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European Journal of Internal Medicine 22 (2011) 448–455 Contents lists available at ScienceDirect European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m Review article Rate vs rhythm control in patients with atrial fibrillation and heart failure: A systematic review and meta-analysis of randomised controlled trials Daniel Caldeira a, Cláudio David a, b,⁎, Cristina Sampaio a, c a b c Clinical Pharmacology and Therapeutics Laboratory, Faculty of Medicine, Lisbon, Portugal Department of Cardiology, Santa Maria University Hospital, Lisbon, Portugal Institute of Molecular Medicine, Lisbon, Portugal a r t i c l e i n f o Article history: Received 9 January 2011 Received in revised form 27 April 2011 Accepted 2 May 2011 Available online 30 June 2011 Keywords: Rate Rhythm Atrial fibrillation Heart failure Hospitalisation Mortality a b s t r a c t Background: Atrial fibrillation (AF) is a common arrhythmia that can promote or worsen heart failure (HF). Our purpose was to compare the effects of rate and rhythm control in patients with atrial fibrillation and heart failure. Methods: We developed a systematic search in August 2010 through CENTRAL and MEDLINE databases to identify randomised controlled trials (RCTs) comparing rate control with rhythm control in patients with both AF and HF. We analysed mortality, hospitalisations, stroke/thromboembolic events, quality of life, and drugs adverse events. Relative risks (RR) and 95% confidence intervals (95% CI) were calculated for mortality and hospitalisations. The remaining outcomes were analysed qualitatively. Results: Four RCTs with a total of 2486 patients with atrial fibrillation and heart failure were identified. Mortality and stroke/thromboembolic events were not significantly different in rate and rhythm control arms [RR 1.03; 95% CI: 0.90–1.17] and [RR 1.09; 95% CI: 0.61–1.96], respectively. Hospitalisations were less frequent with rate control than with rhythm control [RR 0.92; 95% CI: 0.86–0.98; p = 0.008], in 3 studies involving 2425 patients. Number needed to treat to prevent one hospitalisation was 19 patients. Conclusions: In patients with AF and HF, rate control compared with rhythm control showed inferior risk of hospitalisation. © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. 1. Introduction Atrial fibrillation (AF) and heart failure (HF) are important cardiac disorders and the prevalence of both is increasing [1–3]. Atrial fibrillation can worsen HF or lead to this condition through tachycardia-mediated cardiomyopathy [4–7], and patients with HF have increased risk for atrial fibrillation [8]. Forty-one percent of patients with HF will experience AF during their lifetime and 42% of patients with AF will have congestive heart failure (CHF) [9]. Whether AF is a risk factor of death in HF patients is still unclear [9–13] and its prognostic significance in the presence of left ventricular systolic dysfunction is controversial [14–16]. The treatment of AF patients follows one of two possible strategies: (1) Rate control: control ventricular rate with beta-blockers, nondihydropyridine calcium-channel blocker and/or digitalis. ⁎ Corresponding author at: Laboratório de Farmacologia Clínica e Terapêutica. Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa, 1649028, Portugal. E-mail address: [email protected] (C. David). (2) Rhythm control: restore and maintain sinus rhythm with electrical cardioversion and/or antiarrhythmic agents. It is known that rate and rhythm control strategies have similar results in patients with atrial fibrillation [17]. AF–CHF (Atrial Fibrillation and Congestive Heart Failure) randomised controlled trial assessed the effects of referred strategies in patients with both atrial fibrillation and heart failure. This study showed similarity in the efficacy of rate and rhythm control [18]. Nevertheless some other studies also evaluated rate vs rhythm control approaches in patients with atrial fibrillation and heart failure. The aim of this review was to systematically review randomised controlled trials to compare rate control with rhythm control in patients with atrial fibrillation and heart failure, regarding relevant clinical outcomes. 2. Methods 2.1. Searching A searching strategy was developed in August 2010 using CENTRAL (Cochrane Library issue April 2010) and MEDLINE databases 0953-6205/$ – see front matter © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2011.05.001 D. Caldeira et al. / European Journal of Internal Medicine 22 (2011) 448–455 for identification of relevant studies. There were no language restrictions. References of original studies were comprehensively searched. Subgroup and post-hocanalyses of some studies were also retrieved. The electronic search was taken using the following keywords: “rate”, “beta-blocker”, “acebutolol”, “atenolol”, “bisoprolol”, “carvedilol”, “esmolol”, “metoprolol”, “nadolol”, “pindolol”, “propranolol”, “timolol”, “calcium-channel blocker”, “verapamil”, “diltiazem”, “digitalis”, “digoxin”, “rhythm”, “amiodarone”, “propafenone”, “disopyramide”, “dofetilide”, “flecainide”, “ibutilide”, “sotalol”, “dronedarone” and “azimilide”, “atrial fibrillation”, “heart failure” and “ventricular dysfunction”. Boolean operators AND and OR were used to combine the terms. 