Population selection
Before matching, there were 31,194 individuals with a prescription for ACE inhibitors, 13,377 with a prescription for ARBs, and 27,500 with a prescription for CCBs at the index date. After matching, there were 18,895 patients in each arm of the ACE inhibitor and CCB paired cohorts and 10,623 in each arm of the ARB and CCB paired cohorts (Figure 1).
Study participants
ACE inhibitors versus calcium channel blockers
Before matching, the mean age of users of ACE inhibitors and CCBs was 60.8 years and 67.4, respectively (Table 1). The proportion that were male was slightly higher for users of ACE inhibitors than users of CCBs (48.8% vs 45.6%, respectively). A similar proportion were current smokers but a greater proportion of users of ACE inhibitors were overweight or obese compared to users of CCBs (77.7% vs 69.1%, respectively).
Duration of hypertension was slightly longer for users of ACE inhibitors than CCBs (9.8 years vs 8.6 years, respectively). Systolic and diastolic BP, cholesterol, and renal function were similar across both groups. The prevalence of comorbidities was also similar between groups, except for cancers and respiratory disease, which were slightly more common in the CCB cohort.
21.9% of the CCB cohort had previously used an ACE inhibitor and 26.4% of the ACE inhibitor cohort had previously used a CCB. Prescription of other antihypertensives was similar between groups except for thiazide diuretics, which was slightly more common in the ACE inhibitor cohort (18.5% in users of ACE inhibitors vs 14.3% in users of CCBs). Prescriptions of statins were also similar between both cohorts.
Following propensity score matching, users of ACE inhibitors and CCBs were similar in age (64.7 years vs 63.4 years, respectively). Other characteristics were well balanced, including demographic, behavioural and metabolic risk factors, comorbidities and prescriptions (Table1).
Angiotensin II receptor blockers versus calcium channel blockers
Before matching, the mean age of users of ARBs was younger than users of CCBs (63.8 years vs 67.4, respectively [Table 1]). However, the proportion of males was slightly lower in users of ARBs than CCBs (40.2% vs 45.6%, respectively). A smaller proportion of users of ARBs were current smokers compared to users of CCBs (7.9% vs 12.7%, respectively). A greater proportion of users of ARBs were overweight or obese than users of CCBs (79.1% vs 69.1%).
The ARB cohort had a longer mean duration of hypertension than the CCB cohort (11.4 years vs 8.6, respectively) and a younger mean age at hypertension diagnosis (52.4 years vs 58.8). BP, cholesterol and renal function were similar between groups, as was the prevalence of comorbidities.
63.0% of users of ARBs had previously used an ACE inhibitor, compared to 21.9% of users of CCBs. 40.3% of the ARB cohort had previously used a CCB while 6.9% of the CCB cohort had previously used an ARB. Users of ARBs were more likely than users of CCBs to have been prescribed thiazide diuretics as well as other antihypertensive drugs. However, the proportion with a prescription for statins was slightly greater in the CCB cohort.
Following propensity score matching, characteristics were well balanced between both groups, including demographic characteristics, behavioural risk factors, metabolic profile, comorbidities, and prescriptions (Table 1).
Outcomes
ACE inhibitors versus calcium channel blockers
Before matching, 148 individuals (0.47%) in the ACE inhibitor cohort developed suspected or confirmed COVID-19 during 14,733 person-years of follow-up, representing a crude incidence rate of 10.1 per 1000 person-years (Table 2). 126 individuals (0.46%) in the CCB cohort developed suspected or confirmed COVID-19 during 12,985 person-years, representing a crude incidence rate of 9.70 per 1000 person-years in the CCB cohort. The unadjusted hazard ratio for suspected/confirmed COVID-19 comparing the ACE inhibitor cohort to the CCB cohort (as the reference) was 1.04 (95% CI 0.82 to 1.31), which fell slightly to 1.01 (95% 0.78 to 1.30) after adjusting for measured confounders.
