Methods

A systematic literature search was done using subject terms “ACE inhibitors,” “angiotensin receptor blockers,” “direct renin inhibitors,” “aliskiren,” and “angioedema” and using the names of individual ACE inhibitors and ARBs in the PubMed, CENTRAL, and EMBASE databases to identify articles from 1980 through October 2011. The search was limited to studies in human subjects in peer-reviewed journals. There was no language restriction for the search. Reference lists of identified articles, meta-analyses, and bibliographies of original articles were also reviewed. Authors of individual articles were contacted if data were not available. To be included in the analysis, a trial had to fulfill the following criteria: (1) randomized clinical trial comparing ACE inhibitors, ARBs, or direct renin inhibitors (DRIs) to other antihypertensive drugs (including placebo) or to each other; (2) trials that enrolled ≥100 patients; (3) mean duration of study of ≥8 weeks; and (4) information about angioedema. Studies in which ACE inhibitors or ARBs were added as a second- or third-line agent were excluded from the analysis.

Two reviewers (A.K. and R.S.B.) extracted the data independently and in duplicate. Disagreements were resolved by arbitration (J.R. or O.W.P.) and consensus was reached after discussion. We extracted baseline demographics, duration of intervention, cohort of patients enrolled, and outcome of interest for our analysis.

Quality of studies was assessed using methods recommended by the Cochrane Collaboration tools for assessing risk of bias based on 7 components. For each component, studies were described as a low, high, or unclear risk of bias. Studies with 7 of 7 components were considered as low-risk, 6 of 7 components as intermediate risk, and <6 of 7 components as high-risk for bias.

Statistical analysis was done in line with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using Review Manager (RevMan) [Computer program] (Version 5.0.23 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.) Incidence of angioedema was pooled separately for ACE inhibitors, ARBs, DRIs, and all their comparisons by weighing the incident rate of each trial by the inverse of the variance. Head-to-head comparison was made between ACE inhibitors and ARBs where data were available. Heterogeneity was assessed using I ² statistics. I ² is the proportion of total variation observed between trials attributable to differences between trials rather than to sampling error (chance) and we considered an I ² <25% as low and an I ² >75% as high. Effect sizes were calculated by the Peto method because it is regarded as the most optimal approach for analysis with fewer events in individual trials. Publication bias was estimated visually by funnel plots and/or using the Begg test and the weighted regression test of Egger et al.

Subgroup analysis was performed for incidence of angioedema for ACE inhibitors and ARBs based on (1) baseline patient population in the study (black vs nonblack), (2) cohort of patients enrolled (heart failure vs nonheart failure), (3) risk of bias in a trial, and (4) duration of study (≤1 vs >1 year). Comparison was also made between patients on ARBs with a history of ACE inhibitor intolerance and those without exposure to an ACE inhibitor. We estimated differences between subgroups according to tests of interaction.

Results

In total, 3,545 articles were identified by the search criteria, of which 221 full-text articles were assessed for eligibility. Forty trials enrolling 206,596 participants (mean age 62 years, 61% men) and a mean follow-up duration of 123 weeks met the inclusion criteria ( Figure 1 ) . Twenty-seven trials were excluded because of lack of data on angioedema with ACE inhibitor or ARB therapy. An additional 7 trials were excluded because an ACE inhibitor or an ARB was added as a second- or third-line agent for therapy.

Selection of studies. ACEi = angiotensin-converting enzyme inhibitor.

Of the 40 trials that were included, 26 trials compared ACE inhibitors to other antihypertensive drugs (including placebo) with 74,857 patients in the ACE inhibitor arm (mean age 63 years, 64% men) and 232,523 person-years of follow-up; 19 trials with 35,479 patients (mean age 61 years, 59% men) and 122,293 person-years of follow-up were included in the ARB group; and 2 trials with 5,141 patients and 1,735 person-years of follow-up were in the DRI arm. There were 7 trials with 34,381 patients comparing ACE inhibitors head to head with ARBs ( Table 1 ).

Of 26 included studies that investigated ACE inhibitors, 18 studies reported adequate generation of an allocation sequence and adequate allocation concealment, and 20 reported adequate masking of participants, personnel, and outcome assessors. From the quality assessment, 18 were deemed as low-bias risk trials and the rest as high-bias risk. Similarly with ARBs, 14 studies were deemed as low-bias risk trials and the rest as high risk.

Patients were screened before randomization (run-in phase) in 15 studies with ACE inhibitors and 12 studies with ARBs. Three of 7,488 patients (0.04%) developed angioedema during the run-in-phase of those treated with enalapril in the Studies of Left Ventricular Dysfunction (SOLVD) trial, 40 of 29,019 patients (0.14%) treated with any of the 3 drug regimens of ramipril, telmisartan, or combination of ramipril and telmisartan developed angioedema in the Ongoing telmisartan Alone and in Combination with Ramipril Global End Point Trial (ONTARGET) before randomization, and 1 of 7,121 patients (0.01%) developed angioedema of those treated with perindopril in the Perindopril in Perindopril Protection against Recurrent Stroke Study (PROGRESS) trial. In studies in patients with previous ACE intolerance, 39 of 1,013 patients (3.8%) in the candesartan group had a history of angioedema with ACE inhibitors in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Alternative trial, 75 of 5,926 patients (1.3%) had a history of angioedema with ACE inhibitors in the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) trial.

