- Email: [email protected]
β blockers, atrial fibrillation, and heart failure
Comment
thrice daily rapid-acting insulin analogue, is better than basal-bolus insulin for HbA1c and bodyweight outcomes with no increase in hypoglycaemia.6 This is an intriguing approach. However, how frequent injections and glucose monitoring for insulin titration will fit into current treatment regimens is unclear. Third, combination with a GLP-1 agonist seems to provide a relative resistance to the hypoglycaemic effects of insulin, perhaps as a result of improved alpha-cell function.7 Understanding the details of this effect are crucial. Perhaps the most practical and immediate issue is whether the fixed-dose combinations of a GLP-1 agonist and basal insulin in development will supersede other approaches. This is an unsettled question, but it seems likely that fixed-dose combinations will be welcomed in view of their convenience and efficacy. Findings from the DUAL-18 and DUAL-29 studies show a 1·9% HbA1c reduction in patients using a pen device that at full dose delivers insulin degludec 50 units and liraglutide 1·8 mg, with dosing determined by use of a simple titration algorithm based solely on fasting glucose monitoring. Furthermore, with slow titration and lower total exposure to the GLP-1 agonist, gastrointestinal adverse effects with the combined product in the doublemasked DUAL-2 study were similar to insulin alone.9 The major barrier to widespread adoption of these treatments is cost—both GLP-1 agonists and insulin analogues are among the most expensive in diabetes care. One can hope that some incremental cost savings will come with combined products. It has been a 20-year journey, but the combination of GLP-1 agonist and basal insulin has finally arrived as a more powerful and safer alternative to insulin in the management of type 2 diabetes.
Laura A Young, *John B Buse Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599–7172, USA [email protected] This work supported by the National Institutes of Health (5K23AT004946 and 1UL1TR001111). LAY has received research funding from Boehringer Ingelheim, Eli Lilly, GI Dynamics, Halozyme Therapeutics, Johnson & Johnson, Lexicon, Medtronic, Novo Nordisk, Orexigen Therapeutics, PhaseBio Pharmaceuticals, Sanofi, Scion NeuroStim, Takeda, and ToleRx. JBB is an investigator or consultant without direct financial benefit under contracts between his employer and the following companies: Amylin, Andromeda, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dance Biopharm, Elcelyx Therapeutics, Eli Lilly, GI Dynamics, GlaxoSmithKline, Halozyme Therapeutics, Hoffmann-La Roche, Intarcia Therapeutics, Johnson & Johnson, Lexicon, LipoScience, Medtronic, Merck, Metavention, Novo Nordisk, Orexigen Therapeutics, Osiris Therapeutics, Pfizer, PhaseBio Pharmaceuticals, Quest Diagnostics, Sanofi, Santarus, Scion NeuroStim, Takeda, ToleRx, and TransTech Pharma. JBB is a consultant to PhaseBio Pharmaceuticals and receives stock options and payments. 1
2
3 4
5
6
7 8
9
Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet 2014; published online Sept 12. http://dx.doi.org/10.1016/S01406736(14)61335-0. Gutniak M, Orskov C, Holst JJ, Ahrén B, Efendic S. Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus. N Engl J Med 1992; 326: 1316–22. Eng J. Exendin peptides. Mt Sinai J Med 1992; 59: 147–49. Kolterman OG, Buse JB, Fineman MS, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 3082–89. Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2011; 154: 103–12. Jendle J, Rosenstock J, Blonde L, et al. Better glycemic control and less weight gain with once-weekly dulaglutide vs. once-daily insulin glargine, both combined with premeal insulin lispro, in type 2 diabetes patients (AWARD-4). Abstract 962-P. Diabetes 2014; 63 (suppl 1): A246. Dunning BE, Foley JE, Ahren B. Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia 2005; 48: 1700–13. Gough SCL, Bode B, Woo V, et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocinol 2014; published online Sept 2. http://dx.doi. org/10.1016/S2213-8587(14)70174-3. Buse JB, Vilsbøll T, Thurman J, et al, on behalf of the NN9068-3912 (DUAL-II) Trial Investigators. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care 2014; published online Aug 11. DOI:10.2337/dc14-0785.
