Comment
Science Photo Library
Dual antiplatelet therapy and non-cardiovascular mortality
Published Online November 16, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)62125-5 See Articles page 792
756
According to recent guidelines from the European Society of Cardiology,1 dual antiplatelet therapy should be pursued for 6–12 months after acute coronary syndromes or drug-eluting stent implantation; thereafter, patients should be switched to single antiplatelet therapy. However, the optimum length of dual antiplatelet therapy in patients with stable coronary artery disease is highly controversial. Recurrent events might be due to either new-plaque rupture or complications related to previous revascularisations, and it has been suggested that extended dual antiplatelet therapy could protect patients with stable coronary artery disease even beyond 1 year after percutaneous coronary intervention. However, extended dual antiplatelet therapy leads to an increased risk of bleeding. Data from registries, which have included high-risk patients and focused on the risk of stent thrombosis, have suggested a benefit of prolonged (ie, >1 year) dual antiplatelet therapy after percutaneous coronary intervention with a first generation drug-eluting stent.2–5 Conversely, data from recent randomised trials,6–9 which have included low-risk patients and new generations of drug-eluting stents, suggested no benefit of such a strategy. The DAPT Study,10 in which patients with cardiovascular disease were randomly assigned 12 months after percutaneous coronary intervention to aspirin alone or dual antiplatelet therapy for an additional 18 months, is the only randomised study powered sufficiently to address the effect of extended dual antiplatelet therapy on hard clinical endpoints. The study enrolled 25 682 patients within 72 h after the index percutaneous coronary intervention and finally randomised 11 648 of them at 12 months. Both coprimary efficacy endpoints, stent thrombosis and major adverse cardiac and cerebrovascular events (a composite of death, myocardial infarction, and stroke), were significantly decreased in patients taking prolonged dual antiplatelet therapy. By contrast, prolonged dual antiplatelet therapy significantly increased the risk of bleeding (the trial’s safety endpoint). Unexpectedly, the DAPT Study investigators noted a significant increase in all-cause mortality in the dual antiplatelet therapy group compared with the aspirin alone group at study completion (HR 1·36, 95% CI 1·02–1·82 at 33 months), driven exclusively by an increase in non-cardiovascular mortality (2·23, 1·32–3·78 at
30 months). According to the investigators, this increase in non-cardiovascular mortality was not entirely related to an increase in bleeding-related deaths. However, this finding logically calls for caution when interpreting the data from this study. Because the DAPT Study10 was not designed to analyse mortality precisely, Sammy Elmariah and colleagues11 now report in The Lancet a systematic review and meta-analysis that included 14 trials (69 644 patients) assessing the effect of extended duration versus no or short duration dual antiplatelet therapy on mortality. The authors included trials of patients presenting in various clinical settings (ie, stable coronary artery disease, acute coronary syndromes, peripheral artery disease, stroke, and atrial fibrillation). The researchers noted that, compared with aspirin alone or short duration dual antiplatelet therapy (≤6 months), extended therapy was not associated with an increase in all-cause mortality (HR 1·05, 95% credible interval 0·96–1·19) or non-cardiovascular mortality (1·04, 0·90–1·26). These results were consistent in a post-hoc analysis of patients with coronary artery disease (ten studies). After metaregression, treatment duration had no significant effect on mortality across studies. However, caution should be taken when interpreting these results in view of the wellknown limitations of meta-analyses, especially those that are study-based rather than based on individual patient data. Additionally, the selected nature of the populations included by Elmariah and colleagues11 might not be representative of current practice in patients with stable coronary artery disease. Indeed, cardiovascular mortality was the main cause of death, and was two to three times more frequent than non-cardiovascular mortality. However, there is now evidence that non-cardiovascular mortality represents the main cause of death (ie, in some two thirds of patients) in real-life contemporary practice.12,13 Additionally, of the ten studies of patients with coronary artery disease included by Elmariah and colleagues, six compared a 12-month dual antiplatelet therapy period with no dual antiplatelet therapy or a shorter duration of therapy, which makes it difficult to draw conclusions about the real effect of extended dual antiplatelet therapy after 1 year following the index percutaneous coronary intervention. www.thelancet.com Vol 385 February 28, 2015
