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

Cascia Day^1*Lovemore Mapahla^1,2Melissa Ribeiro¹Mimi Deetlefs¹Cathryn McDougall¹Adelein Engelbrecht³Sarah Lydia PEDRETTI¹Jonathan Peter^1*

• ¹University of South Africa - Cape Town Campus, Parow, South Africa
• ²Stellenbosch University, Stellenbosch, South Africa
• ³Western Cape Government, Cape Town, South Africa

Introduction Angiotensin converting enzyme inhibitors (ACEI) have proven mortality and morbidity benefit in cardiovascular disease. ACEI angioedema (AE-ACEI) is a potentially life-threatening adverse drug reaction that is reported more frequently in African American populations. However, the clinical profile of AE-ACEI is poorly characterized in African populations. Methods 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 > two years. Cases were defined as patients who had angioedema while using an ACEI. Information regarding demographics and clinical history was captured via both interviews and folder review. Results 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, and they were excluded. 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 <30 days of initiating ACEI therapy in 31.1% (70/225), with median treatment time to AE-ACEI of 6.9 years (IQR 2.9; 13). 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. Conclusion 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 and further mechanistic studies are warranted in additional African populations.