Correspondence
was only slight, the proportion of creatinine clearance between both groups could be important because creatinine—and any formulae based on it—gives a less accurate estimation of glomerular filtration than other formuale, such as that based on cystatin C, especially in patients with mild renal impairment. 2 Second, in patients with atrial fibrillation, individuals with a more deteriorated New York Heart Association functional class, albeit low in number, could have affected trial outcomes. As a result, the proportion of patients receiving diuretics and aldosterone antagonists is higher in the atrial fibrillation group than the sinus rhythm group. Therefore, both factors could have distorted the results. Third, only 58% of patients with atrial fibrillation were receiving oral anticoagulants, which could possibly affect trial outcomes. Finally, the most noteworthy overlooked point is the potential interactions between β blockers and digoxin (along with the total dose of β blockers in each group).3 This interaction, especially in patients with mild renal impairment, is likely to have offset the beneficial effects of β blockers in patients with heart failure and atrial fibrillation. We believe β blockers are still safe as the main drug for patients with heart failure and atrial fibrillation when used cautiously. We declare no competing interests.
*Juan I Pérez-Calvo, Marta Sánchez-Marteles, José L Morales-Rull [email protected] Servicio de Medicina Interna, Hospital Clínico Universitario Lozano Blesa, Facultad de Medicina, Zaragoza, Spain (JIP-C, MS-M); and Instituto de Investigación de Aragón (JIP-C); and Servicio de Medicina Interna, Hospital Universitario Arnau de Vilanova, Lleida, Spain (JLM-R) 1
1618
Kotecha D, Holmes J, Krum H, et al, on behalf of the Beta-Blockers in Heart Failure Collaborative Group. Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet 2014; 384: 2235–43.
2
3
Manzano-Fernández S, Flores-Blanco PJ, Pérez-Calvo JI, et al. Comparison of risk prediction with the CKD-EPI and MDRD equations in acute decompensated heart failure. J Card Fail 2013; 19: 583–91. van Veldhuisen DJ. Low-dose digoxin in patients with heart failure. Less toxic and at least as effective? J Am Coll Cardiol 2002; 39: 954–56.
In their Article,1 Dipak Kotecha and colleagues state that β blockers should not be preferred compared with other heart rate control drugs in patients with heart failure, reduced ejection fraction, and atrial fibrillation, which is misleading. Their study did not compare the efficacy and safety of β blockers with those of other drugs; therefore on the basis of their study alone, Kotecha and colleagues cannot state that β blockers are more beneficial or harmful in those patient populations compared with the other drugs. Results from other studies2 have shown that available heart rate control drugs (eg, digoxin, non-dihydropyridine calcium-channel blockers, and amiodarone) are either less effective or have substantial safety issues.2 Digoxin is not an effective drug when used alone for heart rate control and has been associated with increased mortality in patients with atrial fibrillation in observational studies. 2,3 Non-dihydropyridine calcium-channel blockers are negative inotropes and are therefore contraindicated in patients with heart failure and reduced ejection fraction. 2 Amiodarone has been associated with serious long-term side-effects. 2 β blockers, however, were not associated with increased adverse events.1 Therefore, on the basis of available evidence, a β blocker should still be regarded as the safest drug for heart rate control in patients with heart failure, reduced ejection fraction, and atrial fibrillation. A strong conclusion made on the basis of post-hoc subgroup analysis can be misleading.4 If such findings are presented as definitive conclusions, patients might be denied effective interventions.
I declare no competing interests.
Rahman Shah [email protected] Veterans Affairs Medical Center, School of Medicine, Section of Cardiovascular Medicine, University of Tennessee, Memphis, TN 38104, USA 1
2
3
4
Kotecha D, Holmes J, Krum H, et al, on behalf of the Beta-Blockers in Heart Failure Collaborative Group. Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet 2014; 384: 2235–43. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Europace 2010; 12: 1360–420. Turakhia MP, Santangeli P, Winkelmayer WC, et al. Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study. J Am Coll Cardiol 2014; 64: 660–68. Sun X, Ioannidis JP, Agoritsas T, et al. How to use a subgroup analysis: users’ guide to the medical literature. JAMA 2014; 311: 405–11.