Comment
Taking the results of the DAPT Study10 and those of the present meta-analysis11 together, the following points are clear. First, extended dual antiplatelet therapy significantly decreases the risk of ischaemic events, especially stent thrombosis and myocardial infarction, but increases the risk of bleeding. One size may not fit all, and physicians should precisely assess each individual (in terms of risk–benefit ratio) when it comes to making a decision about whether to pursue or shorten dual antiplatelet therapy. If extended dual antiplatelet therapy definitely benefits some patients, it might also be deleterious for others. Second, there is no need to take the decision to pursue or not to pursue dual antiplatelet therapy beyond 6 or 12 months immediately after the index percutaneous coronary intervention. Patients should be prescribed dual antiplatelet therapy for 6–12 months and then be re-assessed at each timepoint if they are event-free. In the DAPT Study, more than 10% of the patients had an event within the first year after percutaneous coronary intervention. All intercurrent ischaemic or bleeding events might change the initial decision to pursue longterm dual antiplatelet therapy. Third, according to recent literature, non-cardiovascular mortality is now the main cause of death in patients with stable coronary artery disease,12,13 and studies included in the present meta-analysis do not reflect this pattern. Thus, clear-cut conclusions on the effect of extended dual antiplatelet therapy on non-cardiovascular mortality cannot be made, even if the present meta-analysis11 provides reassuring data, suggesting that extended dual antiplatelet therapy does not increase non-cardiovascular mortality.
Gilles Lemesle Hôpital Cardiologique, Centre Hospitalier Régional et Universitaire de Lille, 59000 Lille, France; Faculté de Médecine de Lille, Lille, France; and INSERM UMR744, Institut Pasteur de Lille, Lille, France [email protected] I declare no competing interests. 1
2
3
4 5
6
7
8
9
10 11
12
13
Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013; 34: 2949–3003. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 2007; 116: 745–54. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA 2007; 297: 159–68. Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med 2010; 362: 1374–82. Schulz S, Schuster T, Mehilli J, et al. Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period. Eur Heart J 2009; 30: 2714–21. Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012; 125: 505–13. Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012; 60: 1340–48. Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014; 129: 304–12. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012; 125: 2015–26. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med (in press). Elmariah S, Mauri L, Doros G, et al. Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis. Lancet 2014: published online Nov 16. http://dx.doi.org/10.1016/S01406736(14)62052-3. Bauters C, Deneve M, Tricot O, Meurice T, Lamblin N. Prognosis of patients with stable coronary artery disease (from the CORONOR Study). Am J Cardiol 2014; 113: 1142–45. Spoon DB, Psaltis PJ, Singh M, et al. Trends in cause of death after percutaneous coronary intervention. Circulation 2014; 129: 1286–94.
Cardiology: a call for papers The Lancet is planning a special issue to coincide with the European Society of Cardiology congress to be held on Aug 29–Sept 2, 2015 in London, UK. We will consider high quality original research papers that will influence clinical practice—especially those that describe the results of randomised trials. Please submit via our online submission system, and state in your covering letter that the submission is in response to this call for papers. The deadline for regular submissions is May 25, 2015. If your manuscript www.thelancet.com Vol 385 February 28, 2015
is accepted for a Hot Line session at the congress, the deadline for submissions is July 31. If your work is being presented at the meeting and falls under an embargo policy, please tell us the date, time, and manner of presentation (poster or oral). If your paper is accepted here, publication on our website can be scheduled to coincide with the presentation.