2.2. Selection Inclusion criteria featured randomised controlled trials (RCT) comparing pharmacological approaches of rate control and rhythm control (including non-invasive procedures of electrical cardioversion) in patients with atrial fibrillation and heart failure. Heart failure was defined as the presence of NYHA ≥ class II symptoms or systolic dysfunction (left ventricular ejection fraction b 50%). Studies in postoperative and post-percutaneous AF were excluded. Trials that evaluated invasive catheter ablation techniques as first intervention were not considered for analysis. 449 Studies were required to have intention-to-treat analysis or provide data that allows this type of calculation. Clinically relevant studies' outcomes were retrieved and pooled analysis was made when possible. 2.3. Validity assessment The quality of data reporting of the retrieved trials was assessed by PEDro score [19]. This score is based on the presence/absence of 11 items: eligibility criteria, random allocation, allocation concealment, similar baseline characteristics, blinding of all subjects, blinding of therapists, blinding of outcome assessors, crossover rate b 15%, intention-to treat analysis, statistical comparisons between groups and measures of variability. 2.4. Data abstraction Studies from searching strategy that met the criteria outlined above were assessed by one review author and checked by another. Data entry into software was also double checked. All disagreements were solved by consensus. 2.5. Quantitative data synthesis The statistical analyses were performed using the RevMan version 5.0.23, provided by Cochrane Collaboration. Dichotomous outcomes were analysed by Mantel–Haenszel method and relative risk (RR) was calculated. Uncertainty in results was expressed using 95% confidence intervals (CI). The results estimates were based on fixed effects model or random effects model according with heterogeneity. Statistical heterogeneity was assessed using the I² test. It was assumed if I² N 50%. Clinical heterogeneity was assessed by authors based on the interventions and studied populations. Numbers needed to treat (NNT) were calculated in the outcomes with statistically significant results. 3. Results Fig. 1. Flowchart of studies selection. By screening of records obtained Medline and CENTRAL we found 198 citations. One-hundred fifty eight records were not relevant and/ or did not have the required design (RCT). Remaining 40 studies were selected for full-text assessment and some were excluded for the following reasons: seventeen did not compare rate vs rhythm control (Fig. 1), six were post-operative and ten studies did not report data for a heart failure/systolic dysfunction subgroup; Major trials such as HOT-CAFÉ (How to Treat Chronic Atrial Fibrillation), STAF (Strategies of Treatment of Atrial Fibrillation), PIAF (Pharmacological Intervention in Atrial Fibrillation) and J-RHYTHM (Japanese Rhythm Management Trial for Atrial Fibrillation) were not included due to this latter reason [20–23]. One study was excluded due to the lack of data necessary to analyse on an intention-to-treat basis. For quantitative analysis we used data of four RCTs from 6 studies [18,24–26]. AF–CHF and CAFE-II enrolled exclusively patients with both AF and HF [18,26]; RACE (Rate Control vs Electrical Cardioversion for Persistent Atrial Fibrillation Study) and AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) studies were general atrial fibrillation RCTs with post-hoc reports of HF subgroup's data [24,25,27,28]. Analysed populations included a total of 2486 patients with paroxysmal or persistent atrial fibrillation and heart failure. Table 1 shows the main characteristics of each study. PEDro scores of the selected trials ranged between 6 and 7 (scale maximum of 11). All trials had unblinded interventions. In the quantitative analysis, we used random effects' method due to the existence of clinical heterogeneity, particularly different sequences or combinations of drugs and differences between the studies populations. 450 D. Caldeira et al. / European Journal of Internal Medicine 22 (2011) 448–455 Fig. 2. Forest plot comparing rate and rhythm control for total mortality in patients with AF and HF. Table 2 shows the pooled results of the following outcomes. 3.1. Mortality Individual studies comparing rate and rhythm control did not find significant differences in mortality despite a trend favouring rhythm control in RACE patients with atrial fibrillation and heart failure [27]. In our meta-analysis the difference also did not achieve significance with a risk ratio of 1.03 (CI 0.90–1.17) (Fig. 2). 