Correspondence
With the completion of the Human Genome Project, interest in the provision of patient-centred approaches for clinical diagnosis and treatment of disease that allow for individual variability, known as precision medicine or personalised medicine, has increased. On the basis of the belief that only genetics can be used to definitively explain common features of our physiology and pathophysiology, our genome might be able to accurately indicate the individual risk of developing a life threatening impairment during our lifetimes. However, human responses to even the most extreme environmental challenges are not all the same, as exemplified by the differing adaptations to high altitude, in which low oxygen is the main stimulus for adaption but physiological and genetic adaptations differ ie, between ethnic groups (Tibetans, Ethiopians, and Andeans) with lifelong multigenerational exposure to high altitude.1 Similarly, whether genomic science will soon provide in-depth understanding of common hereditary factors in, for example, heart disease, cancer, diabetes, mental illness, and neurodegeneration is also unknown.2 The previously mentioned idea, known as “common-disease common-variant” hypothesis, for most major medical conditions has in fact been rejected by the Human Genome Project. An ideal genetic test for clinical purposes would have 100% sensitivity and specificity an d identify a genetic disorder that is highly penetrable. Additionally, the test would need to be clinically actionable and provide information that could not otherwise be obtained in normal clinical practice. Unfortunately, few genetic markers have these characteristics. Usually, the presence of a particular genetic www.thelancet.com Vol 385 April 25, 2015
polymorphism or haploid pattern is associated with only a slight increase in the risk of development of a certain disease or a differential response to a therapeutic drug. Gene scores for several risk variants are also typically not clinically informative. These scores are not useful for complex cardiovascular disorders and diabetes in which large gene-environment interactions are known to exist and in behavioural interventions that have proven to be highly effective at lowering of patient risk of disease and in secondary prevention. 3 As shown in human migration studies and changing disease patterns over time (eg, obesity and diabetes), our physical activity and dietary habits, versus only genetic factors, have the biggest effect on disease risk. Novel ideas also suggest soft inheritance with mechanisms such as maternal-fetal programming that makes human phenotypes more complicated than simply being based on coding regions of DNA.4 Another challenge of precision medicine, in the case of cancer, is that targeted drug therapy based on the analysis of tumour mutations might only kill susceptible clones, which would leave resistant and adaptive cells to cause a drug-resistant recurrence. Implementation of precision medicine would need each person’s genetic profile to be obtained, raising complex ethical, legal, financial, and social issues. On the basis of these well founded concerns and key biological and behavioural barriers, careful and critical debate about the role of the precision medicine framework in the future of medicine is needed. Treatment schemes that are difficult to validate could become increasingly driven by the politically favoured funding of genetic and molecular research with so-called big science initiatives because of the mistaken belief that this research will create a healthy society.5 Although precision medicine will almost certainly
be used in niche applications, if widely implemented, it could be a distraction from low cost and effective population-wide interventions and policies. We believe precision medicine is not the route to a healthy world and instead urge a renewed and increased focus on public health and prevention.
TEK IMAGE/Science Photo Library
Is precision medicine the route to a healthy world?
We declare no competing interests. The views expressed are those of the authors and not necessarily those of their institutions.
*John H Coote, Michael J Joyner [email protected] School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK (JHC); and Mayo Clinic, Rochester, MN, USA (MJJ) 1
2
3
4 5
Beall CM. Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia. Int Comp Biol 2006; 46: 18–24. Noble D, Jablonka E, Joyner MJ, Muller GB, Omholt SW. Evolution evolves: physiology returns to centre stage. J Physiol 2014; 592: 2237–44. Joyner MJ, Prendergast FG. Chasing Mendel: five questions for personalized medicine. J Physiol 2014; 592: 2381–88. Archer E. The mother of all problems. New Sci 2015; 225: 32–33. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med 2015; 372: 793–95.
