- Email: [email protected]
Key issues for global cardiovascular medicine
Comment
5
6
7 8 9
van de Wal RM, Asselbergs FW, Plokker HW, et al. High prevalence of microalbuminuria in chronic heart failure patients. J Card Fail 2005; 11: 602–06. Jackson CE, Solomon SD, Gerstein HC, et al, for the CHARM Investigators and Committees. Albuminuria in chronic heart failure: prevalence and prognostic importance. Lancet 2009; 374: 543–50. Weir MR. Microalbuminuria and cardiovascular disease. Clin J Am Soc Nephrol 2007; 2: 581–90. Comper WD, Hilliard LM, Nikolic-Paterson DJ, Russo LM. Disease-dependent mechanisms of albuminuria. Am J Physiol Renal Physiol 2008; 295: F1589–600. Damman K, van Deursen VM, Navis G, et al. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009; 53: 582–88.
10 11
12
13
Wegria R, Capeci NE, Blumenthal MR, et al. The pathogenesis of proteinuria in the acutely congested kidney. J Clin Invest 1955; 34: 737–43. Damman K, van Veldhuisen DJ, Navis G, et al. Urinary neutrophil gelatinase associated lipocalin (NGAL), a marker of tubular damage, is increased in patients with chronic heart failure. Eur J Heart Fail 2008; 10: 997–1000. Hillege HL, Fidler V, Diercks GF, et al, for the Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 2002; 106: 1777–82. Ninomiya T, Perkovic V, de Galan BE, et al, on behalf of the ADVANCE Collaborative Group. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol 2009; 20: 1813–21.
Key issues for global cardiovascular medicine See Editorial page 501
508
The European Society of Cardiology Congress brings together thousands of specialists and other stakeholders in cardiovascular medicine to exchange knowledge about one of the world’s leading causes of death and disability—cardiovascular disease. Atherosclerosis, no longer just the scourge of countries traditionally regarded as economically privileged, has emerged as a health threat in rapidly developing countries worldwide. The growing awareness of cardiovascular disease as a huge global problem is shown by the participation of countries from all over the world at the congress. The society is to be commended for making educational resources available to so many, and for providing a forum for knowledge sharing and cultural exchange among people who, although coming from diverse backgrounds, share a common purpose in combating heart disease. Despite the progress that we will hear at the congress, current efforts will not be enough to reduce the overall burden of the disease or guarantee the best amelioration of death and symptoms in those who already have cardiovascular disease. As long as lifestyle-fuelled epidemics of obesity and diabetes continue, together with ageing of the global population, sharper focus and redoubled efforts are needed to address these issues. We have had the privilege of working together to generate new knowledge for almost two decades through a clinical research network—the Virtual Coordinating Centre for Global Collaborative Cardiovascular Research (VIGOUR) group (panel).1 In several communications that have included our group and a network of young cardiovascular experts, we have identified five key issues that must be addressed by the global cardiovascular community to complement the excellent efforts of professional societies.
First, despite the proliferation of clinical trials and outcomes research in the global cardiovascular community, we still lack sufficient evidence for many conditions to make the best decisions, either on behalf of or in conjunction with patients.2 Thus, we must not merely sustain but substantially expand our research capabilities. Second, incorporation of knowledge into routine practice has fallen far short worldwide, resulting in substantial unnecessary loss of life and function. As the focus on efficiency in clinical practice grows, clinical research, with its demands on resources and time, is pushed aside and is increasingly relegated to the burgeoning for-profit research industry.3 These trends in turn create a great risk of reducing the application of research into clinical practice. Cardiovascular specialists, however, are poised to become leaders in creating the learning health systems of the future, in which the right combination of information technology and cultural change within the profession, driven by registries linked to electronic health records, will transform our caredelivery systems into continuous networks for cardiovascular medicine. However, because of the global reach of cardiovascular disease and its growing effect on developing countries, engagement of physicians from these nations in building such systems will be crucial to the success of these efforts. Third, we are in the midst of extraordinary technological changes that allow us to generate and apply knowledge in ways that were unimaginable even a decade ago. Our understanding of biology is being revolutionised as novel genomic and imaging technologies enable the reclassification of common diseases. With each passing week, new discoveries www.thelancet.com Vol 374 August 15, 2009
Comment
