Review Article
Effects of RAAS Blockers on Atrial Fibrillation Prophylaxis: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials
Journal of Cardiovascular Pharmacology and Therapeutics 1-17 ª The Author(s) 2016 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248415619490 cpt.sagepub.com
Sandip Chaugai, MD1, Wen Yeng Meng, MD1, and Amir Ali Sepehry, MSc, PhD2,3
Abstract Background: Impact of atrial fibrillation on clinical outcomes is well recognized, and application of renin–angiotensin–aldosterone system (RAAS) blockers for the prevention of atrial fibrillation (AF) is a theoretically appealing concept. However, clinical trials have yielded inconsistent results. Methods: A pooled study of 26 randomized controlled trials (RCTs) assessing the efficacy of RAAS blockers on AF prophylaxis was performed. Results: A total of 28 reports from 26 randomized controlled trials enrolled 165 387 patients, with an overall 24% reduction in the incidence of AF (odds ratio [OR]: 0.76, 95% confidence interval [CI]: 0.68-0.85], P ¼ .000). Forty-nine percent reduction in the incidence of AF (OR: 0.51, 95% CI: 0.30-0.85, P ¼ .010) in systolic heart failure was observed, whereas no significant effect was observed in patients with diastolic heart failure, postmyocardial infarction, and high cardiovascular disease risk. There was a 19% (OR: 0.81, 95% CI: 0.67-1.00, P ¼ .037) reduction in new-onset and 54% (OR: 0.46, 95% CI: 0.33-0.62, P ¼ .000) reduction in recurrent AF in hypertensive patients with 39% (OR: 0.61, 95% CI: 0.44-0.84, P ¼ .003) risk reduction against calcium blockers and 41% (OR: 0.59, 95% CI: 0.44-0.80, P ¼ .001) risk reduction against b blockers. Angiotensin-receptor blocker appeared marginally superior to angiotensin-converting enzyme inhibitor in primary and secondary prevention. Conclusion: This study suggests that RAAS blockade effectively suppresses AF in systolic heart failure, and hypertensives derive greater benefit against new-onset and recurrent AF compared to b blockers, calcium channel blockers, and diuretics. Keywords atrial fibrillation, RAAS blockers, ACE I, ARB, b blockers, calcium channel blockers, diuretics, CVD risk, hypertension, heart failure
Background Impact of atrial fibrillation (AF) on major adverse clinical outcomes including mortality, heart failure, and stroke in participants with heart failure, myocardial infarction (MI), hypertension, or high cardiovascular disease (CVD) risk factors is well recognized, and prevention of AF in these patient populations is highly desirable.1-3 Ability of antihypertensive drugs such as renin–angiotensin–aldosterone system (RAAS) blockers, b blockers (BBs), and calcium channel blockers (CCBs) to suppress AF has been an area of high interest. Among these, RAAS blockers appear to be the most appealing therapeutic agents based on our current understanding of the proarrhythmic effects of RAAS on AF onset, progression, and persistence.4 Clinical trials have yielded inconsistent results with some showing impressive effects of RAAS blockade (Losartan Intervention For End Point Reduction in Hypertension [LIFE]), whereas others failing to show any benefit (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events [ACTIVE-I] and Gruppo Italiano per lo Studio della Sopravvivenza nell 0Infarto Miocardico, Atrial
Fibrillation [GISSI-AF]) on AF prevention. Major antihypertensive drug classes, especially RAAS blockers and BBs, remain the cornerstone of management of heart failure and MI, irrespective of their role in primary prevention of AF. From clinical perspective, knowledge of comparative efficacy of these drugs against
1
Department of Internal Medicine, Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 2 Graduate Program in Neuroscience, College for Interdisciplinary Studies, University of British Columbia, Vancouver, British Columbia, Canada 3 Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada Manuscript submitted: July 25, 2015; accepted: October 19, 2015. Corresponding Author: Sandip Chaugai, Department of Internal Medicine, Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Email: [email protected]
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AF prophylaxis in hypertensives is essential to curb the excess morbidity and mortality incited by AF before the onset of heart failure or MI. This is especially important in hypertensives with AF as hypertension is present in almost two-third of patients with AF and is associated with adverse clinical outcomes.5 Further, a distinction between systolic and diastolic heart failure is essential considering their differential therapeutic response to RAAS blockers. These remain unexplored in previous meta-analysis. Further, disappointing results of recent a priori designed secondary prevention trials challenge our understanding of secondary AF prevention by RAAS blockade, especially in the absence of concomitant antiarrhythmic drug (AAD) therapy.
Methods Data Sources and Search Strategy A systematic review and meta-analysis was performed in accordance with the standards set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.6,7 Electronic databases PubMed, EMBASE, and Cochrane Collaboration of Controlled Clinical Trials registery were searched using the key words ‘‘beta blockers,’’ ‘‘calcium channel blockers,’’ ‘‘angiotensin,’’ ‘‘angiotensin converting enzyme inhibitors,’’ ‘‘angiotensin receptor blockers,’’ ‘‘individual names in these drug classes,’’ ‘‘atrial fibrillation,’’ ‘‘ atrial arrhythmia,’’ ‘‘hypertension,’’ ‘‘heart failure,’’ and ‘‘myocardial infarction.’’ Additionally, references of retrieved articles and previous meta-analysis were manually searched to identify studies not captured by our primary search strategy. No restrictions were imposed on dates of publication, but the search was restricted to trials published in English. The final search was run on December 1, 2014.
Study Selection Randomized controlled trials (RCTs) of RAAS blockers against AF prophylaxis in patients with heart failure, MI, hypertension, or CVD risk factors were screened. Exclusion criteria were uncontrolled studies, application of AAD or electrical cardioversion as part of the treatment protocol in the trial, enrollment of specialized patient populations such as postcardiac surgery, case reports, reviews, studies not reporting the outcome of interest, and no access to full text for quality assessment and data extraction. Studies were categorized into ‘‘heart failure’’ enrolling participants with systolic and/or diastolic heart failure, ‘‘post MI’’ enrolling patients after acute MI, ‘‘high CVD risk’’ enrolling participants with traditional CVD risk factors, and ‘‘hypertension’’ restricted to trials enrolling all participants with blood pressure (BP) >140/90 or on antihypertensive therapy.
Data Extraction and Quality Assessment Data were extracted in duplicate by 2 independent reviewers (Drs Chaugai and Meng), and disagreements were resolved by consensus. The methodological quality of each trial was
evaluated for risk of bias using standard criteria: random sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessor; incomplete outcome ascertainment; selective reporting; and other potential sources of bias as recommended by the Cochrane Collaboration (Table 1).