Of 74,857 patients on ACE inhibitors, 394 developed angioedema during a mean duration of 129 weeks with a weighted incidence of 0.30% (95% confidence interval [CI] 0.28 to 0.32). Of 35,479 patients on ARBs, 52 developed angioedema during a mean duration of 120 weeks with a weighted incidence of 0.11% (95% CI 0.09 to 0.13). Of 5,141 patients on aliskiren, 7 developed angioedema during a mean duration of 24 weeks with an incidence of 0.13% (95% CI 0.07 to 0.19). Incidence of angioedema was highest with omapatrilat (1.7%; which never made it to market), followed by placebo (0.07%), thiazides (0.05%), and calcium channel blockers (0.03%; Figure 2 ) .

Weighted incidence of angioedema for renin–angiotensin system inhibitors and their comparators. Percent values represent incidence of angioedema; 95% confidence intervals are presented (error bars) . CCBs = calcium channel blockers. Other abbreviation as in Figure 1 .

Head-to-head comparison between ACE inhibitors and ARBs was available in 7 trials. Risk of angioedema with ACE inhibitor therapy was 2.2 times higher than with ARB therapy (95% CI 1.50 to 3.34, p <0.0001; Figure 3 ) . There was no heterogeneity and the test for bias was negative (p = 0.82, Egger test).

Head-to-head comparison of angiotensin-converting enzyme inhibitors (ACE I) and angiotensin receptor blockers on risk of angioedema. M-H = Mantel–Haenszel test; Other abbreviations as in Table 1 .

Head-to-head comparison between ACE inhibitors and placebo was available in 10 trials ( Figure 4 ) . Risk of angioedema with ACE inhibitor therapy was 2.8 times higher than with placebo (95% CI 1.63 to 4.79, p = 0.0002). In 7 trials comparing ARBs to placebo, there was no significant difference in risk of angioedema (95% CI 0.39 to 3.61, p = 0.77). There was no heterogeneity between the 2 groups. Thus, fixed effects model was used for analysis (p = 0.76, Egger test).

Head-to head comparison of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers to placebo on risk of angioedema. Abbreviation as in Table 1 .

Incidence of angioedema in black patients (0.92%) on ACE inhibitors was 2 times as high as in nonblack patients (0.44%, p <0.0001). Similarly, incidence of angioedema in patients with heart failure (0.49%) was 1.8 times higher compared to patients without heart failure (0.27%, p <0.0001). In low-risk bias trials, incidence of angioedema (0.27%) was lower than in those with high-risk bias (0.67%, p <0.0001). In studies with duration ≤1 year, incidence of angioedema (0.64%) was around 2.3 times higher compared to studies with >1 year duration (0.27%, p <0.0001; Table 2 ).

Table 2

Sensitivity analysis

Subgroup	Number of Studies	Number of Patients	Weighted Incidence of Angioedema	Ratio of RR (95% CI)	Interaction p Value
Angiotensin-converting enzyme inhibitors
Black	3	4,893	0.92%	2.05 (1.68–2.49)	<0.0001
Nonblack	3	19,964	0.44%
Heart failure	7	15,974	0.49%	1.81 (1.58–2.08)	<0.0001
Nonheart failure	19	58,883	0.27%
Risk of bias					<0.0001
Low	18	61,047	0.27%	0.40 (0.36–0.44)
High	8	13,810	0.67%
Duration					<0.0001
≤1 year	9	15,445	0.64%	2.32 (2.11–2.53)
>1 year	17	59,412	0.27%
Angiotensin receptor blockers ⁎
Heart failure	6	12,852	0.29%	3.16 (2.20–4.53)	<0.0001
Nonheart failure	13	22,627	0.09%
Risk of bias
Low	14	34,387	0.12%	0.38 (0.14–0.96)	0.04
High	5	1,092	0.32%
Duration
≤1 year	7	1,909	0.31%	2.81 (1.34–5.92)	0.006
>1 year	12	33,570	0.11%
Angiotensin-converting enzyme inhibitor intolerance
Yes	3	7,801	0.11%	1.05 (0.65–1.68)	0.84
No	16	27,678	0.11%

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Impact of Drug Eluting Stent Length on Outcomes of Percutaneous Coronary Intervention (from the EVENT Registry)
2. Bleeding Risk and Major Adverse Events in Patients With Previous Ulcer on Oral Anticoagulation Therapy
3. Importance of Physical Fitness on Predictive Effect of Body Mass Index and Weight Gain on Incident Atrial Fibrillation in Healthy Middle-Age Men
4. Comparison of Heart Rate Recovery After the Six-Minute Walk Test to Cardiopulmonary Exercise Testing in Patients With Heart Failure and Reduced and Preserved Ejection Fraction

Stay updated, free articles. Join our Telegram channel

Join