Adverse Effects of Combination Angiotensin II Receptor Blockers

REVIEW ARTICLE Adverse Effects of Combination Angiotensin II Receptor Blockers Plus Angiotensin-Converting Enzyme Inhibitors for Left Ventricular Dysfunction A Quantitative Review of Data From Randomized Clinical Trials Christopher O. Phillips, MD, MPH; Amir Kashani, MS, MD; Dennis K. Ko, MD; Gary Francis, MD; Harlan M. Krumholz, MD, SM Background: We performed a meta-analysis of ran- Results: Four studies (N=17 337; mean follow-up, 25 domized controlled trials to assess ongoing concerns about months [range, 11-41 months]) were selected. Combina- the safety profile of combination angiotensin II receptor tion ARB plus ACE inhibitor vs control treatment that in- blockers (ARBs) plus angiotensin-converting enzyme cluded ACE inhibitors was associated with significant in- (ACE) inhibitors in symptomatic left ventricular creases in medication discontinuations because of adverse dysfunction. effects in patients with chronic heart failure (RR, 1.38 [95% CI, 1.22-1.55]) or in patients with acute myocardial in- Methods: MEDLINE (January 1966–December 2006) farction with symptomatic left ventricular dysfunction (RR, and Web sites for the National Institute of Health Clini- 1.17 [95% CI, 1.03-1.34]), and for both conditions there cal Trials and the Food and Drug Administration were were significant increases in worsening renal function (RR, 2.17 [95% CI, 1.59-2.97] and RR, 1.61 [95% CI, 1.31-1.98], searched for eligible RCTs that included 500 or more sub- respectively), hyperkalemia (RR, 4.87 [95% CI, 2.39-9.94] jects, had a follow-up of 3 months or longer, and re- and RR, 1.33 [95% CI, 0.90-1.98], respectively; the latter ported adverse effects. We used a random effects model was not significant), and symptomatic hypotension (RR, to calculate the relative risk (RR) and 95% confidence 1.50 [95% CI, 1.09-2.07], and RR, 1.48 [95% CI, 1.33-3.18], interval (CI) for the following outcome measures: medi- respectively). cation discontinuations because of adverse effects, worsening renal function (an increase in serum creatinine level Conclusion: Combination ARB plus ACE inhibitor therapy of Ͼ0.5 mg/dL [to convert to micromoles per liter, mul- in subjects with symptomatic left ventricular dysfunction tiply by 88.4]), hyperkalemia (serum potassium level Ͼ5.5 was accompanied by marked increases in adverse effects. mEq/L [to convert to millimoles per liter, multiply by 1]), and symptomatic hypotension. Arch Intern Med. 2007;167(18):1930-1936 UAL SUPPRESSION OF THE tional large clinical trial investigating the renin angiotensin aldo- efficacy of combination ARB plus ACE in- sterone system with com- hibitor therapy vs background treatment Author Affiliations: that includes ACE inhibitors in subjects Department of General Internal bination therapy that in- Medicine and Section of cludes angiotensin II type with acute myocardial infarction (AMI) Hospital Medicine, The I receptor blockers (ARBs) and angioten- and symptomatic left ventricular (LV) dys- D 20 Cleveland Clinic Lerner College sin-converting enzyme (ACE) inhibitors function has been published, and the of Medicine, Cleveland, Ohio is gaining interest among heart failure (HF) results lend further support for the com- (Dr Phillips); Yale University experts.1-13 However, current guidelines for bination strategy in reducing HF hospital- School of Medicine and recommended pharmacotherapy in pa- izations but not overall mortality. Despite Yale–New Haven Hospital Center for Outcomes Research tients with HF have not endorsed this ap- 14,15 and Evaluation, New Haven, proach. This strategy could be very im- CME course available online Connecticut (Drs Kashani and portant given the continuing high www.archinternmed.com Krumholz); Division of mortality and morbidity among patients Cardiology, The Cleveland with HF. Prior reviews of this strategy sug- the initial enthusiasm for combination ARBs Clinic (Dr Francis); and gested that there was no conclusive evi- plus ACE inhibitors as a viable therapeu- Division of Cardiology, Schulich dence for a survival advantage from com- tic option for subsets of patients with symp- Hearth Center, Sunnybrook Health Sciences Centre, bination ARB plus ACE inhibitor therapy; tomatic LV dysfunction, concerns about ad- Institute for Clinical Evaluative however, there were significant reduc- verse effects including severe or life- 21-31 Sciences, Toronto, Ontario, tions in HF hospitalizations in subjects threatening hyperkalemia persist and Canada (Dr Ko). with chronic HF.16-19 Recently, an addi- may limit the application of this strategy. (REPRINTED) ARCH INTERN MED/ VOL 167 (NO. 18), OCT 8, 2007 WWW.ARCHINTERNMED.COM 1930 ©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Accordingly, we conducted a sys- allocation of 