Association between antihypertensive treatment and adverse events: systematic review and meta-analysis

Abstract

Objective To examine the association between antihypertensive treatment and specific adverse events. Design Systematic review and meta-analysis. Eligibility criteria Randomised controlled trials of adults receiving antihypertensives compared with placebo or no treatment, more antihypertensive drugs compared with fewer antihypertensive drugs, or higher blood pressure targets compared with lower targets. To avoid small early phase trials, studies were required to have at least 650 patient years of follow-up. Information sources Searches were conducted in Embase, Medline, CENTRAL, and the Science Citation Index databases from inception until 14 April 2020. Main outcome measures The primary outcome was falls during trial follow-up. Secondary outcomes were acute kidney injury, 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 (τ 2 ). Results Of 15 023 articles screened for inclusion, 58 randomised controlled trials were identified, including 280 638 participants followed up for a median of 3 (interquartile range 2-4) years. Most of the trials (n=40, 69%) had a low risk of bias. Among seven trials reporting data for falls, no evidence was found of an association with antihypertensive treatment (summary risk ratio 1.05, 95% confidence interval 0.89 to 1.24, τ 2 =0.009). Antihypertensives were associated with an increased risk of acute kidney injury (1.18, 95% confidence interval 1.01 to 1.39, τ 2 =0.037, n=15), hyperkalaemia (1.89, 1.56 to 2.30, τ 2 =0.122, n=26), hypotension (1.97, 1.67 to 2.32, τ 2 =0.132, n=35), and syncope (1.28, 1.03 to 1.59, τ 2 =0.050, n=16). The heterogeneity between studies assessing acute kidney injury and hyperkalaemia events was reduced when focusing on drugs that affect the renin angiotensin-aldosterone system. Results were robust to sensitivity analyses focusing on adverse events leading to withdrawal from each trial. Antihypertensive treatment was associated with a reduced risk of all cause mortality, cardiovascular death, and stroke, but not of myocardial infarction. Conclusions This meta-analysis found no evidence to suggest that antihypertensive treatment is associated with falls but found evidence of an association with mild (hyperkalaemia, hypotension) and severe adverse events (acute kidney injury, syncope). These data could be used to inform shared decision making between doctors and patients about initiation and continuation of antihypertensive treatment, especially in patients at high risk of harm because of previous adverse events or poor renal function. Registration PROSPERO CRD42018116860.

Prevention and management of hyperkalemia in patients treated with renin–angiotensin–aldosterone system inhibitors

“…4 Among the medications that lead to hyperkalemia, the most clinically important are RAAS inhibitors, which include angiotensin-converting-enzyme inhibitors, angiotensinreceptor blockers and mineralocorticoid receptor antagonists. [4][5][6] Although there is heterogeneity among studies, a systematic review and meta-analysis of 20 studies found that hyperkalemia is nearly twice as common (risk ratio 1.89, 95% confidence interval 1.56-2.30) in patients on drugs that act on the RAAS. 5 Moreover, data from clinical trials have also shown an increase in the incidence of hyperkalemia in patients with CKD or heart failure on RAAS inhibitor therapy.…”

“…[4][5][6] Although there is heterogeneity among studies, a systematic review and meta-analysis of 20 studies found that hyperkalemia is nearly twice as common (risk ratio 1.89, 95% confidence interval 1.56-2.30) in patients on drugs that act on the RAAS. 5 Moreover, data from clinical trials have also shown an increase in the incidence of hyperkalemia in patients with CKD or heart failure on RAAS inhibitor therapy. 12 An episode of hyperkalemia puts patients at risk of a second episode.…”

“…3 However, these medications may trigger or exacerbate hyperkalemia. [4][5][6][7] Some guidelines now recommend initiating and up-titrating these medications to the highest approved dose that the patient can tolerate to optimize clinical outcomes. 8,9 Therefore, anticipation and prompt management of hyperkalemia is crucial for patients prescribed these medications.…”

Observed and expected serious adverse event rates in randomised clinical trials for hypertension: an observational study comparing trials that do and do not focus on older people

“… 5 , 17 , 21 Furthermore, associated risks of RAAS drugs such as renal dysfunction, orthostatic hypotension, syncope, and polypharmacy are likely to be greater in older people. 22 …”

Prévention et traitement de l’hyperkaliémie chez les patients sous inhibiteurs du système rénine–angiotensine–aldostérone

“…Ces patients pren nent généralement des inhibiteurs du système rénine-angio tensine-aldostérone (SRAA) pour réduire les risques d'aggravation de l'IRC et de complications cardiovasculaires 3 . Il arrive toutefois que ces médicaments déclenchent ou exa cerbent l'hyperkaliémie [4][5][6][7] . Certaines lignes directrices recom mandent désormais l'instauration de ces médicaments et l'augmentation de la posologie jusqu'à la dose maximale approuvée et tolérée par les patients afin d'optimiser l'issue cli nique 8,9 .…”