β blockers, atrial fibrillation, and heart failure β blockers have revolutionised the treatment of patients with heart failure and reduced ejection fraction. In quick succession, the results of three pivotal trials showed a reduction in relative risk of about a third in death from any cause with these drugs.1–3 Based on the highest level of evidence, β blockers are strongly recommended in clinical guidelines for the management of heart failure and reduced ejection fraction.4,5 These guidelines state that β blockers www.thelancet.com Vol 384 December 20/27, 2014
are indicated in all patients, except those with atrioventricular block, bradycardia, and asthma. Dipak Kotecha and colleagues6 raise a surprising and important clinical question in The Lancet. In a meta-analysis, using individual-patient data from 18 254 patients enrolled in ten trials of β blockers in heart failure and reduced ejection fraction, the investigators noted that cardiac rhythm at study entry modified the response to therapy. Specifically, the treatment effect
See Articles page 2235
2181
Comment
Scientifica, Visuals Unlimited/Science Photo Library
size, as judged by reduction in all-cause mortality, seemed to be less in the 3066 patients in atrial fibrillation (hazard ratio 0·97, 95% CI 0·83–1·14) than in the 13 946 not in atrial fibrillation (0·73, 0·67–0·80). Kotecha and colleagues confirm and expand on the findings of an earlier report,7 addressing additional outcomes and exploring the effect of β blockers in specific patient subgroups. The apparent difference in response to treatment did not seem to be attributable to differences in β blocker dose, discontinuation rate, or reduction in heart rate with β blocker treatment (although we only know about heart rate at rest and not during exercise). Patients with atrial fibrillation differed in a number of important ways from those without atrial fibrillation—eg, they were older, more often men, had worse symptoms, and were more commonly treated with digoxin and amiodarone. Adjustment for these differences did not, however, change the results of the investigators’ analysis, although we are not sure how complete this adjustment was or whether it is ever possible to adjust fully for differences (measured and, especially, unmeasured). Some aspects of the dataset make certain analyses difficult or impossible. For example, there could be an adverse drug interaction between β blockers and digoxin in patients with atrial fibrillation. However, because most of the patients with atrial fibrillation were treated with digoxin, this possibility cannot be explored reliably. Physicians and patients will want to know whether Kotecha and colleagues’ findings are credible and what they mean for clinical practice. Conventionally, examination of treatment effect in subgroups is discouraged, not least because small numbers of events in these subgroups might lead to unreliable conclusions.8 Although the number of patients with atrial fibrillation (and events) in the present metaanalysis is reasonably large, the 95% CI around the point estimate for the treatment hazard ratios do not completely exclude the possibility of some clinical benefit. For example, the hazard ratio for the composite of death or hospitalisation for cardiovascular reasons, in the comparison of β blockers versus placebo in patients with atrial fibrillation, was 0·89 (95% CI 0·80–1·01). Moreover, some important subgroups of the patients with atrial fibrillation were small, notably the number of patients with mild symptoms; it is quite possible that the effect of β blockers might be different in patients with less severe heart failure and atrial fibrillation than in those 2182
with advanced heart failure and atrial fibrillation. The effect in other important subgroups is not reported— eg, β blockers are of proven benefit in patients with myocardial infarction but the effect in this subgroup is not described.9 Clinical experience also makes the present findings seem counterintuitive. Often, a rapid ventricular rate in patients with atrial fibrillation seems to precipitate or worsen heart failure, even leading to hospital admission, whereas control of the ventricular rate in patients with atrial fibrillation seems to improve heart failure. β blockers are an effective means of controlling the ventricular rate in patients with atrial fibrillation.10 Why then did β blockers in patients with atrial fibrillation not reduce the risk of hospital admission for worsening heart failure? Although it is possible that our clinical impressions are wrong, this seems to be a paradox. Other considerations do not clarify the matter either. The often transient nature of atrial fibrillation might cast doubt on an analysis based on the assessment of rhythm at one timepoint. It is likely that many patients in atrial fibrillation at the time of randomisation reverted to sinus rhythm, and many of those in sinus rhythm at baseline developed atrial fibrillation. This fact might make the apparently large difference in the treatment effect between the two groups somewhat surprising. However, the recent finding that higher heart rates are not associated with worse outcome in patients with atrial fibrillation (whereas they are in patients without atrial fibrillation) might support the findings of Kotecha and colleagues.11 What should we do? The results of the present meta-analysis suggest that β blockers are unlikely to be harmful to patients with heart failure and reduced ejection fraction and atrial fibrillation. Because these patients are particularly high risk, it is our view that as the possibility of benefit remains, practice should not change until these new findings are scrutinised further.12 Additional issues should be addressed before any conclusions are drawn, such as the possibility of a drug interaction between digoxin and β-blocker treatment, unmeasured confounding such as a conduction system disease or pacemaker use, potential benefit in patients with previous myocardial infarction, and whether patients with milder symptoms might respond differently to those with more advanced disease. Perhaps the greatest concern of all is that we have no clear explanation for the current findings. www.thelancet.com Vol 384 December 20/27, 2014
Comment
*John J V McMurray, Dirk J van Veldhuisen British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8QQ, Scotland, UK (JJVM); and Department of Cardiology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands (DJvV) [email protected]
7
8
9
We declare no competing interests. 1 2
3
4
5
6
CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 353: 9–13. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001–07. Packer M, Coats AJS, Fowler MB, et al, for the Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344: 1651–58. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012; 14: 803–69. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62: e147–239. 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.
