To examine the association between antihypertensive treatment and specific adverse events.
Systematic review and meta-analysis.
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.
Searches were conducted in Embase, Medline, CENTRAL, and the Science Citation Index databases from inception until 14 April 2020.
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 (τ2).
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, τ2=0.009). Antihypertensives were associated with an increased risk of acute kidney injury (1.18, 95% confidence interval 1.01 to 1.39, τ2=0.037, n=15), hyperkalaemia (1.89, 1.56 to 2.30, τ2=0.122, n=26), hypotension (1.97, 1.67 to 2.32, τ2=0.132, n=35), and syncope (1.28, 1.03 to 1.59, τ2=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.
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.
PROSPERO CRD42018116860.
High blood pressure (hypertension) is one of the leading modifiable risk factors for cardiovascular disease worldwide,
In the UK, guidelines for managing patients with multimorbidity suggest doctors weigh the risk of diseases with the benefits and risks of treatments and make personalised treatment recommendations.
Currently few definitive data are available from meta-analyses of randomised controlled trials on the risks of specific harm outcomes that could be used to facilitate personalised decision making in patients with hypertension. We systematically reviewed evidence from trials and large observational studies to determine the association between antihypertensive treatment and specific adverse events such as falls, acute kidney injury, and electrolyte abnormalities.
We performed a systematic review and meta-analysis of randomised controlled trials and large observational studies examining the association between antihypertensive treatment and adverse events. The study is reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.
To capture all randomised controlled trials reporting the association between antihypertensive treatment and adverse events we searched Embase(OvidSP), Medline(OvidSP), Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library), and the Science Citation Index (Web of Science Core Collection). Searches were undertaken from inception of the databases until 14 April 2020, and no language restrictions were applied. In this review we focused on randomised controlled trials, which are less prone to bias from confounding by indication.
Eligible studies included participants aged 18 years or older, compared individuals receiving antihypertensive treatment (single agents) with those receiving placebo or no treatment, more antihypertensive drugs compared with fewer antihypertensive drugs, or one blood pressure target compared with another. Although these study designs examine different types of intervention, all compared more antihypertensive treatment with less antihypertensive treatment, enabling the potential association with adverse events to be determined. Trials were also required to present data describing the association between antihypertensive treatment and at least one adverse event. Randomised controlled trials were included if they reported 50 or more adverse events in each specific category or had at least 650 patient years of follow-up.
To ensure study selection and data analysis remained manageable by avoiding small, early phase mechanistic studies, we specified a priori the limit on patient years of follow-up and number of outcome events. We chose the specific criteria to ensure each included study was large enough to accrue outcome events and provide reliable effect estimates. These criteria assumed an incidence of the primary outcome (falls) of 7.8 events per 100 patient years of follow-up, which would accrue at least 50 outcome events in each study.
We excluded studies in specialist populations (children, pregnant women), and case reports, case series, or before and after studies. At least two members of the review team (AA, MS, BP, SF, CK, AD, JPS) independently reviewed study titles, abstracts, and full text articles. At each stage, the entire review team screened a proportion of articles to ensure consistency of decision making. Disagreements were resolved by a third reviewer (JPS).
Outcomes of interest were prespecified based on those reported in recent large scale trials of blood pressure lowering treatment.
AA, MH, LA, AD, and BL extracted data from eligible studies. Two reviewers independently entered outcome data into a Microsoft Excel spreadsheet (2016 version, Redmond, WA). A second reviewer then manually cross checked these, referring to the original source data when discrepancies were identified. After an initial consistency check involving extraction of data from 10 articles, one reviewer extracted study descriptive data.
Data were extracted on populations studied, interventions tested, length of follow-up, effect measures (estimates and confidence intervals for rate ratios, odds ratios, and hazard ratios), and numbers of patients experiencing adverse events and cardiovascular or mortality outcomes.
The methodological quality and risk of bias of individual studies was assessed using the Cochrane risk of bias tool (for randomised controlled trials).
Summary effect estimates describing the association between all antihypertensive drug classes (combined) and adverse events were derived using a random effects meta-analysis. For uncommon adverse events (approximately less than 10% of the population experience an event), rate ratios (for rate outcomes), odds ratios (for binary outcomes), and hazard ratios (for time-to-event outcomes) were considered reasonably similar and combined provided they had the same directional interpretation.
Heterogeneity was summarised using the estimate of between study variance (τ2) and 95% prediction intervals for the treatment effect in a new study. The proportion of variability in effect estimates due to between study heterogeneity was summarised using I2.