Panel: VIGOUR centres Argentina • Estudios Cardiologicos Latino America (ECLA) BV, Sante Fe, Argentina • Trials ArgeNtina Group Organization (TANGO), Buenos Aires, Argentina Australia • Flinders Coordinating Centre, Flinders Medical Centre Cardiovascular Unit, Bedford Park, SA, Australia • NHMRC-Clinical Trials Centre, University of Syndey, Camperdown, NSW, Australia Belgium Leuven Coordinating Centre, University Hospital Gasthuisberg, Leuven, Belgium Canada Canadian VIGOUR Centre, University of Alberta, Edmonton, AB, Canada New Zealand Green Lane Coordinating Centre, Avondale, Auckland, New Zealand USA Duke Clinical Research Institute, Durham, NC, USA
offer the possibility of earlier diagnosis, pre-emptive prevention based on risk assessment, or therapeutics stratified on the basis of genetic difference or biosignatures derived from complex arrays of gene products, proteins, metabolites, and functional imaging. If practitioners are to exploit these advances for the benefit of their patients, they will need the support of lifelong transformational educational efforts. We contend that professional groups should have a major role in improving physicians’ abilities to transfer knowledge more rapidly across traditional boundaries. Fourth, because of the global burden of cardiovascular disease, current research and educational funding mechanisms are not equal to the challenges posed by this epidemic. As we are reminded that biology is not a linear array of molecular interactions but a multidimensional community of systems, the implications for clinical trials are astounding. The number of people needed as research participants will continue to increase, especially as we recognise the potential hazard of failing to validate presumed subgroup findings in independent populations and the necessity of doing broad comparative effectiveness studies. Whereas industry energetically continues to develop novel products, contributions of the www.thelancet.com Vol 374 August 15, 2009
public sector in cardiovascular medicine, by contrast, are anaemic. This situation is perhaps understandable because of concerns about expending tax revenues outside the countries in which the taxes were paid. Nevertheless, the success of clinical research in cardiovascular medicine needs increased engagement and funding support from professional societies and governmental sources, such as the US National Institutes of Health, even when efforts span international boundaries. Fifth, we are concerned about the next generation of cardiovascular leaders within a profession characterised by unique demands. During our training, the academic fabric included recognition of the fact that clinical leaders need appropriate resources, time, and support to maintain the scholarly culture that is so crucial for medicine’s preferred future. Within our institutions and in many others we visit, the over-riding imperative for efficiency in medical practice, as well as increasingly bureaucratic approaches to grant funding (effort reporting), have devoured much of the time that was hitherto available for mentoring and spirited discussion. Much of the research enterprise has become a two-tiered system, with a wide gulf between those who design and lead international research and the thousands of investigators who enrol patients in trials. Such a situation can prove both dispiriting and limiting within an enterprise that ideally should be shared by all involved. But, rather than simply lament this turn of events, we plan to experiment with modern methods of social networking (eg, Facebook and Twitter) to overcome barriers to communication and engagement. As cardiovascular physicians, there is no greater gratification for us than observing the trajectory of an idea that alleviates the suffering caused by cardiovascular disease: first, from the laboratory to patients through clinical trials and then, after being proven in trials, by reducing death and disability in practice. If we are to catalyse the enterprise to achieve these aims in the best way, we must solve these five issues with vigour. Robert M Califf, for the Virtual Coordinating Centre for Global Collaborative Cardiovascular Research (VIGOUR) organisation Duke Translational Medicine Institute, Duke University Medical Center, Durham, NC 27710, USA robert.califf@duke.edu I thank Jonathan McCall of the Duke Clinical Research Institute, who provided editorial support for this Comment. I receive research grants from Merck, Novartis Pharmaceutical, Schering Plough Corporation, and Scius; payments for work done under these contracts, portions of which support my salary, are made to Duke
509
Comment
University. I also receive reimbursement for educational activities or consulting fees from Acumed, Amylin, the Annenberg Center, Avalere Health, Bayer, Biogen, Boehringer Ingelheim, Boston Scientific, Brandeis University, Five Prime, GlaxoSmithKline, Johnson & Johnson, Heart.org (Conceptis), Kowa Research Institute, Eli Lilly, Medtronic, Merck, Nitrox LLC, Novartis Pharmaceutical, Roche, Sanofi-Aventis, Schering Plough, Scius, Targacept, the University of Florida, Vertex, and Vivus; all revenues from educational activities are paid to Duke University, and all income from consulting activities is donated to non-profit organisations (most being donated to the clinical research fellowship fund of the Duke Clinical Research Institute). I hold equity in Nitrox LLC.