Data Synthesis and Statistical Analysis The measurement data were pooled across studies and analyzed using random-effects meta-analysis model with inverse variance weighting. These are presented as odds ratios (ORs) with 95% confidence intervals (CIs). The magnitude of heterogeneity present was estimated using the I2 statistic, an estimate of the proportion of the total observed variance that is attributed to the ‘‘between-study variance’’. Random-effects meta-regression analysis was performed to identify potential effect modifiers. All P values are 2 tailed with the statistical significance set at .05. All statistical analyses were performed using STATA software 12.0.
Results Study Selection The flow diagram of study selection is shown in Figure 1. Of the initial 4739 hits, 113 articles were retrieved for detailed evaluation for potential inclusion. Tables 2 and 3 summarize the design and baseline characteristics of the included studies. Twenty-eight reports from 26 RCTs (2 reports from LIFE and Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity [CHARM] trials each) enrolled a total of 165 387 patients with 75 899 in the RAAS blockers arm and 89 488 in the control arm followed up for an average of 1 to 6 years. Fourteen placebo controlled trials, 4 heart failure,21-24 2 post-MI,25,26 and 8 high CVD risk,13-20 and 13 reports from 12 actively controlled trials in hypertensive participants3,8-12,27-33 were included in the meta-analysis. Eight trials used angiotensin-converting enzyme inhibitor (ACE I),13,15,21,25-28,31 17 trials used angiotensin-receptor blocker (ARB),3,8,11,12,14,16-20,22-24,29,30,32,33 and 2 trials were designed with parallel ACE I and ARB arms.9,10 Table 4 summarizes the results of the meta-analysis. Incidence of AF. Overall, there was a 24% reduction in the incidence of AF (OR: 0.76, 95% CI: 0.68-0.85, P ¼ .000; Figure 2). The degree of heterogeneity in the treatment effect was I2 ¼ 78.2% and P ¼ .000. Post hoc exclusion of all the trials with a sample size less than 500 decreased the observed treatment effect to 10% (OR: 0.90, 95% CI: 0.83-0.97, P ¼ .008; Supplementary Figure 1). The degree of heterogeneity in the treatment effect also declined to I2 ¼ 55.8% and P ¼ .002. Further subgroup analysis was performed considering the significant variation in effect size between trial groups, primary and secondary AF prevention, and the experimental therapy used, that is, ACE I and ARB.
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Chaugai et al
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Table 1. Risk of Bias Across Studies Included in the Meta-Analysis.
Trials
Adequate Sequence Generation
Allocation Concealment
Blinding (Patient Investigator)
Blinding (Morbidity)
Incomplete Outcome Data Addressed
Free of Selective Outcome Reporting
Free of Other Bias
DIABHYCAR PRoFESS HOPE TRANSCEND GISSI-AF ACTIVE-I ROADMAP NAVIGATOR SOLVD Val HeFT CHARM I-PRESERVE TRACE GISSI-3 CAPPP STOP-2 LIFE VALUE ALLHAT-2 Fogari et al (1)8 Fogari et al (2)9 Fogari et al (3)10 Fogari et al (4)11 J Rhythm II Galzerano et al12 NTP-AF
Yes Unclear Yes Yes Yes Yes Yes Yes Yes Unclear No Yes Unclear Yes No Unclear Unclear Yes Yes Unclear Unclear Yes Unclear Unclear Unclear Yes
Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear Yes Yes Unclear Yes Unclear Unclear Yes Yes Yes Unclear Yes Yes Unclear Yes Unclear No
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes Yes Yes No Yes Yes Yes No No No
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear Unclear Unclear Yes Unclear Unclear
Yes Yes Yes Yes No Yes No Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes
Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear Yes
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Abbreviations: ACTIVE-I, Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; ALLHAT-2, Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial 2; CAPPP, Captopril Prevention Project; CHARM, Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity; DIABHYCAR, type 2 DIABetes, Hypertension, CArdiovascular Events and Ramipril; GISSI-AF, Gruppo Italiano per lo Studio della Sopravvivenza nell 0Infarto Miocardico, Atrial Fibrillation; HOPE, Heart Outcomes Prevention Evaluation; I-PRESERVE, Irbesartan in Heart Failure with Preserved Ejection Fraction; J RHYTHM II, The Japanese Rhythm Management Trial II for Atrial Fibrillation; LIFE, Losartan Intervention For End Point Reduction in Hypertension; NAVIGATOR, Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; NTP-AF, Nifedipine versus Telmisartan on Prevention of AF; PRoFESS, Prevention Regimen for Effectively Avoiding Second Strokes; ROADMAP, Randomized Olmesartan and Diabetes Microalbuminuria Prevention; SOLVD, Studies Of Left Ventricular Dysfunction; STOP-2, Swedish Trial in Old patients with Hypertension-2; TRACE, TRAndolapril Cardiac Evaluation; TRANSCEND, Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease; Val HeFT, Valsartan Heart Failure Trial; VALUE, Valsartan Antihypertensive Long-term Use Evaluation.
Comparison between ACE I and ARB. Overall, ACE I therapy was associated with 23% reduction in the incidence of AF (OR: 0.77, 95% CI: 0.63-0.94, P ¼ .010) and ARB therapy was associated with a 29% reduction in the incidence of AF (OR: 0.71, 95% CI: 0.61-0.83, P ¼ .000; Supplementary Figure 2). In primary prevention, ACE I therapy showed a modest trend toward fewer AF (OR: 0.86, 95% CI: 0.71-1.04, P ¼ .117), whereas ARB therapy was associated with a 13% reduction in the incidence of AF (OR: 0.87, 95% CI: 0.79-0.96, P ¼ .015; Figure 3). In secondary prevention, ACE I caused 56% risk reduction (OR: 0.44, 95% CI: 0.30-0.64, P ¼ .000), whereas ARB caused 58% reduction in the incidence of recurrent AF (OR: 0.42, 95% CI: 0.28-0.62, P ¼ .015; Figure 3).
Figure 2). The degree of heterogeneity in the treatment effect was I2 ¼ 85.9% and P ¼ .001. Post hoc exclusion of the smallest trial Studies Of Left Ventricular Dysfunction (SOLVD) that enrolled participants with lowest mean left ventricle ejection fraction (LVEF) and showed the largest risk reduction decreased the heterogeneity to 30.1% with an accompanying decline in observed treatment effect to 31% (Figure 2). High CVD risk, diastolic heart failure, and post-MI. No significant effect of RAAS blocker therapy was observed in patients with high CVD risk (OR: 0.97, 95% CI: 0.89-1.06, P ¼ .505), diastolic heart failure (OR: 1.02, 95% CI: 0.80-1.31, P ¼ .877), or post-MI (OR: 0.72, 95% CI: 0.41-1.27, P ¼ .259), albeit only 2 trials were available in each of the last 2 categories.