Sensitivity analyses were undertaken focusing on adverse events reported as a reason for study withdrawal. Meta-regression was used to examine the association between observed treatment effects and study quality. Small study effects (potential publication bias) were explored using contour enhanced funnel plots for outcomes reported in 10 or more studies.
No other subgroup analyses were undertaken by patient level characteristics (eg, age), owing to the risk of ecological bias.
All analyses were undertaken using Stata version 16 (StataCorp, College Station, TX).
This study was developed with the help of our patient and public advisor. As a member of our study advisory group, they commented on the study protocol. We also held a focus group with seven older adults during the study to discuss broader issues related to drugs for cardiovascular disease prevention and adverse events, which informed the interpretation of this work.
A total of 15 023 unique articles were identified from the literature searches, of which 119 records were screened from reference lists of included articles and previous meta-analyses. After screening of the title, abstract, and full text, 63 articles originating from 58 randomised controlled trials
Selection of studies for inclusion in review. *Hand searches of reference lists of included studies and recent meta-analyses of blood pressure lowering trials
A total of 280 638 participants were included in the primary analyses from 58 unique randomised controlled trials. Forty eight studies compared a single drug treatment with placebo and 10 studies compared a high blood pressure target with a lower blood pressure target in the intervention and control groups (
Summary of included randomised controlled trials
Trial name, year, reference | Population characteristics | Total sample | Follow-up | Mean (SD) age (years): intervention; control | Mean (SD) baseline sBP (mm Hg): intervention: control | Intervention | Comparator |
---|---|---|---|---|---|---|---|
AASK 2002 | African-Americans with renal disease | 1094 | 3.8 years | 54.5 (10.9); 54.7 (10.4) | 152 (25); 149 (23) | Mean atrial pressure target ≤92 mm Hg | Mean atrial pressure target 102-107 mm Hg |
ACCORD 2010 | Type 2 diabetes | 4733 | 5.6 years | 62.2 (6.8); 62 (6.9) | 139.0 (16.1) 139.4 (15.5) | BP target <120 mm Hg | BP target <140 mm Hg |
ACEi progressive renal insufficiency study group 1996 | Renal dysfunction | 583 | 3 years | 51 (13); 51 (12) | 142 (17); 144 (17) | Benazepril | Placebo |
ADVANCE 2014 | Type 2 diabetes | 11 140 | 4.3 years | 66 (6); 66 (7) | 145 (22); 145 (21) | Perindopril+indapamide | Placebo |
AIRE 1993 | Acute myocardial infarction+evidence of heart failure | 1986 | 15 months | 64.9 (10); 65.1 (10.8) | NS (28% hypertensive) | Ramipril | Placebo |
ALTITUDE 2012 | Type 2 diabetes | 8561 | 2.6 years | 64.6 (9.6); 64.4 (9.9) | 137.3 (16.2); 137.3 (16.7) | Aliskiren | Placebo |
ASPIRE 2011 | Post-myocardial infarction | 820 | 36 weeks | 61 (12); 59 (12) | 121.6 (16.1); 121.7 (16.2) | Aliskiren | Placebo |
BEST 2001 | NYHA class III or IV heart failure | 2708 | 2 years | 60 (12.6); 60 (12.3) | 117 (18.2); 117 (17.8) | Bucindolol | Placebo |
BHAT 1982 | Admitted to hospital with acute myocardial infarction | 3837 | 2 years | 54.7 (NS); 54.9 (NS) | 112.3 (NS); 111.7 (NS) | Propranolol | Placebo |
Cardio-Sis 2009 | No diabetes with hypertension | 1111 | 2 years | 67 (7); 67 (7) | 163.3 (11.3); 163.3 (11.1) | BP target <120 mm Hg | BP target <130 mm Hg |