1
2
3
Mark DB, Van de Werf FJ, Simes RJ, et al. Cardiovascular disease on a global scale: defining the path forward for research and practice. Eur Heart J 2007; 28: 2678–84. Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA 2009; 301: 831–41. Glickman SW, McHutchison JG, Peterson ED, et al. Ethical and scientific implications of the globalization of clinical research. N Engl J Med 2009; 360: 816–23.
Who is ineligible for warfarin in atrial fibrillation? Stroke is a disastrous complication of atrial fibrillation. Patients with atrial fibrillation have a five times higher stroke risk than those without this common arrhythmia.1 Thromboembolism from the functionally asystolic left atrium is thought to cause the stroke. Oral anticoagulation with vitamin K antagonists, mainly warfarin, reduces the stroke risk to a third of that seen without antithrombotic therapy.2 However, anticoagulants are patient-unfriendly, difficult to monitor, and are associated with a risk of severe bleeding of at least 1% per year. Alternative anticoagulant therapy with the oral direct thrombin inhibitor ximelagatran was shown to be equally effective in two megatrials,3 but showed unacceptable liver toxicity that prohibited regulatory approval. The only other antithrombotic strategy available in atrial fibrillation is aspirin, which showed efficacy against thromboembolism versus placebo but proved to be inferior to warfarin.2 In atrial fibrillation, aspirin, although inexpensive, patientfriendly, and relatively safe, is indicated only in warfarinineligible patients. A more intense antiplatelet therapy (ie, aspirin plus clopidogrel, which is a successful
CHADS2 score Mean age (years)
ACTIVE-A (warfarin ineligible)
ACTIVE-W (warfarin eligible)
Aspirin (n=3782)
Aspirin+clopidogrel (n=3335)
2·0 70
Aspirin+clopidogrel (n=3722) 2·0 70
2·0 71
Warfarin (n=3371) 2·0 71
Total strokes (per year)
3·3
2·4*
2·4
1·4*
Disabling and fatal strokes (per year)
2·1
1·6*
1·7
1·3†
Major bleeds (per year)
1·3
2·0
2·0
2·2
Strokes or major bleed (per year)
2·5
1·2*
1·0
0·6*
*p<0·01, aspirin vs aspirin+clopidogrel. †p<0·05, aspirin+clopidogrel vs warfarin.
Table: Baseline features and outcome of the two major trials of double antiplatelet therapy in stroke prevention in atrial fibrillation
510
treatment for acute coronary syndromes with and without ST-segment elevation4–6) has been tested in the large ACTIVE-W trial.7 In that study double antiplatelet therapy proved to be inferior to warfarin in stroke prevention in atrial fibrillation, and was associated with an at least as high bleeding risk. Thus there was no clear alternative for high-risk patients with atrial fibrillation, who for one reason or another are ineligible for warfarin. Recently, the ACTIVE-A trial was published.8 In total, 7554 patients who had atrial fibrillation and were ineligible for oral anticoagulation were randomised to double antiplatelet therapy (clopidogrel 75 mg plus aspirin 75–100 mg daily) or to aspirin alone, and were followed up for 3·6 years. The endpoint of disabling or fatal stroke was reduced by 26% by the double antiplatelet strategy (1·6% per year) compared with aspirin alone (2·1% per year, p<0·001). Major bleeding was significantly increased by 57% from 1·3% per year with aspirin alone to 2·0% per year with double antiplatelet treatment. Also the rate of haemorrhagic stroke doubled (0·2% per year vs 0·4% per year, respectively, p<0·001). Vascular mortality was not affected by double antiplatelet therapy. ACTIVE-A clearly showed that more intense antiplatelet therapy is better than single antiplatelet treatment for stroke prevention in atrial fibrillation, which suggests an important role for platelets in the pathogenesis of stroke in patients with atrial fibrillation. The benefit against ischaemic stroke outweighs the risk of severe bleeding and therefore patients who are ineligible for warfarin should be treated with double antiplatelet therapy rather than single antiplatelet treatment. But the question is: how ineligible is ineligible for warfarin? In the ACTIVE-A trial, 50% of the candidates for the trial were considered ineligible for warfarin by their physicians, a quarter by the patients themselves, www.thelancet.com Vol 374 August 15, 2009
5
6
7 8 9
van de Wal RM, Asselbergs FW, Plokker HW, et al. High prevalence of microalbuminuria in chronic heart failure patients. J Card Fail 2005; 11: 602–06. Jackson CE, Solomon SD, Gerstein HC, et al, for the CHARM Investigators and Committees. Albuminuria in chronic heart failure: prevalence and prognostic importance. Lancet 2009; 374: 543–50. Weir MR. Microalbuminuria and cardiovascular disease. Clin J Am Soc Nephrol 2007; 2: 581–90. Comper WD, Hilliard LM, Nikolic-Paterson DJ, Russo LM. Disease-dependent mechanisms of albuminuria. Am J Physiol Renal Physiol 2008; 295: F1589–600. Damman K, van Deursen VM, Navis G, et al. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009; 53: 582–88.
