Risk factors for angiotensin converting enzyme inhibitor angioedema in a South African population

Angiotensin converting enzyme inhibitors (ACEI) have proven mortality and morbidity benefit in hypertension, ischemic heart disease, heart failure, and renal disease and are among the most prescribed medications globally. ACEI angioedema (AE-ACEI) is a potentially life-threatening adverse drug reaction that is reported to occur more frequently in African American populations. However, the clinical profile of AE-ACEI is poorly characterized in diverse African populations.

A case-controlled cohort study with enrolment of AE-ACEI cases and drug-tolerant controls in Cape Town, South Africa. Univariable and multivariable analysis was performed. Controls were defined as patients tolerating ACEI for a minimum of two years. Cases were defined as patients who had angioedema while using an ACEI, patients with a history of angioedema while not on an ACEI were excluded. Cases and controls were recruited from the same demographic areas, including both hospitals and clinics. Information regarding demographics and clinical history was captured via both in person interviews and folder review.

A total of 237 AE-ACEI cases, and 466 ACEI tolerant controls were enrolled from seven sites in Cape Town. Features of IgE-mediated immediate drug hypersensitivity were present in 24 cases, which excluded them from analysis. The median age was 58 years (IQR: 47; 67) and 57% were female. AE-ACEI cases more frequently had Black genetic ancestry compared to controls [53% (81/154), vs. 29% (146/407), p < 0.001]. AE-ACEI occurred within 30 days of initiating ACEI therapy in only 31.1% (70/225), with median treatment time to AE-ACEI of 6.9 years (IQR: 2.9; 13). The ACEI tolerant controls were using ACEI for median 9.5 years (IQR: 5; 15.5). All AE-ACEI cases developed swelling above the shoulders, involving the lips and tongue in 72% (165/213) and 50% (107/213) cases respectively. Hospitalisation for AE-ACEI was required in 82% (175/213), however only two patients were intubated, and there were no mortalities. In multivariable analysis traditional risk factors of age, gender, immunosuppression and atopy did not differ between cases and controls. Black genetic ancestry [aOR 15.4 (95% CI 2.94-283), p value = 0.01] and calcium channel blocker use [aOR 1.77 (95% CI 1.17-2.72), p value = 0.008] were significant risk factors for developing AE-ACEI. Cardiac failure, chronic kidney disease, and statin use reduced the risk of AE-ACEI in this model.

In this South African population, Black genetic ancestry and calcium channel blocker use were the major risk factors for AE-ACEI. The majority of AE-ACEI occurred after several years of treatment, with most cases involving the lip and/or tongue. Long-term follow-up, genetic, and further mechanistic studies are warranted in additional diverse African populations.