The association between antihypertensive treatment and adverse events: a systematic review and meta-analysis of 58 randomised controlled trials including 280,638 patients
Stevens R., McManus R., Sheppard J.
<p><strong>Objectives:</strong> There are many meta-analyses of randomised controlled trials (RCTs) which examine the efficacy of antihypertensive treatment, but few have studied the potential harms. The aim of this study was to examine the association between antihypertensive treatment and specific adverse events.</p> <p><strong>Design:</strong> Systematic review and meta-analysis of RCTs.</p> <p><strong>Eligibility criteria:</strong> Articles were eligible if they examined adults taking antihypertensive treatment compared to placebo/no treatment, more treatment vs. less treatment, or higher blood pressure targets vs. lower targets. To avoid small early phase trials, studies were required to have at least 650 patient-years of follow-up.</p> <p><strong>Information sources:</strong> Searches were conducted in Embase, MEDLINE, Cochrane CENTRAL and the Science Citation Index databases from inception until 14/04/2020.</p> <p><strong>Main outcome measures:</strong> The primary outcome was falls at any time point during trial follow-up. Secondary outcomes were acute kidney injury (AKI), fractures, gout, hyperkalaemia, hypokalaemia, hypotension and syncope. Additional outcomes related to death and major cardiovascular events were extracted. Risk of bias was assessed using the Cochrane risk of bias tool, and random-effects meta-analysis was used to pool rate ratios, odds ratios and hazard ratios across studies allowing for between-study heterogeneity (tau2).</p> <p><strong>Results:</strong> A total of 15,023 articles were screened for inclusion and 58 RCTs were identified, including 280,638 participants, followed-up for a median of 3 years (IQR 2-4). The majority of trials (69%) had a low risk of bias. Across seven trials, there was no evidence of an association between antihypertensive treatment and falls (summary risk ratio [RR] 1.05, 95%CI 0.89-1.24, tau2=0.009). Antihypertensives were associated with an increased risk of AKI (RR 1.18, 95%CI 1.01-1.39, tau2=0.037, n=15), hyperkalaemia (RR 1.89, 95%CI 1.56-2.30, tau2=0.122, n=26), hypotension (RR 1.97, 95%CI 1.67-2.32, tau2=0.132, n=35) and syncope (RR 1.28, 95%CI 1.03-1.59, tau2=0.050, n=16). The heterogeneity between studies assessing AKI and hyperkalaemia events was reduced when focussing on medications affecting the renin angiotensin-aldosterone system. Results were robust to sensitivity analyses focusing on adverse events leading to withdrawal from each trial. Antihypertensive therapy was associated with a reduced risk of all-cause mortality, cardiovascular death and stroke, but not myocardial infarction.</p> <p><strong>Conclusions:</strong> This meta-analysis does not suggest that antihypertensive treatment is associated with falls, but provides evidence of an association with other mild/severe adverse events, some of which were drug class specific. These data may be used to inform shared decision-making between physicians and patients regarding antihypertensive initiation and continuation, especially in patients at high risk of harm.</p>