10
11
12
Rienstra M, Damman K, Mulder BA, Van Gelder IC, McMurray JJ, van Veldhuisen DJ. Beta-blockers and outcome in heart failure and atrial fibrillation: a meta-analysis. JACC Heart Fail 2013; 1: 21–28. Yusuf S, Wittes J, Probstifield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991; 266: 93–98. Houghton T, Freemantle N, Cleland JG. Are beta-blockers effective in patients who develop heart failure soon after myocardial infarction? A meta-regression analysis of randomised trials. Eur J Heart Fail 2000; 2: 333–40. Khand AU, Rankin AC, Martin W, Taylor J, Gemmell I, Cleland JG. Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure? J Am Coll Cardiol 2003; 42: 1944–51. Castagno D, Skali H, Takeuchi M, et al; CHARM Investigators. Association of heart rate and outcomes in a broad spectrum of patients with chronic heart failure: results from the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity) program. Association of heart rate and outcomes in a broad spectrum of patients with chronic heart failure: results from the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity) program. J Am Coll Cardiol 2012; 59: 1785–95. Olsson LG, Swedberg K, Ducharme A, et al, CHARM Investigators. Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. J Am Coll Cardiol 2006; 47: 1997–2004.
Governments must do more to address interpersonal violence The Global status report on violence prevention 2014,1 jointly published by WHO, UNDP, and the UN Office on Drugs and Crime, was launched on Dec 11, 2014. For the first time, it assesses national efforts to address interpersonal violence, which includes child maltreatment, youth violence, intimate partner violence, sexual violence, and elder abuse. It identifies gaps in violence prevention and suggests how to fill them. It does so by describing the extent to which 133 participating countries covering 88% of the world’s population are collecting data on interpersonal violence, implementing violence-prevention programmes, enacting and enforcing relevant laws, and providing victim services. This report aims to gauge countries’ progress in implementing the recommendations of the 2002 World report on violence and health2 and the linked World Health Assembly resolution of 2003.3 Globally, interpersonal violence affects hundreds of millions of people. Of all adults, one in four report having been physically abused as children;4 one in five women and one in ten men report having been sexually abused as children;5 one in three women report having been victims of physical or sexual www.thelancet.com Vol 384 December 20/27, 2014
intimate partner violence in their lifetime;6 and one in 17 people aged 65 years and older report being abused in the past month.7 Hundreds of thousands of victims receive emergency medical care every year.1 Interpersonal violence contributes to lifelong ill health and to leading causes of death such as heart disease, cancer, and HIV/AIDS, largely due to victims’ increased risk of adopting health-risk behaviours such as smoking, alcohol and drug misuse, and unsafe sex.2 New estimates in the report show that interpersonal violence resulted in some 475 000 homicides in 2012, of which 82% were males.1 Additionally, they reveal that, from 2000 to 2012, homicide rates fell by 16% globally (from 8·0 to 6·7 per 100 000 population). This decrease was particularly marked in high-income countries (ie, a decrease of 39%, from 6·2 to 3·8 per 100 000 population), but falls of 10–13% also occurred in low-income and middle-income countries. For 2012, the estimates also show that, globally, 48% of all homicides involved a firearm, whereas in low-income and middle-income countries in the Americas this figure was 75%. Although more than half of participating countries report having national population-based survey data
Published Online December 11, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)62124-3
2183