CCS-I 1997 | Acute myocardial infarction | 14 962 | 4 weeks | 61.2 (10.7); 61 (10.6) | 127 (24); 126 (24) | Captopril | Placebo |
CHARM -Preserved 2003 | NYHA class II-IV heart failure | 3023 | Median 36.6 months | 67.2 (11.1); 67.1 (11.1) | 136.0 (18.6); 136.3 (18.3) | Candesartan | Placebo |
CHARM-ADDED 2003 | NYHA class II-IV heart failure | 2548 | 3.5 years | 64 (10.7); 64.1 (11.3) | 124.7 (18.6); 125.6 (18.6) | Candesartan | Placebo |
CHARM-Alternative 2003 | Heart failure | 2028 | 2.7 years | 66.3 (11); 66.8 (10.5) | 129.9 (19.0); 130.3 (18.5) | Candesartan | Placebo |
Collaborative Study Group 2001 | Type 2 diabetes with nephropathy | 1715 | 2.6 years | 59.3 (7.1), 59.7 (7.9); 58.3 (8.2) | 160 (20); 159 (19); 158 (20) | Irbesartan or Amlodipine | Placebo |
CONSENSUS II 1992 | Post-myocardial infarction | 6090 | 6 months | 65.7 (NS); 65.8 (NS) | 133 (NS); 134 (NS) | Enalapril | Placebo |
DIME 2014 | No diabetes, hypertension | 1130 | 4.4 years | 63 (10); 63 (10) | 154 (11); 154 (10) | Thiazide diuretic | No thiazide diuretic |
Dutch TIA Trial 1993 | Previous transient ischaemic attack | 1473 | 2.6 years | 50 (NS); 54 (NS) | 157 (25) and 158 (24) | Atenolol | Placebo |
EMPHASIS-HF 2011 | NYHA class II heart failure | 2737 | 1.75 years | 68.6 (7.7); 68.6 (7.6) | 124 (17); 124 (17) | Eplerenone | Placebo |
EUROPA 2003 | Stable coronary heart disease without heart failure | 12 218 | 4.2 years | 60 (9); 60 (9) | 137 (16); 137 (15) | Perindopril | Placebo |
EWPHE 1991 | >60 years with raised BP | 822 | 5 years | 72 (8); 72 (8) | 183 (16); 183 (16) | Hydrochlorothiazide+triamterene | Placebo |
GISSI-3 1994 | Myocardial infarction within 24 hours | 9442 | 6 weeks | NS | NS | Lisinopril | No treatment |
GISSI-AF 2009 | Atrial fibrillation and underlying CVD | 1442 | 1 year | 67.5 (9.5); 68.2 (8.9) | 138.2 (16.7); 139.0 (16.9) | Valsartan | Placebo |
Hypertension in diabetes study IV 1996 | Type 2 diabetes | 758 | 5 years | 57 (7.9) all patients | 160 (19); 160 (20) | Atenolol or Captopril with BP target <150/<85 mm Hg | BP target <180/<105 mm Hg |
HOPE Trial | >55 years, high CVD risk | 9297 | 5 years | 66 (7); 66 (7) | 139 (20); 139 (20) | Ramipril | Placebo |
HOPE-3 2016 | Men >55 years and women >65 years with one CVD risk factor or more | 12 705 | 5.5 years | 65.7 (6.4); 65.8 (6.4) | 138.2 (14.7); 137.9 (14.8) | Candesartan+Hydrochlorothiazide | Placebo |
HYVET Trial | >80 years with hypertension | 3845 | 2.1 years | 84/84 | 173 and 173 | Indapamide and/or perindopril | Placebo |
INFINITY 2019 | >75 years, hypertension, white matter lesions | 199 | 3 years | 80.9 (4.4); 80.3 (3.8) | 149.7 (15.4); 152.0 (17.5) | sBP target ≤130 mm Hg | sBP target ≤145 mm Hg |
Intensive Antihypertensive Treatment for Elderly 2013 | >70 years with hypertension | 724 | 4 years | 76.6 (4.6); 76.5 (4.5) | 158.8 (16.0); 160.3 (16.9) | BP target <140/90 mm Hg | BP target <150/90 mm Hg |
I-PRESERVE 2008 | Heart failure | 4128 | 4.1 years | 72 (7); 72 (7) | 137 (15); 136 (15) | Irbesartan | Placebo |
MACB 1995 | Referred for coronary artery bypass grafting | 967 | 2 years | Median age 64 in both groups | Median sBP 120 mm Hg in both groups | Metoprolol | Placebo |
MERIT-HF 2000 | NYHA class II-IV heart failure | 3991 | 1 year | 63.9 (NS); 63.7 (NS) | Not stated (44% of cohort hypertensive) | Metoprolol | Placebo |
MRC 1985 | Patients with mild hypertension | 17 354 | 5.5 years | 51 (NS); 53 (NS) | 158 (men); 165 (women) | Bendroflumethiazide or propranolol | Placebo |
