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Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications

Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications Key Points Question Which classes of IMPORTANCE Antihypertension medications have been associated with prevention of antihypertension medications are cardiovascular events, although less is known about the comparative effectiveness of different reported to be associated with medication classes. reductions in first-in-trial cardiovascular events? OBJECTIVE To compare contemporary aggregated first-in-trial cardiovascular events among Findings In this systematic review and patients with hypertension and no substantial comorbidities. network meta-analysis of 46 randomized clinical trials that performed DATA SOURCES The PubMed, Embase, and Cochrane Library databases were systematically direct comparisons of individual searched for articles published between January 1, 1990, and October 24, 2017. antihypertension medication classes among 248 887 patients with STUDY SELECTION Randomized clinical trials that tested commonly used antihypertension hypertension and no substantial medications (angiotensin-converting enzyme inhibitors, dihydropyridine calcium channel blockers, comorbidities, angiotensin-converting nondihydropyridine calcium channel blockers, β-blockers, angiotensin receptor blockers, and enzyme inhibitors, dihydropyridine diuretics) and that reported selected cardiovascular outcomes for at least 6 months of follow-up. calcium channel blockers, and diuretics were reported to be similarly effective in DATA EXTRACTION AND SYNTHESIS The analysis was conducted from October 2017 to December reducing cardiovascular death, stroke, 2019. Two reviewers extracted the number of cardiovascular events at the end of treatment for all and overall cardiovascular events. study groups. For each outcome, a frequentist network meta-analysis was used to compare risk Angiotensin-converting enzyme reductions between medication classes (random-effects models weighted by the inverse variance). inhibitors and diuretics were reported to The dose-response association between a 10–mm Hg reduction of systolic blood pressure and a be the most effective in reducing 5–mm Hg reduction of diastolic blood pressure and the risk of first-in-trial cardiovascular events was myocardial infarction and estimated. revascularization, respectively. MAIN OUTCOMES AND MEASURES First-in-trial cardiovascular events, including cardiovascular Meaning The reported effects of death, myocardial infarction, stroke, and revascularization. different antihypertension medication classes were largely similar, with only RESULTS In this systematic review and network meta-analysis, data were pooled from 46 eligible nuanced differences. clinical trials (248 887 total participants with a mean [SD] age of 65.6 [5.8] years; 52.8% men). In the network meta-analysis, compared with placebo, angiotensin-converting enzyme inhibitors, Supplemental content dihydropyridine calcium channel blockers, and thiazide diuretics were reported to be similarly effective in reducing overall cardiovascular events (25%), cardiovascular death (20%), and stroke Author affiliations and article information are listed at the end of this article. (35%); angiotensin-converting enzyme inhibitors were reported to be the most effective in reducing the risk of myocardial infarction (28%); and diuretics were reported to be the most effective in reducing revascularization (33%). In the metaregression analyses, each 10–mm Hg reduction in systolic blood pressure and 5-mm Hg reduction in diastolic blood pressure was significantly associated with a lower risk of cardiovascular death, stroke, and overall cardiovascular events. (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 1/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications Abstract (continued) CONCLUSIONS AND RELEVANCE In this network meta-analysis of clinical trials of patients with hypertension and no substantial comorbidities, different classes of antihypertension medications were associated with similar benefits in reducing cardiovascular events. Future studies should compare the effectiveness of combinations of antihypertension medications in reducing cardiovascular events. JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 Introduction Hypertension is the most prevalent risk factor for mortality and disability-adjusted life-years worldwide. Cardiovascular disease remains the leading cause of death globally, accounting for 17.7 million deaths in 2015, which represented 31% of all deaths worldwide. Hypertension is an important factor in cardiovascular disease. In 2010, it was estimated that one-third of the world’s adult population had hypertension. The introduction of the American College of Cardiology and the American Heart Association hypertension guidelines in 2017 resulted in higher estimates of the 5,6 number of people with hypertension. Knowledge of optimal first-line antihypertension medications for the prevention of cardiovascular events and mortality will be important for clinical decision-making. Moreover, the identification of treatments that are most effective for controlling hypertension and subsequent cardiovascular events and mortality and that have the least harmful effects is imperative to guide clinicians and decrease cardiovascular disease burdens worldwide. Previous meta-analyses have examined the efficacy of antihypertension treatments in reducing 7,8 cardiovascular events. These meta-analyses have used pairwise comparisons of only 2 classes of antihypertension medications; however, pairwise meta-analysis does not enable comparison of multiple classes of medications. Only 1 network meta-analysis has compared the effectiveness of different classes of antihypertension medications in preventing cardiovascular events, but this meta- analysis was published more than 15 years ago and included medications, such as α-blockers, that are less frequently used in contemporary health care. To provide an updated perspective on the comparative efficacy of antihypertension medications, we conducted a network meta-analysis to compare the reported effects of different classes of antihypertension medications that are currently used to reduce the risk of individual cardiovascular events (cardiovascular death, myocardial infarction, stroke, and revascularization) and to examine the medications’ reported effectiveness in reducing the overall risk of any cardiovascular event. Findings from this study will be relevant for the contemporary clinical management of hypertension, especially in light of the new American College of Cardiology and American Heart Association hypertension guidelines. Methods We conducted a network meta-analysis of randomized clinical trials that tested antihypertension medications. This study followed the Preferred Reporting Items for Systematic Reviews and Meta- analyses (PRISMA) guidelines for systematic reviews and meta-analyses. Data Sources and Study Selection We systematically searched the PubMed, Embase, and Cochrane Library databases for articles published between January 1, 1990, and October 24, 2017. The search terms used included hypertension, hypertension and agents, and antihypertensive agents (a detailed list of search terms is available in the eMethods in the Supplement. There were no language restrictions. JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 2/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications We included studies meeting the following criteria: (1) randomized clinical trials; (2) published during or after 1990; (3) included nonpregnant adults 18 years or older without chronic kidney disease, diabetic nephropathy, or organ transplants (which are risk factors for secondary hypertension) and without myocardial infarction and/or stroke within the previous 6 months; (4) evaluated antihypertension medications, including angiotensin-converting enzyme (ACE) inhibitors, dihydropyridine calcium channel blockers (DH CCBs), nondihydropyridine calcium channel blockers (non–DH CCBs), β-blockers, angiotensin receptor blockers (ARBs), and diuretics compared with control groups receiving placebo, standard treatment, or health education; (5) reported incidence of cardiovascular disease events (cardiovascular death, myocardial infarction, stroke, and/or coronary revascularization [either percutaneous coronary intervention or coronary artery bypass grafting]); and (6) reported data from at least 6 months of follow-up. In addition, we excluded studies that reported myocardial infarction and/or stroke within the previous 3 months; studies that focused on patients with chronic kidney disease, diabetic nephropathy, or organ transplants (which are risk factors for secondary hypertension); and studies that were not focused on patients with hypertension. To minimize concerns about the heterogeneity of outcome ascertainment across studies, we only included studies in which cardiovascular events were adjudicated by physicians using similar criteria and assessing patients’ medical records. Study selection followed 3 steps. First, 2 of us (J.W. and A.J.K.) independently screened the titles of studies. Second, the same 2 reviewers screened and selected abstracts, and disagreements were resolved by a third reviewer (M.K.A.). Third, the 2 reviewers (J.W. and A.J.K.) examined the full text of articles for confirmation of inclusion. Disagreements were resolved by consensus or, when necessary, by the third reviewer (M.K.A.). Data Extraction and Quality Assessment Two of us (J.W. and A.J.K.) independently extracted data from studies that met inclusion criteria using a standardized extraction form. The data extracted included sample size, participant characteristics (age and sex), study country, follow-up duration, types of antihypertension medications and comparator groups, and number of first-in-trial cases for each outcome. Cardiovascular death was defined as death related to cardiovascular disease or death that could be calculated using all-cause mortality minus noncardiovascular-related death. We used nonfatal myocardial infarction and stroke if they were indicated or could be calculated, and we used total (fatal and nonfatal) myocardial infarction and stroke as outcomes if the numbers of nonfatal myocardial infarction and stroke could not be derived. Revascularization included any percutaneous coronary intervention or coronary artery bypass grafting reported in the clinical trials. The overall cardiovascular events were calculated as the aggregation of cardiovascular death, myocardial infarction, stroke, and revascularization. We assessed the quality of the included studies using the Jadad scale, which measures the methodologic quality of randomized clinical trials on a scale of 0 to 5, with 0 indicating very low and 5 indicating rigorous quality. This scale assesses the risk of bias based on 3 domains: randomization (including mention of randomization and appropriate method of randomization), blinding (including mention of blinding and appropriate blinding), and consideration of all patients (ie, the outcomes of all patients in the clinical trial are known and, if no data are reported, the reason for missing data is stated). A study could be assigned a maximum of 2 points each for the domains of randomization and blinding and 1 point for the domain of consideration of all patients, for a possible maximum score of 5. Two of us (J.W. and A.J.K.) conducted the quality assessment and assigned quality scores (continuous measure) for each study. Studies scoring 3 or more points were deemed to have a low risk of bias, and studies scoring less than 3 points were deemed to have a high risk of bias. Data Synthesis and Analysis The analysis was conducted from October 2017 to December 2019. We first conducted a pairwise meta-analysis of placebo-clinical trials to estimate the direct effect on reducing cardiovascular events JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 3/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications reported for each agent compared with placebo. The risk difference (per 1000 persons) and the numbers needed to treat were calculated for each type of medication. We conducted a frequentist network meta-analysis with random-effects models to estimate the aggregate reductions in cardiovascular events and revascularization for each type of antihypertension medication compared with placebo and with each other. We used Stata software, version 14.0 (StataCorp), for all analyses using the network command. This approach is an extension of the method proposed by DerSimonian and Laird, and the performance of this model has been satisfactory. The model contains a component of inconsistency variance, which is a source of variation in addition to between-study heterogeneity. We reported risk ratios (RRs) and corresponding 95% CIs, and we calculated a pooled RR and 95% CI for each intervention group separately from each placebo group. For each medication class, we assessed heterogeneity across studies using the maximum likelihood method. We examined the magnitude of a common heterogeneity variance for the network (τ ) as an indicator of the extent of heterogeneity among included studies in terms of the range of expected treatment estimates (RRs and 95% CIs). Any τ values under 0.25 were considered acceptable heterogeneity; values between 0.25 and 1.0 represented moderately high heterogeneity; and values greater than 1.0 represented very high heterogeneity. We assessed the general within-network inconsistency between direct effects (comparison between specific agents and placebo) and indirect comparisons (comparisons other than direct within each outcome) for each outcome using χ tests. If no general inconsistency was detected, the inconsistency between each of 2 agents was tested by calculating the differences in direct effects 17,18 and indirect comparisons using their SEs. We considered evidence of inconsistency if P values were less than .05. We assessed potential publication bias by inspecting the symmetry of funnel plots for each outcome. We conducted metaregression analyses to examine the dose-response relationship between each within-treatment 10–mm Hg reduction in systolic blood pressure and 5–mm Hg reduction in diastolic blood pressure (regardless of intervention groups) over time and to assess the incidence of cardiovascular events (including overall and individual types of cardiovascular events, with the log RRs of cardiovascular events as dependent variables). The coefficient of metaregression was 2 2 2 weighted by 1 divided by the sum of σ and τ , with σ representing the SE of the estimated effect in i i 2 20 the particular clinical trial and with τ representing the between-study variance. In addition, we reported rates of adverse