title: Comparative effectiveness of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular disease prevention
Creators: name: Alosaimi, Manal Eid
Publisher: name: University of Glasgow
Year: 2022

description: Background: The renin–angiotensin–aldosterone system (RAAS) plays a crucial role in the development of hypertension, and in the pathogenesis and progression of atherosclerosis, leading to cardiovascular diseases (CVD). ACEIs and ARBs inhibit the RAAS at different targets and achieve comparable BP reductions. Of the two groups, ARBs have a superior safety and tolerability profile. However, there are reports of divergent effects from ACEI and ARBs based on the meta-analyses of clinical trials. ACEIs reduce the risk of MI, cardiovascular (CV) mortality and allcause mortality, whereas ARBs do not. Clinical practice guidelines consider ACEIs and ARBs equivalent, and a comprehensive and up to date assessment of the ‘ARB paradox’ is important to inform future guidelines and ensure safe clinical practice. Objectives: The main objectives of the current thesis are: 1) to investigate the comparative effectiveness of ACEIs and ARBs for preventing CV morbidity and mortality in patients with or at high-risk of CVDs; and 2) to assess the relative contribution of BP-dependent and independent mechanisms on reducing the risk of CV morbidity and mortality, as achieved by ACEIs and ARBs. Methodologies for answering the research questions: A systematic review and meta-analysis of randomized-control trials (RCTs), was performed in addition to a random-effects meta-regression analysis. Pre-specified outcomes, including, myocardial infarction (MI), angina pectoris, stroke, heart failure (HF), all-cause mortality, and CV death were assessed. In addition, specific pre-specified subgroups of patients, including drug subclasses, comparator drugs, population clinical setting, and mean age (years), were evaluated to demonstrate the differential benefits when comparing ACEIs and ARBs. Results: The results for the meta-analysis and meta-regression analysis are divided here into four chapters (4 to 7) according to the CV outcomes for ACEIs and ARBs. In total, 97 RCTs, with 317,984 participants with or at high-risk of CVDs were included in this systematic review, over an average duration of 3.03 years. ACEIs and ARBs with risk of coronary artery disease events: The pooled data shows that there was a significant 16% (RR, 0.84; 95% CI 0.79–0.90; p&lt;0.00001) reduction in the risk of incident MI in relation to ACEI therapy compared control group with no evidence of statistical heterogeneity among the trials (I2=0%.). In contrast, there was no overall benefit identified from ARB therapy (RR, 0.97; 95% CI 0.89-1.06; p= 0.55; I2=30%). The evidence from the direct comparison trials showed no distinction between ACEIs and ARBs in terms of MI risk (RR 1.02; 95% CI 0.95–1.09; p=0.64; I2=0%)). Furthermore, I have shown through a meta-regression analysis that nearly half (9% relative risk reduction) of the protective effect of ACEI on MI risk occurs independently of any BP lowering effect. Both ACEI and ARB therapies have no impact in terms of their capacity to reduce the risk of angina pectoris. Considerable heterogeneity was observed among the effect estimates for ACEIs and ARBs (I 2 : 58% and 61% respectively), which limits the author’s capacity to formulate definitive conclusions. ACEIs and ARBs in preventing stroke: According to this systematic review, the analyses reveal that both ACEIs and ARBs provide a reduction in stroke risk compared with placebo; by 14% (RR, 0.86; 95% CI 0.76-0.98; p=0.02; I2=26%) and 9% (RR, 0.91; 95% CI 0.85-1.00; p=0.05; I2=0%) respectively. Based on direct comparison trials, there appear to be a 4% lesser stroke lowering affect from ARB therapy than noted for ACEI (RR, 0.96; 95% CI 0.87-1.06; p=0.42; I 2=0%), but this finding did not achieve statistical significance. In the meta-regression analysis, both ACEI and ARB therapies have respective risk ratios for stroke reduction that are significantly related to the magnitude of the BP reduction. ACEIs versus ARBs for HF prevention: This overview suggests that ACEIs showed a 20% lower HF risk compared with placebo (RR, 0.80; 95% CI 0.74, 0.87; P= 0.00001). Similarly, ARBs had a 14% lower HF risk compared with placebo (RR, 0.86; 95% CI 0.80–0.92; p&lt; 0.00001). This comparable finding was confirmed in direct comparison trials (RR,1.03; 95% CI 0.97–1.09; p=0.37; I2=0%). However, when analyzing trials with active therapy as the comparator group, ARB appeared to be beneficial, with a 13% significant reduction of HF risk, and no added benefit emerging for ACEIs. BP reduction was a major determinant of the risk reduction achieved by ACEIs, while the ARB effect occurred independently of BP reduction. ACEIs versus ARBs with risk of CV and all-cause mortality: ACEIs are associated with a 9% (RR, 0.91; 95% CI 0.86- 0.97; P=0.002) and 5% (RR, 0.95; 95% CI 0.91- 0.98; p=0.003) relative risk reduction in CV and all-cause mortality respectively. No statistical variation was apparent across the studies (I2=0%). Meanwhile, no such benefit was seen with ARB-based therapy. Direct comparison trials showed that both ACEIs and ARBs were equivalent in terms of the CV (RR, 1.04; 95% CI 0.98-1.10; p=0.16; I2=0%) and all mortality risk (RR, 1.03; 95% CI 0.98-1.08; p=0.20; I 2=0%). The magnitude of the observed risk-reduction seen with ACEIs could be attributed to the magnitude of the BP reduction. Consistent findings involving a series of sensitivity analyses were expected to support the strength of this association. Conclusions: In summary, this study used data from 317,984 participants with or at high-risk of CVDs, suggesting that ARBs are as effective as ACEIs at mitigating potential risk from CV events and mortality. The finding from the direct comparison trials also supports the view that ARBs may be slightly more protective than ACEIs against risk of stroke. The reduction in stroke risk brought about by ACEI and ARB is largely attributable to BP reduction. The magnitude of the risk reduction for HF, CV and all-mortality by ACEIs appear to have largely been driven by the magnitude of the BP reduction. The beneficial effect independent of BP reduction of ACEI on MI risk and ARB on HF risk warrants further study.