10 11
12
13
Wegria R, Capeci NE, Blumenthal MR, et al. The pathogenesis of proteinuria in the acutely congested kidney. J Clin Invest 1955; 34: 737–43. Damman K, van Veldhuisen DJ, Navis G, et al. Urinary neutrophil gelatinase associated lipocalin (NGAL), a marker of tubular damage, is increased in patients with chronic heart failure. Eur J Heart Fail 2008; 10: 997–1000. Hillege HL, Fidler V, Diercks GF, et al, for the Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 2002; 106: 1777–82. Ninomiya T, Perkovic V, de Galan BE, et al, on behalf of the ADVANCE Collaborative Group. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol 2009; 20: 1813–21.
Key issues for global cardiovascular medicine See Editorial page 501
508
The European Society of Cardiology Congress brings together thousands of specialists and other stakeholders in cardiovascular medicine to exchange knowledge about one of the world’s leading causes of death and disability—cardiovascular disease. Atherosclerosis, no longer just the scourge of countries traditionally regarded as economically privileged, has emerged as a health threat in rapidly developing countries worldwide. The growing awareness of cardiovascular disease as a huge global problem is shown by the participation of countries from all over the world at the congress. The society is to be commended for making educational resources available to so many, and for providing a forum for knowledge sharing and cultural exchange among people who, although coming from diverse backgrounds, share a common purpose in combating heart disease. Despite the progress that we will hear at the congress, current efforts will not be enough to reduce the overall burden of the disease or guarantee the best amelioration of death and symptoms in those who already have cardiovascular disease. As long as lifestyle-fuelled epidemics of obesity and diabetes continue, together with ageing of the global population, sharper focus and redoubled efforts are needed to address these issues. We have had the privilege of working together to generate new knowledge for almost two decades through a clinical research network—the Virtual Coordinating Centre for Global Collaborative Cardiovascular Research (VIGOUR) group (panel).1 In several communications that have included our group and a network of young cardiovascular experts, we have identified five key issues that must be addressed by the global cardiovascular community to complement the excellent efforts of professional societies.
First, despite the proliferation of clinical trials and outcomes research in the global cardiovascular community, we still lack sufficient evidence for many conditions to make the best decisions, either on behalf of or in conjunction with patients.2 Thus, we must not merely sustain but substantially expand our research capabilities. Second, incorporation of knowledge into routine practice has fallen far short worldwide, resulting in substantial unnecessary loss of life and function. As the focus on efficiency in clinical practice grows, clinical research, with its demands on resources and time, is pushed aside and is increasingly relegated to the burgeoning for-profit research industry.3 These trends in turn create a great risk of reducing the application of research into clinical practice. Cardiovascular specialists, however, are poised to become leaders in creating the learning health systems of the future, in which the right combination of information technology and cultural change within the profession, driven by registries linked to electronic health records, will transform our caredelivery systems into continuous networks for cardiovascular medicine. However, because of the global reach of cardiovascular disease and its growing effect on developing countries, engagement of physicians from these nations in building such systems will be crucial to the success of these efforts. Third, we are in the midst of extraordinary technological changes that allow us to generate and apply knowledge in ways that were unimaginable even a decade ago. Our understanding of biology is being revolutionised as novel genomic and imaging technologies enable the reclassification of common diseases. With each passing week, new discoveries www.thelancet.com Vol 374 August 15, 2009
Comment
Panel: VIGOUR centres Argentina • Estudios Cardiologicos Latino America (ECLA) BV, Sante Fe, Argentina • Trials ArgeNtina Group Organization (TANGO), Buenos Aires, Argentina Australia • Flinders Coordinating Centre, Flinders Medical Centre Cardiovascular Unit, Bedford Park, SA, Australia • NHMRC-Clinical Trials Centre, University of Syndey, Camperdown, NSW, Australia Belgium Leuven Coordinating Centre, University Hospital Gasthuisberg, Leuven, Belgium Canada Canadian VIGOUR Centre, University of Alberta, Edmonton, AB, Canada New Zealand Green Lane Coordinating Centre, Avondale, Auckland, New Zealand USA Duke Clinical Research Institute, Durham, NC, USA