Placebo-Controlled Trials Systolic heart failure. Renin–angiotensin–aldosterone system blocker therapy was associated with a 49% reduction in the incidence of AF (OR: 0.51, 95% CI: 0.30-0.85, P ¼ .010;
Actively Controlled Trials A total of 13 reports from 12 trials were included in the analysis, with 8 reporting AF recurrence, 3 new-onset AF, and 2 total
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4739 References identified from MEDLINE, EMBASE and Cochrane collaboration
4467 references remained after duplicate removal
4350 references excluded after abstract screening
117 references assessed for potential inclusion
28 reports included in the meta analysis (26 trials, 2 reports each from LIFE and CHARM trial)
Figure 1. Search flow diagram for studies included.
Subgroup Analysis
heterogeneity (I2 ¼ 75.7% and P ¼ .002). Limiting the analysis to trials reporting new-onset AF alone, 19% reduction in the incidence of new-onset AF (OR: 0.81, 95% CI: 0.67-1.00, P ¼ .037; Figure 5) without significant heterogeneity (I2 ¼ 69.7% and P ¼ .037) was noted. Renin–angiotensin–aldosterone system blocker therapy was associated with a 54% reduction in the incidence of recurrent AF in secondary prevention trials (OR: 0.46, 95% CI: 0.33-0.62, P ¼ .000). The degree of heterogeneity in the treatment effect was I2 ¼ 60.6% and P ¼ .013.
Drug class Beta-blocker trials. Renin–angiotensin–aldosterone system blocker therapy was associated with a 40% reduction in the incidence of AF (OR: 0.60, 95% CI: 0.44-0.81, P ¼ .001; Figure 4). No significant heterogeneity was observed (I2 ¼ 48.4% and P ¼ .121).
Persistent AF in hypertension. Renin–angiotensin–aldosterone system blocker therapy was associated with a 34% reduction in the incidence of persistent AF (OR: 0.66, 95% CI: 0.450.95, P ¼ .027). No significant heterogeneity was observed (I2 ¼ 30.6% and P ¼ .229; Figure 6).
AF. Overall, RAAS blocker therapy was associated with a 37% reduction in the incidence of AF (OR: 0.63, 95% CI: 0.50-0.78, P ¼ .000; Figure 2). The degree of heterogeneity in the treatment effect was I2 ¼ 83.7% and P ¼ .000. In fixed-effects model, RAAS blocker therapy was associated with a 23% reduction in the incidence of AF (OR: 0.77, 95% CI: 0.720.84, P ¼ .000).
Calcium channel blocker trials. Overall, RAAS blocker therapy was associated with a 39% reduction in the incidence of AF (OR: 0.61, 95% CI: 0.44-0.84, P ¼ .003; Figure 4). The degree of heterogeneity in the treatment effect was I2 ¼ 86.9% and P ¼ .000. Post hoc exclusion of The Japanese Rhythm Management Trial II for Atrial Fibrillation (J RHYTHM II), which reported only the incidence rate of persistent AF, did not affect the results. Primary versus secondary (recurrent) AF prevention in hypertension. Renin–angiotensin–aldosterone system blocker therapy showed a trend toward protection in primary prevention trials (OR: 0.88, 95% CI: 0.73-1.05, P ¼ .158; Figure 2) with significant
Discussion The results of the current meta-analysis based on 165 387 patients suggested that RAAS blockade results in a statistically significant 24% reduction in the risk of AF. Participants with systolic dysfunction appear to derive the greatest benefit with 49% reduction in the risk of AF, whereas the pooled estimates from high CVD risk, diastolic heart failure, and post-MI trials failed to show evidence of therapeutic benefit. Overall, 37% reduction in the risk of AF was noted in hypertension with 54% risk reduction in recurrent AF prevention and 19% risk reduction against new-onset AF. Overall, RAAS blockers were associated with 40% lower risk of AF against BB and 39%
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Valsartan þ amlodipine Valsartan/ramipril Telmisartan/ramipril Telmisartan Candesartan Telmisartan Telmisartan
Enalapril Valsartan Candesartan Irbesartan Trandolapril Lisinopril Captopril Enalapril/lisinopril Losartan
Amlodipine Amlodipine Amlodipine Amlodipine Carvedilol Amlodipine
All AF All AF New onset New onset Recurrence Recurrence New onset New onset
AF Type
AF Reported As
NA Adverse event NA Adverse event Post hoc Biannual ECG 2 NA 1 TTM 1 ECG þ TTM 2 NA Post hoc ECG/investigator reported Post hoc ECG/HM Post hoc Adverse event 2 Adverse event 1 NA Post hoc Regular ECG Post hoc In-hospital ECG 2 Adverse event 2 Adverse event 2 Annual ECG
End Point
HTN HTN HTN HTN HTN HTN
þ AF þ MS þ AF þ AF þ AF þ AF þ AF
Recurrence Recurrence Recurrence Recurrence Recurrence Recurrence
Recurrence
1 1 1 1 1 1
1
Monthly ECG/HM Monthly ECG/HM Monthly ECG/HM ECG/HM Monthly ECG/HM Regular ECG/HM
Monthly ECG/HM
New onset New onset New onset All AF New onset New onset All AF All AF New onset/ recurrence HTN þ CVD risk factors New onset 2 Annual ECG HTN þ CVD risk factors New onset Post hoc Biannual ECG
Heart failure (LVSD) Heart failure (LVSD) Heart failure (LVSD/DD) Heart failure (LVDD) Post-MI þ LVSD Post-MI HTN HTN HTN þ LVH
DM þ Proteinuria Postischemic stroke CVD risk factors HTN CVD risk factors HTN AF þ CVD risk factors AF þ CVD risk factors DM þ normoalbuminuria IGT þ CVD risk factors
Inclusion Criteria
Amlodipine Amlodipine þ cholorthalidone Atenolol þ amlodipine HTN þ DM þ AF
Placebo Placebo Placebo Placebo Placebo Placebo Diuretic/BB Diuretic/BB or CCB Atenolol
Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo
Control Drug
8.6 12 12 12 12 24
12
50.4 58.8
34.8 23 37.7 49.5 24-48 1.5 73.2 60 57.2
47 30 54 56 12 49.2 44.4 78
Follow-Up, months
Abbreviations: ACTIVE-I, Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; AF, atrial fibrillation; ALLHAT-2, Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial 2; BB, b blocker; CAPPP, Captopril Prevention Project; CCB, calcium channel blocker; CHARM, Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity; CVD, cardiovascular disease; DD, diastolic dysfunction; DIABHYCAR, type 2 DIABetes, Hypertension, CArdiovascular Events and Ramipril; DM, diabetes mellitus; ECG, electrocardiogram; GISSI-AF, Gruppo Italiano per lo Studio della Sopravvivenza nell 0Infarto Miocardico, Atrial Fibrillation; HM, Holter monitoring; HOPE, Heart Outcomes Prevention Evaluation; HTN, hypertension; IGT, impaired glucose tolerance; I-PRESERVE, Irbesartan in Heart Failure with Preserved Ejection Fraction; J RHYTHM II, The Japanese Rhythm Management Trial II for Atrial Fibrillation; LIFE, Losartan Intervention For End Point Reduction in Hypertension; LVDD, left ventricular diastolic dysfunction; LVH, left ventricle hypertrophy; LVSD, left ventricular systolic dysfunction; MI, myocardial infarction; MS, multiple sclerosis; NA, not available; NAVIGATOR, Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; NTP-AF, Nifedipine versus Telmisartan on Prevention of AF; PRoFESS, Prevention Regimen for Effectively Avoiding Second Strokes; ROADMAP, Randomized Olmesartan and Diabetes Microalbuminuria Prevention; SOLVD, Studies Of Left Ventricular Dysfunction; STOP-2: Swedish Trial in Old Patients with hypertension-2; TRACE, TRAndolapril Cardiac Evaluation; TRANSCEND, Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease; TTM, transtelephonic monitoring; Val HeFT, Valsartan Heart Failure Trial; VALUE, Valsartan Antihypertensive Long-term Use Evaluation. a Values are mean or percentage.
