The impact of age and gender on reporting of cough and angioedema with RAS inhibitors: A case/non-case in VigiBase

Background: Little is known about the effect of age and gender on reporting of cough/ angioedema with renin angiotensin system (RAS) inhibitors (angiotensin- converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and aliskiren, a direct renin inhibitor (DRI). Objectives: To assess the impact of age and sex on the occurrence of cough/angioedema with RAS inhibitors using information reported to the World Health Organization (WHO) global individual case safety report database (VigiBase). Methods: A case/non-case study was performed in VigiBase. Cases were defined as reports of cough/angioedema and non-cases were all reports of other adverse events. Age was divided into 6 categories: infant and childhood (0-11 years), adolescence (12- 19 years), young adulthood (20-39 years), middle adulthood (40-59 years), elderly (60-79 years) and late elderly (≥80 years). Logistic regression analysis was used to assess the association between reporting of cough/ angioedema with each class of RAS inhibitors stratified by age/ sex and to control for confounding. Results: The reporting of cough with ACE inhibitors was significantly higher in women than in men (adjusted reporting odds ratio (ROR): 29.2, 95%CI (28.5-29.9) for men versus 44, 95%CI (43.2-44.8) for women). There was no difference in reporting of cough with ARBs and DRI between men and women. In contrast, the reporting of angioedema with ACE inhibitors and ARBs was significantly higher in men than women but for DRI (aliskiren), women had significantly higher ROR than men. For the effect of age, the reporting of cough with ACE inhibitors was significantly increased with age until reaching a plateau at 60 years and the reporting of angioedema with ACE inhibitors was significantly increased with age until 80 years. Age had only a slight effect on reporting of cough/angioedema with ARBs and DRI. Conclusions: Age and sex have substantial effects on reporting of cough/angioedema with RAS inhibitors especially with ACE inhibitors. Further studies are needed to study both factors on occurrence of cough/ angioedema with RAS inhibitors and to elucidate the underlying mechanism involved.