Authors’ reply We thank Rahman Shah and Juan Pérez-Calvo and colleagues for their correspondence and interest in our Article.1 The Beta-Blockers in Heart Failure Collaborative Group analysis is the most robust and powerful assessment of the efficacy of β blockers published.2 We were able to include individual patient data from nearly all of the placebo-controlled randomised trials, with a sample size of about 14 000 participants in the sinus rhythm group and more than 3000 in the atrial fibrillation group.1 These individual data permitted a unique assessment of treatment efficacy and safety in patients with heart failure, reduced ejection fraction, and concomitant atrial fibrillation, which have previously been underpowered. Pérez-Calvo and colleagues correctly comment on the differences between patients with sinus rhythm and atrial fibrillation, and we acknowledge that our analysis is limited by the inevitable variation between prognostic factors across subgroups. The difference in renal function was small, of little clinical relevance, and with no evidence that β blockers are www.thelancet.com Vol 385 April 25, 2015
was only slight, the proportion of creatinine clearance between both groups could be important because creatinine—and any formulae based on it—gives a less accurate estimation of glomerular filtration than other formuale, such as that based on cystatin C, especially in patients with mild renal impairment. 2 Second, in patients with atrial fibrillation, individuals with a more deteriorated New York Heart Association functional class, albeit low in number, could have affected trial outcomes. As a result, the proportion of patients receiving diuretics and aldosterone antagonists is higher in the atrial fibrillation group than the sinus rhythm group. Therefore, both factors could have distorted the results. Third, only 58% of patients with atrial fibrillation were receiving oral anticoagulants, which could possibly affect trial outcomes. Finally, the most noteworthy overlooked point is the potential interactions between β blockers and digoxin (along with the total dose of β blockers in each group).3 This interaction, especially in patients with mild renal impairment, is likely to have offset the beneficial effects of β blockers in patients with heart failure and atrial fibrillation. We believe β blockers are still safe as the main drug for patients with heart failure and atrial fibrillation when used cautiously. We declare no competing interests.
*Juan I Pérez-Calvo, Marta Sánchez-Marteles, José L Morales-Rull [email protected] Servicio de Medicina Interna, Hospital Clínico Universitario Lozano Blesa, Facultad de Medicina, Zaragoza, Spain (JIP-C, MS-M); and Instituto de Investigación de Aragón (JIP-C); and Servicio de Medicina Interna, Hospital Universitario Arnau de Vilanova, Lleida, Spain (JLM-R) 1
1618
Kotecha D, Holmes J, Krum H, et al, on behalf of the Beta-Blockers in Heart Failure Collaborative Group. Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet 2014; 384: 2235–43.
2
3
Manzano-Fernández S, Flores-Blanco PJ, Pérez-Calvo JI, et al. Comparison of risk prediction with the CKD-EPI and MDRD equations in acute decompensated heart failure. J Card Fail 2013; 19: 583–91. van Veldhuisen DJ. Low-dose digoxin in patients with heart failure. Less toxic and at least as effective? J Am Coll Cardiol 2002; 39: 954–56.
In their Article,1 Dipak Kotecha and colleagues state that β blockers should not be preferred compared with other heart rate control drugs in patients with heart failure, reduced ejection fraction, and atrial fibrillation, which is misleading. Their study did not compare the efficacy and safety of β blockers with those of other drugs; therefore on the basis of their study alone, Kotecha and colleagues cannot state that β blockers are more beneficial or harmful in those patient populations compared with the other drugs. Results from other studies2 have shown that available heart rate control drugs (eg, digoxin, non-dihydropyridine calcium-channel blockers, and amiodarone) are either less effective or have substantial safety issues.2 Digoxin is not an effective drug when used alone for heart rate control and has been associated with increased mortality in patients with atrial fibrillation in observational studies. 2,3 Non-dihydropyridine calcium-channel blockers are negative inotropes and are therefore contraindicated in patients with heart failure and reduced ejection fraction. 2 Amiodarone has been associated with serious long-term side-effects. 2 β blockers, however, were not associated with increased adverse events.1 Therefore, on the basis of available evidence, a β blocker should still be regarded as the safest drug for heart rate control in patients with heart failure, reduced ejection fraction, and atrial fibrillation. A strong conclusion made on the basis of post-hoc subgroup analysis can be misleading.4 If such findings are presented as definitive conclusions, patients might be denied effective interventions.
I declare no competing interests.
Rahman Shah [email protected] Veterans Affairs Medical Center, School of Medicine, Section of Cardiovascular Medicine, University of Tennessee, Memphis, TN 38104, USA 1
2
3
4
Kotecha D, Holmes J, Krum H, et al, on behalf of the Beta-Blockers in Heart Failure Collaborative Group. Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet 2014; 384: 2235–43. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Europace 2010; 12: 1360–420. Turakhia MP, Santangeli P, Winkelmayer WC, et al. Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study. J Am Coll Cardiol 2014; 64: 660–68. Sun X, Ioannidis JP, Agoritsas T, et al. How to use a subgroup analysis: users’ guide to the medical literature. JAMA 2014; 311: 405–11.
Authors’ reply We thank Rahman Shah and Juan Pérez-Calvo and colleagues for their correspondence and interest in our Article.1 The Beta-Blockers in Heart Failure Collaborative Group analysis is the most robust and powerful assessment of the efficacy of β blockers published.2 We were able to include individual patient data from nearly all of the placebo-controlled randomised trials, with a sample size of about 14 000 participants in the sinus rhythm group and more than 3000 in the atrial fibrillation group.1 These individual data permitted a unique assessment of treatment efficacy and safety in patients with heart failure, reduced ejection fraction, and concomitant atrial fibrillation, which have previously been underpowered. Pérez-Calvo and colleagues correctly comment on the differences between patients with sinus rhythm and atrial fibrillation, and we acknowledge that our analysis is limited by the inevitable variation between prognostic factors across subgroups. The difference in renal function was small, of little clinical relevance, and with no evidence that β blockers are www.thelancet.com Vol 385 April 25, 2015