123/246 262/129 188/190 158/160 70/62 74/75
Fogari et al (2)9 Fogari et al (3)10 Fogari et al (4)11 Yamashita et al (J RHYTHM II)32 Galzerano et al12 Du et al (NTP-AF)33
6872/6888 Valsartan 6702/18630 Lisinopril
Schmieder et al (VALUE)30 Haywood et al (ALLHAT-2)31
148/148
186/188 2205/2190 3191/3188 2067/2061 790/787 8865/8846 5492/5493 2205/4409 4448/4403
Vermes et al (SOLVD)21 Maggioni et al (Val HeFT)22 Ducharme et al (CHARM)23 Massie et al (I-PRESERVE)24 Pedersen et al (TRACE)25 Pizzetti et al (GISSI-3)26 Hansson et al (CAPPP)27 Hansson et al (STOP-2)28 Wachtell et al (LIFE)29
Fogari et al (1)8
2443/2469 10 146/10 186 4291/4044 2954/2972 722/720 4518/4498 2232/2215 4631/4675
Marre et al (DIABHYCAR)13 Diener et al (PRoFESS)14 Salehian et al (HOPE)15 Yusuf et al (TRANSCEND)16 Disertori et al (GISSI-AF)17 Yusuf et al (ACTIVE-I)18 Haller et al (ROADMAP)19 Latini et al (NAVIGATOR)20 Ramipril Telmisartan Ramipril Telmisartan Valsartan Irbesartan Telmisartan Valsartan
Case/Control Size Treatment Drug
Trial Information
Table 2. Basic Characteristics of the Included Studies.a
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Journal of Cardiovascular Pharmacology and Therapeutics
Table 3. Baseline Characteristics of Trial Participants.a Trial Information Vermes et al (SOLVD)21 Maggioni et al (Val HeFT)22 Ducharme et al (CHARM)23 Massie et al (I-PRESERVE)24
Trial Information Pedersen et al (TRACE)25 Pizzetti et al (GISSI-3)26
Age, years Male, %
Baseline SBP/DBP
Baseline CAD Stroke HF HHF/IHF DYSL PAD LVH LVH AAD, %
89.92
128.15/78.9 19.93 20.45 93.35
NA
62.7 65.95 72
80 68.4 40
121/72 6.7 25.75 58.7 130.85/76.5 55.05 28.42 76.5 136.5/79 88.5 27.5 40
NA 8.75 10
Age, years
Male, %
Baseline SBP/DBP
HTN
DM
CAD Stroke
HF
68 NA
71.5 22.2
120/77.5 >100/NA
22 29.9
13 15.6
80.5 48.3
NA NA
22 14.5
79 84.9
DSBP/DBP
DM
CAD
HF
Age, Male, years %
Hansson et al (CAPPP)27 Hansson et al (STOP-2)28 Wachtell et al (LIFE)29 Schmieder et al (VALUE)30 Haywood et al (ALLHAT-2)31 Fogari et al (1)8 Fogari et al (2)9 Fogari et al (3)10 Fogari et al (4)11 Yamashita et al (J RHYTHM II)32 Galzerano et al12 Du et al (NTP-AF)33
52.55 76 66.9 67.25 66.9 65.5 64.99 66 68.24 65.58 55.82 61.75
Marre et al (DIABHYCAR)13 Salehian et al (HOPE)15 Diener et al (PRoFESS)14 Yusuf et al (TRANSCEND)16 Disertori et al (GISSI-AF)17 Yusuf et al (ACTIVE-I)18 Haller et al (ROADMAP)19 Latini et al (NAVIGATOR)20
DM
57.05
Trial Information
Trial information
HTN
Age, Male, years %
53.47 66.8 46 57.55 53.13 47.97 51.38 45.78 46.03 68.87 69.69 61.72
Baseline SBP/DBP 160.7/98.95 194/98 174.4/97.8 154.65/87.5 146.25/84 150.75/93.85 153/95 154.28/94.27 155.48/94.37 140.1/81.75 153.9/95.59 160.29/92.59
4.3/57.7
NA
NA
NA
26.7
4.8
100 6.7/58.7 100 NA 100 63.5/25
NA NA 31
NA NA NA
NA 27 NA 38.8 30.5 59.5
13 11.7 8.5
11/8 5.2 1.32 34.7/16.75 10.9 8 27.9/15.85 13 16 16.25/9.05 30 45.8 11.59/8.81 36.16 25.23 24.05/16.2 100 0 16.13/12.4 0 0 16.1/12.63 MS 100 NA 17.88/13.73 NA 0. 10/3 9.11 3.46 29.59/19.18 NA NA 33.7/16.55 0 0
Baseline SBP/DBP
DSBP/DBP
HTN
65.1
69.93 145.45/82.3
2.96/2.17
55.68 100
66 66.1 66.9
73.25 66.4 57.02
139/79 144.1/83.8 141/81.9
100
3/2.5 46.85 2.9 (DMBP) 74 2.25 (DMBP) 76.4
DM
CAD 6
38.45 80.45 28.24 16.2 35.74 74.55
Killip class 1 DYSL PAD
LVH
LVEF
Baseline AAD
NA NA
33 NA
NR NR
Stroke DYSL PAD
LVH
Baseline AAD
NA NA
NA NA
0.26 1.52 NA NA NA 1.9 3.9 NA NA NA 0 8 NA 6 100 NA 19.8 NA 13.9 6 0
Effects of RAAS Blockers on Atrial Fibrillation Prophylaxis: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials
Journal of Cardiovascular Pharmacology and Therapeutics 1-17 ª The Author(s) 2016 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248415619490 cpt.sagepub.com
Sandip Chaugai, MD1, Wen Yeng Meng, MD1, and Amir Ali Sepehry, MSc, PhD2,3
Abstract Background: Impact of atrial fibrillation on clinical outcomes is well recognized, and application of renin–angiotensin–aldosterone system (RAAS) blockers for the prevention of atrial fibrillation (AF) is a theoretically appealing concept. However, clinical trials have yielded inconsistent results. Methods: A pooled study of 26 randomized controlled trials (RCTs) assessing the efficacy of RAAS blockers on AF prophylaxis was performed. Results: A total of 28 reports from 26 randomized controlled trials enrolled 165 387 patients, with an overall 24% reduction in the incidence of AF (odds ratio [OR]: 0.76, 95% confidence interval [CI]: 0.68-0.85], P ¼ .000). Forty-nine percent reduction in the incidence of AF (OR: 0.51, 95% CI: 0.30-0.85, P ¼ .010) in systolic heart failure was observed, whereas no significant effect was observed in patients with diastolic heart failure, postmyocardial infarction, and high cardiovascular disease risk. There was a 19% (OR: 0.81, 95% CI: 0.67-1.00, P ¼ .037) reduction in new-onset and 54% (OR: 0.46, 95% CI: 0.33-0.62, P ¼ .000) reduction in recurrent AF in hypertensive patients with 39% (OR: 0.61, 95% CI: 0.44-0.84, P ¼ .003) risk reduction against calcium blockers and 41% (OR: 0.59, 95% CI: 0.44-0.80, P ¼ .001) risk reduction against b blockers. Angiotensin-receptor blocker appeared marginally superior to angiotensin-converting enzyme inhibitor in primary and secondary prevention. Conclusion: This study suggests that RAAS blockade effectively suppresses AF in systolic heart failure, and hypertensives derive greater benefit against new-onset and recurrent AF compared to b blockers, calcium channel blockers, and diuretics. Keywords atrial fibrillation, RAAS blockers, ACE I, ARB, b blockers, calcium channel blockers, diuretics, CVD risk, hypertension, heart failure
