A review of expert opinions by international experts in angioedema and emergency medicine notes that both angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) should be avoided in case of a life-threatening attack of angioedema. For patients with less severe reactions to ACEi, ARBs may be used with close monitoring if benefits outweigh the risks, such as in chronic heart failure. [1]
Per the 2015 British Society for Allergy and Clinical Immunology (BSACI) guideline, given the occasional reports of ARB-associated angioedema, use of ARBs in individuals with ACEi-related angioedema has been questioned but is not contraindicated. The guideline makes no further recommendations on stepwise challenging algorithms in this scenario. [2]
A meta-analysis of randomized controlled trials (RCTs) evaluating the use of ARBs in 8,320 patients with intolerance to ACEis found angioedema/anaphylaxis to be rare, with placebo-like tolerability with incidences of 0.12% for ARBs and 0.07% for placebo. The risk of angioedema was nonsignificant compared to placebo (1.62; 95% confidence interval [CI] 0.17 to 15.79). The authors found that ARBs are well tolerated in patients with ACEi intolerance. [3]
Another meta-analysis examined an RCT and two retrospective cohorts which included a population of patients who were given an ARB after previously experiencing angioedema after taking an ACEi and who were followed up for at least one month for the development of angioedema. It was found that the risk of developing subsequent angioedema while taking an ARB was 9.4% (95% CI 1.6% to 17%), and the risk of developing confirmed angioedema was 3.5% (95% CI 0.0% to 9.2%). The authors concluded that the data, though limited, suggests that an ARB can be used in patients with prior ACEi intolerance, provided that they are suitably advised on the risk of recurrent angioedema. [4]
According to a review article of two randomized controlled studies and one meta-analysis, ARBs may be an alternative option for patients with angioedema induced by an ACEi when there is a high therapeutic need for angiotensin inhibition. As noted above, the data estimates persistent angioedema to be 9.4% (95% CI 1.6% to 17%) for possible cases and 3.5% (95% CI 0.0% to 9.2%) for confirmed cases. Angioedema related to ARBs is considered to be less severe and occurs earlier compared to angioedema induced by ACEi therapy. It is suggested that ARB treatment should be initiated with observation, education on the signs of angioedema, and proper emergency management. [5]
Additionally, a meta-analysis of RCTs in patients on ACEis (26 RCTs; n= 74,857), ARBs (19 RCTs; n= 35,479), or direct renin inhibitor (DRI; 2 trials; n= 5,141) aimed to determine the risk of angioedema associated with each therapeutic class. In head-to-head comparisons from seven trials, the risk of angioedema with ACE inhibitors was 2.2 times higher than with ARBs (95% CI 1.5 to 3.3). On the other hand, in seven trials comparing ARBs to placebo, there was no significant difference in risk of angioedema (95% CI 0.39 to 3.61, p= 0.77). Incidence of angioedema was higher in heart failure trials compared to hypertension or coronary artery disease trials for both ACEi and ARBs. Subgroup analysis did not observe a higher incidence of angioedema in patients with ACEi intolerance (0.11%) compared to those without ACE inhibitor intolerance (0.11%, p= 0.84). The authors concluded that the incidence of angioedema with ARBs was less than half that with ACE inhibitors and not significantly different from placebo. As many trials only reported adverse effects occurring in greater than 1% of patients, there’s a possibility of underestimating the overall incidence of angioedema. [6]
Lastly, a 2015 review discusses the risk of recurrence of angioedema after switching from ACEis to ARBs and explains that the lack of effect on bradykinin metabolism may lead to a lower incidence of angioedema, as reported in the meta-analysis above. It should be noted that most reported recurrent angioedema upon initiation of ARBs occurred shortly after substitution, suggesting residual effects from previous ACEi regimens. With combined data, switching ACEis to ARBs in patients with previous ACEi-induced angioedema is considered safe. However, close monitoring of these patients is still mandatory. Again, medications from both therapeutic classes should be avoided in patients with a previous severe, life-threatening ACEi angioedema. [7]