effects, such as edema, headache, cough, and hypotension or dizziness, that are associated with antihypertension medications and placebo among studies with available information. Results Our systematic search yielded 4933 articles (Figure 1). We identified an additional 71 articles from bibliographies of relevant reports and reviews. In total, the systematic review and network meta- analysis included 47 published articles from 46 clinical trials, with 248 887 participants and 28 658 first-in-trial cardiovascular events. Owing to the small number of studies reporting different medication combination permutations and non–DH CCBs, we did not report data for fixed-dose antihypertension combination medications in the network meta-analysis. Figure 2 shows the network plot depicting the different antihypertension medication classes and comparisons tested. Among included studies, 15 tested ACE inhibitors, 23 tested DH CCBs, 4 tested non–DH CCBs, 8 tested β-blockers, 12 tested ARBs, and 13 tested thiazide diuretics. Four studies were from North America, 18 from Europe, 16 from Asia, 1 from Oceania, and 7 from multiple regions across continents. The mean (SD) age of participants was 65.6 (5.8) years (range, 51.8-83.8 years), and 52.8% (range, 28.2%-100.0%) were men. The mean (SD) baseline systolic blood pressure was 161.3 (13.6) mm Hg (range, 129-195 mm Hg). A total of 14 studies included placebo, health education, or JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 4/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications conventional education in their control groups, and 35 studies reported direct treatment comparisons (3 of which included placebo and 2 treatment agents). The mean (SD) follow-up time was 3.7 (1.5) years (range, 1.0-10.0 years). Across all included clinical trials with particular classes of antihypertension medications, the frequency of use for each type of antihypertension medication Figure 1. PRISMA Diagram of Literature Search and Selection 4933 Articles identified from 3 databases 71 Articles identified from other sources 2905 Articles from PubMed 1968 Articles from Embase 60 Articles from Cochrane Library 749 Duplicates excluded 4255 Articles screened 4043 Excluded (case report or review, not a randomized clinical trial, no comparison group, no conclusive outcomes, special population [pregnant, diabetic nephropathy, or end-stage renal disease], or follow-up <6 mo) 212 Articles reviewed for full text 165 Excluded (subanalysis for an included study, all groups of drugs in same class, or not focused on patients with hypertension) Reasons for exclusion were not categorized by individual article because each article may have met 47 Included in qualitative and quantitative analyses multiple exclusion criteria. Figure 2. Network Plot of Antihypertension Medications ACEi + DH CCB + diuretic ACEi + non-DH CCB ARB ACEi + DH CCB ACEi + diuretic ARB + diuretic BB ACEi Non-DH CCB BB + diuretic DH CCB + ARB ACEi indicates angiotensin-converting enzyme Diuretic inhibitor; ARB, angiotensin receptor blocker; BB, β-blocker; DH CCB, dihydropyridine calcium channel blocker; and non–DH CCB, nondihydropyridine calcium Placebo DH CCB channel blocker. JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 5/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications was similar between studies, with the participants’ mean age above and below 65 years. By region of study, ACE inhibitors, β-blockers, and diuretics were more frequently used in Europe, DH CCBs were more frequently used in Asia and Europe, and ARBs were more frequently used in Asia. The prevalence of baseline cardiovascular disease and diabetes was similar among participants using each class of antihypertension medications. The characteristics of all 46 included studies are available in eTable 1 in the Supplement. For all 46 clinical trials included in the analysis, the mean (SD) overall systolic and diastolic blood pressure changes among those reported were −18.0 (8.7) mm Hg and −10.1 (4.7) mm Hg, respectively. The overall risk of cardiovascular events was 11.5%. Among the adverse effect profile, edema was prevalent among 0.5% of participants receiving ACE inhibitors, 17.1% of participants receiving DH CCBs or non–DH CCBs, 8.7% of participants receiving β-blockers, 15.1% of participants receiving ARBs, 9.9% of participants receiving diuretics, and 3.7% of participants receiving placebo. Cough was prevalent among 8.3% of participants receiving ACE inhibitors, 9.6% of participants receiving DH CCBs or non–DH CCBs, 4.1% of participants receiving β-blockers, 2.7% of participants receiving ARBs, 5.4% of participants receiving diuretics, and 16.1% of participants receiving placebo. Headache or hypotension was prevalent among 0.7% of participants receiving ACE inhibitors, 7.9% of participants receiving DH CCBs or non–DH CCBs, 1.4% of participants receiving β-blockers, 10.8% of participants receiving ARBs, 7.4% of participants receiving diuretics, and 8.8% of participants receiving placebo. Dizziness was prevalent among 1.7% of participants receiving ACE inhibitors, 7.5% of participants receiving DH CCBs or non–DH CCBs, 9.1% of participants receiving β-blockers, 14.8% of participants receiving ARBs, 9.0% of participants receiving diuretics, and 10.2% of participants receiving placebo. Comparative Efficacy An assessment of the absolute risk differences in cardiovascular events among placebo-clinical trials that compared antihypertension medications with placebo indicated that all 5 types of antihypertension medications were associated with larger decreases in cardiovascular events than placebo. Compared with placebo, DH CCBs were reported to reduce the risk of cardiovascular death by 7 cases per 1000 persons; ACE inhibitors and diuretics were reported to decrease myocardial infarction risk by 24 cases and 10 cases per 1000 persons, respectively; and DH CCBs and diuretics were reported to reduce stroke risk by 16 cases and 21 cases per 1000 persons, respectively (eTable 2 in the Supplement). Based on these results, 143 people would need to be treated with DH CCBs to prevent 1 cardiovascular death. To prevent 1 myocardial infarction, 42 people would need to be treated with ACE inhibitors and 100 people with diuretics. To prevent 1 stroke, 63 people would need to be treated with DH CCBs and 48 people with diuretics. Network Meta-analysis In the network meta-analysis comparing placebo vs medication groups, for cardiovascular death, we noted that ACE inhibitors, DH CCBs, ARBs, and diuretics were all associated with 15% to 22% relative risk reductions. The specific relative risk reductions were as follows: for ACE inhibitors, 20% reduction (95% CI, 9%-30%; RR, 0.80; 95% CI, 0.70-0.91); for DH CCBs, 20% reduction (95% CI, 11%-29%; RR, 0.80; 95% CI, 0.71-0.89); for ARBs, 15% reduction (95% CI, 3%-26%; RR, 0.85; 95% CI, 0.74-0.97); and for diuretics, 22% reduction (95% CI, 12%-31%; RR, 0.78; 95% CI, 0.69-0.88). For myocardial infarction, ACE inhibitors, DH CCBs, and β-blockers were associated with 20% to 28% relative risk reductions. The specific relative risk reductions were as follows: for ACE inhibitors, 28% reduction (95% CI, 12%-41%; RR, 0.72; 95% CI, 0.59-0.88); for DH CCBs, 21% reduction (95% CI, 4%-34%; RR, 0.79; 95% CI, 0.66-0.96); and for β-blockers, 20% reduction (95% CI, 1%-35%; RR, 0.80; 95% CI, 0.65-0.99). For stroke, all classes of medications were associated with 19% to 39% relative risk reductions. The specific relative risk reductions were as follows: for ACE inhibitors, 34% reduction (95% CI, 20%-45%; RR, 0.66; 95% CI, 0.55-0.80); for DH CCBs, 39% reduction (95% CI, 30%-48%; RR, 0.61; JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 6/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications 95% CI, 0.52-0.70); for β-blockers, 20% reduction (95% CI, 2%-33%; RR, 0.80; 95% CI, 0.67-0.98); for ARBs, 31% reduction (95% CI, 17%-42%; RR, 0.69; 95% CI, 0.58-0.83); and for diuretics, 37% reduction (95% CI, 24%-47%; RR, 0.63; 95% CI, 0.53-0.76). For revascularization, diuretics were associated with a 33% relative risk reduction (95% CI, 5%-53%; RR, 0.67; 95% CI, 0.47-0.95). For overall cardiovascular events, all classes of medications were each associated with a 17% to 29% relative risk reduction (Figure 3). The specific relative risk reductions were as follows: for ACE inhibitors, 29% reduction (95% CI, 17%-40%; RR, 0.71; 95% CI, 0.60-0.83); for DH CCBs, 27% reduction (95% CI, 16%-36%; RR, 0.73; 95% CI, 0.64-0.84); for β-blockers, 17% reduction (95% CI, 2%-30%; RR, 0.83; 95% CI, 0.70-0.98); for ARBs, 21% reduction (95% CI, 6%-33%; RR, 0.79; 95% CI, 0.67-0.94); and for diuretics, 27% reduction (95% CI, 15%-38%; RR, 0.73; 95% CI, 0.62-0.85). These data indicate that, according to effect sizes, ACE inhibitors, DH CCBs, and diuretics were associated with similarly significant reductions in the risk of overall cardiovascular events and cardiovascular death. The greatest reductions in myocardial infarction risk were associated with ACE inhibitors, and DH CCBs and diuretics were associated with similarly significant reductions in the risk of stroke. Diuretics were associated with similarly significant reductions in the risk of revascularization. However, their 95% CIs overlapped. Figure 3. Network Meta-analysis Comparing Single Class of Antihypertension Medications With Placebo for Treatment of Cardiovascular Events A Cardiovascular death B Myocardial infarction Risk Ratio Risk Ratio Agent (95% CI) Less Risk More Risk Agent (95% CI) Less Risk More Risk ACE inhibitor 0.80 (0.70-0.91) ACE inhibitor 0.72 (0.59-0.88) DH CCB 0.80 (0.71-0.89) DH CCB 0.79 (0.66-0.96) ß Blocker 0.99 (0.87-1.13) ß Blocker 0.80 (0.65-0.99) ARB 0.85 (0.74-0.97) ARB 0.89 (0.72-1.10) Diuretic 0.78 (0.69-0.88) Diuretic 0.82 (0.67-1.00) 0 0.5 1.0 1.5 0.5 1.0 1.5 Risk Ratio Risk Ratio C Stroke D Revascularization Risk Ratio Risk Ratio Agent (95% CI) Less Risk More Risk Agent (95% CI) Less Risk More Risk ACE inhibitor 0.66 (0.55-0.80) ACE inhibitor 0.73 (0.50-1.06) DH CCB 0.61 (0.52-0.70) DH CCB 0.70 (0.48-1.03) ß Blocker 0.80 (0.67-0.98) ß Blocker 0.84 (0.56-1.25) ARB 0.69 (0.58-0.83) ARB 0.72 (0.49-1.07) Diuretic 0.63 (0.53-0.76) Diuretic 0.67 (0.47-0.95) 0.4 0.6 0.8 1.0 1.2 0.4 0.7 1.0 1.3 Risk Ratio Risk Ratio E Overall cardiovascular events Risk Ratio Agent (95% CI) Less Risk More Risk ACE inhibitor 0.71 (0.60-0.83) DH CCB 0.73 (0.64-0.84) ß Blocker 0.83 (0.70-0.98) ARB 0.79 (0.67-0.94) Diuretic 0.73 (0.62-0.85) 0 0.5 1.0 1.5 Risk Ratio ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; DH CCB, dihydropyridine calcium channel blocker; and error bars, 95% CI. JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 7/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications Consistency, Heterogeneity, Bias, and Sensitivity In terms of the risk of bias assessment, we found that studies were of moderate quality (mean score, 4.0 of 5.0 possible points), in which randomization had a mean (SD) score of 1.8 (1.0) of 2.0 points, blinding had a mean (SD) score of 1.1 (0.5) of 2.0 points, and consideration of all patients had a mean (SD) score of 1.0 (1.0) of 1.0 point. No study was considered to have a high risk of bias. Visual examination of funnel plots indicated that no significant publication bias was present for cardiovascular death, myocardial infarction, stroke, revascularization, and overall cardiovascular events (eFigure 1 in the Supplement). No general inconsistency of treatment effect on each outcome was found, with all P values greater than .05. By individual treatment, no significant inconsistency was detected among different classes of antihypertension medications (eTable 3 in the Supplement). No significant treatment effect heterogeneity was detected, as none of the τ values was equal to or greater than 0.25 (eFigure 2 in the Supplement). In metaregressions of blood pressure reduction with cardiovascular events, blood pressure reduction was associated with reductions in cardiovascular events. In particular, each 10–mm Hg reduction in systolic blood pressure was significantly associated with a 13% lower risk of cardiovascular death (RR, 0.87; 95% CI, 0.77-0.99), a 17% lower risk of stroke (RR, 0.83; 95% CI, 0.72-0.97), and a 14% lower risk of overall cardiovascular events (RR, 0.86; 95% CI, 0.78-0.96). Each 5–mm Hg reduction in diastolic blood pressure was significantly associated with a 14% lower risk of cardiovascular death (RR, 0.86; 95% CI, 0.74-1.00), a 20% lower risk of stroke (RR, 0.80; 95% CI, 0.67-0.95), and a 16% lower risk of overall cardiovascular events (RR, 0.84; 95% CI, 0.74-0.96; eTable 4 in the Supplement). Discussion From 46 randomized clinical trials that examined the effect of the most commonly used antihypertension medications on preventing cardiovascular events, pooled results showed that ACE inhibitors, DH CCBs, and diuretics were reported to be similarly effective in preventing cardiovascular death (approximately 20% reduction compared with placebo), stroke (approximately 35% reduction compared with placebo), and overall cardiovascular events (approximately 30% reduction compared with placebo). Angiotensin-converting enzyme inhibitors were reported to be the most effective in preventing myocardial infarction (approximately 30% reduction compared with placebo). Diuretics were reported to be the most effective in reducing revascularization (approximately 30% compared with placebo). Our study provides the most current evidence to date on the comparative efficacy of antihypertension medications reported to reduce cardiovascular events in randomized clinical trials. Furthermore, to our knowledge, this is the first meta-analysis to pool the results of studies that tested the efficacy of antihypertension medications in reducing the risk of revascularization. Our results are consistent with those reported in previous meta-analyses of randomized clinical 8,9 9 trials. Psaty et al found that low-dose diuretics were reported to be the most effective treatment for preventing the occurrence of cardiovascular mortality. Law et al indicated that for stroke, all antihypertension medication classes were reported to have similar risk reduction effects for a given reduction in blood pressure. Our findings further supported the evidence indicating that the reported differences of the effects on reducing cardiovascular events between medication classes are small. We also provided more up-to-date information regarding the reported efficacy of antihypertension medications in reducing cardiovascular events. A recent systematic multinational analysis, the Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Hypertension (LEGEND-HTN) study, used observational data encompassing millions of patients and found that diuretics were associated with advantages in reducing various cardiovascular events compared with