β blockers in patients with heart failure and atrial fibrillation The results from the study by Dipak Kotecha and colleagues1 are surprising. In view of the differences between patients with heart failure and sinus rhythm and patients with atrial fibrillation, Kotecha and colleagues’ warning against the use of β blockers needs to be viewed in context and several important points have been overlooked. First, the renal function (estimated glomerular filtration rate 64 mL/min vs 61 mL/min) of patients with sinus rhythm and basal functional status was improved compared with patients with atrial fibrillation. Although the difference
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1617
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
With the completion of the Human Genome Project, interest in the provision of patient-centred approaches for clinical diagnosis and treatment of disease that allow for individual variability, known as precision medicine or personalised medicine, has increased. On the basis of the belief that only genetics can be used to definitively explain common features of our physiology and pathophysiology, our genome might be able to accurately indicate the individual risk of developing a life threatening impairment during our lifetimes. However, human responses to even the most extreme environmental challenges are not all the same, as exemplified by the differing adaptations to high altitude, in which low oxygen is the main stimulus for adaption but physiological and genetic adaptations differ ie, between ethnic groups (Tibetans, Ethiopians, and Andeans) with lifelong multigenerational exposure to high altitude.1 Similarly, whether genomic science will soon provide in-depth understanding of common hereditary factors in, for example, heart disease, cancer, diabetes, mental illness, and neurodegeneration is also unknown.2 The previously mentioned idea, known as “common-disease common-variant” hypothesis, for most major medical conditions has in fact been rejected by the Human Genome Project. An ideal genetic test for clinical purposes would have 100% sensitivity and specificity an d identify a genetic disorder that is highly penetrable. Additionally, the test would need to be clinically actionable and provide information that could not otherwise be obtained in normal clinical practice. Unfortunately, few genetic markers have these characteristics. Usually, the presence of a particular genetic www.thelancet.com Vol 385 April 25, 2015
polymorphism or haploid pattern is associated with only a slight increase in the risk of development of a certain disease or a differential response to a therapeutic drug. Gene scores for several risk variants are also typically not clinically informative. These scores are not useful for complex cardiovascular disorders and diabetes in which large gene-environment interactions are known to exist and in behavioural interventions that have proven to be highly effective at lowering of patient risk of disease and in secondary prevention. 3 As shown in human migration studies and changing disease patterns over time (eg, obesity and diabetes), our physical activity and dietary habits, versus only genetic factors, have the biggest effect on disease risk. Novel ideas also suggest soft inheritance with mechanisms such as maternal-fetal programming that makes human phenotypes more complicated than simply being based on coding regions of DNA.4 Another challenge of precision medicine, in the case of cancer, is that targeted drug therapy based on the analysis of tumour mutations might only kill susceptible clones, which would leave resistant and adaptive cells to cause a drug-resistant recurrence. Implementation of precision medicine would need each person’s genetic profile to be obtained, raising complex ethical, legal, financial, and social issues. On the basis of these well founded concerns and key biological and behavioural barriers, careful and critical debate about the role of the precision medicine framework in the future of medicine is needed. Treatment schemes that are difficult to validate could become increasingly driven by the politically favoured funding of genetic and molecular research with so-called big science initiatives because of the mistaken belief that this research will create a healthy society.5 Although precision medicine will almost certainly
be used in niche applications, if widely implemented, it could be a distraction from low cost and effective population-wide interventions and policies. We believe precision medicine is not the route to a healthy world and instead urge a renewed and increased focus on public health and prevention.
TEK IMAGE/Science Photo Library
Is precision medicine the route to a healthy world?
We declare no competing interests. The views expressed are those of the authors and not necessarily those of their institutions.
*John H Coote, Michael J Joyner [email protected] School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK (JHC); and Mayo Clinic, Rochester, MN, USA (MJJ) 1
2
3
4 5
Beall CM. Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia. Int Comp Biol 2006; 46: 18–24. Noble D, Jablonka E, Joyner MJ, Muller GB, Omholt SW. Evolution evolves: physiology returns to centre stage. J Physiol 2014; 592: 2237–44. Joyner MJ, Prendergast FG. Chasing Mendel: five questions for personalized medicine. J Physiol 2014; 592: 2381–88. Archer E. The mother of all problems. New Sci 2015; 225: 32–33. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med 2015; 372: 793–95.
β blockers in patients with heart failure and atrial fibrillation The results from the study by Dipak Kotecha and colleagues1 are surprising. In view of the differences between patients with heart failure and sinus rhythm and patients with atrial fibrillation, Kotecha and colleagues’ warning against the use of β blockers needs to be viewed in context and several important points have been overlooked. First, the renal function (estimated glomerular filtration rate 64 mL/min vs 61 mL/min) of patients with sinus rhythm and basal functional status was improved compared with patients with atrial fibrillation. Although the difference
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1617
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