thrice daily rapid-acting insulin analogue, is better than basal-bolus insulin for HbA1c and bodyweight outcomes with no increase in hypoglycaemia.6 This is an intriguing approach. However, how frequent injections and glucose monitoring for insulin titration will fit into current treatment regimens is unclear. Third, combination with a GLP-1 agonist seems to provide a relative resistance to the hypoglycaemic effects of insulin, perhaps as a result of improved alpha-cell function.7 Understanding the details of this effect are crucial. Perhaps the most practical and immediate issue is whether the fixed-dose combinations of a GLP-1 agonist and basal insulin in development will supersede other approaches. This is an unsettled question, but it seems likely that fixed-dose combinations will be welcomed in view of their convenience and efficacy. Findings from the DUAL-18 and DUAL-29 studies show a 1·9% HbA1c reduction in patients using a pen device that at full dose delivers insulin degludec 50 units and liraglutide 1·8 mg, with dosing determined by use of a simple titration algorithm based solely on fasting glucose monitoring. Furthermore, with slow titration and lower total exposure to the GLP-1 agonist, gastrointestinal adverse effects with the combined product in the doublemasked DUAL-2 study were similar to insulin alone.9 The major barrier to widespread adoption of these treatments is cost—both GLP-1 agonists and insulin analogues are among the most expensive in diabetes care. One can hope that some incremental cost savings will come with combined products. It has been a 20-year journey, but the combination of GLP-1 agonist and basal insulin has finally arrived as a more powerful and safer alternative to insulin in the management of type 2 diabetes.
Laura A Young, *John B Buse Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599–7172, USA [email protected] This work supported by the National Institutes of Health (5K23AT004946 and 1UL1TR001111). LAY has received research funding from Boehringer Ingelheim, Eli Lilly, GI Dynamics, Halozyme Therapeutics, Johnson & Johnson, Lexicon, Medtronic, Novo Nordisk, Orexigen Therapeutics, PhaseBio Pharmaceuticals, Sanofi, Scion NeuroStim, Takeda, and ToleRx. JBB is an investigator or consultant without direct financial benefit under contracts between his employer and the following companies: Amylin, Andromeda, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dance Biopharm, Elcelyx Therapeutics, Eli Lilly, GI Dynamics, GlaxoSmithKline, Halozyme Therapeutics, Hoffmann-La Roche, Intarcia Therapeutics, Johnson & Johnson, Lexicon, LipoScience, Medtronic, Merck, Metavention, Novo Nordisk, Orexigen Therapeutics, Osiris Therapeutics, Pfizer, PhaseBio Pharmaceuticals, Quest Diagnostics, Sanofi, Santarus, Scion NeuroStim, Takeda, ToleRx, and TransTech Pharma. JBB is a consultant to PhaseBio Pharmaceuticals and receives stock options and payments. 1
2
3 4
5
6
7 8
9
Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet 2014; published online Sept 12. http://dx.doi.org/10.1016/S01406736(14)61335-0. Gutniak M, Orskov C, Holst JJ, Ahrén B, Efendic S. Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus. N Engl J Med 1992; 326: 1316–22. Eng J. Exendin peptides. Mt Sinai J Med 1992; 59: 147–49. Kolterman OG, Buse JB, Fineman MS, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 3082–89. Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2011; 154: 103–12. Jendle J, Rosenstock J, Blonde L, et al. Better glycemic control and less weight gain with once-weekly dulaglutide vs. once-daily insulin glargine, both combined with premeal insulin lispro, in type 2 diabetes patients (AWARD-4). Abstract 962-P. Diabetes 2014; 63 (suppl 1): A246. Dunning BE, Foley JE, Ahren B. Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia 2005; 48: 1700–13. Gough SCL, Bode B, Woo V, et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocinol 2014; published online Sept 2. http://dx.doi. org/10.1016/S2213-8587(14)70174-3. Buse JB, Vilsbøll T, Thurman J, et al, on behalf of the NN9068-3912 (DUAL-II) Trial Investigators. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care 2014; published online Aug 11. DOI:10.2337/dc14-0785.