other classes of medications. This finding is different than that of our study, which indicated that diuretics had similar reported effectiveness in reducing cardiovascular events compared with ACE inhibitors and DH CCBs and that ACE inhibitors appeared to be most effective in JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 8/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications reducing myocardial infarction. The difference in findings may be owing to the varied study designs (randomized clinical trials vs observational studies), and it is not clear to what extent the LEGEND-HTN study may be subject to selection bias. Network meta-analysis allowed us to compare medication classes with placebo both directly (ie, among the included placebo-clinical trials) and indirectly (ie, among all of the included studies). The comparisons between medications and placebo indicated slight differences between direct and overall comparisons. The network comparisons were more precise (ie, they had narrower 95% CIs). It is also worth noting that the association between decreasing blood pressure and reduced 22,23 cardiovascular events was smaller than that obtained from observational studies. The reason may be that most participants in clinical trials, including those receiving placebo, were motivated to reduce their blood pressure and, in a number of cases, were also treated with other medications. In addition, participants’ motivation may have led them to engage in healthy lifestyle habits, such as choosing healthier diet patterns, exercising, and avoiding tobacco and alcohol use. Dietary modification can and should be a complementary effort in trying to reduce BP and many dietary patterns are supported by robust evidence. This finding also calls for future studies that examine the associations between antihypertension medications and lifestyle in preventing cardiovascular events among patients with hypertension. However, although the effect size for the association between decreasing blood pressure and reduced cardiovascular events was small, some of the differences were statistically significant. Limitations Our study was limited by the relatively small number of studies included in the network meta- analysis, so we lacked the statistical power to conduct subgroup analyses to examine whether the association of antihypertension medications with reduced cardiovascular events could be the consequence of different factors (eg, age, sex, or baseline blood pressure level). Although the results from this analysis may serve as a source of reference, a comprehensive study based on demographic factors and comorbidities is needed to assess which class of antihypertension medication should be recommended for reducing adverse cardiovascular outcomes. The newly published American College of Cardiology and American Heart Association guidelines for hypertension identify a wider range of individuals with early hypertension and prehypertension, and our study can guide first-line medication choices. In addition, the 46 clinical trials we studied were mostly performed in North America, western Europe, and East Asia, and more data are needed regarding patients in South Asia and Africa, which cumulatively compose a large proportion of the world’s population. Another important limitation of our study is that we did not include results for combinations of antihypertension medications because there were too few studies with data for each permutation of combinations. However, this lack of studies suggests that the efficacy of several groups of combinations, such as β-blockers and diuretics, will need to be studied more frequently in the future. Recent findings have indicated that treatment with low doses of 3 antihypertensive medications is associated with an increased proportion of patients who achieved target blood pressure compared with standard care, and quarter-dose therapies with combined medications were reported to be more effective, with fewer adverse events, in reducing blood pressure compared with standard monotherapy. Conclusions The present network meta-analysis indicated that major first-line antihypertension medications, including ACE inhibitors, DH CCBs, β-blockers, ARBs, and diuretics, were all reported to be effective in reducing cardiovascular events compared with placebo. Furthermore, ACE inhibitors, DH CCBs, and diuretics appeared to be similarly effective in reducing cardiovascular deaths, stroke, and overall cardiovascular events. Compared with other antihypertension medications, ACE inhibitors appeared to be the medications of choice to prevent myocardial infarction, and diuretics appeared to be the JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 9/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications optimal choice to reduce revascularization. The differences between medication classes were generally small in terms of their associations with reducing cardiovascular events. Future studies should compare the effectiveness of multiple antihypertension medications in combination with individual antihypertension medications in reducing cardiovascular events. ARTICLE INFORMATION Accepted for Publication: December 18, 2019. Published: February 21, 2020. doi:10.1001/jamanetworkopen.2019.21618 Open Access: This is an open access article distributed under the terms of the CC-BY License.©2020WeiJetal. JAMA Network Open. Corresponding Author: Jingkai Wei, MSPH, PhD, Department of Epidemiology, Milken Institute School of Public Health, George Washington University, 950 New Hampshire Ave NW, Washington, DC 20052 (jwei25@gwu.edu). Author Affiliations: Department of Epidemiology, Milken Institute School of Public Health, George Washington University, Washington, DC (Wei); Emory Global Diabetes Research Center, Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia (Galaviz, Magee, Narayan, Ali); Nutrition and Health Sciences Doctoral Program, Laney Graduate School, Emory University, Atlanta, Georgia (Kowalski); Division of Endocrinology, Metabolism and Lipids, Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia (Haw); Department of Family and Preventive Medicine, School of Medicine, Emory University, Atlanta, Georgia (Ali). Author Contributions: Dr Wei had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Galaviz, Magee, Haw, Narayan, Ali. Acquisition, analysis, or interpretation of data: Wei, Galaviz, Kowalski, Magee, Narayan, Ali. Drafting of the manuscript: Wei. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Wei, Galaviz, Magee. Obtained funding: Ali. Administrative, technical, or material support: Kowalski, Ali. Supervision: Galaviz, Haw, Narayan, Ali. Conflict of Interest Disclosures: Dr Galaviz reported receiving grants from the Institute for Health Metrics and Evaluation during the conduct of the study. Dr Ali reported receiving grants from Merck & Co outside the submitted work. No other disclosures were reported. Funding/Support: This project was funded by Disease Control Priorities Network grant UWSC7007 from the Bill & Melinda Gates Foundation and partially supported by grant P30DK111024 from the National Institute of Diabetes and Digestive and Kidney Diseases (Drs Narayan, Galaviz, and Ali). Role of the Funder/Sponsor: The funding sources 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. REFERENCES 1. Forouzanfar MH, Alexander L, Anderson HR, et al; GBD 2013 Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(10010):2287-2323. doi:10.1016/S0140-6736(15)00128-2 2. World Health Organization. Cardiovascular diseases (CVDs). World Health Organization website. https://www. who.int/mediacentre/factsheets/fs317/en/. Published May 17, 2017. Accessed July 1, 2017. 3. Franklin SS, Wong ND. Hypertension and cardiovascular disease: contributions of the Framingham heart study. 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Effects of different dietary interventions on blood pressure: systematic review and meta-analysis of randomized controlled trials. Hypertension. 2016;67(4):733-739. doi:10.1161/ HYPERTENSIONAHA.115.06853 SUPPLEMENT. eMethods. Search Terms eTable 1. Cardiovascular Events and Outcomes by Randomized Treatment eTable 2. Absolute Risk Differences of Cardiovascular Events Comparing Each Type of Antihypertension Medication to Placebo From Network Meta-analysis eTable 3. Inconsistency Test Between Direct and Indirect Treatment Comparisons in Mixed Treatment Comparisons eTable 4. Bivariate Meta-regression on the 10 mm Hg Reduction of Blood Pressure and Change of Cardiovascular Events eFigure 1. Funnel Plots of Studies of Antihypertension Medications and Effects of Prevention on Cardiovascular Death, Myocardial Infarction, Stroke, Revascularization, and Overall Cardiovascular Events eFigure 2. Inconsistency Plots of Studies of Antihypertension Medications and Effects of Prevention on Cardiovascular Death, Myocardial Infarction, Stroke, Revascularization, and Overall Cardiovascular Events eReferences. JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 12/12 Supplementary Online Content Wei J, Galaviz KI, Kowalski AJ, Magee MJ, Haw JS, Narayan KMV, Ali MK. Comparison of cardiovascular events among users of different classes of antihypertension drugs: a systematic review and network meta- analysis. JAMA Netw Open. Published February 21, 2020. doi:10.1001/jamanetworkopen.2019.21618 eMethods. Search Terms eTable 1. Cardiovascular Events and Outcomes by Randomized Treatment eTable 2. Absolute Risk Differences of Cardiovascular Events Comparing Each Type of Blood Pressure Lowering Drug to Placebo From Network Meta-analysis eTable 3. Inconsistency Test Between Direct and Indirect Treatment Comparisons in Mixed Treatment Comparisons eTable 4. Bivariate Meta-regression on the 10 mm Hg Reduction of Blood Pressure and Change of Cardiovascular Events eFigure 1. Funnel Plots of Studies of Blood Pressure Lowering Drugs and Effects of Prevention on Cardiovascular Death, Myocardial Infarction, Stroke, Revascularization, and Overall Cardiovascular Events eFigure 2. Inconsistency Plots of Studies of Blood Pressure Lowering Drugs and Effects of Prevention on Cardiovascular Death, Myocardial Infarction, Stroke, Revascularization, and Overall Cardiovascular Events eReferences. This supplementary material has been provided by the authors to give readers additional information about their work. © 2020 Wei J et al. JAMA Netw Open. All rights reserved. eMethods. Search Terms ("hypertension"[MeSH Terms] OR "hypertension"[All Fields]) AND (("antihypertensive agents"[Pharmacological Action] OR "antihypertensive agents"[MeSH Terms] OR "antihypertensive agents"[All Fields]) OR ("sodium chloride symporter inhibitors"[Pharmacological Action] OR "sodium chloride symporter inhibitors"[MeSH Terms] OR "sodium chloride symporter inhibitors"[All Fields]) OR "thiazide diuretics"[All Fields] OR ("adrenergic beta-antagonists"[Pharmacological Action] OR "adrenergic beta- antagonists"[MeSH Terms] OR "adrenergic beta-antagonists"[All Fields]) OR ("angiotensin-converting enzyme inhibitors"[Pharmacological Action] OR "angiotensin-converting enzyme inhibitors"[MeSH Terms] OR "angiotensin-converting enzyme inhibitors"[All Fields]) OR ("angiotensin receptor antagonists"[Pharmacological Action] OR "angiotensin receptor antagonists"[MeSH Terms] OR "angiotensin receptor antagonists"[All Fields]) OR ("calcium channel blockers"[Pharmacological Action] OR "calcium channel blockers"[MeSH Terms] OR "calcium channel blockers"[All Fields]) OR ("vasodilator agents"[Pharmacological Action] OR "vasodilator agents"[MeSH Terms] OR "vasodilator agents"[All Fields])) AND ((Controlled Clinical Trial[ptyp] OR Randomized Controlled Trial[ptyp]) AND "humans"[MeSH Terms] AND "adult"[MeSH Terms]) AND ("1990/01/01"[PDAT] : "2030/12/31"[PDAT]) © 2020 Wei J et al. JAMA Netw Open. All rights reserved. eTable 1. Cardiovascular Events and Outcomes by Randomized Treatment Study Sample Follow-Up Treatment Cardiovascular Events Age Male, % Region Size Time Death MI Stroke CABG/PCI 1 * DEMAND, 2011 126 3 years 0 - - - 60.2 61.9 Italy ACEi/DH CCB Slovenia 127 ACEi 0 - - - 61.9 64.6 127 Placebo 2 - - - 60.4 69.3 FEVER, 2005 4841 40 months DH CCB 73 - 177 4 61.5 61.8 China 4870 Placebo 101 - 251 11 61.5 60.5 MRC, 1992 1081 5.8 years Diuretics 66 - 45 - 70 42.0 UK 1102 BB 95 - 56 - 70 41.4 2213 Placebo 180 - 134 - 70 41.8 SHEP, 1991 2365 4.5 years Diuretics 90 50 96 49 71.6 43.7 US 2371 Placebo 112 74 149 69 71.5 42.7 STOP, 1991 812 25 months BB/Diuretics 36 19 26 - 75.6 37 Sweden 815 Placebo 63 22 41 - 75.7 37 Syst-China, 1998 1253 2 years DH CCB 33 4 35 - 66.4 63.6 China 1141 Placebo 44 4 41 - 66.7 65 Syst-Eur, 1997 2398 2 years DH CCB 59 26 34 - 70.3 32.5 Europe 2297 Placebo 77 31 57 - 70.2 33.8 Sun, Ming, 1997 1040 10 years DH CCB - - 37 - 51.8 53.0 China 1040 Placebo - - 79 - Sun, Z. Q, 2010 2530 15 months ACEi/Diuretics/DH - - 24 - 56.4 43.8 China CCB 2454 Education - - 52 - 56.2 41.8 HYVET Pilot, 2003 426 13 months Diuretics 23 - - - 83.8 37.1 Europe 431 ACEi 22 - - - 83.7 36.0 426 Standard 19 - - - 83.8 36.6 11,12 UKPDS, 1998 400 9 years ACEi - 61 21 - 56.3 51.0 UK 358 BB - 46 17 - 56 57.0 390 Standard - 69 34 - 56.5 58.0 ABCD, 1998 235 67 months DH CCB 10 22 11 - 57.2 68.1 US 235 ACEi 5 5 7 - 57.7 66.8 ACCOMPLISH, 2008 5744 3 years ACE/DH CCB 107 125 112 334 68.4 60.0 US Europe 5762 ACE/Diuretics 134 159 133 386 68.3 61.0 ALLHAT, 2002 15255 4.9 years Diuretics 992 - 675 1113 66.9 53.0 US 9048 DH CCB 592 - 377 725 66.9 52.7 9054 ACEi 609 - 457 718 66.9 53.8 ASCOT, 2005 9639 5.5 years DH CCB 263 429 327 167 63 77.0 Europe © 2020 Wei J et al. JAMA Netw Open. All rights reserved. 