Multicentre Diltiazem Postinfarction Trial 1988 | Admitted to hospital with acute myocardial infarction | 2466 | 25 months | 58 (10); 58 (10) | NS | Diltiazem | Placebo |
NAVIGATOR 2010 | Type 2 diabetes | 9306 | 6.3 years | 63.7 (6.8) 63.8 (6.8) | 139.4 (17.8) and 139.9 (17.1) | Valsartan | Placebo |
NICOLE 2003 | <75 years and previous successful angioplasty | 819 | 3 years | 60.4 (NS); 60.2 (NS) | NS (40% of cohort hypertensive) | Nisoldipine | Placebo |
NILVAD 2018 | Alzheimer’s disease | 511 | 1.5 years | 73.1 (8.7); 72.8 (7.8) | 138 (14); 137 (14) | Nilvadipine | Placebo |
ONTARGET 2008 | Existing vascular disease or diabetes | 25 620 | 4.5 years | 66.4 (7.2) 66.4 (7.1) 66.5 (7.3) | 141.8 (17.4); 141.7 (17.2); 141.9 (17.6) | Ramipril or telmisartan | Ramipril+telmisartan combination |
ORIENT 2011 | Type 2 diabetes with poor renal function | 566 | 3.4 years | 59.1 (8.1)/; 59.2 (8.1) | 141.7 (17.0) 140.8 (18.0) | Olmesartan | Placebo |
PEACE 2004 | Myocardial infarction or bypass in past 3 months | 8290 | 4.8 years | 64 (8); 64 (8) | 134 (17) and 133 (17) | Trandolapril | Placebo |
PRoFESS 2008 | >55 years and ischaemic stroke | 20 332 | 2.5 years | 66.1 (8.6); 66.2 (8.6) | 144.1 (16.4) 144.2 (16.7) | Telmisartan | Placebo |
PROGRESS 2001 | Previous stroke or transient ischaemic attack | 6105 | 4 years | 64 (10); 64 (10) | 147 (19); 147 (19) | Perindopril+indapamide | Placebo |
ROADMAP Trial | Type 2 diabetes | 4447 | 3.2 years | 57.7 (8.8); 57.8 (8.6) | 137 (16); 136 (15) | Olmesartan | Placebo |
SANDS 2009 | Native Americans with type 2 diabetes | 548 | 3 years | 55.8 (9.3); 57.4 (9.3) | 128.7 (14.7) 132.6 (16.4) | BP target <115/75 mm Hg | BP target <130/80 mm Hg |
SENIORS 2005 | >70 years with heart failure | 2128 | 1.5 years | 76.1 (4.8); 76.1 (4.6) | 138.6 (20.1) 139.5 (21.1) | Nebivolol | Placebo |
SHEP 1991 | >60 years with ISH | 4736 | 5 years | 71.6 (6.7); 71.5 (6.7) | 170.5 (9.5) 170.1 (9.2) | Chlorthalidone with or without atenolol or reserpine | Placebo |
SOLVD 1992 | Heart failure with ejection fraction <0.35 | 2569 | 41.4 months | 60.7 (NS); 61.0 (NS) | 125.3 (NS); 124.5 (NS) | Enalapril | Placebo |
Spironolactone and mild heart failure 2016 | NYHA class II heart failure | 139 | 10 years | 66.7 (1.3); 65.5 (1.3) | 120.6 (1.3); 121.3 (1.4) | Spironolactone+standard treatment | Standard treatment |
SPRINT 2015 | >50 years with increased CVD risk, no diabetes | 9361 | 3.26 years | 67.9 (9.4); 67.9 (9.5) | 139.7 (15.8); 139.7 (15.4) | BP target <120 mm Hg | BP target <140 mm Hg |
SPS3 2013 | Stroke within past 6 months | 3020 | 3.7 years | 63 (11); 63 (11) | 142 (19); 144 (19) | BP target <130 mm Hg | BP target 130-149 mm Hg |
The Norwegian Multicenter Study 1981 | Admitted to hospital with acute myocardial infarction | 1884 | 17 months | 60.3 (NS); 61.4 (NS) | NS | Timolol | Placebo |
TRACE 1995 | Admitted to hospital with acute myocardial infarction | 1749 | 24 to 50 months | 67.7 (NS); 67.3 (NS) | 122 (NS); 120 (NS) | Trandolapril | Placebo |
TRANSCEND 2008 | CVD or diabetes with end organ damage | 5926 | Median 56 months | 66.9 (7.3); 66.9 (7.4) | 140.7 (16.8); 141.3 (16.4) | Telmisartan | Placebo |
TROPHY 2006 | Prehypertensive population | 772 | 4 years | 48.6 (7.9); 48.3 (8.2) | 133.9 (4.3); 134.1 (4.2) | Candesartan | Placebo |
VA NEPHRON-D 2013 | Type 2 diabetes+moderate to severe proteinuria | 1448 | 2.2 years | 64.5 (7.9); 64.7 (7.7) | 136.9 (16.5); 137.0 (16.0) | Losartan+lisinopril | Losartan+placebo |