β blockers, atrial fibrillation, and heart failure β blockers have revolutionised the treatment of patients with heart failure and reduced ejection fraction. In quick succession, the results of three pivotal trials showed a reduction in relative risk of about a third in death from any cause with these drugs.1–3 Based on the highest level of evidence, β blockers are strongly recommended in clinical guidelines for the management of heart failure and reduced ejection fraction.4,5 These guidelines state that β blockers www.thelancet.com Vol 384 December 20/27, 2014
are indicated in all patients, except those with atrioventricular block, bradycardia, and asthma. Dipak Kotecha and colleagues6 raise a surprising and important clinical question in The Lancet. In a meta-analysis, using individual-patient data from 18 254 patients enrolled in ten trials of β blockers in heart failure and reduced ejection fraction, the investigators noted that cardiac rhythm at study entry modified the response to therapy. Specifically, the treatment effect
See Articles page 2235
2181
Comment
Scientifica, Visuals Unlimited/Science Photo Library
size, as judged by reduction in all-cause mortality, seemed to be less in the 3066 patients in atrial fibrillation (hazard ratio 0·97, 95% CI 0·83–1·14) than in the 13 946 not in atrial fibrillation (0·73, 0·67–0·80). Kotecha and colleagues confirm and expand on the findings of an earlier report,7 addressing additional outcomes and exploring the effect of β blockers in specific patient subgroups. The apparent difference in response to treatment did not seem to be attributable to differences in β blocker dose, discontinuation rate, or reduction in heart rate with β blocker treatment (although we only know about heart rate at rest and not during exercise). Patients with atrial fibrillation differed in a number of important ways from those without atrial fibrillation—eg, they were older, more often men, had worse symptoms, and were more commonly treated with digoxin and amiodarone. Adjustment for these differences did not, however, change the results of the investigators’ analysis, although we are not sure how complete this adjustment was or whether it is ever possible to adjust fully for differences (measured and, especially, unmeasured). Some aspects of the dataset make certain analyses difficult or impossible. For example, there could be an adverse drug interaction between β blockers and digoxin in patients with atrial fibrillation. However, because most of the patients with atrial fibrillation were treated with digoxin, this possibility cannot be explored reliably. Physicians and patients will want to know whether Kotecha and colleagues’ findings are credible and what they mean for clinical practice. Conventionally, examination of treatment effect in subgroups is discouraged, not least because small numbers of events in these subgroups might lead to unreliable conclusions.8 Although the number of patients with atrial fibrillation (and events) in the present metaanalysis is reasonably large, the 95% CI around the point estimate for the treatment hazard ratios do not completely exclude the possibility of some clinical benefit. For example, the hazard ratio for the composite of death or hospitalisation for cardiovascular reasons, in the comparison of β blockers versus placebo in patients with atrial fibrillation, was 0·89 (95% CI 0·80–1·01). Moreover, some important subgroups of the patients with atrial fibrillation were small, notably the number of patients with mild symptoms; it is quite possible that the effect of β blockers might be different in patients with less severe heart failure and atrial fibrillation than in those 2182
with advanced heart failure and atrial fibrillation. The effect in other important subgroups is not reported— eg, β blockers are of proven benefit in patients with myocardial infarction but the effect in this subgroup is not described.9 Clinical experience also makes the present findings seem counterintuitive. Often, a rapid ventricular rate in patients with atrial fibrillation seems to precipitate or worsen heart failure, even leading to hospital admission, whereas control of the ventricular rate in patients with atrial fibrillation seems to improve heart failure. β blockers are an effective means of controlling the ventricular rate in patients with atrial fibrillation.10 Why then did β blockers in patients with atrial fibrillation not reduce the risk of hospital admission for worsening heart failure? Although it is possible that our clinical impressions are wrong, this seems to be a paradox. Other considerations do not clarify the matter either. The often transient nature of atrial fibrillation might cast doubt on an analysis based on the assessment of rhythm at one timepoint. It is likely that many patients in atrial fibrillation at the time of randomisation reverted to sinus rhythm, and many of those in sinus rhythm at baseline developed atrial fibrillation. This fact might make the apparently large difference in the treatment effect between the two groups somewhat surprising. However, the recent finding that higher heart rates are not associated with worse outcome in patients with atrial fibrillation (whereas they are in patients without atrial fibrillation) might support the findings of Kotecha and colleagues.11 What should we do? The results of the present meta-analysis suggest that β blockers are unlikely to be harmful to patients with heart failure and reduced ejection fraction and atrial fibrillation. Because these patients are particularly high risk, it is our view that as the possibility of benefit remains, practice should not change until these new findings are scrutinised further.12 Additional issues should be addressed before any conclusions are drawn, such as the possibility of a drug interaction between digoxin and β-blocker treatment, unmeasured confounding such as a conduction system disease or pacemaker use, potential benefit in patients with previous myocardial infarction, and whether patients with milder symptoms might respond differently to those with more advanced disease. Perhaps the greatest concern of all is that we have no clear explanation for the current findings. www.thelancet.com Vol 384 December 20/27, 2014
Comment
*John J V McMurray, Dirk J van Veldhuisen British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8QQ, Scotland, UK (JJVM); and Department of Cardiology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands (DJvV) [email protected]
7
8
9
We declare no competing interests. 1 2
3
4
5
6
CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 353: 9–13. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001–07. Packer M, Coats AJS, Fowler MB, et al, for the Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344: 1651–58. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012; 14: 803–69. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62: e147–239. 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.