Background Impact of atrial fibrillation (AF) on major adverse clinical outcomes including mortality, heart failure, and stroke in participants with heart failure, myocardial infarction (MI), hypertension, or high cardiovascular disease (CVD) risk factors is well recognized, and prevention of AF in these patient populations is highly desirable.1-3 Ability of antihypertensive drugs such as renin–angiotensin–aldosterone system (RAAS) blockers, b blockers (BBs), and calcium channel blockers (CCBs) to suppress AF has been an area of high interest. Among these, RAAS blockers appear to be the most appealing therapeutic agents based on our current understanding of the proarrhythmic effects of RAAS on AF onset, progression, and persistence.4 Clinical trials have yielded inconsistent results with some showing impressive effects of RAAS blockade (Losartan Intervention For End Point Reduction in Hypertension [LIFE]), whereas others failing to show any benefit (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events [ACTIVE-I] and Gruppo Italiano per lo Studio della Sopravvivenza nell 0Infarto Miocardico, Atrial
Fibrillation [GISSI-AF]) on AF prevention. Major antihypertensive drug classes, especially RAAS blockers and BBs, remain the cornerstone of management of heart failure and MI, irrespective of their role in primary prevention of AF. From clinical perspective, knowledge of comparative efficacy of these drugs against
1
Department of Internal Medicine, Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 2 Graduate Program in Neuroscience, College for Interdisciplinary Studies, University of British Columbia, Vancouver, British Columbia, Canada 3 Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada Manuscript submitted: July 25, 2015; accepted: October 19, 2015. Corresponding Author: Sandip Chaugai, Department of Internal Medicine, Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Email: [email protected]
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AF prophylaxis in hypertensives is essential to curb the excess morbidity and mortality incited by AF before the onset of heart failure or MI. This is especially important in hypertensives with AF as hypertension is present in almost two-third of patients with AF and is associated with adverse clinical outcomes.5 Further, a distinction between systolic and diastolic heart failure is essential considering their differential therapeutic response to RAAS blockers. These remain unexplored in previous meta-analysis. Further, disappointing results of recent a priori designed secondary prevention trials challenge our understanding of secondary AF prevention by RAAS blockade, especially in the absence of concomitant antiarrhythmic drug (AAD) therapy.
Methods Data Sources and Search Strategy A systematic review and meta-analysis was performed in accordance with the standards set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.6,7 Electronic databases PubMed, EMBASE, and Cochrane Collaboration of Controlled Clinical Trials registery were searched using the key words ‘‘beta blockers,’’ ‘‘calcium channel blockers,’’ ‘‘angiotensin,’’ ‘‘angiotensin converting enzyme inhibitors,’’ ‘‘angiotensin receptor blockers,’’ ‘‘individual names in these drug classes,’’ ‘‘atrial fibrillation,’’ ‘‘ atrial arrhythmia,’’ ‘‘hypertension,’’ ‘‘heart failure,’’ and ‘‘myocardial infarction.’’ Additionally, references of retrieved articles and previous meta-analysis were manually searched to identify studies not captured by our primary search strategy. No restrictions were imposed on dates of publication, but the search was restricted to trials published in English. The final search was run on December 1, 2014.
Study Selection Randomized controlled trials (RCTs) of RAAS blockers against AF prophylaxis in patients with heart failure, MI, hypertension, or CVD risk factors were screened. Exclusion criteria were uncontrolled studies, application of AAD or electrical cardioversion as part of the treatment protocol in the trial, enrollment of specialized patient populations such as postcardiac surgery, case reports, reviews, studies not reporting the outcome of interest, and no access to full text for quality assessment and data extraction. Studies were categorized into ‘‘heart failure’’ enrolling participants with systolic and/or diastolic heart failure, ‘‘post MI’’ enrolling patients after acute MI, ‘‘high CVD risk’’ enrolling participants with traditional CVD risk factors, and ‘‘hypertension’’ restricted to trials enrolling all participants with blood pressure (BP) >140/90 or on antihypertensive therapy.
Data Extraction and Quality Assessment Data were extracted in duplicate by 2 independent reviewers (Drs Chaugai and Meng), and disagreements were resolved by consensus. The methodological quality of each trial was
evaluated for risk of bias using standard criteria: random sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessor; incomplete outcome ascertainment; selective reporting; and other potential sources of bias as recommended by the Cochrane Collaboration (Table 1).