3.2. Hospitalisations Hospitalisation data were retrieved from 3 trials with 2425 patients. None of the studies individually showed statistically significant differences but AF–CHF showed benefit of rate control in the first year after enrolment (p = 0.001) and a tendency favouring rate control (p = 0.06) when the study was analysed in full length. AF–CHF was the study that provided more information about hospitalisation causes. This non-significant disproportion in hospitalisations was due to atrial fibrillation (9% rate control vs 14% rhythm control, p = 0.001) and bradyarrhythmias (3% rate control vs 6% rhythm control, p = 0.02). Rhythm control patients were more commonly treated with electrical cardioversion (59% vs 9% of rate control, p b 0.001) [18]. Pooled analysis of hospitalisations showed a RR of 0.92 (CI 0.86– 0.98, p = 0.008) favouring rate control (Fig. 3). Number needed to treat (NNT) with rate control (vs. rhythm control) to prevent one hospitalisation was 19. rhythm control. Fourteen of the nineteen patients who experienced thromboembolic events had inadequate anticoagulant therapy with INR (international normalised ratio) below the desired level [24]. AF–CHF only provided hazard ratio for stroke (0.74; 95% CI 0.40– 135). For quantitative analysis we have assumed the proportional hazards ratio model and used this risk estimate as risk ratio. According with AF–CHF abstract stroke incidence was 4% for rate control and 3% for rhythm control groups. Inputted events used to approximate risk ratio to hazards ratio also correspond, respectively, to 4% (25/694 = 3.6%) and 3% (18/682 = 2.6%) of stroke incidence in rate and rhythm control arms [18]. Meta-analysis did not show statistically significant result with RR of 1.09 and 95% confidence interval between 0.61 and 1.96 (Fig. 4). 3.4. Quality of life Only two RCTs, RACE and CAFÉ-II, reported the quality of life effects of rate and rhythm control, but obtained results were heterogeneous [26,27]. Scales used to assess this outcome were different amongst trials producing different conclusions. In RACE study Short-form 36 instrument showed that rate control improved physical role limitations, social functioning and mental health subscales, whereas rhythm control only improved this last subscale [27]. In CAFÉ-II, rhythm control was superior to rate control in the global score of Short-form 36 version II as well as mental and physical functioning subgroup, but in the same study when Minnesota Living With Heart Failure (MLWHF) questionnaire was applied no difference was found between interventions [26]. 3.3. Stroke/Thromboembolic complications 3.5. Used drugs and adverse events Only two trials provided data on this outcome with both studies showing similarities in rate and rhythm control interventions regarding thromboembolic events. In RACE study thromboembolic events were seen in 8 of the 130 patients assigned to rate control and in 11 of 131 patients treated with rhythm control strategy. No statistical significance was found (p = 0.49). In rate control group 85% of patients were on continuous anticoagulation during all trial compared with 66% of patients under AF–CHF and AFFIRM had data about used drugs and RACE reported data on adverse events. In AF–CHF beta-blockers were preferentially used for rate control (88% of the patients). Digoxin was used in 75% of patients and calcium-channel blockers in 3%. Preferred drug for rhythm control was amiodarone which was used by 82% of the patients. About 80% of patients assigned to rhythm control also used beta-blockers. Sotalol Fig. 3. Forest plot comparing rate and rhythm control for hospitalisations in patients with AF and HF. D. Caldeira et al. / European Journal of Internal Medicine 22 (2011) 448–455 451 Fig. 4. Forest plot comparing rate and rhythm control for stroke/thromboembolic events in patients with AF and HF. and dofetilide were used in 2% and less than 1% of rhythm control group, respectively. More than 90% of patients in both groups used angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. In AFFIRM, rhythm control patients were mainly treated with amiodarone or sotalol. Dofetilide was used in 0.6% of these patients [25]. Data of antiarrhythmics used in patients with both atrial fibrillation and heart failure was not available. In this trial beta-blockers were the preferred drugs for rate control in patients with AF and HF [28]. In RACE analysis of patients with AF and HF, drug adverse events were less frequent in rate control than rhythm control. Digoxin intoxication induced ventricular tachycardia in one patient on rate control treatment, whilst amiodarone and flecainide induced other brady- and tachyarrhythmias in 8 patients on rhythm control strategy [27]. 