9618 BB 342 474 422 214 63 77.0 BENEDICT-B, 2011 138 4.5 years ACEi/Non-DH CCB 2 2 4 6 62.3 75.4 Italy 143 ACEi 7 1 4 7 62.4 72.0 COLM, 2014 2568 3.3 years DH CCB/ARB 13 9 60 - 73.6 51.5 Japan 2573 Diuretics/ARB 18 16 62 - 73.6 51.7 CONVINCE, 2003 8179 3 years Non-DH CCB 152 133 133 - 65.6 43.8 Multiple 8297 BB/Diuretics 143 128 166 - 65.6 46.2 ELSA, 2002 1157 4 years BB 8 17 14 - 55.9 55.4 Europe 1177 DH CCB 4 18 9 - 56.1 54.2 FACET, 1998 189 3.5 years ACEi - 10 4 7 62.8 63.5 Italy 191 DH CCB - 13 10 8 63.3 55.5 GLANT, 1995 980 1 year ACEi 1 1 5 - 60 44.4 Japan 956 DH CCB 0 0 11 - 60 44.0 INSIGHT, 2000 3157 51 months DH CCB 60 61 55 - 65 46.1 Europe 3164 Diuretics 52 56 63 - 46.6 Israel INVEST, 2003 11267 2 years Non-DH CCB 431 151 131 280 66 48.1 Multiple 11309 BB 431 153 148 275 66.1 47.7 J-MIND, 2001 228 2 years DH CCB - 1 5 - 60.2 48.7 Japan 208 ACEi - 1 2 - 59.9 52.4 JMIC-B, 2003 828 3 years DH CCB 6 16 16 81 65 67.6 Japan 822 ACEi 6 13 16 75 64 70.0 LIFE, 2002 4605 4.8 years ARB 204 198 232 261 66.9 46.0 US 4508 BB 234 188 309 284 66.9 46.0 Europe MAPHY, 1991 1609 5 years BB 29 82 21 6 40 to 100 Europe 1625 Diuretics 34 109 18 8 64 100 MIDAS, 1996 442 3 years DH CCB 3 6 6 11 58.2 79.9 US 441 Diuretics 3 5 3 10 58.7 75.7 MOSES, 2005 681 2.5 years ARB - - 236 - 67.7 53.6 Germany 671 DH CCB - - 134 - 68.1 54.8 Austria NAGOYA HEART, 2012 575 3.2 years ARB - 7 13 29 63 66.0 Japan 575 DH CCB - 3 16 26 63 66.0 NICS-EH, 1999 204 5 years DH CCB 2 2 1 - 69.7 40.2 Japan 210 Diuretics 0 2 0 - 69.9 26.2 NORDIL, 2000 5410 4.5 years Non-DH CCB - 183 159 - 60.5 48.5 Sweden 5471 Diuretics/BB - 157 196 - 60.3 48.7 Norway OSCAR, 2012 578 3 years ARB - - 24 - 73.6 43.9 Japan 586 ARB/DH CCB - - 15 - 73.6 44.5 PATE, 2000 699 3 years ACEi - 1 11 - 70 38.3 Japan 1049 DH CCB - 5 17 - 69 43.3 © 2020 Wei J et al. JAMA Netw Open. All rights reserved. SHELL, 2003 940 32 months Diuretics 13 14 38 4 72.4 37.8 Italy 942 DH CCB 16 12 37 2 72.3 39.6 STOP-2, 1999 2213 4 years Diuretics/BB 221 154 237 - 76 32.0 Sweden 2205 ACEi 226 139 215 - 76.1 33.7 2196 DH CCB 212 179 207 - 75.9 34.0 VALUE, 2004 7649 4.2 years ARB 304 369 322 - 67.2 57.6 Multiple 7596 DH CCB 304 313 281 - 67.3 57.5 VART, 2011 510 3.4 years ARB 0 2 10 - 60 56.9 Japan 511 DH CCB 0 1 10 - 60 57.5 VHAS, 1997 707 2 years Diuretics 4 5 4 3 53.9 50.1 Italy 707 Non-DH CCB 5 5 3 4 54.5 47.8 SANBPS, 2003 3044 4.1 years ACEi 84 50 91 - 72 50 Australia 3039 Diuretics 82 71 94 - 71.9 48 CTHPCETG, 2011 1110 3.6 years ARB - - 17 - 63 51.0 Japan 1089 BB - - 27 - 63.2 50.5 1094 Diuretics - - 12 - 63.1 50.5 E-COST, 2005 1053 3.1 years ARB 0 10 47 - - 44.5 Japan 995 Conventional 0 23 77 - - 51.8 HYVET, 2014 1922 1.8 years ACE/Diuretics 88 9 23 - 83.5 39.5 Multiple 1900 Placebo 110 11 28 - CAPPP, 1999 5492 6.1 years ACEi 70 137 173 - 52.4 54.9 Sweden 5493 BB/Diuretics 81 128 127 - 52.7 52.0 SCOPE, 2003 2477 3.7 years ARB 145 54 68 - 76.4 35.2 Europe 2460 Placebo 152 47 93 - 76.4 35.8 HIJ-CREATE, 2009 1024 4.2 years ARB 28 29 45 256 65.0 81.8 Japan 1025 ACEi 25 26 49 271 64.5 78.6 Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; DH CCB, dihydropyridine calcium channel blocker; nDH CCB: BB, beta blocker; ARB, angiotensin receptor blocker; MI, myocardial infarction; CABG, coronary artery bypass surgery; PCI, percutaneous coronary intervention. © 2020 Wei J et al. JAMA Netw Open. All rights reserved. eTable 2. Absolute Risk Differences of Cardiovascular Events Comparing Each Type of Blood Pressure Lowering Drug to Placebo From Network Meta-analysis Drug Cardiovascular Death Myocardial Infarction Stroke Revascularization Overall ACEi vs. placebo -0.005 (-0.027, 0.016) -0.024 (-0.036, -0.011) -0.035 (-0.070, 0.001) - -0.037 (-0.082, 0.009) DH CCB vs. placebo -0.007 (-0.011, -0.003) -0.001 (-0.005, 0.003) -0.016 (-0.025, -0.006) -0.001 (-0.003, 0.0001) -0.013 (-0.031, 0.005) BB vs. placebo 0.005 (-0.015, 0.025) -0.048 (-0.100, 0.003) -0.020 (-0.048, 0.008) - -0.042 (-0.123, 0.039) ARB vs. placebo -0.000 (-0.002, 0.002) -0.005 (-0.021, 0.011) -0.020 (-0.041, 0.002) - -0.028 (-0.063, 0.007) Diuretics vs. placebo -0.010 (-0.022, 0.003) -0.010 (-0.019, -0.001) -0.021 (-0.031, -0.011) -0.008 (-0.017, 0.0005) -0.028 (-0.061, 0.005) Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; DH CCB, dihydropyridine calcium channel blocker; BB, beta blocker; ARB, angiotensin receptor blocker. © 2020 Wei J et al. JAMA Netw Open. All rights reserved. eTable 3. Inconsistency Test Between Direct and Indirect Treatment Comparisons in Mixed Treatment Comparisons Cardiovascular Mortality Side Direct Indirect Difference p>z Coefficient SE Coefficient SE Coefficient SE ACEi placebo 0.04 0.30 -0.23 0.07 0.28 0.31 0.37 DH CCB placebo -0.33 0.10 -0.18 0.07 -0.15 0.12 0.22 BB placebo 0.05 0.12 -0.03 0.08 0.08 0.15 0.57 ARB placebo -0.05 0.11 -0.23 0.09 0.18 0.14 0.20 Diuretics placebo -0.20 0.09 -0.30 0.08 0.10 0.13 0.42 Myocardial Infarction Side Direct Indirect Difference p>z Coefficient SE Coefficient SE Coefficient SE ACEi placebo -0.15 0.18 -0.41 0.13 0.26 0.22 0.24 DH CCB placebo -0.20 0.26 -0.23 0.11 -0.03 0.28 0.91 BB placebo -0.29 0.19 -0.19 0.13 -0.10 0.23 0.67 ARB placebo -0.11 0.19 -0.12 0.13 0.01 0.23 0.95 Diuretics placebo -0.39 0.20 -0.12 0.12 -0.27 0.23 0.25 Stroke Side Direct Indirect Difference p>z Coefficient SE Coefficient SE Coefficient SE ACEi placebo -0.54 0.30 -0.40 0.10 -0.15 0.32 0.56 DH CCB placebo -0.46 0.11 -0.54 0.11 0.09 0.15 0.57 BB placebo -0.29 0.17 -0.18 0.12 -0.12 0.21 0.58 ARB placebo -0.43 0.15 -0.33 0.11 -0.09 0.19 0.63 Diuretics placebo -0.41 0.14 -0.50 0.12 0.09 0.19 0.64 Revascularization Side Direct Indirect Difference p>z Coefficient SE Coefficient SE Coefficient SE DH CCB placebo -1.01 0.58 -0.27 0.20 -0.73 0.62 0.24 Diuretics placebo -0.34 0.19 -1.07 0.59 0.73 0.62 0.24 Overall Cardiovascular Events Side Direct Indirect Difference p>z Coefficient SE Coefficient SE Coefficient SE ACEi placebo -0.18 0.18 -0.40 0.10 0.22 0.21 0.30 DH CCB placebo -0.31 0.11 -0.31 0.10 -0.002 0.15 0.99 BB placebo -0.19 0.15 -0.18 0.11 -0.01 0.18 0.97 ARB placebo -0.30 0.15 -0.19 0.11 -0.11 0.18 0.56 Diuretics placebo -0.26 0.13 -0.36 0.11 -0.10 0.17 0.56 Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; DH CCB, dihydropyridine calcium channel blocker; BB, beta blocker; ARB, angiotensin receptor blocker. © 2020 Wei J et al. JAMA Netw Open. All rights reserved. eTable 4. Bivariate Meta-regression on the 10 mm Hg Reduction of Blood Pressure and Change of Cardiovascular Events 10 mm Hg Systolic Blood Pressure Reduction Cardiovascular Events RR (95% CI) CVD mortality 0.87 (0.77, 0.99) Myocardial infarction 0.95 (0.77, 1.17) Stroke 0.83 (0.72, 0.97) Revascularization 0.75 (0.50, 1.13) Overall 0.86 (0.78, 0.96) 5 mm Hg Diastolic Blood Pressure Reduction Cardiovascular Events RR (95% CI) CVD mortality 0.86 (0.74, 1.00) Myocardial infarction 0.95 (0.75, 1.21) Stroke 0.80 (0.67, 0.95) Revascularization 0.68 (0.42, 1.09) Overall 0.84 (0.74, 0.96) Abbreviation: RR, risk ratio. © 2020 Wei J et al. JAMA Netw Open. All rights reserved. eFigure 1. Funnel Plots of Studies of Blood Pressure Lowering Drugs and Effects of Prevention on Cardiovascular Death, Myocardial Infarction, Stroke, Revascularization, and Overall Cardiovascular Events A. Cardiovascular death -4 -2 0 2 4 Effect size centred at comparison-specific pooled effect (y - ) iXY XY Placebo vs dCCB ACEi vs Placebo ACEi vs dCCB ACEi vs ACEi+dCCB ACEi vs ACEi+ndCCB ACEi vs ARB ACEi+Diuretics vs Placebo ACEi vs BB+Diuretics ACEi vs Diuretics ACEi+CCB+Diuretics vs Placebo BB vs Placebo ARB vs BB ACEi+dCCB vs Placebo ACEi+Diuretics vs ACEi+dCCB ARB vs dCCB ARB vs Placebo BB vs ndCCB BB+Diuretics vs Placebo Diuretics vs Placebo BB vs Diuretics BB+Diuretics vs dCCB BB+Diuretics vs ndCCB Diuretics vs dCCB Diuretics vs ndCCB BB vs dCCB B. Myocardial infarction -4 -2 0 2 4 Effect size centred at comparison-specific pooled effect (y - ) iXY XY ACEi vs dCCB ACEi vs ACEi+ndCCB ACEi vs ARB ACEi vs BB ACEi vs BB+Diuretics ACEi vs Diuretics ACEi vs Placebo ACEi+Diuretics vs ACEi+dCCB ARB vs BB ACEi+Diuretics vs Placebo ARB vs dCCB ARB vs Placebo BB vs dCCB BB vs ndCCB BB vs Diuretics BB vs Placebo BB+Diuretics vs dCCB BB+Diuretics vs ndCCB BB+Diuretics vs Diuretics BB+Diuretics vs Placebo Diuretics vs dCCB Diuretics vs ndCCB Diuretics vs Placebo Placebo vs dCCB © 2020 Wei J et al. JAMA Netw Open. All rights reserved. 1.5 1.5 2 1 0 1 0 C. Stroke -4 -2 0 2 4 Effect size centred at comparison-specific pooled effect (y - ) iXY XY TD vs dCCB TD vs ndCCB dCCB+ARB vs ARB+TD ACE vs dCCB ACE vs ACE+ndCCB ACE vs TD ACE vs ARB ACE vs BB ACE vs BB+TD ACE vs Placebo ACE+TD vs ACE+dCCB ACE+TD vs Placebo ACE+dCCB+TD vs Placebo ARB vs TD ARB vs dCCB ARB vs dCCB+ARB ARB vs BB ARB vs Placebo BB vs TD BB vs dCCB BB vs ndCCB BB vs Placebo BB+TD vs ndCCB BB+TD vs dCCB BB+TD vs Placebo Placebo vs TD Placebo vs dCCB D. Revascularization -2 -1 0 1 2 Effect size centred at comparison-specific pooled effect (y - ) iXY XY ACE vs ACE+ndCCB ACE vs ARB ACE vs TD ACE vs dCCB ACE+dCCB vs ACE+TD ARB vs BB ARB vs dCCB BB vs dCCB BB vs ndCCB Placebo vs TD Placebo vs dCCB TD vs dCCB TD vs ndCCB © 2020 Wei J et al. JAMA Netw Open. All rights reserved. 1.5 1 0 1 0 E. Overall cardiovascular events -4 -2 0 2 4 Effect size centred at comparison-specific pooled effect (y - ) iXY XY Placebo vs dCCB dCCB+ARB vs ARB+Diuretics ACEi vs Placebo ACEi vs dCCB ACEi vs ACEi+dCCB ACEi vs ACEi+ndCCB ACEi vs ARB ACEi vs BB+Diuretics ACEi vs Diuretics ACEi+Diuretics vs ACEi+dCCB ACEi+Diuretics vs Placebo ACEi+dCCB+Diuretics vs Placebo ARB vs Placebo ARB vs dCCB ACEi+dCCB vs Placebo ACEi vs BB ARB vs Diuretics BB vs Placebo BB vs ndCCB BB vs Diuretics BB+Diuretics vs Placebo ARB vs dCCB+ARB ARB vs BB BB+Diuretics vs dCCB BB+Diuretics vs ndCCB Diuretics vs Placebo Diuretics vs dCCB Diuretics vs ndCCB BB vs dCCB © 2020 Wei J et al. JAMA Netw Open. All rights reserved. 1.5 2 1 0 eFigure 2. Inconsistency Plots of Studies of Blood Pressure Lowering Drugs and Effects of Prevention on Cardiovascular Death, Myocardial Infarction, Stroke, Revascularization, and Overall Cardiovascular Events A. Cardiovascular death 95%CI Loop-specific Loop IF (truncated) Heterogeneity( ) ACEi-ACEi+dCCB-Placebo 1.74 (0.00,6.73) 0.000 ACEi+Diuretics-ACEi+dCCB-Placebo 1.15 (0.00,4.19) 0.000 ACEi-BB+Diuretics-Placebo 0.64 (0.00,1.38) 0.001 BB-BB+Diuretics-Placebo-ndCCB 0.54 (0.01,1.07) 0.000 BB+Diuretics-Diuretics-Placebo-ndCCB 0.50 (0.00,1.91) 0.001 ACEi-Placebo-dCCB 0.40 (0.00,1.04) 0.000 ARB-Placebo-dCCB 0.29 (0.00,0.66) 0.000 ACEi-Diuretics-Placebo 0.24 (0.00,0.87) 0.000 ACEi-ARB-Placebo 0.24 (0.00,1.06) 0.000 Diuretics-Placebo-dCCB 0.18 (0.00,0.50) 0.000 BB-BB+Diuretics-dCCB-ndCCB 0.17 (0.00,0.52) 0.000 ACEi-ARB-dCCB 0.13 (0.00,0.69) 0.000 BB-Placebo-dCCB 0.12 (0.00,0.50) 0.000 ARB-BB-dCCB 0.12 (0.00,0.41) 0.000 BB-Diuretics-dCCB 0.12 (0.00,0.43) 0.000 ACEi-BB+Diuretics-Diuretics-ndCCB 0.10 (0.00,1.44) 0.000 ACEi-ARB-BB-Diuretics 0.10 (0.00,0.72) 0.000 BB+Diuretics-Diuretics-dCCB-ndCCB 0.06 (0.00,1.41) 0.000 ACEi-Diuretics-dCCB 0.06 (0.00,0.28) 0.000 ARB-BB-Placebo 0.05 (0.00,0.42) 0.000 ACEi-BB+Diuretics-dCCB 0.03 (0.00,0.29) 0.000 BB-Diuretics-ndCCB 0.01 (0.00,1.35) 0.000 BB-Diuretics-Placebo 0.01 (0.00,0.43) 0.000 0 0 2 4 6 7 © 2020 Wei J et al. JAMA Netw Open. All rights reserved. B. Myocardial infarction 95%CI Loop-specific Loop IF (truncated) Heterogeneity( ) ACEi-BB-dCCB 0.47 (0.00,1.14) 0.032 BB+Diuretics-Diuretics-Placebo 0.41 (0.00,1.14) 0.000 ARB-Placebo-dCCB 0.40 (0.00,1.63) 0.149 BB-Diuretics-dCCB 0.36 (0.04,0.68) 0.000 BB-Diuretics-Placebo 0.34 (0.00,0.91) 0.000 ACEi-ARB-dCCB 0.34 (0.00,1.13) 0.034 ACEi-BB-BB+Diuretics-ndCCB 0.34 (0.00,0.85) 0.000 BB-BB+Diuretics-Placebo-ndCCB 0.32 (0.00,1.09) 0.000 ACEi-Diuretics-Placebo 0.31 (0.00,0.80) 0.000 BB-Diuretics-ndCCB 0.28 (0.00,1.57) 0.000 ACEi-Placebo-dCCB 0.28 (0.00,1.09) 0.034 ACEi-ARB-BB 0.25 (0.00,0.91) 0.000 ACEi-Diuretics-dCCB 0.25 (0.00,0.49) 0.000 BB+Diuretics-Placebo-dCCB 0.22 (0.00,1.02) 0.000 BB-Placebo-dCCB 0.21 (0.00,0.82) 0.000 ARB-BB-Placebo 0.20 (0.00,0.72) 0.000 Diuretics-Placebo-dCCB 0.20 (0.00,0.81) 0.000 BB-BB+Diuretics-dCCB-ndCCB 0.11 (0.00,0.52) 0.000 ACEi-BB+Diuretics-dCCB 0.06 (0.00,0.77) 0.044 ACEi-BB+Diuretics-Diuretics 0.06 (0.00,0.50) 0.013 ACEi-ARB-Placebo 0.05 (0.00,0.75) 0.000 ARB-BB-dCCB 0.04 (0.00,0.31) 0.000 ACEi-BB-Diuretics 0.03 (0.00,0.50) 0.000 BB+Diuretics-Diuretics-ndCCB 0.03 (0.00,1.31) 0.000 ACEi-BB+Diuretics-Placebo 0.02 (0.00,0.72) 0.000 BB+Diuretics-Diuretics-dCCB 0.01 (0.00,0.32) 0.000 0 0 1 1 2 2 *** Loop(s) [ACEi-BB-Placebo] are formed only by multi-arm trial(s) - Consistent by definition © 2020 Wei J et al. JAMA Netw Open. All rights reserved. C. Stroke 95%CI Loop-specific Loop IF (truncated) Heterogeneity( ) BB-TD-ndCCB 0.50 (0.00,2.16) 0.027 ARB-BB-TD 0.46 (0.00,1.28) 0.000 ACE-BB-Placebo 0.43 (0.00,1.30) 0.000 ACE-ARB-dCCB 0.39 (0.00,1.07) 0.043 ACE-BB+TD-dCCB 0.38 (0.00,1.14) 0.071 ACE-BB-dCCB 0.35 (0.00,1.08) 0.011 BB-Placebo-TD 0.35 (0.00,1.00) 0.010 ACE-BB-TD 0.34 (0.00,1.09) 0.005 ARB-Placebo-TD 0.34 (0.00,1.13) 0.000 ACE-ARB-BB 0.34 (0.00,1.09) 0.000 ACE-ARB-TD 0.33 (0.00,1.17) 0.000 ARB-BB-dCCB 0.30 (0.00,0.96) 0.053 BB-BB+TD-Placebo-ndCCB 0.26 (0.00,0.88) 0.000 BB-BB+TD-dCCB-ndCCB 0.22 (0.00,0.58) 0.000 ARB-Placebo-dCCB 0.21 (0.00,0.75) 0.044 ACE-TD-dCCB 0.18 (0.00,0.42) 0.000 ACE-Placebo-TD 0.18 (0.00,0.75) 0.000 ARB-BB-Placebo 0.17 (0.00,0.56) 0.000 ACE-ARB-Placebo 0.17 (0.00,0.87) 0.000 BB+TD-TD-dCCB-ndCCB 0.15 (0.00,1.67) 0.000 BB+TD-Placebo-dCCB 0.13 (0.00,0.78) 0.016 ARB-TD-dCCB 0.12 (0.00,1.03) 0.038 BB-Placebo-dCCB 0.12 (0.00,0.57) 0.012 ACE-BB+TD-Placebo 0.11 (0.00,0.84) 0.000 BB-TD-dCCB 0.11 (0.00,0.46) 0.000 ACE-BB-BB+TD-ndCCB 0.08 (0.00,1.00) 0.032 ACE-Placebo-dCCB 0.06 (0.00,0.73) 0.016 Placebo-TD-dCCB 0.05 (0.00,0.33) 0.000 ACE-BB+TD-TD-ndCCB 0.05 (0.00,1.63) 0.022 BB+TD-Placebo-TD-ndCCB 0.05 (0.00,1.64) 0.000 0 0 1 2 3 3 D. Revascularization 95%CI Loop-specific Loop IF (truncated) Heterogeneity( ) Placebo-TD-dCCB 0.75 (0.00,1.95) 0.000 ACE-ARB-dCCB 0.16 (0.00,0.71) 0.000 ACE-TD-dCCB 0.15 (0.00,0.92) 0.000 BB-TD-dCCB-ndCCB 0.07 (0.00,1.59) 0.000 ARB-BB-dCCB 0.04 (0.00,0.61) 0.000 0 0 1 1 2 2 © 2020 Wei J et al. JAMA Netw Open. All rights reserved. E. Overall cardiovascular events 95%CI Loop-specific Loop IF (truncated) Heterogeneity( ) ACEi-ACEi+dCCB-Placebo 1.42 (0.00,6.37) 0.000 ACEi+Diuretics-ACEi+dCCB-Placebo 1.20 (0.00,4.23) 0.000 ACEi-BB-dCCB 0.47 (0.00,1.00) 0.012 ARB-BB-Diuretics 0.45 (0.00,1.20) 0.000 ACEi-ARB-dCCB 0.45 (0.00,0.95) 0.028 ARB-Diuretics-Placebo 0.39 (0.00,1.50) 0.042 ACEi-ARB-Diuretics 0.35 (0.00,1.11) 0.002 ACEi-BB-Diuretics 0.33 (0.00,1.06) 0.034 ACEi-Placebo-dCCB 0.29 (0.00,0.80) 0.024 ACEi-BB+Diuretics-dCCB 0.29 (0.00,0.83) 0.035 ACEi-ARB-BB 0.27 (0.00,0.60) 0.000 BB-BB+Diuretics-Placebo-ndCCB 0.27 (0.00,0.83) 0.010 ARB-BB-dCCB 0.26 (0.00,0.87) 0.054 BB-Diuretics-Placebo 0.26 (0.00,1.13) 0.097 ARB-Placebo-dCCB 0.23 (0.00,0.83) 0.074 ACEi-BB+Diuretics-Placebo 0.23 (0.00,0.70) 0.011 BB-BB+Diuretics-dCCB-ndCCB 0.19 (0.02,0.37) 0.000 BB+Diuretics-Diuretics-Placebo-ndCCB 0.19 (0.00,0.93) 0.000 ACEi-ARB-Placebo 0.15 (0.00,1.07) 0.095 BB-Diuretics-ndCCB 0.15 (0.00,1.63) 0.130 ACEi-Diuretics-dCCB 0.13 (0.00,0.40) 0.009 ARB-BB-Placebo 0.13 (0.00,0.87) 0.075 BB-Diuretics-dCCB 0.13 (0.00,0.58) 0.021 ACEi-BB-BB+Diuretics-ndCCB 0.13 (0.00,0.53) 0.004 BB+Diuretics-Placebo-dCCB 0.12 (0.00,0.94) 0.063 BB-Placebo-dCCB 0.09 (0.00,0.66) 0.050 ACEi-BB+Diuretics-Diuretics-ndCCB 0.09 (0.00,0.80) 0.003 ACEi-BB-Placebo 0.06 (0.00,0.74) 0.000 Diuretics-Placebo-dCCB 0.06 (0.00,0.42) 0.017 ARB-Diuretics-dCCB 0.04 (0.00,0.90) 0.029 ACEi-Diuretics-Placebo 0.04 (0.00,0.36) 0.003 BB+Diuretics-Diuretics-dCCB-ndCCB 0.03 (0.00,0.72) 0.000 0 0 2 4 6 7 © 2020 Wei J et al. 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Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications

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American Medical Association
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Copyright 2020 Wei J et al. JAMA Network Open.