Data Synthesis and Statistical Analysis The measurement data were pooled across studies and analyzed using random-effects meta-analysis model with inverse variance weighting. These are presented as odds ratios (ORs) with 95% confidence intervals (CIs). The magnitude of heterogeneity present was estimated using the I2 statistic, an estimate of the proportion of the total observed variance that is attributed to the ‘‘between-study variance’’. Random-effects meta-regression analysis was performed to identify potential effect modifiers. All P values are 2 tailed with the statistical significance set at .05. All statistical analyses were performed using STATA software 12.0.
Results Study Selection The flow diagram of study selection is shown in Figure 1. Of the initial 4739 hits, 113 articles were retrieved for detailed evaluation for potential inclusion. Tables 2 and 3 summarize the design and baseline characteristics of the included studies. Twenty-eight reports from 26 RCTs (2 reports from LIFE and Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity [CHARM] trials each) enrolled a total of 165 387 patients with 75 899 in the RAAS blockers arm and 89 488 in the control arm followed up for an average of 1 to 6 years. Fourteen placebo controlled trials, 4 heart failure,21-24 2 post-MI,25,26 and 8 high CVD risk,13-20 and 13 reports from 12 actively controlled trials in hypertensive participants3,8-12,27-33 were included in the meta-analysis. Eight trials used angiotensin-converting enzyme inhibitor (ACE I),13,15,21,25-28,31 17 trials used angiotensin-receptor blocker (ARB),3,8,11,12,14,16-20,22-24,29,30,32,33 and 2 trials were designed with parallel ACE I and ARB arms.9,10 Table 4 summarizes the results of the meta-analysis. Incidence of AF. Overall, there was a 24% reduction in the incidence of AF (OR: 0.76, 95% CI: 0.68-0.85, P ¼ .000; Figure 2). The degree of heterogeneity in the treatment effect was I2 ¼ 78.2% and P ¼ .000. Post hoc exclusion of all the trials with a sample size less than 500 decreased the observed treatment effect to 10% (OR: 0.90, 95% CI: 0.83-0.97, P ¼ .008; Supplementary Figure 1). The degree of heterogeneity in the treatment effect also declined to I2 ¼ 55.8% and P ¼ .002. Further subgroup analysis was performed considering the significant variation in effect size between trial groups, primary and secondary AF prevention, and the experimental therapy used, that is, ACE I and ARB.
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Table 1. Risk of Bias Across Studies Included in the Meta-Analysis.
Trials
Adequate Sequence Generation
Allocation Concealment
Blinding (Patient Investigator)
Blinding (Morbidity)
Incomplete Outcome Data Addressed
Free of Selective Outcome Reporting
Free of Other Bias
DIABHYCAR PRoFESS HOPE TRANSCEND GISSI-AF ACTIVE-I ROADMAP NAVIGATOR SOLVD Val HeFT CHARM I-PRESERVE TRACE GISSI-3 CAPPP STOP-2 LIFE VALUE ALLHAT-2 Fogari et al (1)8 Fogari et al (2)9 Fogari et al (3)10 Fogari et al (4)11 J Rhythm II Galzerano et al12 NTP-AF
Yes Unclear Yes Yes Yes Yes Yes Yes Yes Unclear No Yes Unclear Yes No Unclear Unclear Yes Yes Unclear Unclear Yes Unclear Unclear Unclear Yes
Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear Yes Yes Unclear Yes Unclear Unclear Yes Yes Yes Unclear Yes Yes Unclear Yes Unclear No
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes Yes Yes No Yes Yes Yes No No No
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear Unclear Unclear Yes Unclear Unclear
Yes Yes Yes Yes No Yes No Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes
Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear Yes
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Abbreviations: ACTIVE-I, Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; ALLHAT-2, Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial 2; CAPPP, Captopril Prevention Project; CHARM, Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity; DIABHYCAR, type 2 DIABetes, Hypertension, CArdiovascular Events and Ramipril; GISSI-AF, Gruppo Italiano per lo Studio della Sopravvivenza nell 0Infarto Miocardico, Atrial Fibrillation; HOPE, Heart Outcomes Prevention Evaluation; I-PRESERVE, Irbesartan in Heart Failure with Preserved Ejection Fraction; J RHYTHM II, The Japanese Rhythm Management Trial II for Atrial Fibrillation; LIFE, Losartan Intervention For End Point Reduction in Hypertension; NAVIGATOR, Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; NTP-AF, Nifedipine versus Telmisartan on Prevention of AF; PRoFESS, Prevention Regimen for Effectively Avoiding Second Strokes; ROADMAP, Randomized Olmesartan and Diabetes Microalbuminuria Prevention; SOLVD, Studies Of Left Ventricular Dysfunction; STOP-2, Swedish Trial in Old patients with Hypertension-2; TRACE, TRAndolapril Cardiac Evaluation; TRANSCEND, Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease; Val HeFT, Valsartan Heart Failure Trial; VALUE, Valsartan Antihypertensive Long-term Use Evaluation.
Comparison between ACE I and ARB. Overall, ACE I therapy was associated with 23% reduction in the incidence of AF (OR: 0.77, 95% CI: 0.63-0.94, P ¼ .010) and ARB therapy was associated with a 29% reduction in the incidence of AF (OR: 0.71, 95% CI: 0.61-0.83, P ¼ .000; Supplementary Figure 2). In primary prevention, ACE I therapy showed a modest trend toward fewer AF (OR: 0.86, 95% CI: 0.71-1.04, P ¼ .117), whereas ARB therapy was associated with a 13% reduction in the incidence of AF (OR: 0.87, 95% CI: 0.79-0.96, P ¼ .015; Figure 3). In secondary prevention, ACE I caused 56% risk reduction (OR: 0.44, 95% CI: 0.30-0.64, P ¼ .000), whereas ARB caused 58% reduction in the incidence of recurrent AF (OR: 0.42, 95% CI: 0.28-0.62, P ¼ .015; Figure 3).
Figure 2). The degree of heterogeneity in the treatment effect was I2 ¼ 85.9% and P ¼ .001. Post hoc exclusion of the smallest trial Studies Of Left Ventricular Dysfunction (SOLVD) that enrolled participants with lowest mean left ventricle ejection fraction (LVEF) and showed the largest risk reduction decreased the heterogeneity to 30.1% with an accompanying decline in observed treatment effect to 31% (Figure 2). High CVD risk, diastolic heart failure, and post-MI. No significant effect of RAAS blocker therapy was observed in patients with high CVD risk (OR: 0.97, 95% CI: 0.89-1.06, P ¼ .505), diastolic heart failure (OR: 1.02, 95% CI: 0.80-1.31, P ¼ .877), or post-MI (OR: 0.72, 95% CI: 0.41-1.27, P ¼ .259), albeit only 2 trials were available in each of the last 2 categories.