Val-HeFT 2001 | Heart failure | 5010 | 23 months | 62.4 (11.1) 63.0 (11) | 123.0 (18.4) 124.0 (18.6) | Valsartan | Placebo |
VALIANT 2003 | Myocardial infarction with left ventricular systolic dysfunction | 11 703 | 2 years | 65.0 (11.8) 64.9 (11.8) 64.6 (11.9) | 123 (NS) overall mean | Valsartan or captopril | Valsartan+captopril (dual treatment) |
VA-NHLBI 1978 | 21-50 years with mild hypertension | 1012 | 2 year | 37.5 (NS); 37.5 (NS) | Mean diastolic BP 93 mm Hg | Chlorthalidone and reserpine | Placebo |
CVD=cardiovascular disease; NYHA=New York Heart Association; NS=not stated; sBP=systolic blood pressure; ISH=isolated systolic hypertension.
Supplementary table 2 presents the risk of bias assessment for individual trials. Most of the trials (n=40, 69%) had a low risk of bias (
Summary of risk of bias assessment across all included randomised controlled trials
Seven randomised controlled trials reported data for the primary outcome of falls (
Random effects meta-analysis of randomised controlled trials examining the association between antihypertensive treatment and falls
In analyses examining adverse events across all drug classes, antihypertensive treatment was associated with an increased risk of acute kidney injury (summary risk ratio 1.18, 95% confidence interval 1.01 to 1.39, n=15 studies;
Random effects meta-analysis of randomised controlled trials examining the association between antihypertensive treatment and acute kidney injury
Main analyses showing meta-analysis results from trials reporting the association between antihypertensive treatment and adverse events and cardiovascular and mortality outcomes
Outcome | No of studies | Sample size | Events | Effect size (95% CI)* | I2 (%) | τ2 | 95% prediction interval | |||
---|---|---|---|---|---|---|---|---|---|---|
Intervention group | Control group | Intervention group | Control group | |||||||
Falls | 7 | 14 719 | 14 762 | 913 | 877 | 1.05 (0.89 to 1.24) | 31.5 | 0.009 | 0.77 to 1.43 | |
Acute kidney injury | 15 | 43 467 | 52 133 | 909 | 785 | 1.18 (1.01 to 1.39) | 48.1 | 0.037 | 0.76 to 1.85 | |
Fractures | 5 | 6447 | 6466 | 230 | 267 | 0.93 (0.58 to 1.48) | 53.8 | 0.062 | 0.36 to 2.41 | |
Gout | 5 | 16 524 | 16 137 | 249 | 26 | 3.84 (0.95 to 15.57) | 84.3 | 1.374 | 0.11 to 138.91 | |
Hyperkalaemia | 26 | 57 604 | 61 795 | 2749 | 1880 | 1.89 (1.56 to 2.30) | 71.8 | 0.121 | 0.90 to 3.98 | |
Hypokalaemia | 12 | 19 748 | 19 528 | 517 | 274 | 1.54 (0.63 to 3.75) | 94.3 | 1.612 | 0.08 to 29.98 | |
Hypotension | 35 | 88 575 | 93 547 | 5390 | 3121 | 1.97 (1.67 to 2.32) | 85.1 | 0.132 | 0.92 to 4.18 | |
Syncope | 16 | 51 072 | 51 189 | 644 | 543 | 1.28 (1.03 to 1.59) | 42.9 | 0.050 | 0.75 to 2.17 | |
All cause mortality | 32 | 128 619 | 128 729 | 11 831 | 13 018 | 0.93 (0.88 to 0.98) | 50.4 | 0.008 | 0.77 to 1.12 | |
Cardiovascular death | 21 | 92 676 | 92 733 | 6341 | 6890 | 0.92 (0.86 to 0.99) | 54.6 | 0.011 | 0.73 to 1.16 | |
Myocardial infarction | 19 | 75 002 | 75 301 | 2900 | 3255 | 0.94 (0.85 to 1.03) | 40.7 | 0.013 | 0.73 to 1.21 | |
Stroke | 17 | 104 153 | 104 366 | 3220 | 3733 | 0.84 (0.76 to 0.93) | 44.8 | 0.013 | 0.64 to 1.09 |
Adverse events reported as risk ratios and cardiovascular and mortality outcomes reported as hazard ratios (in studies reporting outcome as time to event). Binary and rate outcomes for cardiovascular and mortality outcomes are presented in supplementary figures 15-17.