4. Discussion This review evaluated important outcomes in patients with atrial fibrillation and heart failure. AF–CHF was the larger analysed trial designed to detect differences in cardiovascular mortality between interventions. The inclusion of CAFÉ-II trial and subgroup analysis of RACE and AFFIRM studies contributed with additional information to the review and increased meta-analysis power resulting in significant differences in hospitalisation outcome. Here we discuss the analysed outcomes according with existing evidence: 4.1. Mortality Mortality was similar in rate and rhythm control in the four individual RCTs and in the meta-analysis. This was concordant to what was already known for AF not restricted to HF patients [18,24–29]. Our study strengthens actual evidence showing that the choice of one specific pharmacological strategy (rate or rhythm control) for patients with AF and HF does not affect survival. Rate control beta-blockers are keystones of heart failure therapy because they showed to reduced mortality in placebo-controlled trials, but CIBIS-II post-hoc analysis in HF patients with AF suggested that carvedilol was not useful [30–32]. Table 1 Trials' main characteristics. Trials RACE [20,23] AFFIRM [21,24] AF–CHF [18] CAFE-II [22] AF population Recurrent persistent AF or flutter for less than 1 year Paroxysmal or persistent AF less than 1 year Persistent AF Heart failure NYHA II–III Likely to be recurrent AF in pts older than 65 years old with risk factors for stroke or death LVEF less than 50% NYHA II–III No. pts Age Male Anticoagulation 261 69 (mean) 65% Acenocoumarol or fenprocoumon 4 weeks before and after electrical cardioversion. Rate arm anticoagulated if more than 65 year-old or cardiac disease. Digitalis, non-dihydropyridine calcium-channel blocker and beta-blocker Electrical cardioversion and sotalol, flecainide, propafenone or amiodarone 2.3 ± 0.6 Composite of cardiovascular death, heart failure, embolism, bleeding, pacemaker implantation, severe adverse effects of drugs In patients with mild to moderate CHF, rate control is not inferior to rhythm control. However, if sinus rhythm can be maintained, outcome may be improved. 7 LVEF equal or less than 35% and NYHA II–IV 1376 67 (mean) 82% Recommended for all pts: ACC/ AHA/ESC 2006 AF guidelines Rate intervention Rhythm intervention Years follow-up Primary outcome Conclusions in HF subset PEDro score 788 71% N65 years 75% Both arms anticoagulated, if after 4–12 weeks with antiarrhythmic agents sinus rhythm is restored, anticoagulation could be stopped Beta-blocker, non-dihydropiridine calcium-channel blocker and digoxin. Many antiarrhythmic agents and/or electrical cardioversion 3.5 (mean) All-cause mortality There was no significant improvement in mortality, hospitalisation, and NYHA class with the strategy of rhythm control in mild, moderate or severe ejection left ventricular dysfunction. 6 Beta-blocker and digoxin. AV nodal ablation and pacemaker (if refractory) Electrical cardioversion and amiodarone (or sotalol or dofetilide) 3.1 ± 1.6 Cardiovascular death Primary outcome was not different in both interventions. Hospitalizations were more frequent in rhythm control. 6 61 72 ± 7 84% Recommendeda for all pts: warfarin (INR 2–3) Digoxin and beta-blocker Amiodarone and electrical cardioversion 1.2 (median) QoL SF-36vII at 1 year Rhythm control improved the primary outcome, LV function and NT-proBNP. NYHA and 6MWT were similar in both interventions. 7 6MWT = 6-minutes walk test; ACC = American College of Cardiology; AF = atrial fibrillation; AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management; AF–CHF = Atrial Fibrillation and Congestive Heart Failure; AHA = American Heart Association; AV = atrioventricular; CAFÉ-II = Controlled study of rate vs rhythm control in patients with chronic atrial fibrillation and heart failure; CHF = congestive heart failure; ESC = European Society of Cardiology; LV = left ventricular; LVEF = Left Ventricular Ejection Fraction; NYHA = New York Heart Association Class; QoL SF-36vII = Quality of Life Short Form-36 version II; RACE = Rate Control vs Electrical Cardioversion for Persistent Atrial Fibrillation Study. 452 D. Caldeira et al. / European Journal of Internal Medicine 22 (2011) 448–455 Table 2 Summary of results. Outcome Trials Patients Rate/Rhythm patients RR [95%CI] p value for RR NNT Mortality 4 2486 1235/1251 0.69 - Hospitalisations 3 2425 1204/1221 0.008 19 Stroke/Thromboembolic events 2 1637 824/813 1.03 [0.90–1.17] 0.92 [0.86–0.98] 1.09 [0.61–1.96] 0.77 - Digitalis did not show to reduce mortality in HF patients [33]. A cohort of patients with AF and HF treated with digoxin alone had death rates similar to patients without rate control treatment and had higher mortality compared with patients treated with beta-blockers alone or beta-blockers in association with digoxin [34]. Amiodarone, a commonly used antiarrhythmic drug, showed heterogeneous mortality results in patients with HF [35–38], whilst class I antiarrhythmic agents can increase death rate [13]. Dronedarone, an antiarrhythmic agent with similarities to amiodarone but without iodine-related adverse reactions showed to be harmful in patients with severe HF [39]. In patients with atrial fibrillation, dronedarone reduced cardiovascular mortality [40,41] and appeared to be safe in patients with AF and stable HF [40,42,43]. 