The effects of rhythm control strategies versus rate control strategies for atrial fibrillation and atrial flutter: A systematic review with meta-analysis and Trial Sequential Analysis

Abstract

Background: Atrial fibrillation and atrial flutter may be managed by either a rhythm control strategy or a rate control strategy but the evidence on the clinical effects of these two intervention strategies is unclear. Our objective was to assess the beneficial and harmful effects of rhythm control strategies versus rate control strategies for atrial fibrillation and atrial flutter.

Methods: We searched CENTRAL, MEDLINE, Embase, LILACS, Web of Science, BIOSIS, Google Scholar, clinicaltrials.gov, TRIP, EU-CTR, Chi-CTR, and ICTRP for eligible trials comparing any rhythm control strategy with any rate control strategy in patients with atrial fibrillation or atrial flutter published before November 2016. Our primary outcomes were all-cause mortality, serious adverse events, and quality of life. Our secondary outcomes were stroke and ejection fraction. We performed both random-effects and fixed-effect meta-analysis and chose the most conservative result as our primary result. We used Trial Sequential Analysis (TSA) to control for random errors. Statistical heterogeneity was assessed by visual inspection of forest plots and by calculating inconsistency (I2) for traditional meta-analyses and diversity (D2) for TSA. Sensitivity analyses and subgroup analyses were conducted to explore the reasons for substantial statistical heterogeneity. We assessed the risk of publication bias in meta-analyses consisting of 10 trials or more with tests for funnel plot asymmetry. We used GRADE to assess the quality of the body of evidence.

Results: 25 randomized clinical trials (n = 9354 participants) were included, all of which were at high risk of bias. Meta-analysis showed that rhythm control strategies versus rate control strategies significantly increased the risk of a serious adverse event (risk ratio (RR), 1.10; 95% confidence interval (CI), 1.02 to 1.18; P = 0.02; I2 = 12% (95% CI 0.00 to 0.32); 21 trials), but TSA did not confirm this result (TSA-adjusted CI 0.99 to 1.22). The increased risk of a serious adverse event did not seem to be caused by any single component of the composite outcome. Meta-analysis showed that rhythm control strategies versus rate control strategies were associated with better SF-36 physical component score (mean difference (MD), 6.93 points; 95% CI, 2.25 to 11.61; P = 0.004; I2 = 95% (95% CI 0.94 to 0.96); 8 trials) and ejection fraction (MD, 4.20%; 95% CI, 0.54 to 7.87; P = 0.02; I2 = 79% (95% CI 0.69 to 0.85); 7 trials), but TSA did not confirm these results. Both meta-analysis and TSA showed no significant differences on all-cause mortality, SF-36 mental component score, Minnesota Living with Heart Failure Questionnaire, and stroke.

Conclusions: Rhythm control strategies compared with rate control strategies seem to significantly increase the risk of a serious adverse event in patients with atrial fibrillation. Based on current evidence, it seems that most patients with atrial fibrillation should be treated with a rate control strategy unless there are specific reasons (e.g., patients with unbearable symptoms due to atrial fibrillation or patients who are hemodynamically unstable due to atrial fibrillation) justifying a rhythm control strategy. More randomized trials at low risk of bias and low risk of random errors are needed.

Trial registration: PROSPERO CRD42016051433.

Fig 1. PRISMA flow diagram.

We screened 16 952 records and included 56 publications of 25 trials in this systematic review.

Fig 2. Forest plot of the meta-analysis of all-cause mortality.

Meta-analysis showed no significant difference between rhythm control strategies and rate control strategies when assessing all-cause mortality.

Fig 3. Trial Sequential Analysis of all-cause mortality.

Trial Sequential Analysis (TSA) showed that there was not enough information to confirm or reject a risk ratio reduction of 15% (TSA-adjusted confidence interval 0.90 to 1.22). The Z-curve (the blue line) does not cross any boundaries.

Fig 4. Forest plot of the meta-analysis of serious adverse events.

Meta-analysis showed that rhythm control strategies versus rate control strategies significantly increased the risk of a serious adverse event.

Fig 5. Trial Sequential Analysis of serious adverse events.

Trial Sequential Analysis (TSA) of serious adverse events showed that there was not enough information to confirm or reject a RRR of 15% (TSA-adjusted confidence interval 0.99 to 1.22). The Z-curve (the blue line) does not cross any boundaries.

Fig 6. Forest plot of the meta-analysis of quality of life (the Short Form (36) physical component score (SF-36 PCS)).

Meta-analysis showed that rhythm control strategies versus rate control strategies significantly increased the quality of life measured by SF-36 PCS.

Fig 7. Trial Sequential Analysis of quality of life (the Short Form (36) physical component score (SF-36 PCS)).

Trial Sequential Analysis showed that there was not enough information to confirm or reject a mean difference of 4.81 points (TSA-adjusted confidence interval -3.16 to 17.02). The Z-curve (the blue line) does not cross any boundaries.

Fig 8. Forest plot of the meta-analysis of stroke.

Meta-analysis showed no significant difference between rhythm control strategies and rate control strategies when assessing stroke.

Fig 9. Trial Sequential Analysis of stroke.

Trial Sequential Analysis (TSA) showed that there was not enough information to confirm or reject a risk ratio reduction of 15% (TSA-adjusted confidence interval 0.33 to 3.28). The Z-curve (the blue line) does not cross any boundaries.

Fig 10. Forest plot of the meta-analysis of ejection fraction.

Meta-analysis showed that rhythm control strategies versus rate control strategies significantly increased the ejection fraction.

Fig 11. Trial Sequential Analysis of ejection fraction.

Trial Sequential Analysis (TSA) showed that there was not enough information to confirm or reject a mean difference of 4.20% (TSA-adjusted confidence interval -2.37 to 10.77). The Z-curve (the blue line) does not cross any boundaries.