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2574-3805
DOI
10.1001/jamanetworkopen.2019.21618
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Abstract

Key Points Question Which classes of IMPORTANCE Antihypertension medications have been associated with prevention of antihypertension medications are cardiovascular events, although less is known about the comparative effectiveness of different reported to be associated with medication classes. reductions in first-in-trial cardiovascular events? OBJECTIVE To compare contemporary aggregated first-in-trial cardiovascular events among Findings In this systematic review and patients with hypertension and no substantial comorbidities. network meta-analysis of 46 randomized clinical trials that performed DATA SOURCES The PubMed, Embase, and Cochrane Library databases were systematically direct comparisons of individual searched for articles published between January 1, 1990, and October 24, 2017. antihypertension medication classes among 248 887 patients with STUDY SELECTION Randomized clinical trials that tested commonly used antihypertension hypertension and no substantial medications (angiotensin-converting enzyme inhibitors, dihydropyridine calcium channel blockers, comorbidities, angiotensin-converting nondihydropyridine calcium channel blockers, β-blockers, angiotensin receptor blockers, and enzyme inhibitors, dihydropyridine diuretics) and that reported selected cardiovascular outcomes for at least 6 months of follow-up. calcium channel blockers, and diuretics were reported to be similarly effective in DATA EXTRACTION AND SYNTHESIS The analysis was conducted from October 2017 to December reducing cardiovascular death, stroke, 2019. Two reviewers extracted the number of cardiovascular events at the end of treatment for all and overall cardiovascular events. study groups. For each outcome, a frequentist network meta-analysis was used to compare risk Angiotensin-converting enzyme reductions between medication classes (random-effects models weighted by the inverse variance). inhibitors and diuretics were reported to The dose-response association between a 10–mm Hg reduction of systolic blood pressure and a be the most effective in reducing 5–mm Hg reduction of diastolic blood pressure and the risk of first-in-trial cardiovascular events was myocardial infarction and estimated. revascularization, respectively. MAIN OUTCOMES AND MEASURES First-in-trial cardiovascular events, including cardiovascular Meaning The reported effects of death, myocardial infarction, stroke, and revascularization. different antihypertension medication classes were largely similar, with only RESULTS In this systematic review and network meta-analysis, data were pooled from 46 eligible nuanced differences. clinical trials (248 887 total participants with a mean [SD] age of 65.6 [5.8] years; 52.8% men). In the network meta-analysis, compared with placebo, angiotensin-converting enzyme inhibitors, Supplemental content dihydropyridine calcium channel blockers, and thiazide diuretics were reported to be similarly effective in reducing overall cardiovascular events (25%), cardiovascular death (20%), and stroke Author affiliations and article information are listed at the end of this article. (35%); angiotensin-converting enzyme inhibitors were reported to be the most effective in reducing the risk of myocardial infarction (28%); and diuretics were reported to be the most effective in reducing revascularization (33%). In the metaregression analyses, each 10–mm Hg reduction in systolic blood pressure and 5-mm Hg reduction in diastolic blood pressure was significantly associated with a lower risk of cardiovascular death, stroke, and overall cardiovascular events. (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 1/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications Abstract (continued) CONCLUSIONS AND RELEVANCE In this network meta-analysis of clinical trials of patients with hypertension and no substantial comorbidities, different classes of antihypertension medications were associated with similar benefits in reducing cardiovascular events. Future studies should compare the effectiveness of combinations of antihypertension medications in reducing cardiovascular events. JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 Introduction Hypertension is the most prevalent risk factor for mortality and disability-adjusted life-years worldwide. Cardiovascular disease remains the leading cause of death globally, accounting for 17.7 million deaths in 2015, which represented 31% of all deaths worldwide. Hypertension is an important factor in cardiovascular disease. In 2010, it was estimated that one-third of the world’s adult population had hypertension. The introduction of the American College of Cardiology and the American Heart Association hypertension guidelines in 2017 resulted in higher estimates of the 5,6 number of people with hypertension. Knowledge of optimal first-line antihypertension medications for the prevention of cardiovascular events and mortality will be important for clinical decision-making. Moreover, the identification of treatments that are most effective for controlling hypertension and subsequent cardiovascular events and mortality and that have the least harmful effects is imperative to guide clinicians and decrease cardiovascular disease burdens worldwide. Previous meta-analyses have examined the efficacy of antihypertension treatments in reducing 7,8 cardiovascular events. These meta-analyses have used pairwise comparisons of only 2 classes of antihypertension medications; however, pairwise meta-analysis does not enable comparison of multiple classes of medications. Only 1 network meta-analysis has compared the effectiveness of different classes of antihypertension medications in preventing cardiovascular events, but this meta- analysis was published more than 15 years ago and included medications, such as α-blockers, that are less frequently used in contemporary health care. To provide an updated perspective on the comparative efficacy of antihypertension medications, we conducted a network meta-analysis to compare the reported effects of different classes of antihypertension medications that are currently used to reduce the risk of individual cardiovascular events (cardiovascular death, myocardial infarction, stroke, and revascularization) and to examine the medications’ reported effectiveness in reducing the overall risk of any cardiovascular event. Findings from this study will be relevant for the contemporary clinical management of hypertension, especially in light of the new American College of Cardiology and American Heart Association hypertension guidelines. Methods We conducted a network meta-analysis of randomized clinical trials that tested antihypertension medications. This study followed the Preferred Reporting Items for Systematic Reviews and Meta- analyses (PRISMA) guidelines for systematic reviews and meta-analyses. Data Sources and Study Selection We systematically searched the PubMed, Embase, and Cochrane Library databases for articles published between January 1, 1990, and October 24, 2017. The search terms used included hypertension, hypertension and agents, and antihypertensive agents (a detailed list of search terms is available in the eMethods in the Supplement. There were no language restrictions. JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 2/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications We included studies meeting the following criteria: (1) randomized clinical trials; (2) published during or after 1990; (3) included nonpregnant adults 18 years or older without chronic kidney disease, diabetic nephropathy, or organ transplants (which are risk factors for secondary hypertension) and without myocardial infarction and/or stroke within the previous 6 months; (4) evaluated antihypertension medications, including angiotensin-converting enzyme (ACE) inhibitors, dihydropyridine calcium channel blockers (DH CCBs), nondihydropyridine calcium channel blockers (non–DH CCBs), β-blockers, angiotensin receptor blockers (ARBs), and diuretics compared with control groups receiving placebo, standard treatment, or health education; (5) reported incidence of cardiovascular disease events (cardiovascular death, myocardial infarction, stroke, and/or coronary revascularization [either percutaneous coronary intervention or coronary artery bypass grafting]); and (6) reported data from at least 6 months of follow-up. In addition, we excluded studies that reported myocardial infarction and/or stroke within the previous 3 months; studies that focused on patients with chronic kidney disease, diabetic nephropathy, or organ transplants (which are risk factors for secondary hypertension); and studies that were not focused on patients with hypertension. To minimize concerns about the heterogeneity of outcome ascertainment across studies, we only included studies in which cardiovascular events were adjudicated by physicians using similar criteria and assessing patients’ medical records. Study selection followed 3 steps. First, 2 of us (J.W. and A.J.K.) independently screened the titles of studies. Second, the same 2 reviewers screened and selected abstracts, and disagreements were resolved by a third reviewer (M.K.A.). Third, the 2 reviewers (J.W. and A.J.K.) examined the full text of articles for confirmation of inclusion. Disagreements were resolved by consensus or, when necessary, by the third reviewer (M.K.A.). Data Extraction and Quality Assessment Two of us (J.W. and A.J.K.) independently extracted data from studies that met inclusion criteria using a standardized extraction form. The data extracted included sample size, participant characteristics (age and sex), study country, follow-up duration, types of antihypertension medications and comparator groups, and number of first-in-trial cases for each outcome. Cardiovascular death was defined as death related to cardiovascular disease or death that could be calculated using all-cause mortality minus noncardiovascular-related death. We used nonfatal myocardial infarction and stroke if they were indicated or could be calculated, and we used total (fatal and nonfatal) myocardial infarction and stroke as outcomes if the numbers of nonfatal myocardial infarction and stroke could not be derived. Revascularization included any percutaneous coronary intervention or coronary artery bypass grafting reported in the clinical trials. The overall cardiovascular events were calculated as the aggregation of cardiovascular death, myocardial infarction, stroke, and revascularization. We assessed the quality of the included studies using the Jadad scale, which measures the methodologic quality of randomized clinical trials on a scale of 0 to 5, with 0 indicating very low and 5 indicating rigorous quality. This scale assesses the risk of bias based on 3 domains: randomization (including mention of randomization and appropriate method of randomization), blinding (including mention of blinding and appropriate blinding), and consideration of all patients (ie, the outcomes of all patients in the clinical trial are known and, if no data are reported, the reason for missing data is stated). A study could be assigned a maximum of 2 points each for the domains of randomization and blinding and 1 point for the domain of consideration of all patients, for a possible maximum score of 5. Two of us (J.W. and A.J.K.) conducted the quality assessment and assigned quality scores (continuous measure) for each study. Studies scoring 3 or more points were deemed to have a low risk of bias, and studies scoring less than 3 points were deemed to have a high risk of bias. Data Synthesis and Analysis The analysis was conducted from October 2017 to December 2019. We first conducted a pairwise meta-analysis of placebo-clinical trials to estimate the direct effect on reducing cardiovascular events JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 3/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications reported for each agent compared with placebo. The risk difference (per 1000 persons) and the numbers needed to treat were calculated for each type of medication. We conducted a frequentist network meta-analysis with random-effects models to estimate the aggregate reductions in cardiovascular events and revascularization for each type of antihypertension medication compared with placebo and with each other. We used Stata software, version 14.0 (StataCorp), for all analyses using the network command. This approach is an extension of the method proposed by DerSimonian and Laird, and the performance of this model has been satisfactory. The model contains a component of inconsistency variance, which is a source of variation in addition to between-study heterogeneity. We reported risk ratios (RRs) and corresponding 95% CIs, and we calculated a pooled RR and 95% CI for each intervention group separately from each placebo group. For each medication class, we assessed heterogeneity across studies using the maximum likelihood method. We examined the magnitude of a common heterogeneity variance for the network (τ ) as an indicator of the extent of heterogeneity among included studies in terms of the range of expected treatment estimates (RRs and 95% CIs). Any τ values under 0.25 were considered acceptable heterogeneity; values between 0.25 and 1.0 represented moderately high heterogeneity; and values greater than 1.0 represented very high heterogeneity. We assessed the general within-network inconsistency between direct effects (comparison between specific agents and placebo) and indirect comparisons (comparisons other than direct within each outcome) for each outcome using χ tests. If no general inconsistency was detected, the inconsistency between each of 2 agents was tested by calculating the differences in direct effects 17,18 and indirect comparisons using their SEs. We considered evidence of inconsistency if P values were less than .05. We assessed potential publication bias by inspecting the symmetry of funnel plots for each outcome. We conducted metaregression analyses to examine the dose-response relationship between each within-treatment 10–mm Hg reduction in systolic blood pressure and 5–mm Hg reduction in diastolic blood pressure (regardless of intervention groups) over time and to assess the incidence of cardiovascular events (including overall and individual types of cardiovascular events, with the log RRs of cardiovascular events as dependent variables). The coefficient of metaregression was 2 2 2 weighted by 1 divided by the sum of σ and τ , with σ representing the SE of the estimated effect in i i 2 20 the particular clinical trial and with τ representing the between-study variance. In addition, we reported rates of adverse effects, such as edema, headache, cough, and hypotension or dizziness, that are associated with antihypertension medications and placebo among studies with available information. Results Our systematic search yielded 4933 articles (Figure 1). We identified an additional 71 articles from bibliographies of relevant reports and reviews. In total, the systematic review