Analyses of outcomes by specific drug class showed that drugs affecting the renin angiotensin-aldosterone system were associated with acute kidney injury (1.26, 1.03 to 1.56, τ2=0.030, I2=39.0%; n=9 studies;
Summary of sensitivity analyses showing important drug class specific associations between antihypertensive treatment and specific adverse events
Outcome | Drug class | No of studies | Sample size | Events | Risk ratio (95% CI) | I2 (%) | τ2 | 95% prediction interval | |||
---|---|---|---|---|---|---|---|---|---|---|---|
Intervention group | Control group | Intervention group | Control group | ||||||||
Acute kidney injury | RAAS | 9 | 33 686 | 42 316 | 514 | 468 | 1.26 (1.03 to1.56) | 39.0 | 0.030 | 0.80 to 1.99 | |
Hyperkalaemia | RAAS | 20 | 47 122 | 51 787 | 2282 | 1541 | 2.03 (1.67 to 2.48) | 51.0 | 0.063 | 1.16 to 3.57 | |
Hypokalaemia | Diuretics | 3 | 3154 | 3114 | 259 | 25 | 10.73 (0.32 to 354.58) | 80.9 | 1.385 | - | |
Gout | Diuretics | 5 | 12 121 | 12 190 | 237 | 29 | 4.48 (0.79 to 26.54) | 85.0 | 1.547 | 0.05 to 388.68 |
RAAS=drugs affecting the renin angiotensin-aldosterone system (eg, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, direct renin inhibitors); diuretics=thiazide and thiazide-like diuretics.
Other generic adverse events such as falls, hypotension, syncope, and fractures were examined by drug class, but no significant drug specific effects were observed (supplementary figures 1 and 12-14).
On average across studies examining outcomes using time-to-event analyses, antihypertensive treatment was associated with a reduction in cardiovascular death (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, τ2=0.011, I2=54.6%, n=21 studies;
Random effects meta-analysis of randomised controlled trials examining the association between antihypertensive treatment and cardiovascular death
Meta-regression examining the relation between the observed treatment effects for each adverse event outcome and study quality found no clear evidence of an association (supplementary table 3). Funnel plots showed asymmetry (potential publication bias) for hyperkalaemia and hypotension events, with smaller studies missing for smaller effect estimates, but this was not evident for other adverse events examined (supplementary figures 18-22).
Supplementary figures 23-27 show the results of sensitivity analyses focusing on studies reporting adverse events that led to participant withdrawal from each trial (summarised in
Sensitivity analyses showing meta-analysis results focusing on trials reporting the association between antihypertensive treatment and adverse events which led to permanent withdrawal from a trial
Outcome | No of studies | Sample size | Events | Risk ratio (95% CI) | I2 (%) | τ2 | 95% prediction interval | |||
---|---|---|---|---|---|---|---|---|---|---|
Intervention group | Control group | Intervention group | Control group | |||||||
Acute kidney injury | 6 | 30 672 | 39 350 | 128 | 146 | 1.34 (0.99 to 1.81) | 0.0 | 0.000 | 0.97 to 1.84 | |
Gout | 2 | 15 998 | 15 959 | 179 | 38 | 3.41 (0.08 to 148.47) | 86.4 | 1.903 | - | |
Hyperkalaemia | 13 | 34 580 | 38 953 | 398 | 189 | 2.28 (1.70 to 3.05) | 22.8 | 0.053 | 1.28 to 4.06 | |
Hypotension | 18 | 51 063 | 56 030 | 1042 | 541 | 2.18 (1.84 to 2.58) | 34.0 | 0.033 | 1.43 to 3.32 | |
Syncope | 6 | 34 146 | 34 289 | 62 | 28 | 2.17 (1.20 to 3.90) | 0.0 | 0.000 | 1.15 to 4.09 |
Data from random effects meta-analyses of 58 randomised controlled trials and more than 280 000 patients with hypertension confirm the known benefit of antihypertensive treatment in reducing the risk of cardiovascular disease.