10
11
12
Rienstra M, Damman K, Mulder BA, Van Gelder IC, McMurray JJ, van Veldhuisen DJ. Beta-blockers and outcome in heart failure and atrial fibrillation: a meta-analysis. JACC Heart Fail 2013; 1: 21–28. Yusuf S, Wittes J, Probstifield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991; 266: 93–98. Houghton T, Freemantle N, Cleland JG. Are beta-blockers effective in patients who develop heart failure soon after myocardial infarction? A meta-regression analysis of randomised trials. Eur J Heart Fail 2000; 2: 333–40. Khand AU, Rankin AC, Martin W, Taylor J, Gemmell I, Cleland JG. Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure? J Am Coll Cardiol 2003; 42: 1944–51. Castagno D, Skali H, Takeuchi M, et al; CHARM Investigators. Association of heart rate and outcomes in a broad spectrum of patients with chronic heart failure: results from the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity) program. Association of heart rate and outcomes in a broad spectrum of patients with chronic heart failure: results from the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity) program. J Am Coll Cardiol 2012; 59: 1785–95. Olsson LG, Swedberg K, Ducharme A, et al, CHARM Investigators. Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. J Am Coll Cardiol 2006; 47: 1997–2004.
Governments must do more to address interpersonal violence The Global status report on violence prevention 2014,1 jointly published by WHO, UNDP, and the UN Office on Drugs and Crime, was launched on Dec 11, 2014. For the first time, it assesses national efforts to address interpersonal violence, which includes child maltreatment, youth violence, intimate partner violence, sexual violence, and elder abuse. It identifies gaps in violence prevention and suggests how to fill them. It does so by describing the extent to which 133 participating countries covering 88% of the world’s population are collecting data on interpersonal violence, implementing violence-prevention programmes, enacting and enforcing relevant laws, and providing victim services. This report aims to gauge countries’ progress in implementing the recommendations of the 2002 World report on violence and health2 and the linked World Health Assembly resolution of 2003.3 Globally, interpersonal violence affects hundreds of millions of people. Of all adults, one in four report having been physically abused as children;4 one in five women and one in ten men report having been sexually abused as children;5 one in three women report having been victims of physical or sexual www.thelancet.com Vol 384 December 20/27, 2014
intimate partner violence in their lifetime;6 and one in 17 people aged 65 years and older report being abused in the past month.7 Hundreds of thousands of victims receive emergency medical care every year.1 Interpersonal violence contributes to lifelong ill health and to leading causes of death such as heart disease, cancer, and HIV/AIDS, largely due to victims’ increased risk of adopting health-risk behaviours such as smoking, alcohol and drug misuse, and unsafe sex.2 New estimates in the report show that interpersonal violence resulted in some 475 000 homicides in 2012, of which 82% were males.1 Additionally, they reveal that, from 2000 to 2012, homicide rates fell by 16% globally (from 8·0 to 6·7 per 100 000 population). This decrease was particularly marked in high-income countries (ie, a decrease of 39%, from 6·2 to 3·8 per 100 000 population), but falls of 10–13% also occurred in low-income and middle-income countries. For 2012, the estimates also show that, globally, 48% of all homicides involved a firearm, whereas in low-income and middle-income countries in the Americas this figure was 75%. Although more than half of participating countries report having national population-based survey data
Published Online December 11, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)62124-3
2183