4.2. Hospitalisations Individually none of the trials showed clear benefit regarding hospitalisations, but the larger trials showed tendency towards lower incidence with rate control. Our meta-analysis showed statisticallysignificant superiority of rate control in this outcome. Digitalis and beta-blockers have proved to reduce hospitalisation risk in heart failure [30,32,33], but no data are available for patients with both atrial fibrillation and heart failure. Antiarrhythmic agent dofetilide reduced the incidence of this outcome in patients with AF and left ventricular dysfunction [44,45]. All trials considered betablockers for heart rate control, but despite the possible benefit, data of AFFIRM and AF–CHF studies reported that dofetilide was only used in less than 1% of rhythm control patients. Hospitalisations were mainly due to bradiarrhythmias or hemodynamic deterioration [18]. AF–CHF trial showed that rhythm control group had a higher incidence of both. The need for repeated cardioversion as inpatients after baseline strategy implementation may have contributed to higher frequency of hospitalisations with rhythm control. Initiation of antiarrhythmic drugs as inpatient or possible negative inotropic effects of these agents could have also contributed to hospitalisations in this latter strategy. In patients with chronic HF taking angiotensin-converting enzyme inhibitors and diuretics, digoxin improved mortality and hospitalisation as a composite outcome [46]. Dronedarone reduced mortality and hospitalisation composite outcome in patients with AF, including in the heart failure subgroup [40]. This opens new perspectives for rhythm control strategy in selected patients with AF and HF. Although hospitalisations were reported to be an independent predictor of death, our quantitative analysis found that rate control may decrease hospitalisations without reducing mortality. Since hospitalisations are a major contributor to the cost of AF and HF our study suggests that the choice of rate control strategy may decrease the economic burden of patients with AF and HF [47–51]. 4.3. Stroke/Thromboembolic complications Rate and rhythm control were not different regarding stroke/ thromboembolic outcome. In RACE trial, these events were mostly associated with inadequate anticoagulation. Low INR is a powerful predictor of stroke in patients with AF [52]. Heart failure alone leads to a small increase in stroke risk, but patients with AF and HF need anticoagulation because thromboembolic events are much more frequent [53,54]. Obtained data should be interpreted carefully because thromboembolic rates in these studies may underestimate real world risk due to the current underuse and inadequate control of anticoagulants [55,56]. 4.4. Quality of life Patients with atrial fibrillation or heart failure have worse quality of life (QoL) than healthy controls [57,58]. Life quality is related to exercise performance in patients with AF and is a predictor of rehospitalisation and mortality in patients with HF [59–62]. QoL data of analysed interventions in patients with AF and HF are still very sparse and heterogeneous, and other studies that evaluated this question in general AF population did not find differences between rate and rhythm control [21,57,63–65]. Better life quality is more likely to be achieved if patients with AF under rate control treatment have maximal heart rate and average resting heart rate below 110 and 80 bpm, respectively [66]. Calciumchannel blockers use is associated with better QoL compared to betablocker in patients with AF taking digitalis [67]. Patients with AF that remain on sinus rhythm have better quality of life and rhythm control drugs have shown to improve this QoL outcome from baseline status [59,68]. Heart failure data have demonstrated that beta-blockers were associated with life quality improvements [69]. 4.5. Drugs adverse events Drug adverse events were reported in RACE and were uncommon, occurring more frequently in rhythm control and were related with other arrhythmias. In patients with HF, beta-blockers are effective and safe, especially if drug uptitration is done with caution [70]. Non-dihydropyridinic calcium-channel blockers have few safety data but due to negative inotropic effects, these drugs are not recommended for patients with HF, particularly those with left ventricular dysfunction. Digoxin alone has raised some safety problems. Against placebo it has prevented hospitalisations, but compared with other drugs/combinations it was associated with higher mortality and worse control of ventricular rate [34,71]. Safety of rhythm control drugs in patients with heart failure has always been a concern [38]. Amiodarone appears to be the drug more effective in converting to and maintaining sinus rhythm but its use is associated to important adverse effects [35]. Actual evidence suggests that