These data will inform shared decision making around initiation and continuation of antihypertensive treatment, especially in patients with a high absolute risk of certain adverse outcomes as a result of previous events or poor renal function. Such discussions will become increasingly important as patients age and develop frailty and multimorbidity that could put them at increased risk of adverse events.
More than 15 000 articles were screened for inclusion in this review and 58 randomised controlled trials including a large number of participants and adverse events were identified. Although power was likely to be sufficient to detect associations between antihypertensive treatment and adverse events, we observed statistically significant heterogeneity across studies, and the resulting prediction intervals were wide. Such heterogeneity might preclude pooling of some treatment effects, so caution should be exercised when interpreting the results. For acute kidney injury and hyperkalaemia events, the observed heterogeneity was partly explained by pooling of different drug classes, and heterogeneity was reduced when we focused on drugs that affect the renin angiotensin-aldosterone system. For other outcomes, the observed heterogeneity could not be explained by study quality or differences in the drug class examined in individual trials; however, populations of interest, interventions, comparators, and study designs varied widely across studies, which could have contributed to the observed variation.
As this review focused on adverse events, selective outcome reporting might also have been a problem. Evidence was found of publication bias for certain outcomes (hyperkalaemia and hypotension), confirming the findings of previous studies that showed adverse events are more likely to be reported in randomised controlled trials when they are statistically significant.
This review focused on large randomised controlled trials with the aim of including those with at least 50 adverse events (and therefore 650 patient years of follow-up). This restriction on study size was chosen to make the review more manageable in terms of screening and analysis and avoid inclusion of numerous small early phase mechanistic studies of varying methodological quality. The cut-off for this inclusion was chosen to ensure studies provided adequately powered estimates of association between treatment and outcomes.
Across all included trials, adverse events were poorly defined and probably varied across studies. For instance, many studies referred to syncope as an outcome, but did not say what type of syncopal event this might have included. A conservative approach to inclusion of outcomes was taken when possible, and only those explicitly stating the outcome of interest were included. For example, trials reporting hypotension or acute kidney injury were included, but those reporting hypotension or dizziness or renal impairment were excluded. Despite this approach, some studies were included that did not specify the thresholds used to define hypotension or acute kidney injury. This could have resulted in some relevant data for certain outcomes being missed, but this meant those that were included were likely to be sufficiently similar to enable pooling in a meta-analysis. Although the quality of adverse event ascertainment is likely to have varied between trials, it would not be expected to vary between treatment arms within trials. Thus it is unlikely that differences in the quality of adverse event ascertainment would have affected the relative treatment effects presented in this review.
We prespecified adverse events of interest based on those reported in recent large scale trials of blood pressure lowering treatment.
For outcomes included in meta-analyses, the time points at which they occurred varied across studies, and so the risk ratios and odds ratios provided relate to a summary across different times. We did synthesise hazard ratios when available, but these were rarely reported.
Few previous meta-analyses have quantified the association between antihypertensive treatment and adverse events. Thomopoulos and colleagues examined the association between antihypertensive treatment and permanent discontinuation of treatment because of adverse events and found that antihypertensives were associated with a near doubling of risk (standardised relative risk 1.89, 95% confidence interval 1.51 to 2.39).
Frey and colleagues
Stratified analyses by drug class suggested that associations with acute kidney injury and hyperkalaemia were mostly driven by the use of drugs that affect the renin angiotensin-aldosterone system (eg, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and direct renin inhibitors). However, no evidence was found of an association with this class of drug and falls, fractures, gout, or hypokalaemia. In analyses that focused on patients prescribed diuretics, a 10-fold increase in the risk of hypokalaemia was observed, but this association was derived from only three trials, with high between study heterogeneity. The pooled effect had large confidence intervals and was not statistically significant. This null finding contrasted with previous studies that recommend routine monitoring of potassium to detect hypokalaemia in patients prescribed diuretics.
Much debate exists in the literature on the association between antihypertensive treatment and falls.
The present data clearly show the benefits and harms of antihypertensive treatment for specific cardiovascular outcomes and adverse events. The data also highlight that certain adverse events might be specific to certain drug classes (eg, renin angiotensin-aldosterone system drugs and acute kidney injury or hyperkalaemia). This detail is important because some adverse events reported in randomised controlled trials might be considered relatively mild and worth the risk when weighed against the substantial benefits of treatment. These new data will allow patients and clinicians to take into consideration these benefits and risks, as has been recommended in clinical guidelines.