offer the possibility of earlier diagnosis, pre-emptive prevention based on risk assessment, or therapeutics stratified on the basis of genetic difference or biosignatures derived from complex arrays of gene products, proteins, metabolites, and functional imaging. If practitioners are to exploit these advances for the benefit of their patients, they will need the support of lifelong transformational educational efforts. We contend that professional groups should have a major role in improving physicians’ abilities to transfer knowledge more rapidly across traditional boundaries. Fourth, because of the global burden of cardiovascular disease, current research and educational funding mechanisms are not equal to the challenges posed by this epidemic. As we are reminded that biology is not a linear array of molecular interactions but a multidimensional community of systems, the implications for clinical trials are astounding. The number of people needed as research participants will continue to increase, especially as we recognise the potential hazard of failing to validate presumed subgroup findings in independent populations and the necessity of doing broad comparative effectiveness studies. Whereas industry energetically continues to develop novel products, contributions of the www.thelancet.com Vol 374 August 15, 2009
public sector in cardiovascular medicine, by contrast, are anaemic. This situation is perhaps understandable because of concerns about expending tax revenues outside the countries in which the taxes were paid. Nevertheless, the success of clinical research in cardiovascular medicine needs increased engagement and funding support from professional societies and governmental sources, such as the US National Institutes of Health, even when efforts span international boundaries. Fifth, we are concerned about the next generation of cardiovascular leaders within a profession characterised by unique demands. During our training, the academic fabric included recognition of the fact that clinical leaders need appropriate resources, time, and support to maintain the scholarly culture that is so crucial for medicine’s preferred future. Within our institutions and in many others we visit, the over-riding imperative for efficiency in medical practice, as well as increasingly bureaucratic approaches to grant funding (effort reporting), have devoured much of the time that was hitherto available for mentoring and spirited discussion. Much of the research enterprise has become a two-tiered system, with a wide gulf between those who design and lead international research and the thousands of investigators who enrol patients in trials. Such a situation can prove both dispiriting and limiting within an enterprise that ideally should be shared by all involved. But, rather than simply lament this turn of events, we plan to experiment with modern methods of social networking (eg, Facebook and Twitter) to overcome barriers to communication and engagement. As cardiovascular physicians, there is no greater gratification for us than observing the trajectory of an idea that alleviates the suffering caused by cardiovascular disease: first, from the laboratory to patients through clinical trials and then, after being proven in trials, by reducing death and disability in practice. If we are to catalyse the enterprise to achieve these aims in the best way, we must solve these five issues with vigour. Robert M Califf, for the Virtual Coordinating Centre for Global Collaborative Cardiovascular Research (VIGOUR) organisation Duke Translational Medicine Institute, Duke University Medical Center, Durham, NC 27710, USA robert.califf@duke.edu I thank Jonathan McCall of the Duke Clinical Research Institute, who provided editorial support for this Comment. I receive research grants from Merck, Novartis Pharmaceutical, Schering Plough Corporation, and Scius; payments for work done under these contracts, portions of which support my salary, are made to Duke
509
Comment
University. I also receive reimbursement for educational activities or consulting fees from Acumed, Amylin, the Annenberg Center, Avalere Health, Bayer, Biogen, Boehringer Ingelheim, Boston Scientific, Brandeis University, Five Prime, GlaxoSmithKline, Johnson & Johnson, Heart.org (Conceptis), Kowa Research Institute, Eli Lilly, Medtronic, Merck, Nitrox LLC, Novartis Pharmaceutical, Roche, Sanofi-Aventis, Schering Plough, Scius, Targacept, the University of Florida, Vertex, and Vivus; all revenues from educational activities are paid to Duke University, and all income from consulting activities is donated to non-profit organisations (most being donated to the clinical research fellowship fund of the Duke Clinical Research Institute). I hold equity in Nitrox LLC.