and network meta- analysis included 47 published articles from 46 clinical trials, with 248 887 participants and 28 658 first-in-trial cardiovascular events. Owing to the small number of studies reporting different medication combination permutations and non–DH CCBs, we did not report data for fixed-dose antihypertension combination medications in the network meta-analysis. Figure 2 shows the network plot depicting the different antihypertension medication classes and comparisons tested. Among included studies, 15 tested ACE inhibitors, 23 tested DH CCBs, 4 tested non–DH CCBs, 8 tested β-blockers, 12 tested ARBs, and 13 tested thiazide diuretics. Four studies were from North America, 18 from Europe, 16 from Asia, 1 from Oceania, and 7 from multiple regions across continents. The mean (SD) age of participants was 65.6 (5.8) years (range, 51.8-83.8 years), and 52.8% (range, 28.2%-100.0%) were men. The mean (SD) baseline systolic blood pressure was 161.3 (13.6) mm Hg (range, 129-195 mm Hg). A total of 14 studies included placebo, health education, or JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 4/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications conventional education in their control groups, and 35 studies reported direct treatment comparisons (3 of which included placebo and 2 treatment agents). The mean (SD) follow-up time was 3.7 (1.5) years (range, 1.0-10.0 years). Across all included clinical trials with particular classes of antihypertension medications, the frequency of use for each type of antihypertension medication Figure 1. PRISMA Diagram of Literature Search and Selection 4933 Articles identified from 3 databases 71 Articles identified from other sources 2905 Articles from PubMed 1968 Articles from Embase 60 Articles from Cochrane Library 749 Duplicates excluded 4255 Articles screened 4043 Excluded (case report or review, not a randomized clinical trial, no comparison group, no conclusive outcomes, special population [pregnant, diabetic nephropathy, or end-stage renal disease], or follow-up <6 mo) 212 Articles reviewed for full text 165 Excluded (subanalysis for an included study, all groups of drugs in same class, or not focused on patients with hypertension) Reasons for exclusion were not categorized by individual article because each article may have met 47 Included in qualitative and quantitative analyses multiple exclusion criteria. Figure 2. Network Plot of Antihypertension Medications ACEi + DH CCB + diuretic ACEi + non-DH CCB ARB ACEi + DH CCB ACEi + diuretic ARB + diuretic BB ACEi Non-DH CCB BB + diuretic DH CCB + ARB ACEi indicates angiotensin-converting enzyme Diuretic inhibitor; ARB, angiotensin receptor blocker; BB, β-blocker; DH CCB, dihydropyridine calcium channel blocker; and non–DH CCB, nondihydropyridine calcium Placebo DH CCB channel blocker. JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 5/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications was similar between studies, with the participants’ mean age above and below 65 years. By region of study, ACE inhibitors, β-blockers, and diuretics were more frequently used in Europe, DH CCBs were more frequently used in Asia and Europe, and ARBs were more frequently used in Asia. The prevalence of baseline cardiovascular disease and diabetes was similar among participants using each class of antihypertension medications. The characteristics of all 46 included studies are available in eTable 1 in the Supplement. For all 46 clinical trials included in the analysis, the mean (SD) overall systolic and diastolic blood pressure changes among those reported were −18.0 (8.7) mm Hg and −10.1 (4.7) mm Hg, respectively. The overall risk of cardiovascular events was 11.5%. Among the adverse effect profile, edema was prevalent among 0.5% of participants receiving ACE inhibitors, 17.1% of participants receiving DH CCBs or non–DH CCBs, 8.7% of participants receiving β-blockers, 15.1% of participants receiving ARBs, 9.9% of participants receiving diuretics, and 3.7% of participants receiving placebo. Cough was prevalent among 8.3% of participants receiving ACE inhibitors, 9.6% of participants receiving DH CCBs or non–DH CCBs, 4.1% of participants receiving β-blockers, 2.7% of participants receiving ARBs, 5.4% of participants receiving diuretics, and 16.1% of participants receiving placebo. Headache or hypotension was prevalent among 0.7% of participants receiving ACE inhibitors, 7.9% of participants receiving DH CCBs or non–DH CCBs, 1.4% of participants receiving β-blockers, 10.8% of participants receiving ARBs, 7.4% of participants receiving diuretics, and 8.8% of participants receiving placebo. Dizziness was prevalent among 1.7% of participants receiving ACE inhibitors, 7.5% of participants receiving DH CCBs or non–DH CCBs, 9.1% of participants receiving β-blockers, 14.8% of participants receiving ARBs, 9.0% of participants receiving diuretics, and 10.2% of participants receiving placebo. Comparative Efficacy An assessment of the absolute risk differences in cardiovascular events among placebo-clinical trials that compared antihypertension medications with placebo indicated that all 5 types of antihypertension medications were associated with larger decreases in cardiovascular events than placebo. Compared with placebo, DH CCBs were reported to reduce the risk of cardiovascular death by 7 cases per 1000 persons; ACE inhibitors and diuretics were reported to decrease myocardial infarction risk by 24 cases and 10 cases per 1000 persons, respectively; and DH CCBs and diuretics were reported to reduce stroke risk by 16 cases and 21 cases per 1000 persons, respectively (eTable 2 in the Supplement). Based on these results, 143 people would need to be treated with DH CCBs to prevent 1 cardiovascular death. To prevent 1 myocardial infarction, 42 people would need to be treated with ACE inhibitors and 100 people with diuretics. To prevent 1 stroke, 63 people would need to be treated with DH CCBs and 48 people with diuretics. Network Meta-analysis In the network meta-analysis comparing placebo vs medication groups, for cardiovascular death, we noted that ACE inhibitors, DH CCBs, ARBs, and diuretics were all associated with 15% to 22% relative risk reductions. The specific relative risk reductions were as follows: for ACE inhibitors, 20% reduction (95% CI, 9%-30%; RR, 0.80; 95% CI, 0.70-0.91); for DH CCBs, 20% reduction (95% CI, 11%-29%; RR, 0.80; 95% CI, 0.71-0.89); for ARBs, 15% reduction (95% CI, 3%-26%; RR, 0.85; 95% CI, 0.74-0.97); and for diuretics, 22% reduction (95% CI, 12%-31%; RR, 0.78; 95% CI, 0.69-0.88). For myocardial infarction, ACE inhibitors, DH CCBs, and β-blockers were associated with 20% to 28% relative risk reductions. The specific relative risk reductions were as follows: for ACE inhibitors, 28% reduction (95% CI, 12%-41%; RR, 0.72; 95% CI, 0.59-0.88); for DH CCBs, 21% reduction (95% CI, 4%-34%; RR, 0.79; 95% CI, 0.66-0.96); and for β-blockers, 20% reduction (95% CI, 1%-35%; RR, 0.80; 95% CI, 0.65-0.99). For stroke, all classes of medications were associated with 19% to 39% relative risk reductions. The specific relative risk reductions were as follows: for ACE inhibitors, 34% reduction (95% CI, 20%-45%; RR, 0.66; 95% CI, 0.55-0.80); for DH CCBs, 39% reduction (95% CI, 30%-48%; RR, 0.61; JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 6/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications 95% CI, 0.52-0.70); for β-blockers, 20% reduction (95% CI, 2%-33%; RR, 0.80; 95% CI, 0.67-0.98); for ARBs, 31% reduction (95% CI, 17%-42%; RR, 0.69; 95% CI, 0.58-0.83); and for diuretics, 37% reduction (95% CI, 24%-47%; RR, 0.63; 95% CI, 0.53-0.76). For revascularization, diuretics were associated with a 33% relative risk reduction (95% CI, 5%-53%; RR, 0.67; 95% CI, 0.47-0.95). For overall cardiovascular events, all classes of medications were each associated with a 17% to 29% relative risk reduction (Figure 3). The specific relative risk reductions were as follows: for ACE inhibitors, 29% reduction (95% CI, 17%-40%; RR, 0.71; 95% CI, 0.60-0.83); for DH CCBs, 27% reduction (95% CI, 16%-36%; RR, 0.73; 95% CI, 0.64-0.84); for β-blockers, 17% reduction (95% CI, 2%-30%; RR, 0.83; 95% CI, 0.70-0.98); for ARBs, 21% reduction (95% CI, 6%-33%; RR, 0.79; 95% CI, 0.67-0.94); and for diuretics, 27% reduction (95% CI, 15%-38%; RR, 0.73; 95% CI, 0.62-0.85). These data indicate that, according to effect sizes, ACE inhibitors, DH CCBs, and diuretics were associated with similarly significant reductions in the risk of overall cardiovascular events and cardiovascular death. The greatest reductions in myocardial infarction risk were associated with ACE inhibitors, and DH CCBs and diuretics were associated with similarly significant reductions in the risk of stroke. Diuretics were associated with similarly significant reductions in the risk of revascularization. However, their 95% CIs overlapped. Figure 3. Network Meta-analysis Comparing Single Class of Antihypertension Medications With Placebo for Treatment of Cardiovascular Events A Cardiovascular death B Myocardial infarction Risk Ratio Risk Ratio Agent (95% CI) Less Risk More Risk Agent (95% CI) Less Risk More Risk ACE inhibitor 0.80 (0.70-0.91) ACE inhibitor 0.72 (0.59-0.88) DH CCB 0.80 (0.71-0.89) DH CCB 0.79 (0.66-0.96) ß Blocker 0.99 (0.87-1.13) ß Blocker 0.80 (0.65-0.99) ARB 0.85 (0.74-0.97) ARB 0.89 (0.72-1.10) Diuretic 0.78 (0.69-0.88) Diuretic 0.82 (0.67-1.00) 0 0.5 1.0 1.5 0.5 1.0 1.5 Risk Ratio Risk Ratio C Stroke D Revascularization Risk Ratio Risk Ratio Agent (95% CI) Less Risk More Risk Agent (95% CI) Less Risk More Risk ACE inhibitor 0.66 (0.55-0.80) ACE inhibitor 0.73 (0.50-1.06) DH CCB 0.61 (0.52-0.70) DH CCB 0.70 (0.48-1.03) ß Blocker 0.80 (0.67-0.98) ß Blocker 0.84 (0.56-1.25) ARB 0.69 (0.58-0.83) ARB 0.72 (0.49-1.07) Diuretic 0.63 (0.53-0.76) Diuretic 0.67 (0.47-0.95) 0.4 0.6 0.8 1.0 1.2 0.4 0.7 1.0 1.3 Risk Ratio Risk Ratio E Overall cardiovascular events Risk Ratio Agent (95% CI) Less Risk More Risk ACE inhibitor 0.71 (0.60-0.83) DH CCB 0.73 (0.64-0.84) ß Blocker 0.83 (0.70-0.98) ARB 0.79 (0.67-0.94) Diuretic 0.73 (0.62-0.85) 0 0.5 1.0 1.5 Risk Ratio ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; DH CCB, dihydropyridine calcium channel blocker; and error bars, 95% CI. JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 7/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications Consistency, Heterogeneity, Bias, and Sensitivity In terms of the risk of bias assessment, we found that studies were of moderate quality (mean score, 4.0 of 5.0 possible points), in which randomization had a mean (SD) score of 1.8 (1.0) of 2.0 points, blinding had a mean (SD) score of 1.1 (0.5) of 2.0 points, and consideration of all patients had a mean (SD) score of 1.0 (1.0) of 1.0 point. No study was considered to have a high risk of bias. Visual examination of funnel plots indicated that no significant publication bias was present for cardiovascular death, myocardial infarction, stroke, revascularization, and overall cardiovascular events (eFigure 1 in the Supplement). No general inconsistency of treatment effect on each outcome was found, with all P values greater than .05. By individual treatment, no significant inconsistency was detected among different classes of antihypertension medications (eTable 3 in the Supplement). No significant treatment effect heterogeneity was detected, as none of the τ values was equal to or greater than 0.25 (eFigure 2 in the Supplement). In metaregressions of blood pressure reduction with cardiovascular events, blood pressure reduction was associated with reductions in cardiovascular events. In particular, each 10–mm Hg reduction in systolic blood pressure was significantly associated with a 13% lower risk of cardiovascular death (RR, 0.87; 95% CI, 0.77-0.99), a 17% lower risk of stroke (RR, 0.83; 95% CI, 0.72-0.97), and a 14% lower risk of overall cardiovascular events (RR, 0.86; 95% CI, 0.78-0.96). Each 5–mm Hg reduction in diastolic blood pressure was significantly associated with a 14% lower risk of cardiovascular death (RR, 0.86; 95% CI, 0.74-1.00), a 20% lower risk of stroke (RR, 0.80; 95% CI, 0.67-0.95), and a 16% lower risk of overall cardiovascular events (RR, 0.84; 95% CI, 0.74-0.96; eTable 4 in the Supplement). Discussion From 46 randomized clinical trials that examined the effect of the most commonly used antihypertension medications on preventing cardiovascular events, pooled results showed that ACE inhibitors, DH CCBs, and diuretics were reported to be similarly effective in preventing cardiovascular death (approximately 20% reduction compared with placebo), stroke (approximately 35% reduction compared with placebo), and overall cardiovascular events (approximately 30% reduction compared with placebo). Angiotensin-converting enzyme inhibitors were reported to be the most effective in preventing myocardial infarction (approximately 30% reduction compared with placebo). Diuretics were reported to be the most effective in reducing revascularization (approximately 30% compared with placebo). Our study provides the most current evidence to date on the comparative efficacy of antihypertension medications reported to reduce cardiovascular events in randomized clinical trials. Furthermore, to our knowledge, this is the first meta-analysis to pool the results of studies that tested the efficacy of antihypertension medications in reducing the risk of revascularization. Our results are consistent with those reported in previous meta-analyses of randomized clinical 8,9 9 trials. Psaty et al found that low-dose diuretics were reported to be the most effective treatment for preventing the occurrence of cardiovascular mortality. Law et al indicated that for stroke, all antihypertension medication classes were reported to have similar risk reduction effects for a given reduction in blood pressure. Our findings further supported the evidence indicating that the reported differences of the effects on reducing cardiovascular events between medication classes are small. We also provided more up-to-date information regarding the reported efficacy of antihypertension medications in reducing cardiovascular events. A recent systematic multinational analysis, the Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Hypertension (LEGEND-HTN) study, used observational data encompassing millions of patients and found that diuretics were associated with advantages in reducing various cardiovascular events compared with other classes of medications. This finding is different than that of our study, which indicated that diuretics had similar reported effectiveness in reducing cardiovascular events compared with ACE inhibitors and DH CCBs and that ACE inhibitors appeared to be most effective in JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 8/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications reducing myocardial infarction. The difference in findings may be owing to the varied study designs (randomized clinical trials vs observational studies), and it is not clear to what extent the LEGEND-HTN study may be subject to selection bias. Network meta-analysis allowed us to compare medication classes with placebo