To submit a paper go to http://ees.elsevier.com/thelancet
Stuart Spencer The Lancet, London EC2Y 5AS, UK
757
Science Photo Library
Dual antiplatelet therapy and non-cardiovascular mortality
Published Online November 16, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)62125-5 See Articles page 792
756
According to recent guidelines from the European Society of Cardiology,1 dual antiplatelet therapy should be pursued for 6–12 months after acute coronary syndromes or drug-eluting stent implantation; thereafter, patients should be switched to single antiplatelet therapy. However, the optimum length of dual antiplatelet therapy in patients with stable coronary artery disease is highly controversial. Recurrent events might be due to either new-plaque rupture or complications related to previous revascularisations, and it has been suggested that extended dual antiplatelet therapy could protect patients with stable coronary artery disease even beyond 1 year after percutaneous coronary intervention. However, extended dual antiplatelet therapy leads to an increased risk of bleeding. Data from registries, which have included high-risk patients and focused on the risk of stent thrombosis, have suggested a benefit of prolonged (ie, >1 year) dual antiplatelet therapy after percutaneous coronary intervention with a first generation drug-eluting stent.2–5 Conversely, data from recent randomised trials,6–9 which have included low-risk patients and new generations of drug-eluting stents, suggested no benefit of such a strategy. The DAPT Study,10 in which patients with cardiovascular disease were randomly assigned 12 months after percutaneous coronary intervention to aspirin alone or dual antiplatelet therapy for an additional 18 months, is the only randomised study powered sufficiently to address the effect of extended dual antiplatelet therapy on hard clinical endpoints. The study enrolled 25 682 patients within 72 h after the index percutaneous coronary intervention and finally randomised 11 648 of them at 12 months. Both coprimary efficacy endpoints, stent thrombosis and major adverse cardiac and cerebrovascular events (a composite of death, myocardial infarction, and stroke), were significantly decreased in patients taking prolonged dual antiplatelet therapy. By contrast, prolonged dual antiplatelet therapy significantly increased the risk of bleeding (the trial’s safety endpoint). Unexpectedly, the DAPT Study investigators noted a significant increase in all-cause mortality in the dual antiplatelet therapy group compared with the aspirin alone group at study completion (HR 1·36, 95% CI 1·02–1·82 at 33 months), driven exclusively by an increase in non-cardiovascular mortality (2·23, 1·32–3·78 at
30 months). According to the investigators, this increase in non-cardiovascular mortality was not entirely related to an increase in bleeding-related deaths. However, this finding logically calls for caution when interpreting the data from this study. Because the DAPT Study10 was not designed to analyse mortality precisely, Sammy Elmariah and colleagues11 now report in The Lancet a systematic review and meta-analysis that included 14 trials (69 644 patients) assessing the effect of extended duration versus no or short duration dual antiplatelet therapy on mortality. The authors included trials of patients presenting in various clinical settings (ie, stable coronary artery disease, acute coronary syndromes, peripheral artery disease, stroke, and atrial fibrillation). The researchers noted that, compared with aspirin alone or short duration dual antiplatelet therapy (≤6 months), extended therapy was not associated with an increase in all-cause mortality (HR 1·05, 95% credible interval 0·96–1·19) or non-cardiovascular mortality (1·04, 0·90–1·26). These results were consistent in a post-hoc analysis of patients with coronary artery disease (ten studies). After metaregression, treatment duration had no significant effect on mortality across studies. However, caution should be taken when interpreting these results in view of the wellknown limitations of meta-analyses, especially those that are study-based rather than based on individual patient data. Additionally, the selected nature of the populations included by Elmariah and colleagues11 might not be representative of current practice in patients with stable coronary artery disease. Indeed, cardiovascular mortality was the main cause of death, and was two to three times more frequent than non-cardiovascular mortality. However, there is now evidence that non-cardiovascular mortality represents the main cause of death (ie, in some two thirds of patients) in real-life contemporary practice.12,13 Additionally, of the ten studies of patients with coronary artery disease included by Elmariah and colleagues, six compared a 12-month dual antiplatelet therapy period with no dual antiplatelet therapy or a shorter duration of therapy, which makes it difficult to draw conclusions about the real effect of extended dual antiplatelet therapy after 1 year following the index percutaneous coronary intervention. www.thelancet.com Vol 385 February 28, 2015
