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Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD006742

Efficacy Endpoints

Mortality, stroke, coronary artery disease, cardiovascular events

Harm Endpoints

Stopping medication due to adverse events

Narrative

Hypertension affects almost 29% of adults in the United States, most of whom are taking medication to lower their blood pressure1. Blood pressure control has been shown to reduce the chances of developing cardiovascular problems and stroke (Mancia et al, 2009), however these reductions are derived from studies of patients with moderate or severe hypertension, and those with a history of prior cardiovascular events such as heart attack or stroke. However, evidence has been unclear on whether pharmacological treatment for previously healthy patients with ‘mild’ hypertension is beneficial.

This review included four randomized-controlled trials enrolling 8,912 subjects with mild elevations in blood pressure (systolic blood pressure 140-159 or diastolic blood pressure 90-99) without preexisting cardiovascular disease. Patient data for individuals satisfying the inclusion criteria were obtained from three studies; pooled data was used from the fourth study since it met the a priori inclusion criteria of having less than 20% of its total subjects with moderately elevated blood pressure.

At a period of four to five years follow up, no differences were seen in mortality, cardiovascular events, CAD, or stroke. Approximately 9% more patients in the treatment arms withdrew due to medication side effects.

Caveats

Studies included in this analysis were of variable quality, some with questionable randomization, incomplete blinding, or partial follow up. Additionally, antihypertensive agents were often older, or used in higher doses than in current practice. Subjects often received non-thiazide diuretics and beta blockers, rather than low-dose thiazides, ACE inhibitors, and calcium-channel blockers, drugs which appear to confer a slight advantage in outcomes2.

Included trials were often powered to detect composite endpoints and underpowered to evaluate individual outcome measures. For low-risk patients with mild hypertension, a study powered to detect differences in mortality or cardiovascular outcomes would require more subjects followed for more time. To account for this some authors have called for trials utilizing intermediate/surrogate endpoints such as left ventricular hypertrophy or microalbuminuria3. We disagree, because of the misleading results that such surrogate markers can often generate.

While data for higher risk patients do suggest a benefit from treatment of hypertension, and the lack of statistically significant benefits in low risk patients may be due to inadequate power, there are important notes of caution here. The high rate of drug discontinuation is concerning. Moreover, it is well known that occasional serious, potentially life threatening adverse events occur with antihypertensives (angioedema with ACE inhibitors, toxicity and bradycardia with beta blockers and calcium channel blockers, electrolyte disturbances with diuretics). These risks are reasonable when there is a proven benefit. In the absence of proof of benefit, the risk of inficting serious harm with the drugs becomes ethically dubious. In one study that represents nearly 80% of the data included, for instance, women experienced higher mortality in the treatment group than in the placebo group4, thus understanding impact on subgroups may be critical. In the final analysis this low-risk population may be a perfect example of a group in whom, despite documented relative risk reductions, extremely small absolute reductions (in rare outcome events) are trumped by increases in harm.

Ultimately, while we require more and higher-quality research to answer this question definitively in a contemporary milieu, these data strike us as being of adequate power and quality to label this intervention as ‘Red’, indicating no benefit. The reversible nature of the harms and the weakness of the data, however, suggest to us that a rating of ‘Black’ (harmful) would convey more certainty than is justified. Although we are aware of clinical guidelines that have come to a different conclusion5, 6, 7, 8, the data analyzed here do not support the treatment of mild hypertension for primary prevention.

Author

Gary Green, MD

Published/Updated

February 2, 2013