both directly (ie, among the included placebo-clinical trials) and indirectly (ie, among all of the included studies). The comparisons between medications and placebo indicated slight differences between direct and overall comparisons. The network comparisons were more precise (ie, they had narrower 95% CIs). It is also worth noting that the association between decreasing blood pressure and reduced 22,23 cardiovascular events was smaller than that obtained from observational studies. The reason may be that most participants in clinical trials, including those receiving placebo, were motivated to reduce their blood pressure and, in a number of cases, were also treated with other medications. In addition, participants’ motivation may have led them to engage in healthy lifestyle habits, such as choosing healthier diet patterns, exercising, and avoiding tobacco and alcohol use. Dietary modification can and should be a complementary effort in trying to reduce BP and many dietary patterns are supported by robust evidence. This finding also calls for future studies that examine the associations between antihypertension medications and lifestyle in preventing cardiovascular events among patients with hypertension. However, although the effect size for the association between decreasing blood pressure and reduced cardiovascular events was small, some of the differences were statistically significant. Limitations Our study was limited by the relatively small number of studies included in the network meta- analysis, so we lacked the statistical power to conduct subgroup analyses to examine whether the association of antihypertension medications with reduced cardiovascular events could be the consequence of different factors (eg, age, sex, or baseline blood pressure level). Although the results from this analysis may serve as a source of reference, a comprehensive study based on demographic factors and comorbidities is needed to assess which class of antihypertension medication should be recommended for reducing adverse cardiovascular outcomes. The newly published American College of Cardiology and American Heart Association guidelines for hypertension identify a wider range of individuals with early hypertension and prehypertension, and our study can guide first-line medication choices. In addition, the 46 clinical trials we studied were mostly performed in North America, western Europe, and East Asia, and more data are needed regarding patients in South Asia and Africa, which cumulatively compose a large proportion of the world’s population. Another important limitation of our study is that we did not include results for combinations of antihypertension medications because there were too few studies with data for each permutation of combinations. However, this lack of studies suggests that the efficacy of several groups of combinations, such as β-blockers and diuretics, will need to be studied more frequently in the future. Recent findings have indicated that treatment with low doses of 3 antihypertensive medications is associated with an increased proportion of patients who achieved target blood pressure compared with standard care, and quarter-dose therapies with combined medications were reported to be more effective, with fewer adverse events, in reducing blood pressure compared with standard monotherapy. Conclusions The present network meta-analysis indicated that major first-line antihypertension medications, including ACE inhibitors, DH CCBs, β-blockers, ARBs, and diuretics, were all reported to be effective in reducing cardiovascular events compared with placebo. Furthermore, ACE inhibitors, DH CCBs, and diuretics appeared to be similarly effective in reducing cardiovascular deaths, stroke, and overall cardiovascular events. Compared with other antihypertension medications, ACE inhibitors appeared to be the medications of choice to prevent myocardial infarction, and diuretics appeared to be the JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 9/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications optimal choice to reduce revascularization. The differences between medication classes were generally small in terms of their associations with reducing cardiovascular events. Future studies should compare the effectiveness of multiple antihypertension medications in combination with individual antihypertension medications in reducing cardiovascular events. ARTICLE INFORMATION Accepted for Publication: December 18, 2019. Published: February 21, 2020. doi:10.1001/jamanetworkopen.2019.21618 Open Access: This is an open access article distributed under the terms of the CC-BY License.©2020WeiJetal. JAMA Network Open. Corresponding Author: Jingkai Wei, MSPH, PhD, Department of Epidemiology, Milken Institute School of Public Health, George Washington University, 950 New Hampshire Ave NW, Washington, DC 20052 (jwei25@gwu.edu). Author Affiliations: Department of Epidemiology, Milken Institute School of Public Health, George Washington University, Washington, DC (Wei); Emory Global Diabetes Research Center, Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia (Galaviz, Magee, Narayan, Ali); Nutrition and Health Sciences Doctoral Program, Laney Graduate School, Emory University, Atlanta, Georgia (Kowalski); Division of Endocrinology, Metabolism and Lipids, Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia (Haw); Department of Family and Preventive Medicine, School of Medicine, Emory University, Atlanta, Georgia (Ali). Author Contributions: Dr Wei had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Galaviz, Magee, Haw, Narayan, Ali. Acquisition, analysis, or interpretation of data: Wei, Galaviz, Kowalski, Magee, Narayan, Ali. Drafting of the manuscript: Wei. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Wei, Galaviz, Magee. Obtained funding: Ali. Administrative, technical, or material support: Kowalski, Ali. Supervision: Galaviz, Haw, Narayan, Ali. Conflict of Interest Disclosures: Dr Galaviz reported receiving grants from the Institute for Health Metrics and Evaluation during the conduct of the study. Dr Ali reported receiving grants from Merck & Co outside the submitted work. No other disclosures were reported. Funding/Support: This project was funded by Disease Control Priorities Network grant UWSC7007 from the Bill & Melinda Gates Foundation and partially supported by grant P30DK111024 from the National Institute of Diabetes and Digestive and Kidney Diseases (Drs Narayan, Galaviz, and Ali). Role of the Funder/Sponsor: The funding sources 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. REFERENCES 1. Forouzanfar MH, Alexander L, Anderson HR, et al; GBD 2013 Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(10010):2287-2323. doi:10.1016/S0140-6736(15)00128-2 2. World Health Organization. Cardiovascular diseases (CVDs). World Health Organization website. https://www. who.int/mediacentre/factsheets/fs317/en/. Published May 17, 2017. Accessed July 1, 2017. 3. Franklin SS, Wong ND. Hypertension and cardiovascular disease: contributions of the Framingham heart study. 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Comprehensive comparative effectiveness and safety of first- line antihypertensive drug classes: a systematic, multinational, large-scale analysis. Lancet. 2019;394(10211): 1816-1826. doi:10.1016/S0140-6736(19)32317-7 22. MacMahon S, Peto R, Collins R, et al. Blood pressure, stroke, and coronary heart disease: part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335(8692):765-774. doi:10.1016/0140-6736(90)90878-9 23. Asia Pacific Cohort Studies Collaboration. Blood pressure and cardiovascular disease in the Asia Pacific region. J Hypertens. 2003;21(4):707-716. doi:10.1097/00004872-200304000-00013 24. Carey RM, Whelton PK; 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association hypertension guideline. Ann Intern Med. 2018;168(5):351-358. doi:10. 7326/M17-3203 25. Webster R, Salam A, de Silva HA, et al; TRIUMPH Study Group. Fixed low-dose triple combination antihypertensive medication vs usual care for blood pressure control in patients with mild to moderate hypertension in Sri Lanka: a randomized clinical trial. JAMA. 2018;320(6):566-579. doi:10.1001/jama.2018.10359 JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 11/12 JAMA Network Open | Cardiology Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications 26. Bennett A, Chow CK, Chou M, et al. Efficacy and safety of quarter-dose blood pressure–lowering agents: a systematic review and meta-analysis of randomized controlled trials. Hypertension. 2017;70(1):85-93. doi:10. 1161/HYPERTENSIONAHA.117.09202 27. Gay HC, Rao SG, Vaccarino V, Ali MK. Effects of different dietary interventions on blood pressure: systematic review and meta-analysis of randomized controlled trials. Hypertension. 2016;67(4):733-739. doi:10.1161/ HYPERTENSIONAHA.115.06853 SUPPLEMENT. eMethods. Search Terms eTable 1. Cardiovascular Events and Outcomes by Randomized Treatment eTable 2. Absolute Risk Differences of Cardiovascular Events Comparing Each Type of Antihypertension Medication to Placebo From Network Meta-analysis eTable 3. Inconsistency Test Between Direct and Indirect Treatment Comparisons in Mixed Treatment Comparisons eTable 4. Bivariate Meta-regression on the 10 mm Hg Reduction of Blood Pressure and Change of Cardiovascular Events eFigure 1. Funnel Plots of Studies of Antihypertension Medications and Effects of Prevention on Cardiovascular Death, Myocardial Infarction, Stroke, Revascularization, and Overall Cardiovascular Events eFigure 2. Inconsistency Plots of Studies of Antihypertension Medications and Effects of Prevention on Cardiovascular Death, Myocardial Infarction, Stroke, Revascularization, and Overall Cardiovascular Events eReferences. JAMA Network Open. 2020;3(2):e1921618. doi:10.1001/jamanetworkopen.2019.21618 (Reprinted) February 21, 2020 12/12 Supplementary Online Content Wei J, Galaviz KI, Kowalski AJ, Magee MJ, Haw JS, Narayan KMV, Ali MK. Comparison of cardiovascular events among users of different classes of antihypertension drugs: a systematic review and network meta- analysis. JAMA Netw Open. Published February 21, 2020. doi:10.1001/jamanetworkopen.2019.21618 eMethods. Search Terms eTable 1. Cardiovascular Events and Outcomes by Randomized Treatment eTable 2. Absolute Risk Differences of Cardiovascular Events Comparing Each Type of Blood Pressure Lowering Drug to Placebo From Network Meta-analysis eTable 3. Inconsistency Test Between Direct and Indirect Treatment Comparisons in Mixed Treatment Comparisons eTable 4. Bivariate Meta-regression on the 10 mm Hg Reduction of Blood Pressure and Change of Cardiovascular Events eFigure 1. Funnel Plots of Studies of Blood Pressure Lowering Drugs and Effects of Prevention on Cardiovascular Death, Myocardial Infarction, Stroke, Revascularization, and Overall Cardiovascular Events eFigure 2. Inconsistency Plots of Studies of Blood Pressure Lowering Drugs and Effects of Prevention on Cardiovascular Death, Myocardial Infarction, Stroke, Revascularization, and Overall Cardiovascular Events eReferences. This supplementary material has been provided by the authors to give readers additional information about their work. © 2020 Wei J et al. JAMA Netw Open. All rights reserved. eMethods. Search Terms ("hypertension"[MeSH Terms] OR "hypertension"[All Fields]) AND (("antihypertensive agents"[Pharmacological Action] OR "antihypertensive agents"[MeSH Terms] OR "antihypertensive agents"[All Fields]) OR ("sodium chloride symporter inhibitors"[Pharmacological Action] OR "sodium chloride symporter inhibitors"[MeSH Terms] OR "sodium chloride symporter inhibitors"[All Fields]) OR "thiazide diuretics"[All Fields] OR ("adrenergic beta-antagonists"[Pharmacological Action] OR "adrenergic beta- antagonists"[MeSH Terms] OR "adrenergic beta-antagonists"[All Fields]) OR ("angiotensin-converting enzyme inhibitors"[Pharmacological Action] OR "angiotensin-converting enzyme inhibitors"[MeSH Terms] OR "angiotensin-converting enzyme inhibitors"[All Fields]) OR ("angiotensin receptor antagonists"[Pharmacological Action] OR "angiotensin receptor antagonists"[MeSH Terms] OR "angiotensin receptor antagonists"[All Fields]) OR ("calcium channel blockers"[Pharmacological Action] OR "calcium channel blockers"[MeSH Terms] OR "calcium channel blockers"[All Fields]) OR ("vasodilator agents"[Pharmacological Action] OR "vasodilator agents"[MeSH Terms] OR "vasodilator agents"[All Fields])) AND ((Controlled Clinical Trial[ptyp] OR Randomized Controlled Trial[ptyp]) AND "humans"[MeSH Terms] AND "adult"[MeSH Terms]) AND ("1990/01/01"[PDAT] : "2030/12/31"[PDAT]) © 2020 Wei J et al. JAMA Netw Open. All rights reserved. eTable 1. Cardiovascular Events and Outcomes by Randomized Treatment Study Sample Follow-Up Treatment Cardiovascular Events Age Male, % Region Size Time Death MI Stroke CABG/PCI 1 * DEMAND, 2011 126 3 years 0 - - - 60.2 61.9 Italy ACEi/DH CCB Slovenia 127 ACEi 0 - - - 61.9 64.6 127 Placebo 2 - - - 60.4 69.3 FEVER, 2005 4841 40 months DH CCB 73 - 177 4 61.5 61.8 China 4870 Placebo 101 - 251 11 61.5 60.5 MRC, 1992 1081 5.8 years Diuretics 66 - 45 - 70 42.0 UK 1102 BB 95 - 56 - 70 41.4 2213 Placebo 180 - 134 - 70 41.8 SHEP, 1991 2365 4.5 years Diuretics 90 50 96 49 71.6 43.7 US 2371 Placebo 112 74 149 69 71.5 42.7 STOP, 1991 812 25 months BB/Diuretics 36 19 26 - 75.6 37 Sweden 815 Placebo 63 22 41 - 75.7 37 Syst-China, 1998 1253 2 years DH CCB 33 4 35 - 66.4 63.6 China 1141 Placebo 44 4 41 - 66.7 65 Syst-Eur, 1997 2398 2 years DH CCB 59 26 34 - 70.3 32.5 Europe 2297 Placebo 77 31 57 - 70.2 33.8 Sun, Ming, 1997 1040 10 years DH CCB - - 37 - 51.8 53.0 China 1040 Placebo - - 79 - Sun, Z. Q, 2010 2530 15 months ACEi/Diuretics/DH - - 24 - 56.4 43.8 China CCB 2454 Education - - 52 - 56.2 41.8 HYVET Pilot, 2003 426 13 months Diuretics 23 - - - 83.8 37.1 Europe 431 ACEi 22 - - - 83.7 36.0 426 Standard 19 - - - 83.8 36.6 11,12 UKPDS, 1998 400 9 years ACEi - 61 21 - 56.3 51.0 UK 358 BB - 46 17 - 56 57.0 390 Standard - 69 34 - 56.5 58.0 ABCD, 1998 235 67 months DH CCB 10 22 11 - 57.2 68.1 US 235 ACEi 5 5 7 - 57.7 66.8 ACCOMPLISH, 2008 5744 3 years ACE/DH CCB 107 125 112 334 68.4 60.0 US Europe 5762 ACE/Diuretics 134 159 133 386 68.3 61.0 ALLHAT, 2002 15255 4.9 years Diuretics 992 - 675 1113 66.9 53.0 US 9048 DH CCB 592 - 377 725 66.9 52.7 9054 ACEi 609 - 457 718 66.9 53.8 ASCOT, 2005 9639 5.5 years DH CCB 263 429 327 167 63 77.0 Europe © 2020 Wei J et al. JAMA Netw Open. All rights reserved. 