Comment
Taking the results of the DAPT Study10 and those of the present meta-analysis11 together, the following points are clear. First, extended dual antiplatelet therapy significantly decreases the risk of ischaemic events, especially stent thrombosis and myocardial infarction, but increases the risk of bleeding. One size may not fit all, and physicians should precisely assess each individual (in terms of risk–benefit ratio) when it comes to making a decision about whether to pursue or shorten dual antiplatelet therapy. If extended dual antiplatelet therapy definitely benefits some patients, it might also be deleterious for others. Second, there is no need to take the decision to pursue or not to pursue dual antiplatelet therapy beyond 6 or 12 months immediately after the index percutaneous coronary intervention. Patients should be prescribed dual antiplatelet therapy for 6–12 months and then be re-assessed at each timepoint if they are event-free. In the DAPT Study, more than 10% of the patients had an event within the first year after percutaneous coronary intervention. All intercurrent ischaemic or bleeding events might change the initial decision to pursue longterm dual antiplatelet therapy. Third, according to recent literature, non-cardiovascular mortality is now the main cause of death in patients with stable coronary artery disease,12,13 and studies included in the present meta-analysis do not reflect this pattern. Thus, clear-cut conclusions on the effect of extended dual antiplatelet therapy on non-cardiovascular mortality cannot be made, even if the present meta-analysis11 provides reassuring data, suggesting that extended dual antiplatelet therapy does not increase non-cardiovascular mortality.
Gilles Lemesle Hôpital Cardiologique, Centre Hospitalier Régional et Universitaire de Lille, 59000 Lille, France; Faculté de Médecine de Lille, Lille, France; and INSERM UMR744, Institut Pasteur de Lille, Lille, France [email protected] I declare no competing interests. 1
2
3
4 5
6
7
8
9
10 11
12
13
Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013; 34: 2949–3003. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 2007; 116: 745–54. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA 2007; 297: 159–68. Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med 2010; 362: 1374–82. Schulz S, Schuster T, Mehilli J, et al. Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period. Eur Heart J 2009; 30: 2714–21. Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012; 125: 505–13. Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012; 60: 1340–48. Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014; 129: 304–12. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012; 125: 2015–26. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med (in press). Elmariah S, Mauri L, Doros G, et al. Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis. Lancet 2014: published online Nov 16. http://dx.doi.org/10.1016/S01406736(14)62052-3. Bauters C, Deneve M, Tricot O, Meurice T, Lamblin N. Prognosis of patients with stable coronary artery disease (from the CORONOR Study). Am J Cardiol 2014; 113: 1142–45. Spoon DB, Psaltis PJ, Singh M, et al. Trends in cause of death after percutaneous coronary intervention. Circulation 2014; 129: 1286–94.
Cardiology: a call for papers The Lancet is planning a special issue to coincide with the European Society of Cardiology congress to be held on Aug 29–Sept 2, 2015 in London, UK. We will consider high quality original research papers that will influence clinical practice—especially those that describe the results of randomised trials. Please submit via our online submission system, and state in your covering letter that the submission is in response to this call for papers. The deadline for regular submissions is May 25, 2015. If your manuscript www.thelancet.com Vol 385 February 28, 2015
is accepted for a Hot Line session at the congress, the deadline for submissions is July 31. If your work is being presented at the meeting and falls under an embargo policy, please tell us the date, time, and manner of presentation (poster or oral). If your paper is accepted here, publication on our website can be scheduled to coincide with the presentation.
To submit a paper go to http://ees.elsevier.com/thelancet
Stuart Spencer The Lancet, London EC2Y 5AS, UK
757