The present data should ideally be combined with information about an individual’s absolute risk of each harm outcome to make informed, personalised treatment decisions. This process is complex and requires real time data, which suggests that tools embedded in electronic health records will be the way forward. Further work is needed to understand better the results of this meta-analysis (which summarises average risk ratios across all participants and studies) in the context of individualised absolute risks so that treatment initiation and discontinuation can be targeted at those with the most to gain.
This review found no evidence of an association between antihypertensive treatment and falls (primary outcome) or fractures but did show a variation in the association between antihypertensive treatment and mild (eg, hypotension without falls) and more severe (eg, acute kidney injury, syncope) adverse events. Some effects were found to be specific to the drug class used. In patients at high risk of drug harms because of previous adverse events or poor renal function, these data should be used to inform shared decision making between doctors and patients around initiation and continuation of antihypertensive treatment.
Many meta-analyses exist of randomised controlled trials that examine the efficacy of antihypertensive treatment, but few have studied potential harms
Existing meta-analyses have focused on the association between antihypertensive treatment and all adverse events, grouping mild and more serious outcomes
The association between antihypertensive treatment and specific adverse events is unclear
In a meta-analysis of 58 randomised controlled trials, including 280 638 participants, no evidence was found of an association between antihypertensive treatment and falls (primary outcome) or fractures
Evidence was, however, found of an association between antihypertensive treatment and potentially both mild (hypotension) and more severe (acute kidney injury, syncope) adverse events
These data might be used to inform shared decision making between doctors and patients about the benefits and harms of initiation and continuation of antihypertensives, especially in those at high risk of harm because of previous adverse events or poor renal function
We thank Margaret Ogden for her advice as a patient and public contributor to this project, and Lucy Curtin for administrative support throughout the project.
The STRAtifying Treatments In the multi-morbid Frail elderlY (STRATIFY) investigators include the authors and: Amitava Banerjee, associate professor in clinical data science and honorary consultant cardiologist, Institute of Health Informatics, University College London; Andrew Clegg, professor of geriatric medicine, University of Leeds and Bradford Teaching Hospitals NHS Foundation Trust; John Gladman, professor of medicine of older people, School of Medicine, University of Nottingham; Simon Griffin, professor of primary care, Department of Public Health and Primary Care, Primary Care Unit, University of Cambridge; and Margaret Ogden, patient and public involvement advisor.
Contributors: JPS conceived the study and wrote the protocol with FDRH, RJM, RS, and RR. NR did the literature searches. AA, MS, BP, SF, CK, AD, and JPS screened articles for inclusion. MH, AA, LA, AD, and BL extracted data for analysis. MH undertook the meta-analysis and produced forest plots and summary results, under supervision of RR. AA and JPS wrote the first draft of the manuscript. All authors revised the manuscript and approved the final version. JPS is the guarantor for this work and accepts full responsibility for the conduct of the study, had access to the data, and controlled the decision to publish. The corresponding author (JPS) attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Funding: This study was funded by the Wellcome Trust and Royal Society through a Sir Henry Dale fellowship held by JPS (ref 211182/Z/18/Z) and the National Institute for Health Research (NIHR) School for Primary Care (project 430). JPS also receives funding through an NIHR Oxford Biomedical Research Centre (BRC) senior fellowship. RJMcM is supported by an NIHR senior investigator award. FDRH acknowledges part support from the NIHR SPCR, the NIHR CLAHRC Oxford, and the NIHR Oxford BRC. BL is supported by a Fonds de recherche du Québec – Santé Postdoctoral Training Fellowship. KIES is funded by an NIHR School for Primary Care Research launching fellowship. MS is supported by the NIHR Oxford BRC. SLF is part funded by the NIHR Oxford BRC and NIHR Applied Research Collaborations Oxford and Thames Valley. JUS was funded by a Cancer Research UK Prevention fellowship (C55650/A21464). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The sponsor and funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Competing interests: All authors have completed the ICMJE uniform disclosure form at
Ethical approval: Not required.
The manuscript’s guarantor (JPS) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as originally planned (and, if relevant, registered) have been explained.
Data sharing: Requests for data sharing should be sent to the corresponding author at james.sheppard@phc.ox.ac.uk.
Dissemination to participants and related patient and public communities: No participants were included in this work. The findings of this work, including a lay summary of the results, will be made available on the study website (
Provenance and peer review: Not commissioned; externally peer reviewed.