What is the incidence of cross-sensitivity between ARBs and ACEis?

What is the incidence of cross-sensitivity between ARBs and ACEis?

Comment by InpharmD Researcher

Studies show that the incidence of cross-reactivity from ACE inhibitor-induced angioedema when switching to an ARB is relatively low, with estimates of angioedema redevelopment being less than 10%. Authors conclude that with observation and education, ARBs can be safely used in patients who previously had angioedema related to ACE inhibitor therapy. There does not appear to be data on attempting an ARB in patients with ACE inhibitor anaphylaxis.

Background

A meta-analysis of randomized controlled trials evaluating the use of angiotensin II receptor blockers (ARBs) in 8,320 patients with intolerance to angiotensin-converting enzyme (ACE) inhibitors found angioedema to be rare, with a 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 ACE inhibitor intolerance. [1]

Another meta-analysis examined a randomized controlled trial and two retrospective cohorts on the population of patients who were given an ARB after previously experiencing angioedema after taking an ACE-inhibitor and followed up for at least one month for the development of angioedema found that risk of developing subsequent angioedema while taking an ARB was 9.4% (95% CI 1.6% to 17%). 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 ACE-inhibitor intolerance, provided that they are suitably advised on the risk of recurrent angioedema. [2]

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 ACE inhibitor when there is a high therapeutic need for angiotensin inhibition. 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 ACE inhibitor therapy. It is suggested that ARB treatment should be initiated with observation, education on the signs of angioedema, and proper emergency management. [3]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the incidence of cross-sensitivity between ARBs and ACEis?

Please see Tables 1-3 for your response.

Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial
Design	Randomized controlled trial N=5,926
Objective	To assess whether telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular disease or diabetes with end-organ damage
Study Groups	Telmisartan (n=2,954) Placebo (n=2,972)
Methods	Inclusion criteria: intolerant to ACE inhibitors with established coronary artery, peripheral vascular or cerebrovascular disease, or diabetes with end-organ damage Exclusion criteria: heart failure, significant primary valvular or cardiac outflow tract obstruction, constrictive pericarditis, complex congenital heart disease, unexplained syncope, planned cardiac surgery or cardiac revascularisation within the previous 3 months, systolic blood pressure over 160 mm Hg, heart transplantation, subarachnoid haemorrhage, significant renal artery stenosis, creatinine levels above 265 μmol/L, proteinuria, hepatic dysfunction Eligible patients were entered into a single blind run-in involving placebo daily for a week followed by 2 weeks of telmisartan 80 mg. At the end of this run-in period, patients were randomized to receive telmisartan 80 mg/day or placebo.
Duration	Median duration of follow-up: 56 months
Outcome Measures	Occurrence of angioedema
Baseline Characteristics		Telmisartan (n=2,954)	Placebo (n=2,972)
	Age, years	66.9 (7.3%)	66.9 (7.4%)
	Women	1280 (43.4%)	1267 (42.6%)
	Seventy-five patients were intolerant to ACE inhibitors due to angioedema/anaphylaxis from both groups, or 1.3% of the study population.
Results		Telmisartan (n=2,954)	Placebo (n=2,972)	p-value
	Occurence of angioedema	2 (0.07%)	3 (0.10%)	p = 0.660
	Of the 75 patients who had a history of angioedema with ACE-inhibitors, only one patient had a recurrence of angioedema, who was in the placebo group.
Adverse Events	Percentage that Discontinued due to Adverse Events (temporary or permanent): 1,090 (36.9%) in the telmisartan group, 1,143 (38.5%) in the placebo group (p= 0.215)
Study Author Conclusions	Based on the data showing the tolerability of telmisartan in patients intolerant to ACE inhibitors, the authors concluded that patients who experienced angioedema can be given telmisartan.
InpharmD Researcher Critique	Based on the data showing the combination of longer duration of treatment, better adherence to telmisartan, and low incidence of angioedema in those who experienced angioedema from ACE inhibitors, that telmisartan can be a safe alternative in those who previously experienced angioedema from ACE inhibitors.

References:
[1] Yusuf S, Teo K, Anderson C, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372(9644):1174-83.

Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial
Design	Randomized, double-blind, placebo-controlled, multicenter, international trial N=2,028
Objective	To assess the effects of candesartan on the risk of cardiovascular death or hospital admission for heart failure in patients with reduced left ventricular ejection fraction and symptomatic heart failure not currently treated with an ACE inhibitor because of previous intolerance
Study Groups	Candesartan (n=1,013) Placebo (n=1,015)
Methods	Inclusion criteria: Age >18 with symptomatic heart failure (NYHA Class II-IV) of at least 4 weeks duration, left-ventricular ejection fraction 40% or less, and intolerance to ACE inhibitors Exclusion criteria: serum-creatinine >3 mg/dL; serum-potassium >5.5 mmol/L, history of marked ACE inhibitor-induced hyperkalemia resulting in either a serum potassium >6.0 mmol/L, or a life-threatening adverse event, known bilateral renal artery stenosis, current symptomatic hypotension, persistent systolic or diastolic hypertension, stroke, acute myocardial infarction, or open heart surgery within the last 4 weeks, previous heart transplant or heart transplant expected to be performed within the next 6 months Participants were randomized to received candesartan (target dose of 32 mg once daily) or a matching placebo.
Duration	Median follow-up: 33.7 months
Outcome Measures	Cardiovascular death or unplanned admission to hospital for the management of worsening CHF, angioedema
Baseline Characteristics		Candensartan (n= 1,013)	Placebo (n=1,015)
	Age, years	66.3 ± 11.0	66.8 ± 10.5
	Women	322 (31.8%)	324 (31.9%)
	Reason for Intolerance of ACE-inhibitor Cough Hypotension Renal dysfunction Angioedema/anaphylaxis Other	704 (69.5%) 143 (14.1%) 134 (13.2%) 39 (3.8%) 101 (10.0%)	751 (74.0%) 119 (11.7%) 100 (9.9%) 44 (4.3%) 109 (10.7%)
Results		Candesartan (n=1,013)	Placebo (n=1,015)	p-value
	CV death or hospital admission for CHF CV death Hospital admission for CHF	334 (33.0%) 219 (21.6%) 207 (20.4%)	406 (40.0%) 252 (24.8%) 286 (28.2%)	0.0004 0.072 <0.0001
	Angioedema	3 (0.2%)*	0
	All three cases of angioedema were from patients who had previous angioedema with ACE inhibitor therapy.
Adverse Events	Percentage that Discontinued due to Adverse Events: candesartan group (21.5%), placebo group (19.3%)
Study Author Conclusions	Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic CHF who were not receiving ACE inhibitors because of intolerance.
InpharmD Researcher Critique	In this study, only one of 39 patients in the candesartan group who also had a history of angioedema with ACE-inhibitors had recurrent angioedema. Based on the data presented by the authors, the use of ARBs in ACE-inhibitor intolerant patients should be used with caution, but should not be contraindicated.

References:
[1] Granger CB, Mcmurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362(9386):772-6.

Angioedema associated with angiotensin-converting enzyme (ACE) inhibitor use: outcome after switching to a different treatment
Design	Retrospective, cohort study N=54
Objective	To report on the outcome of 64 consecutive patients with ACE inhibitor (ACE-I)–related angioedema after discontinuing ACE-I treatment and on the safety of using angiotensin receptor blockers (ARBs) after angioedema is resolved
Study Groups	ARB (n=26) Calcium antagonist (n=14) Othe drug (n=14)
Methods	Inclusion criteria: patients taking an ACE-I who experienced angioedema (with or without urticaria) Exclusion criteria: known causes of angioedema excluded by clinical history that included detailed information about personal and familial allergies Ten patients did not return for the follow-up visit and therefore are not further considered. Of the remaining 54 patients, 26 switched to an ARB, 14 to a calcium channel antagonist, and 14 to other treatments.
Duration	January 1993 to June 2002
Outcome Measures	Resolution of angioedema after discontinuation of ACE-I
Baseline Characteristics		Study patients (N=64)
	Age, years	63
	Male	38 (59%)
Results		ARB (n=26)	Calcium antagonist (n=14)	Othe drug (n=14)
	Disappearance of angioedema	17 (65%)	10 (71%)	10 (71%)
	Reduction of angioedema	4 (15%)	1 (7%)	4 (29%)
	No effect	5 (19%)	3 (21%)	0

Adverse Events	Not studied
Study Author Conclusions	Only a small percentage of patients with ACE inhibitor-related angioedema continue with this symptom when switched to an ARB.
InpharmD Researcher Critique	Limitations include the fact that this was a retrospective study. The doses of medications were not reported.

References:
[1] Cicardi M, Zingale LC, Bergamaschini L, Agostoni A. Angioedema associated with angiotensin-converting enzyme inhibitor use: outcome after switching to a different treatment. Arch Intern Med. 2004;164(8):910-3.