Blood pressure-lowering treatment for the prevention of cardiovascular events in patients with atrial fibrillation: An individual participant data meta-analysis

Abstract

Background: Randomised evidence on the efficacy of blood pressure (BP)-lowering treatment to reduce cardiovascular risk in patients with atrial fibrillation (AF) is limited. Therefore, this study aimed to compare the effects of BP-lowering drugs in patients with and without AF at baseline.

Methods and findings: The study was based on the resource provided by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC), in which individual participant data (IPD) were extracted from trials with over 1,000 patient-years of follow-up in each arm, and that had randomly assigned patients to different classes of BP-lowering drugs, BP-lowering drugs versus placebo, or more versus less intensive BP-lowering regimens. For this study, only trials that had collected information on AF status at baseline were included. The effects of BP-lowering treatment on a composite endpoint of major cardiovascular events (stroke, ischaemic heart disease or heart failure) according to AF status at baseline were estimated using fixed-effect one-stage IPD meta-analyses based on Cox proportional hazards models stratified by trial. Furthermore, to assess whether the associations between the intensity of BP reduction and cardiovascular outcomes are similar in those with and without AF at baseline, we used a meta-regression. From the full BPLTTC database, 28 trials (145,653 participants) were excluded because AF status at baseline was uncertain or unavailable. A total of 22 trials were included with 188,570 patients, of whom 13,266 (7%) had AF at baseline. Risk of bias assessment showed that 20 trials were at low risk of bias and 2 trials at moderate risk. Meta-regression showed that relative risk reductions were proportional to trial-level intensity of BP lowering in patients with and without AF at baseline. Over 4.5 years of median follow-up, a 5-mm Hg systolic BP (SBP) reduction lowered the risk of major cardiovascular events both in patients with AF (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.83 to 1.00) and in patients without AF at baseline (HR 0.91, 95% CI 0.88 to 0.93), with no difference between subgroups. There was no evidence for heterogeneity of treatment effects by baseline SBP or drug class in patients with AF at baseline. The findings of this study need to be interpreted in light of its potential limitations, such as the limited number of trials, limitation in ascertaining AF cases due to the nature of the arrhythmia and measuring BP in patients with AF.

Conclusions: In this meta-analysis, we found that BP-lowering treatment reduces the risk of major cardiovascular events similarly in individuals with and without AF. Pharmacological BP lowering for prevention of cardiovascular events should be recommended in patients with AF.

Fig 1. PRISMA diagram for included trials.

AF, atrial fibrillation; BPLTTC, Blood Pressure Lowering Treatment Trialists’ Collaboration; IPD, individual participant data; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Fig 2. Hazard ratio of major cardiovascular events related to the 1-year difference blood pressure reduction aggregated at trial level.

Risk of major cardiovascular events, for patients with (dashed line) and without (solid line) atrial fibrillation at baseline, regressed against the systolic blood pressure difference between trial arms, plotted on the log scale. Shapes represent the hazard ratio for each trial with the size inversely proportional to the respective standard error. Trials are coded by shape according to the type of patients: atrial fibrillation only (triangle), no atrial fibrillation only (square), and mix of both (circles). Trials are also coded by colour according to type of intervention: placebo-controlled trials (red), drug class comparison trials (blue), and more versus less intense treatment trials (green). Systolic blood pressure difference between trial arms in mm Hg.

Fig 3. Cumulative event rates for the primary outcome (major cardiovascular events) by treatment arm, stratified by presence of atrial fibrillation at baseline.

Shown are estimates of the proportions of patients with major cardiovascular events (primary composite endpoint) according to treatment arm (intervention versus comparator as defined in treatment comparisons in the methods) for patients with atrial fibrillation (top lines) and without atrial fibrillation at baseline (bottom lines). These curves were created for the overall population included in this study without accounting for stratification by trial.

Fig 4. Effect of blood pressure lowering treatment on primary and secondary outcomes, stratified by presence of atrial fibrillation at baseline.

Forest plot displays the HRs and 95% CIs for each outcome adjusted for a 5-mm Hg systolic blood pressure reduction. Further details on adjustment provided in the Methods. P values for test of difference between subgroups. CI, confidence interval; HR, hazard ratio.

Fig 5. Effect of blood pressure-lowering treatment on major cardiovascular events stratified by baseline systolic blood pressure in patients with atrial fibrillation.

Forest plot displays the HRs and 95% CIs for major cardiovascular events for a 5-mm Hg systolic blood pressure reduction in patients with atrial fibrillation with baseline systolic blood pressure below or above 140 mm Hg. P value for test of difference between subgroups. CI, confidence interval; HR, hazard ratio.

Fig 6. Effect of blood pressure-lowering treatment on major cardiovascular events stratified by drug class.

Forest plot displays the HRs and 95% CIs for major cardiovascular events for a 5-mm Hg systolic blood pressure reduction for RAAS inhibitors-based and CCB-based regimens in comparison with placebo or BB with or without Diu. P values for test of difference between subgroups. BB, beta-blocker; CCB, calcium channel blocker; CI, confidence interval; Diu, diuretic; HR, hazard ratio; RAAS, renin-angiotensin-aldosterone system.