500 or more subjects to combination ARB plus ACE inhibitor or stan- tematic review to quantify the mag- 76 Potentially relevant nitude of risk of adverse effects in as- dard therapy for LV dysfunction that in- published reports sociation with combination ARB plus cluded ACE inhibitor; follow-up of 3 identified electronically ACE inhibitor therapy. We com- months or longer; and reports of adverse effects. We chose this sample size limita- pared changes in medication nonad- 49 Excluded based on tion to reduce uncertainty in the esti- title/abstract not relevant herence as assessed by the overall risk mates of adverse effects and to reduce con- to CHF treatment of discontinuation of therapy be- founding due to publication bias and cause of adverse effects and the inci- underpowered studies. We chose the 27 Published articles dence and severity of worsening re- minimum 3-month follow-up period to retrieved for detailed nal function (including elevations in focus our analysis on the long-term ef- evaluation serum creatinine level Ͼ0.5 mg/dL fects of treatment in subjects for whom combination ACE inhibitor plus ARB [to convert to micromoles per liter, 23 Excluded multiply by 88.4] and hyperkalemia therapy could be sustained. The search (Mortality not prespecified strategy is summarized in the Figure. or reported, adverse events [serum potassium level Ͼ5.5 mEq/L not reported, sample size {to convert to millimoles per liter, N < 500, or follow-up < 3 months) multiply by 1}]), and symptomatic DATA EXTRACTION hypotension. We also evaluated whether the occurrence of these end Paired reviewers (C.O.P. and A.K.) in- 4 Randomized controlled dependently reviewed each eligible re- clinical trials included in points differed among patients with the meta-analysis chronic HF vs patients with AMI and port without the use of masking, tabu- lated important trial characteristics, and symptomatic LV dysfunction. assessed methodological quality using Figure. Published reports evaluated for the 5-point Jadad score, which assigns inclusion in the meta-analysis. CHF indicates METHODS points (maximum of 5 points) for the fol- congestive heart failure. lowing: randomization (1 point), method SELECTION OF of randomization generation (1 point), double blinding (2 points), and loss to and 95% confidence interval (CI) for clini- RANDOMIZED TRIALS follow-up (1 point).34 Extracted data also cal efficacy and reported adverse effects included patient demographics such as in each study according to randomized as- We performed this review in accordance signments and pooled the results across with the Quality of Reporting of Meta- age, percentage of LV ejection fraction (LVEF), and comorbidity. Paired re- studies using a fixed-effects model, which analysis (QUOROM) statement and the assumes that interstudy variability is due Consolidated Standards of Reporting viewers (C.O.P. and A.K.) also extracted adverse events according to treat- to random error. We rejected the assump- Trials (CONSORT) Group recommenda- ϫ tion of homogeneity in study effects when tions.32,33 Eligible studies were identified ment groups with the use of 2 2 tables. ␹ Adverse events were abstracted from trial ² test results suggested the presence of by searching MEDLINE (January 1966– significant heterogeneity (PϽ.05). In our December 2006), EMBASE (January reports and corroborated with publicly available data from the FDA Web site. exploration of potential factors that may 1980–December 2006), the Cochrane have contributed to the presence of Library (Controlled Trials Register and Results reflect adverse event counts reported in the primary studies and are heterogeneity, we stratified our analyses Database of Systematic Reviews, all years), by clinical setting (chronic HF or AMI the National Institute of Health Clinical subject to rounding error because some studies reported event counts as a per- with symptomatic LV dysfunction). To es- Trials (http://www.clinicaltrials.gov) and timate and control for this type of quan- the US Food and Drug Administration centage. Discrepancies in data abstrac- tion were resolved by consensus. titative heterogeneity, we also applied a (FDA) Web sites (http://www.FDA random effects statistical model, which .gov), and relevant bibliographies. Be- uses weighting based on inverse vari- cause terminology for HF is standard- STATISTICAL ANALYSIS ance calculated according to DerSimo- ized, we used mostly the following nian and Laird.35 This model gives a meta- medical subject headings (MeSH) for our Outcomes measures were medication estimate of the RR, which represents the search: congestive heart failure, chronic discontinuations because of adverse ef- mean effects of treatment under study heart failure, heart failure, left

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