Placebo-Controlled Trials Systolic heart failure. Renin–angiotensin–aldosterone system blocker therapy was associated with a 49% reduction in the incidence of AF (OR: 0.51, 95% CI: 0.30-0.85, P ¼ .010;
Actively Controlled Trials A total of 13 reports from 12 trials were included in the analysis, with 8 reporting AF recurrence, 3 new-onset AF, and 2 total
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4739 References identified from MEDLINE, EMBASE and Cochrane collaboration
4467 references remained after duplicate removal
4350 references excluded after abstract screening
117 references assessed for potential inclusion
28 reports included in the meta analysis (26 trials, 2 reports each from LIFE and CHARM trial)
Figure 1. Search flow diagram for studies included.
Subgroup Analysis
heterogeneity (I2 ¼ 75.7% and P ¼ .002). Limiting the analysis to trials reporting new-onset AF alone, 19% reduction in the incidence of new-onset AF (OR: 0.81, 95% CI: 0.67-1.00, P ¼ .037; Figure 5) without significant heterogeneity (I2 ¼ 69.7% and P ¼ .037) was noted. Renin–angiotensin–aldosterone system blocker therapy was associated with a 54% reduction in the incidence of recurrent AF in secondary prevention trials (OR: 0.46, 95% CI: 0.33-0.62, P ¼ .000). The degree of heterogeneity in the treatment effect was I2 ¼ 60.6% and P ¼ .013.
Drug class Beta-blocker trials. Renin–angiotensin–aldosterone system blocker therapy was associated with a 40% reduction in the incidence of AF (OR: 0.60, 95% CI: 0.44-0.81, P ¼ .001; Figure 4). No significant heterogeneity was observed (I2 ¼ 48.4% and P ¼ .121).
Persistent AF in hypertension. Renin–angiotensin–aldosterone system blocker therapy was associated with a 34% reduction in the incidence of persistent AF (OR: 0.66, 95% CI: 0.450.95, P ¼ .027). No significant heterogeneity was observed (I2 ¼ 30.6% and P ¼ .229; Figure 6).
AF. Overall, RAAS blocker therapy was associated with a 37% reduction in the incidence of AF (OR: 0.63, 95% CI: 0.50-0.78, P ¼ .000; Figure 2). The degree of heterogeneity in the treatment effect was I2 ¼ 83.7% and P ¼ .000. In fixed-effects model, RAAS blocker therapy was associated with a 23% reduction in the incidence of AF (OR: 0.77, 95% CI: 0.720.84, P ¼ .000).
Calcium channel blocker trials. Overall, RAAS blocker therapy was associated with a 39% reduction in the incidence of AF (OR: 0.61, 95% CI: 0.44-0.84, P ¼ .003; Figure 4). The degree of heterogeneity in the treatment effect was I2 ¼ 86.9% and P ¼ .000. Post hoc exclusion of The Japanese Rhythm Management Trial II for Atrial Fibrillation (J RHYTHM II), which reported only the incidence rate of persistent AF, did not affect the results. Primary versus secondary (recurrent) AF prevention in hypertension. Renin–angiotensin–aldosterone system blocker therapy showed a trend toward protection in primary prevention trials (OR: 0.88, 95% CI: 0.73-1.05, P ¼ .158; Figure 2) with significant
Discussion The results of the current meta-analysis based on 165 387 patients suggested that RAAS blockade results in a statistically significant 24% reduction in the risk of AF. Participants with systolic dysfunction appear to derive the greatest benefit with 49% reduction in the risk of AF, whereas the pooled estimates from high CVD risk, diastolic heart failure, and post-MI trials failed to show evidence of therapeutic benefit. Overall, 37% reduction in the risk of AF was noted in hypertension with 54% risk reduction in recurrent AF prevention and 19% risk reduction against new-onset AF. Overall, RAAS blockers were associated with 40% lower risk of AF against BB and 39%
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Valsartan þ amlodipine Valsartan/ramipril Telmisartan/ramipril Telmisartan Candesartan Telmisartan Telmisartan
Enalapril Valsartan Candesartan Irbesartan Trandolapril Lisinopril Captopril Enalapril/lisinopril Losartan
Amlodipine Amlodipine Amlodipine Amlodipine Carvedilol Amlodipine
All AF All AF New onset New onset Recurrence Recurrence New onset New onset
AF Type
AF Reported As
NA Adverse event NA Adverse event Post hoc Biannual ECG 2 NA 1 TTM 1 ECG þ TTM 2 NA Post hoc ECG/investigator reported Post hoc ECG/HM Post hoc Adverse event 2 Adverse event 1 NA Post hoc Regular ECG Post hoc In-hospital ECG 2 Adverse event 2 Adverse event 2 Annual ECG
End Point
HTN HTN HTN HTN HTN HTN
þ AF þ MS þ AF þ AF þ AF þ AF þ AF
Recurrence Recurrence Recurrence Recurrence Recurrence Recurrence
Recurrence
1 1 1 1 1 1
1
Monthly ECG/HM Monthly ECG/HM Monthly ECG/HM ECG/HM Monthly ECG/HM Regular ECG/HM
Monthly ECG/HM
New onset New onset New onset All AF New onset New onset All AF All AF New onset/ recurrence HTN þ CVD risk factors New onset 2 Annual ECG HTN þ CVD risk factors New onset Post hoc Biannual ECG
Heart failure (LVSD) Heart failure (LVSD) Heart failure (LVSD/DD) Heart failure (LVDD) Post-MI þ LVSD Post-MI HTN HTN HTN þ LVH
DM þ Proteinuria Postischemic stroke CVD risk factors HTN CVD risk factors HTN AF þ CVD risk factors AF þ CVD risk factors DM þ normoalbuminuria IGT þ CVD risk factors
Inclusion Criteria
Amlodipine Amlodipine þ cholorthalidone Atenolol þ amlodipine HTN þ DM þ AF
Placebo Placebo Placebo Placebo Placebo Placebo Diuretic/BB Diuretic/BB or CCB Atenolol
Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo
Control Drug
8.6 12 12 12 12 24
12
50.4 58.8
34.8 23 37.7 49.5 24-48 1.5 73.2 60 57.2
47 30 54 56 12 49.2 44.4 78
Follow-Up, months
Abbreviations: ACTIVE-I, Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; AF, atrial fibrillation; ALLHAT-2, Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial 2; BB, b blocker; CAPPP, Captopril Prevention Project; CCB, calcium channel blocker; CHARM, Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity; CVD, cardiovascular disease; DD, diastolic dysfunction; DIABHYCAR, type 2 DIABetes, Hypertension, CArdiovascular Events and Ramipril; DM, diabetes mellitus; ECG, electrocardiogram; GISSI-AF, Gruppo Italiano per lo Studio della Sopravvivenza nell 0Infarto Miocardico, Atrial Fibrillation; HM, Holter monitoring; HOPE, Heart Outcomes Prevention Evaluation; HTN, hypertension; IGT, impaired glucose tolerance; I-PRESERVE, Irbesartan in Heart Failure with Preserved Ejection Fraction; J RHYTHM II, The Japanese Rhythm Management Trial II for Atrial Fibrillation; LIFE, Losartan Intervention For End Point Reduction in Hypertension; LVDD, left ventricular diastolic dysfunction; LVH, left ventricle hypertrophy; LVSD, left ventricular systolic dysfunction; MI, myocardial infarction; MS, multiple sclerosis; NA, not available; NAVIGATOR, Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; NTP-AF, Nifedipine versus Telmisartan on Prevention of AF; PRoFESS, Prevention Regimen for Effectively Avoiding Second Strokes; ROADMAP, Randomized Olmesartan and Diabetes Microalbuminuria Prevention; SOLVD, Studies Of Left Ventricular Dysfunction; STOP-2: Swedish Trial in Old Patients with hypertension-2; TRACE, TRAndolapril Cardiac Evaluation; TRANSCEND, Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease; TTM, transtelephonic monitoring; Val HeFT, Valsartan Heart Failure Trial; VALUE, Valsartan Antihypertensive Long-term Use Evaluation. a Values are mean or percentage.