1
2
3
Mark DB, Van de Werf FJ, Simes RJ, et al. Cardiovascular disease on a global scale: defining the path forward for research and practice. Eur Heart J 2007; 28: 2678–84. Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA 2009; 301: 831–41. Glickman SW, McHutchison JG, Peterson ED, et al. Ethical and scientific implications of the globalization of clinical research. N Engl J Med 2009; 360: 816–23.
Who is ineligible for warfarin in atrial fibrillation? Stroke is a disastrous complication of atrial fibrillation. Patients with atrial fibrillation have a five times higher stroke risk than those without this common arrhythmia.1 Thromboembolism from the functionally asystolic left atrium is thought to cause the stroke. Oral anticoagulation with vitamin K antagonists, mainly warfarin, reduces the stroke risk to a third of that seen without antithrombotic therapy.2 However, anticoagulants are patient-unfriendly, difficult to monitor, and are associated with a risk of severe bleeding of at least 1% per year. Alternative anticoagulant therapy with the oral direct thrombin inhibitor ximelagatran was shown to be equally effective in two megatrials,3 but showed unacceptable liver toxicity that prohibited regulatory approval. The only other antithrombotic strategy available in atrial fibrillation is aspirin, which showed efficacy against thromboembolism versus placebo but proved to be inferior to warfarin.2 In atrial fibrillation, aspirin, although inexpensive, patientfriendly, and relatively safe, is indicated only in warfarinineligible patients. A more intense antiplatelet therapy (ie, aspirin plus clopidogrel, which is a successful
CHADS2 score Mean age (years)
ACTIVE-A (warfarin ineligible)
ACTIVE-W (warfarin eligible)
Aspirin (n=3782)
Aspirin+clopidogrel (n=3335)
2·0 70
Aspirin+clopidogrel (n=3722) 2·0 70
2·0 71
Warfarin (n=3371) 2·0 71
Total strokes (per year)
3·3
2·4*
2·4
1·4*
Disabling and fatal strokes (per year)
2·1
1·6*
1·7
1·3†
Major bleeds (per year)
1·3
2·0
2·0
2·2
Strokes or major bleed (per year)
2·5
1·2*
1·0
0·6*
*p<0·01, aspirin vs aspirin+clopidogrel. †p<0·05, aspirin+clopidogrel vs warfarin.
Table: Baseline features and outcome of the two major trials of double antiplatelet therapy in stroke prevention in atrial fibrillation
510
treatment for acute coronary syndromes with and without ST-segment elevation4–6) has been tested in the large ACTIVE-W trial.7 In that study double antiplatelet therapy proved to be inferior to warfarin in stroke prevention in atrial fibrillation, and was associated with an at least as high bleeding risk. Thus there was no clear alternative for high-risk patients with atrial fibrillation, who for one reason or another are ineligible for warfarin. Recently, the ACTIVE-A trial was published.8 In total, 7554 patients who had atrial fibrillation and were ineligible for oral anticoagulation were randomised to double antiplatelet therapy (clopidogrel 75 mg plus aspirin 75–100 mg daily) or to aspirin alone, and were followed up for 3·6 years. The endpoint of disabling or fatal stroke was reduced by 26% by the double antiplatelet strategy (1·6% per year) compared with aspirin alone (2·1% per year, p<0·001). Major bleeding was significantly increased by 57% from 1·3% per year with aspirin alone to 2·0% per year with double antiplatelet treatment. Also the rate of haemorrhagic stroke doubled (0·2% per year vs 0·4% per year, respectively, p<0·001). Vascular mortality was not affected by double antiplatelet therapy. ACTIVE-A clearly showed that more intense antiplatelet therapy is better than single antiplatelet treatment for stroke prevention in atrial fibrillation, which suggests an important role for platelets in the pathogenesis of stroke in patients with atrial fibrillation. The benefit against ischaemic stroke outweighs the risk of severe bleeding and therefore patients who are ineligible for warfarin should be treated with double antiplatelet therapy rather than single antiplatelet treatment. But the question is: how ineligible is ineligible for warfarin? In the ACTIVE-A trial, 50% of the candidates for the trial were considered ineligible for warfarin by their physicians, a quarter by the patients themselves, www.thelancet.com Vol 374 August 15, 2009