Evidence-based Pharmacotherapy Of Intervention With Rennin-angiotensin System Inhibitors To Prevent Clinical Endpoints In Hypertensive Patients

Background and ObjectivesClinical decisions have to be made with the best evidence available. Toward this end, we aim to apply evidence-based pharmacotherapy- a cutting-edge interdisciplinary approach integrating evidence-based medicine (EBM) and clinical pharmacology, to provide clinical decisions with the most up-to-date and unbiased evidences on prescribed drugs’efficacy and risk. In order to prevent clinical endpoints in hypertensive patients, the EBM’s method is adopted in this study to produce a Cochrane systematic review which is internationally recognized as the highest-level evidence for drug intervention. Renin-angiotensin system (RAS) inhibitors are widely prescribed for hypertension, especially for hypertensive patients with diabetes, on the results of placebo-controlled trials, that is, they are on the basis of postulated advantages of renal and cardiovascular outcomes. The efficacy of RAS inhibitors compared to other antihypertensive drugs is still unclear. The purpose of this study is to critically evaluate the benefits and harms of RAS inhibitors compared to other first-line antihypertensive drugs in terms of clinical endpoints (all-cause mortality, renal and cardiovascular outcomes) in patients with elevated blood pressure. The findings of this study will fill in the blanks of relevant clinical evidences in the form of Cochrane systematic review.MethodsRelated electronic databases had been searched using specific highly sensitive search strategies for identifying RCTs and reviews in MEDLINE, EMBASE and CENTRAL (Cochrane Central Register of Controlled Trials) respectively. Randomized, active-controlled, double-blind clinical trials with at least 6 months follow-up on patients with primary elevated blood pressure (≥130/85mmHg) which compared RAS inhibitors with other first-line antihypertensive drugs in terms of clinical and surrogate endpoints were included in this review. Patients with proven secondary hypertension were excluded. Two authors independently selected the included trials, evaluated the risk of bias and entered the data for meta-analysis, subgroup analysis and investigation of heterogeneity, and sensitivity analysis, and the quality of the evidences produced in this study had been evaluated.Results41 studies were included, involving 65,511 participants. Primary outcomes, which were clinical endpoints--hard outcomes, were all-cause death, fatal and non-fatal stroke, fatal and non-fatal myocardial infarction (MI), fatal and non-fatal congestive heart failure (HF) requiring hospitalizations, total cardiovascular events (consisted of fatal and non-fatal stroke, fatal and non-fatal MI and fatal and non-fatal congestive heart failure requiring hospitalizations), and end stage renal failure. Secondary outcomes were systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR).Compared with first-line calcium channel blockers (CCBs), first-line RAS inhibitors decreased heart failure (5 RCTs, RR 0.83,95% CI 0.77,0.90, ARR 1.2%) and increased stroke (4 RCTs, RR 1.19,95% CI 1.08,1.32, ARI 0.7%), but were not significantly different for all-cause death (5 RCTs, RR 1.03,95% CI 0.98,1.09), total cardiovascular events (6 RCTs, RR 0.98,95% CI 0.93,1.02), total myocardial infarction (5 RCTs, RR 1.01,95% CI 0.93,1.09) and end stage renal failure (4 RCTs, RR 0.88,95% CI 0.74, 1.05).Compared with first-line β-blockers, first-line RAS inhibitors decreased total cardiovascular events (2 RCTs, RR 0.88,95% CI 0.80,0.98) and decreased stroke (1 RCT, RR 0.75,95% CI 0.63,0.88). First-line β-blockers and first-line RAS inhibitors were not significantly different for all-cause death (1 RCT, RR 0.89,95% CI 0.78,1.01), heart failure (1 RCT, RR 0.95,95% CI 0.76,1.18) and total myocardial infarction (2 RCTs, RR 1.05,95% CI 0.86,1.27).Compared with first-line thiazides, first-line RAS inhibitors increased heart failure (1 RCT, RR 1.19,95% CI 1.07,1.31) and increased stroke (1 RCT, RR 1.14,95% CI 1.02, 1.28), but were not significantly different for all-cause death (1 RCT, RR 1.00,95%CI 0.94,1.07), total cardiovascular events (2 RCTs, RR 1.05,95% CI 1.00,1.11), total myocardial infarction (2 RCTs, RR 0.93,95% CI 0.86,1.01) and end stage renal failure (1 RCT, RR 1.10,95% CI 0.88,1.37).Blood pressure comparisons between RAS inhibitors and other classes showed either no differences or small differences with statistical significance.ConclusionsWhen compared to first-line RAS inhibitors, first-line thiazides caused less heart failure and stroke. Compared with P-blockers, RAS inhibitors reduced total cardiovascular events and stroke. Compared with CCBs, RAS inhibitors reduce heart failure but increase stroke. The magnitude of the reduction in heart failure exceeds the increase in stroke. The small differences in effect on blood pressure between the different classes of drugs did not necessarily correlate with the differences in the hard outcomes.