dofetilide may be the antiarrhythmic drugs with the best safety profile in HF patients [45]. Dronedarone may have a role in patients with mild or moderate heart failure and atrial fibrillation [40]. D. Caldeira et al. / European Journal of Internal Medicine 22 (2011) 448–455 4.6. Other interventions Data of AF–CHF showed that most of patients were treated with a renin–angiotensin–aldosterone system (RAAS) blocker. Its use was balanced in both rate and rhythm arms, but it may influence some outcomes as discussed ahead. RAAS is hyperactivated in heart failure. Angiotensin II levels are elevated and can contribute to atrial fibrillation through cardiac remodelling, fibrosis and direct pro-arrhythmic effects [72,73]. Blockade of RAAS in heart failure has proven to be useful to improve symptoms and survival. In atrial fibrillation, despite positive results of small trials with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs), the studies CAPRAF and GISSIAF showed that ARBs were not effective in the prevention of AF in patients in sinus rhythm with recent history of AF [74–76]. ACTIVE-I study enrolled more than 9000 patients with AF, and preliminary reports showed that irbesartan did not reduce the primary outcome of major cardiovascular events, but HF hospitalisations were significantly lower compared with placebo [77]. Definite results and further analysis of this trial will bring more strong and possibly more precise evidence on this topic. Our purpose was to analyse non-invasive procedures such as drug therapy and electrical cardioversion but the importance of electrophysiological invasive techniques has been increasing. Electrophysiological procedures have been used in an increasing number of patients, particularly in those with drugs-refractory AF. In the subset of patients with AF and HF, atrioventricular node ablation with biventricular pacemaker was exceeded by pulmonary-vein isolation procedure that leads to better left ventricular ejection fraction, functional capacity and quality of life [78]. However long-term follow-up studies are still missing and the efficacy of this intervention in clinical outcomes, such as mortality and hospitalisations, in patients with persistent atrial fibrillation and heart failure is unclear. Future CASTLE-AF results could help to clarify the role of pulmonary-vein isolation in these patients [79]. 453 AFFIRM substudy analysed only left ventricular dysfunction patients. RACE trial only supplied cardiovascular mortality and heart failure hospitalisations. Even using random effects method, pooling such data results limits the strength of conclusions. Including results from post-hoc analysis of randomised controlled trials AFFIRM and RACE cannot exclude selection bias. In the outcomes other than mortality and hospitalisations we could not be more conclusive because information was very sparse and heterogeneous. 5. Conclusion Comparing with rhythm control in patients with HF and AF, rate control significantly reduces hospitalisations. Mortality was similar with both interventions. There was no clear quality of life benefit of any of these interventions. Funding None. Competing interests None to declare. Learning points • Atrial fibrillation and heart failure are diseases with increasing prevalence. • Rate and rhythm control strategies provide similar survival in patients with AF and HF. • Hospitalisations are important contributors to financial burden of AF and HF. • Rate control strategy significantly reduced hospitalisations in patients with AF and HF. 4.7. Implications to practise Patients with AF and HF should be primarily treated with rate control drugs in order to reduce hospitalisations. NNT data shows that to prevent one hospitalisation, a mean of 19 patients would have to be treated with rate control strategy instead of rhythm control. Recent cohort data suggests caution in the use of digoxin not associated with a beta-blocker in rate control [34]. Conflict of interest statement Daniel Caldeira has no relationships with other people or organisations that could inappropriately influence the work. Cláudio David has no relationships with other people or organisations that could inappropriately influence the work. Cristina Sampaio has no relationships with other people or organisations that could inappropriately influence the work. 4.8. Implications to research References Further RCT are needed to provide more precise estimates in outcomes like stroke and to define whether one of these strategies is more likely to improve life quality. Antiarrhythmic agents such as dofetilide in a greater number of patients and/or dronedarone should be tested against rate control agents. 4.9. Limitations The trials included in this review had unblinded methods for patients and medical staff involved in the treatment strategies. This could be explained by the physical nature of electrical cardioversion that is very distinct of rate control procedures. 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