123/246 262/129 188/190 158/160 70/62 74/75
Fogari et al (2)9 Fogari et al (3)10 Fogari et al (4)11 Yamashita et al (J RHYTHM II)32 Galzerano et al12 Du et al (NTP-AF)33
6872/6888 Valsartan 6702/18630 Lisinopril
Schmieder et al (VALUE)30 Haywood et al (ALLHAT-2)31
148/148
186/188 2205/2190 3191/3188 2067/2061 790/787 8865/8846 5492/5493 2205/4409 4448/4403
Vermes et al (SOLVD)21 Maggioni et al (Val HeFT)22 Ducharme et al (CHARM)23 Massie et al (I-PRESERVE)24 Pedersen et al (TRACE)25 Pizzetti et al (GISSI-3)26 Hansson et al (CAPPP)27 Hansson et al (STOP-2)28 Wachtell et al (LIFE)29
Fogari et al (1)8
2443/2469 10 146/10 186 4291/4044 2954/2972 722/720 4518/4498 2232/2215 4631/4675
Marre et al (DIABHYCAR)13 Diener et al (PRoFESS)14 Salehian et al (HOPE)15 Yusuf et al (TRANSCEND)16 Disertori et al (GISSI-AF)17 Yusuf et al (ACTIVE-I)18 Haller et al (ROADMAP)19 Latini et al (NAVIGATOR)20 Ramipril Telmisartan Ramipril Telmisartan Valsartan Irbesartan Telmisartan Valsartan
Case/Control Size Treatment Drug
Trial Information
Table 2. Basic Characteristics of the Included Studies.a
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Journal of Cardiovascular Pharmacology and Therapeutics
Table 3. Baseline Characteristics of Trial Participants.a Trial Information Vermes et al (SOLVD)21 Maggioni et al (Val HeFT)22 Ducharme et al (CHARM)23 Massie et al (I-PRESERVE)24
Trial Information Pedersen et al (TRACE)25 Pizzetti et al (GISSI-3)26
Age, years Male, %
Baseline SBP/DBP
Baseline CAD Stroke HF HHF/IHF DYSL PAD LVH LVH AAD, %
89.92
128.15/78.9 19.93 20.45 93.35
NA
62.7 65.95 72
80 68.4 40
121/72 6.7 25.75 58.7 130.85/76.5 55.05 28.42 76.5 136.5/79 88.5 27.5 40
NA 8.75 10
Age, years
Male, %
Baseline SBP/DBP
HTN
DM
CAD Stroke
HF
68 NA
71.5 22.2
120/77.5 >100/NA
22 29.9
13 15.6
80.5 48.3
NA NA
22 14.5
79 84.9
DSBP/DBP
DM
CAD
HF
Age, Male, years %
Hansson et al (CAPPP)27 Hansson et al (STOP-2)28 Wachtell et al (LIFE)29 Schmieder et al (VALUE)30 Haywood et al (ALLHAT-2)31 Fogari et al (1)8 Fogari et al (2)9 Fogari et al (3)10 Fogari et al (4)11 Yamashita et al (J RHYTHM II)32 Galzerano et al12 Du et al (NTP-AF)33
52.55 76 66.9 67.25 66.9 65.5 64.99 66 68.24 65.58 55.82 61.75
Marre et al (DIABHYCAR)13 Salehian et al (HOPE)15 Diener et al (PRoFESS)14 Yusuf et al (TRANSCEND)16 Disertori et al (GISSI-AF)17 Yusuf et al (ACTIVE-I)18 Haller et al (ROADMAP)19 Latini et al (NAVIGATOR)20
DM
57.05
Trial Information
Trial information
HTN
Age, Male, years %
53.47 66.8 46 57.55 53.13 47.97 51.38 45.78 46.03 68.87 69.69 61.72
Baseline SBP/DBP 160.7/98.95 194/98 174.4/97.8 154.65/87.5 146.25/84 150.75/93.85 153/95 154.28/94.27 155.48/94.37 140.1/81.75 153.9/95.59 160.29/92.59
4.3/57.7
NA
NA
NA
26.7
4.8
100 6.7/58.7 100 NA 100 63.5/25
NA NA 31
NA NA NA
NA 27 NA 38.8 30.5 59.5
13 11.7 8.5
11/8 5.2 1.32 34.7/16.75 10.9 8 27.9/15.85 13 16 16.25/9.05 30 45.8 11.59/8.81 36.16 25.23 24.05/16.2 100 0 16.13/12.4 0 0 16.1/12.63 MS 100 NA 17.88/13.73 NA 0. 10/3 9.11 3.46 29.59/19.18 NA NA 33.7/16.55 0 0
Baseline SBP/DBP
DSBP/DBP
HTN
65.1
69.93 145.45/82.3
2.96/2.17
55.68 100
66 66.1 66.9
73.25 66.4 57.02
139/79 144.1/83.8 141/81.9
100
3/2.5 46.85 2.9 (DMBP) 74 2.25 (DMBP) 76.4
DM
CAD 6
38.45 80.45 28.24 16.2 35.74 74.55
Killip class 1 DYSL PAD
LVH
LVEF
Baseline AAD
NA NA
33 NA
NR NR
Stroke DYSL PAD
LVH
Baseline AAD
NA NA
NA NA
0.26 1.52 NA NA NA 1.9 3.9 NA NA NA 0 8 NA 6 100 NA 19.8 NA 13.9 6 0
