read the study in NEJM

Relevant Reading: A Randomized Trial of Intensive versus Standard Blood-Pressure Control

In-Depth [randomized controlled trial]: HOPE-3 involved 12,705 participants randomized either to combination of candesartan and hydrochlorothiazide or placebo. These participants had an intermediate risk of cardiovascular outcomes (annual risk of major cardiovascular events of approximately 1%). The population had a mean age of 65.7 years, was 46.2% female, and was ethnically diverse. At baseline, the mean sBP in the entire group was 138.1mmHg; the mean decreases from baseline during the trial were 10.0±13.1 and 4.0±12.9 mmHg in the treatment and placebo groups, respectively. These decreases in blood pressure were consistent with respect to dBP and across time in the trial.

In regards to the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke the two groups did not demonstrate any significant difference across a median follow-up of 5.6 years, with an incidence of 4.1% and 4.4% in the treatment and placebo groups (HR=0.93; 95% [CI], 0.79 to 1.10; p=0.40). In terms of the composite of the aforementioned events plus resuscitated cardiac arrest, heart failure, or revascularization, there was again no significant difference (HR=0.95; 95% [CI], 0.81 to 1.11; p=0.51). In terms of safety, there were significantly higher rates of hypotension, dizziness, and light-headedness among participants receiving treatment compared to placebo.

Image: PD

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