9618 BB 342 474 422 214 63 77.0 BENEDICT-B, 2011 138 4.5 years ACEi/Non-DH CCB 2 2 4 6 62.3 75.4 Italy 143 ACEi 7 1 4 7 62.4 72.0 COLM, 2014 2568 3.3 years DH CCB/ARB 13 9 60 - 73.6 51.5 Japan 2573 Diuretics/ARB 18 16 62 - 73.6 51.7 CONVINCE, 2003 8179 3 years Non-DH CCB 152 133 133 - 65.6 43.8 Multiple 8297 BB/Diuretics 143 128 166 - 65.6 46.2 ELSA, 2002 1157 4 years BB 8 17 14 - 55.9 55.4 Europe 1177 DH CCB 4 18 9 - 56.1 54.2 FACET, 1998 189 3.5 years ACEi - 10 4 7 62.8 63.5 Italy 191 DH CCB - 13 10 8 63.3 55.5 GLANT, 1995 980 1 year ACEi 1 1 5 - 60 44.4 Japan 956 DH CCB 0 0 11 - 60 44.0 INSIGHT, 2000 3157 51 months DH CCB 60 61 55 - 65 46.1 Europe 3164 Diuretics 52 56 63 - 46.6 Israel INVEST, 2003 11267 2 years Non-DH CCB 431 151 131 280 66 48.1 Multiple 11309 BB 431 153 148 275 66.1 47.7 J-MIND, 2001 228 2 years DH CCB - 1 5 - 60.2 48.7 Japan 208 ACEi - 1 2 - 59.9 52.4 JMIC-B, 2003 828 3 years DH CCB 6 16 16 81 65 67.6 Japan 822 ACEi 6 13 16 75 64 70.0 LIFE, 2002 4605 4.8 years ARB 204 198 232 261 66.9 46.0 US 4508 BB 234 188 309 284 66.9 46.0 Europe MAPHY, 1991 1609 5 years BB 29 82 21 6 40 to 100 Europe 1625 Diuretics 34 109 18 8 64 100 MIDAS, 1996 442 3 years DH CCB 3 6 6 11 58.2 79.9 US 441 Diuretics 3 5 3 10 58.7 75.7 MOSES, 2005 681 2.5 years ARB - - 236 - 67.7 53.6 Germany 671 DH CCB - - 134 - 68.1 54.8 Austria NAGOYA HEART, 2012 575 3.2 years ARB - 7 13 29 63 66.0 Japan 575 DH CCB - 3 16 26 63 66.0 NICS-EH, 1999 204 5 years DH CCB 2 2 1 - 69.7 40.2 Japan 210 Diuretics 0 2 0 - 69.9 26.2 NORDIL, 2000 5410 4.5 years Non-DH CCB - 183 159 - 60.5 48.5 Sweden 5471 Diuretics/BB - 157 196 - 60.3 48.7 Norway OSCAR, 2012 578 3 years ARB - - 24 - 73.6 43.9 Japan 586 ARB/DH CCB - - 15 - 73.6 44.5 PATE, 2000 699 3 years ACEi - 1 11 - 70 38.3 Japan 1049 DH CCB - 5 17 - 69 43.3 © 2020 Wei J et al. JAMA Netw Open. All rights reserved. SHELL, 2003 940 32 months Diuretics 13 14 38 4 72.4 37.8 Italy 942 DH CCB 16 12 37 2 72.3 39.6 STOP-2, 1999 2213 4 years Diuretics/BB 221 154 237 - 76 32.0 Sweden 2205 ACEi 226 139 215 - 76.1 33.7 2196 DH CCB 212 179 207 - 75.9 34.0 VALUE, 2004 7649 4.2 years ARB 304 369 322 - 67.2 57.6 Multiple 7596 DH CCB 304 313 281 - 67.3 57.5 VART, 2011 510 3.4 years ARB 0 2 10 - 60 56.9 Japan 511 DH CCB 0 1 10 - 60 57.5 VHAS, 1997 707 2 years Diuretics 4 5 4 3 53.9 50.1 Italy 707 Non-DH CCB 5 5 3 4 54.5 47.8 SANBPS, 2003 3044 4.1 years ACEi 84 50 91 - 72 50 Australia 3039 Diuretics 82 71 94 - 71.9 48 CTHPCETG, 2011 1110 3.6 years ARB - - 17 - 63 51.0 Japan 1089 BB - - 27 - 63.2 50.5 1094 Diuretics - - 12 - 63.1 50.5 E-COST, 2005 1053 3.1 years ARB 0 10 47 - - 44.5 Japan 995 Conventional 0 23 77 - - 51.8 HYVET, 2014 1922 1.8 years ACE/Diuretics 88 9 23 - 83.5 39.5 Multiple 1900 Placebo 110 11 28 - CAPPP, 1999 5492 6.1 years ACEi 70 137 173 - 52.4 54.9 Sweden 5493 BB/Diuretics 81 128 127 - 52.7 52.0 SCOPE, 2003 2477 3.7 years ARB 145 54 68 - 76.4 35.2 Europe 2460 Placebo 152 47 93 - 76.4 35.8 HIJ-CREATE, 2009 1024 4.2 years ARB 28 29 45 256 65.0 81.8 Japan 1025 ACEi 25 26 49 271 64.5 78.6 Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; DH CCB, dihydropyridine calcium channel blocker; nDH CCB: BB, beta blocker; ARB, angiotensin receptor blocker; MI, myocardial infarction; CABG, coronary artery bypass surgery; PCI, percutaneous coronary intervention. © 2020 Wei J et al. JAMA Netw Open. All rights reserved. eTable 2. Absolute Risk Differences of Cardiovascular Events Comparing Each Type of Blood Pressure Lowering Drug to Placebo From Network Meta-analysis Drug Cardiovascular Death Myocardial Infarction Stroke Revascularization Overall ACEi vs. placebo -0.005 (-0.027, 0.016) -0.024 (-0.036, -0.011) -0.035 (-0.070, 0.001) - -0.037 (-0.082, 0.009) DH CCB vs. placebo -0.007 (-0.011, -0.003) -0.001 (-0.005, 0.003) -0.016 (-0.025, -0.006) -0.001 (-0.003, 0.0001) -0.013 (-0.031, 0.005) BB vs. placebo 0.005 (-0.015, 0.025) -0.048 (-0.100, 0.003) -0.020 (-0.048, 0.008) - -0.042 (-0.123, 0.039) ARB vs. placebo -0.000 (-0.002, 0.002) -0.005 (-0.021, 0.011) -0.020 (-0.041, 0.002) - -0.028 (-0.063, 0.007) Diuretics vs. placebo -0.010 (-0.022, 0.003) -0.010 (-0.019, -0.001) -0.021 (-0.031, -0.011) -0.008 (-0.017, 0.0005) -0.028 (-0.061, 0.005) Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; DH CCB, dihydropyridine calcium channel blocker; BB, beta blocker; ARB, angiotensin receptor blocker. © 2020 Wei J et al. JAMA Netw Open. All rights reserved. eTable 3. Inconsistency Test Between Direct and Indirect Treatment Comparisons in Mixed Treatment Comparisons Cardiovascular Mortality Side Direct Indirect Difference p>z Coefficient SE Coefficient SE Coefficient SE ACEi placebo 0.04 0.30 -0.23 0.07 0.28 0.31 0.37 DH CCB placebo -0.33 0.10 -0.18 0.07 -0.15 0.12 0.22 BB placebo 0.05 0.12 -0.03 0.08 0.08 0.15 0.57 ARB placebo -0.05 0.11 -0.23 0.09 0.18 0.14 0.20 Diuretics placebo -0.20 0.09 -0.30 0.08 0.10 0.13 0.42 Myocardial Infarction Side Direct Indirect Difference p>z Coefficient SE Coefficient SE Coefficient SE ACEi placebo -0.15 0.18 -0.41 0.13 0.26 0.22 0.24 DH CCB placebo -0.20 0.26 -0.23 0.11 -0.03 0.28 0.91 BB placebo -0.29 0.19 -0.19 0.13 -0.10 0.23 0.67 ARB placebo -0.11 0.19 -0.12 0.13 0.01 0.23 0.95 Diuretics placebo -0.39 0.20 -0.12 0.12 -0.27 0.23 0.25 Stroke Side Direct Indirect Difference p>z Coefficient SE Coefficient SE Coefficient SE ACEi placebo -0.54 0.30 -0.40 0.10 -0.15 0.32 0.56 DH CCB placebo -0.46 0.11 -0.54 0.11 0.09 0.15 0.57 BB placebo -0.29 0.17 -0.18 0.12 -0.12 0.21 0.58 ARB placebo -0.43 0.15 -0.33 0.11 -0.09 0.19 0.63 Diuretics placebo -0.41 0.14 -0.50 0.12 0.09 0.19 0.64 Revascularization Side Direct Indirect Difference p>z Coefficient SE Coefficient SE Coefficient SE DH CCB placebo -1.01 0.58 -0.27 0.20 -0.73 0.62 0.24 Diuretics placebo -0.34 0.19 -1.07 0.59 0.73 0.62 0.24 Overall Cardiovascular Events Side Direct Indirect Difference p>z Coefficient SE Coefficient SE Coefficient SE ACEi placebo -0.18 0.18 -0.40 0.10 0.22 0.21 0.30 DH CCB placebo -0.31 0.11 -0.31 0.10 -0.002 0.15 0.99 BB placebo -0.19 0.15 -0.18 0.11 -0.01 0.18 0.97 ARB placebo -0.30 0.15 -0.19 0.11 -0.11 0.18 0.56 Diuretics placebo -0.26 0.13 -0.36 0.11 -0.10 0.17 0.56 Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; DH CCB, dihydropyridine calcium channel blocker; BB, beta blocker; ARB, angiotensin receptor blocker. © 2020 Wei J et al. JAMA Netw Open. All rights reserved. eTable 4. Bivariate Meta-regression on the 10 mm Hg Reduction of Blood Pressure and Change of Cardiovascular Events 10 mm Hg Systolic Blood Pressure Reduction Cardiovascular Events RR (95% CI) CVD mortality 0.87 (0.77, 0.99) Myocardial infarction 0.95 (0.77, 1.17) Stroke 0.83 (0.72, 0.97) Revascularization 0.75 (0.50, 1.13) Overall 0.86 (0.78, 0.96) 5 mm Hg Diastolic Blood Pressure Reduction Cardiovascular Events RR (95% CI) CVD mortality 0.86 (0.74, 1.00) Myocardial infarction 0.95 (0.75, 1.21) Stroke 0.80 (0.67, 0.95) Revascularization 0.68 (0.42, 1.09) Overall 0.84 (0.74, 0.96) Abbreviation: RR, risk ratio. © 2020 Wei J et al. JAMA Netw Open. All rights reserved. eFigure 1. Funnel Plots of Studies of Blood Pressure Lowering Drugs and Effects of Prevention on Cardiovascular Death, Myocardial Infarction, Stroke, Revascularization, and Overall Cardiovascular Events A. Cardiovascular death -4 -2 0 2 4 Effect size centred at comparison-specific pooled effect (y - ) iXY XY Placebo vs dCCB ACEi vs Placebo ACEi vs dCCB ACEi vs ACEi+dCCB ACEi vs ACEi+ndCCB ACEi vs ARB ACEi+Diuretics vs Placebo ACEi vs BB+Diuretics ACEi vs Diuretics ACEi+CCB+Diuretics vs Placebo BB vs Placebo ARB vs BB ACEi+dCCB vs Placebo ACEi+Diuretics vs ACEi+dCCB ARB vs dCCB ARB vs Placebo BB vs ndCCB BB+Diuretics vs Placebo Diuretics vs Placebo BB vs Diuretics BB+Diuretics vs dCCB BB+Diuretics vs ndCCB Diuretics vs dCCB Diuretics vs ndCCB BB vs dCCB B. Myocardial infarction -4 -2 0 2 4 Effect size centred at comparison-specific pooled effect (y - ) iXY XY ACEi vs dCCB ACEi vs ACEi+ndCCB ACEi vs ARB ACEi vs BB ACEi vs BB+Diuretics ACEi vs Diuretics ACEi vs Placebo ACEi+Diuretics vs ACEi+dCCB ARB vs BB ACEi+Diuretics vs Placebo ARB vs dCCB ARB vs Placebo BB vs dCCB BB vs ndCCB BB vs Diuretics BB vs Placebo BB+Diuretics vs dCCB BB+Diuretics vs ndCCB BB+Diuretics vs Diuretics BB+Diuretics vs Placebo Diuretics vs dCCB Diuretics vs ndCCB Diuretics vs Placebo Placebo vs dCCB © 2020 Wei J et al. JAMA Netw Open. All rights reserved. 1.5 1.5 2 1 0 1 0 C. Stroke -4 -2 0 2 4 Effect size centred at comparison-specific pooled effect (y - ) iXY XY TD vs dCCB TD vs ndCCB dCCB+ARB vs ARB+TD ACE vs dCCB ACE vs ACE+ndCCB ACE vs TD ACE vs ARB ACE vs BB ACE vs BB+TD ACE vs Placebo ACE+TD vs ACE+dCCB ACE+TD vs Placebo ACE+dCCB+TD vs Placebo ARB vs TD ARB vs dCCB ARB vs dCCB+ARB ARB vs BB ARB vs Placebo BB vs TD BB vs dCCB BB vs ndCCB BB vs Placebo BB+TD vs ndCCB BB+TD vs dCCB BB+TD vs Placebo Placebo vs TD Placebo vs dCCB D. Revascularization -2 -1 0 1 2 Effect size centred at comparison-specific pooled effect (y - ) iXY XY ACE vs ACE+ndCCB ACE vs ARB ACE vs TD ACE vs dCCB ACE+dCCB vs ACE+TD ARB vs BB ARB vs dCCB BB vs dCCB BB vs ndCCB Placebo vs TD Placebo vs dCCB TD vs dCCB TD vs ndCCB © 2020 Wei J et al. JAMA Netw Open. All rights reserved. 1.5 1 0 1 0 E. Overall cardiovascular events -4 -2 0 2 4 Effect size centred at comparison-specific pooled effect (y - ) iXY XY Placebo vs dCCB dCCB+ARB vs ARB+Diuretics ACEi vs Placebo ACEi vs dCCB ACEi vs ACEi+dCCB ACEi vs ACEi+ndCCB ACEi vs ARB ACEi vs BB+Diuretics ACEi vs Diuretics ACEi+Diuretics vs ACEi+dCCB ACEi+Diuretics vs Placebo ACEi+dCCB+Diuretics vs Placebo ARB vs Placebo ARB vs dCCB ACEi+dCCB vs Placebo ACEi vs BB ARB vs Diuretics BB vs Placebo BB vs ndCCB BB vs Diuretics BB+Diuretics vs Placebo ARB vs dCCB+ARB ARB vs BB BB+Diuretics vs dCCB BB+Diuretics vs ndCCB Diuretics vs Placebo Diuretics vs dCCB Diuretics vs ndCCB BB vs dCCB © 2020 Wei J et al. JAMA Netw Open. All rights reserved. 1.5 2 1 0 eFigure 2. Inconsistency Plots of Studies of Blood Pressure Lowering Drugs and Effects of Prevention on Cardiovascular Death, Myocardial Infarction, Stroke, Revascularization, and Overall Cardiovascular Events A. Cardiovascular death 95%CI Loop-specific Loop IF (truncated) Heterogeneity( ) ACEi-ACEi+dCCB-Placebo 1.74 (0.00,6.73) 0.000 ACEi+Diuretics-ACEi+dCCB-Placebo 1.15 (0.00,4.19) 0.000 ACEi-BB+Diuretics-Placebo 0.64 (0.00,1.38) 0.001 BB-BB+Diuretics-Placebo-ndCCB 0.54 (0.01,1.07) 0.000 BB+Diuretics-Diuretics-Placebo-ndCCB 0.50 (0.00,1.91) 0.001 ACEi-Placebo-dCCB 0.40 (0.00,1.04) 0.000 ARB-Placebo-dCCB 0.29 (0.00,0.66) 0.000 ACEi-Diuretics-Placebo 0.24 (0.00,0.87) 0.000 ACEi-ARB-Placebo 0.24 (0.00,1.06) 0.000 Diuretics-Placebo-dCCB 0.18 (0.00,0.50) 0.000 BB-BB+Diuretics-dCCB-ndCCB 0.17 (0.00,0.52) 0.000 ACEi-ARB-dCCB 0.13 (0.00,0.69) 0.000 BB-Placebo-dCCB 0.12 (0.00,0.50) 0.000 ARB-BB-dCCB 0.12 (0.00,0.41) 0.000 BB-Diuretics-dCCB 0.12 (0.00,0.43) 0.000 ACEi-BB+Diuretics-Diuretics-ndCCB 0.10 (0.00,1.44) 0.000 ACEi-ARB-BB-Diuretics 0.10 (0.00,0.72) 0.000 BB+Diuretics-Diuretics-dCCB-ndCCB 0.06 (0.00,1.41) 0.000 ACEi-Diuretics-dCCB 0.06 (0.00,0.28) 0.000 ARB-BB-Placebo 0.05 (0.00,0.42) 0.000 ACEi-BB+Diuretics-dCCB 0.03 (0.00,0.29) 0.000 BB-Diuretics-ndCCB 0.01 (0.00,1.35) 0.000 BB-Diuretics-Placebo 0.01 (0.00,0.43) 0.000 0 0 2 4 6 7 © 2020 Wei J et al. JAMA Netw Open. All rights reserved. B. Myocardial infarction 95%CI Loop-specific Loop IF (truncated) Heterogeneity( ) ACEi-BB-dCCB 0.47 (0.00,1.14) 0.032 BB+Diuretics-Diuretics-Placebo 0.41 (0.00,1.14) 0.000 ARB-Placebo-dCCB 0.40 (0.00,1.63) 0.149 BB-Diuretics-dCCB 0.36 (0.04,0.68) 0.000 BB-Diuretics-Placebo 0.34 (0.00,0.91) 0.000 ACEi-ARB-dCCB 0.34 (0.00,1.13) 0.034 ACEi-BB-BB+Diuretics-ndCCB 0.34 (0.00,0.85) 0.000 BB-BB+Diuretics-Placebo-ndCCB 0.32 (0.00,1.09) 0.000 ACEi-Diuretics-Placebo 0.31 (0.00,0.80) 0.000 BB-Diuretics-ndCCB 0.28 (0.00,1.57) 0.000 ACEi-Placebo-dCCB 0.28 (0.00,1.09) 0.034 ACEi-ARB-BB 0.25 (0.00,0.91) 0.000 ACEi-Diuretics-dCCB 0.25 (0.00,0.49) 0.000 BB+Diuretics-Placebo-dCCB 0.22 (0.00,1.02) 0.000 BB-Placebo-dCCB 0.21 (0.00,0.82) 0.000 ARB-BB-Placebo 0.20 (0.00,0.72) 0.000 Diuretics-Placebo-dCCB 0.20 (0.00,0.81) 0.000 BB-BB+Diuretics-dCCB-ndCCB 0.11 (0.00,0.52) 0.000 ACEi-BB+Diuretics-dCCB 0.06 (0.00,0.77) 0.044 ACEi-BB+Diuretics-Diuretics 0.06 (0.00,0.50) 0.013 ACEi-ARB-Placebo 0.05 (0.00,0.75) 0.000 ARB-BB-dCCB 0.04 (0.00,0.31) 0.000 ACEi-BB-Diuretics 0.03 (0.00,0.50) 0.000 BB+Diuretics-Diuretics-ndCCB 0.03 (0.00,1.31) 0.000 ACEi-BB+Diuretics-Placebo 0.02 (0.00,0.72) 0.000 BB+Diuretics-Diuretics-dCCB 0.01 (0.00,0.32) 0.000 0 0 1 1 2 2 *** Loop(s) [ACEi-BB-Placebo] are formed only by multi-arm trial(s) - Consistent by definition © 2020 Wei J et al. JAMA Netw Open. All rights reserved. C. Stroke 95%CI Loop-specific Loop IF (truncated) Heterogeneity( ) BB-TD-ndCCB 0.50 (0.00,2.16) 0.027 ARB-BB-TD 0.46 (0.00,1.28) 0.000 ACE-BB-Placebo 0.43 (0.00,1.30) 0.000 ACE-ARB-dCCB 0.39 (0.00,1.07) 0.043 ACE-BB+TD-dCCB 0.38 (0.00,1.14) 0.071 ACE-BB-dCCB 0.35 (0.00,1.08) 0.011 BB-Placebo-TD 0.35 (0.00,1.00) 0.010 ACE-BB-TD 0.34 (0.00,1.09) 0.005 ARB-Placebo-TD 0.34 (0.00,1.13) 0.000 ACE-ARB-BB 0.34 (0.00,1.09) 0.000 ACE-ARB-TD 0.33 (0.00,1.17) 0.000 ARB-BB-dCCB 0.30 (0.00,0.96) 0.053 BB-BB+TD-Placebo-ndCCB 0.26 (0.00,0.88) 0.000 BB-BB+TD-dCCB-ndCCB 0.22 (0.00,0.58) 0.000 ARB-Placebo-dCCB 0.21 (0.00,0.75) 0.044 ACE-TD-dCCB 0.18 (0.00,0.42) 0.000 ACE-Placebo-TD 0.18 (0.00,0.75) 0.000 ARB-BB-Placebo 0.17 (0.00,0.56) 0.000 ACE-ARB-Placebo 0.17 (0.00,0.87) 0.000 BB+TD-TD-dCCB-ndCCB 0.15 (0.00,1.67) 0.000 BB+TD-Placebo-dCCB 0.13 (0.00,0.78) 0.016 ARB-TD-dCCB 0.12 (0.00,1.03) 0.038 BB-Placebo-dCCB 0.12 (0.00,0.57) 0.012 ACE-BB+TD-Placebo 0.11 (0.00,0.84) 0.000 BB-TD-dCCB 0.11 (0.00,0.46) 0.000 ACE-BB-BB+TD-ndCCB 0.08 (0.00,1.00) 0.032 ACE-Placebo-dCCB 0.06 (0.00,0.73) 0.016 Placebo-TD-dCCB 0.05 (0.00,0.33) 0.000 ACE-BB+TD-TD-ndCCB 0.05 (0.00,1.63) 0.022 BB+TD-Placebo-TD-ndCCB 0.05 (0.00,1.64) 0.000 0 0 1 2 3 3 D. Revascularization 95%CI Loop-specific Loop IF (truncated) Heterogeneity( ) Placebo-TD-dCCB 0.75 (0.00,1.95) 0.000 ACE-ARB-dCCB 0.16 (0.00,0.71) 0.000 ACE-TD-dCCB 0.15 (0.00,0.92) 0.000 BB-TD-dCCB-ndCCB 0.07 (0.00,1.59) 0.000 ARB-BB-dCCB 0.04 (0.00,0.61) 0.000 0 0 1 1 2 2 © 2020 Wei J et al. JAMA Netw Open. All rights reserved. E. Overall cardiovascular events 95%CI Loop-specific Loop IF (truncated) Heterogeneity( ) ACEi-ACEi+dCCB-Placebo 1.42 (0.00,6.37) 0.000 ACEi+Diuretics-ACEi+dCCB-Placebo 1.20 (0.00,4.23) 0.000 ACEi-BB-dCCB 0.47 (0.00,1.00) 0.012 ARB-BB-Diuretics 0.45 (0.00,1.20) 0.000 ACEi-ARB-dCCB 0.45 (0.00,0.95) 0.028 ARB-Diuretics-Placebo 0.39 (0.00,1.50) 0.042 ACEi-ARB-Diuretics 0.35 (0.00,1.11) 0.002 ACEi-BB-Diuretics 0.33 (0.00,1.06) 0.034 ACEi-Placebo-dCCB 0.29 (0.00,0.80) 0.024 ACEi-BB+Diuretics-dCCB 0.29 (0.00,0.83) 0.035 ACEi-ARB-BB 0.27 (0.00,0.60) 0.000 BB-BB+Diuretics-Placebo-ndCCB 0.27 (0.00,0.83) 0.010 ARB-BB-dCCB 0.26 (0.00,0.87) 0.054 BB-Diuretics-Placebo 0.26 (0.00,1.13) 0.097 ARB-Placebo-dCCB 0.23 (0.00,0.83) 0.074 ACEi-BB+Diuretics-Placebo 0.23 (0.00,0.70) 0.011 BB-BB+Diuretics-dCCB-ndCCB 0.19 (0.02,0.37) 0.000 BB+Diuretics-Diuretics-Placebo-ndCCB 0.19 (0.00,0.93) 0.000 ACEi-ARB-Placebo 0.15 (0.00,1.07) 0.095 BB-Diuretics-ndCCB 0.15 (0.00,1.63) 0.130 ACEi-Diuretics-dCCB 0.13 (0.00,0.40) 0.009 ARB-BB-Placebo 0.13 (0.00,0.87) 0.075 BB-Diuretics-dCCB 0.13 (0.00,0.58) 0.021 ACEi-BB-BB+Diuretics-ndCCB 0.13 (0.00,0.53) 0.004 BB+Diuretics-Placebo-dCCB 0.12 (0.00,0.94) 0.063 BB-Placebo-dCCB 0.09 (0.00,0.66) 0.050 ACEi-BB+Diuretics-Diuretics-ndCCB 0.09 (0.00,0.80) 0.003 ACEi-BB-Placebo 0.06 (0.00,0.74) 0.000 Diuretics-Placebo-dCCB 0.06 (0.00,0.42) 0.017 ARB-Diuretics-dCCB 0.04 (0.00,0.90) 0.029 ACEi-Diuretics-Placebo 0.04 (0.00,0.36) 0.003 BB+Diuretics-Diuretics-dCCB-ndCCB 0.03 (0.00,0.72) 0.000 0 0 2 4 6 7 © 2020 Wei J et al. 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Published: Feb 21, 2020

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