Following propensity score matching, 83 individuals (0.44%) in the ACE inhibitor cohort had suspected or diagnosed COVID-19 during 8923 person-years of follow-up, representing a crude incidence rate of 9.30 per 1000 person-years. 85 individuals (0.45%) in the CCB cohort developed suspected or confirmed COVID-19 during 8932 person-years of follow-up representing a crude incidence rate of 9.5 per 1000 person-years. The unadjusted hazard ratio for suspected/confirmed COVID-19 comparing the ACE inhibitor cohort to the CCB cohort was 0.98 (95% CI 0.72 to 1.32). Upon adjustment for measured confounders, the hazard ratio was 0.92 (95% 0.68 to 1.26; Figure 2).
Similar results were found in the sensitivity analyses for the primary outcome. When comparing hypertensive users of ACE inhibitors with or without CCBs to those using CCBs alone, the adjusted hazard ratio was 0.95 (95% CI 0.72 to 1.25) following propensity score matching. When including individuals with diabetes mellitus, ischemic heart disease, stroke, transient ischaemic attack and peripheral vascular disease, the adjusted hazard ratio for COVID-19 after propensity score matching was 0.91 (95% CI 0.74 to 1.12). When including individuals with any comorbidities, the adjusted hazard ratio after propensity score matching was similarly 0.98 (95% CI 0.81 to 1.18; Figure 3).
The propensity score-matched analysis for all-cause mortality produced a statistically non-significant adjusted hazard ratio of 1.25 (95% CI 0.90 to 1.73). The negative control analysis similarly found no statistically significant association between prescription of ACE inhibitors and accidents, trauma or fractures compared to prescription of CCBs (adjusted HR 0.95 (95% CI 0.77 to 1.17).
Angiotensin II receptor blockers versus calcium channel blockers
Before matching, 99 individuals (0.74%) in the ARB cohort developed suspected or confirmed COVID-19 over a follow-up of 6308 person-years, representing a crude incidence rate of 15.7 per 1000 person-years. 126 (0.46%) in the CCB cohort developed suspected or confirmed COVID-19 over a follow-up of 12,985 person-years, representing a crude incidence rate of 9.7 per 1000 person-years. The unadjusted hazard ratio for suspected or confirmed COVID-19 when comparing the ARB cohort to the CCB cohort (as the reference) was 1.62 (95% CI 1.24 to 2.10). After adjustment for measured confounders, the hazard ratio was slightly attenuated to 1.51 (95% CI 1.12 to 2.03), although remained statistically significant.
After propensity score matching, 79 individuals (0.74%) in the ARB cohort developed suspected or confirmed COVID-19 over 5010 person-years of follow-up, representing a crude incidence rate of 15.8 per 1000 person-years. In the CCB cohort, 58 individuals (0.55%) developed suspected or confirmed COVID-19 over 5016 years of follow-up, representing a crude incidence rate of 11.6 per 1000 person-years. The unadjusted hazard ratio when comparing the ARB cohort to the CCB cohort was 1.36 (95% CI 0.97 to 1.91). After adjustment for measured confounders, the hazard ratio increased slightly to 1.38 (95% CI 0.98 to 1.95; Figure 2).
These findings were attenuated in sensitivity analyses when comparing users of ARBs with or without concurrent use of CCBs to propensity score-matched individuals using CCBs alone (adjusted HR 1.18, 95% CI 0.86 to 1.61). When only excluding individuals with either heart failure or CKD, the adjusted hazard ratio was slightly attenuated compared to the primary analysis but statistically significant after propensity score matching (adjusted HR 1.28, 95% CI 1.00 to 1.63). This was similarly found when including propensity score-matched individuals with any comorbidity (adjusted HR 1.24, 95% CI 1.00 to 1.54; Figure 3).
There was no statistically significant difference in all-cause mortality between users of ARBs compared to users of CCBs after propensity score matching (adjusted HR 0.85, 95% CI 0.56 to 1.30). Similarly, there was no association between use of ARBs and the negative control outcome of accidents, trauma and fractures when compared to propensity score matched users of CCBs (adjusted HR 0.97, 95% CI 0.74 to 1.27).