- Email: [email protected]
Antithrombotic Regimens in Patients With Atrial Fibrillation and Coronary Disease
Accepted Manuscript Antithrombotic Regimens in Patients with Atrial Fibrillation and Coronary Disease: Optimizing Efficacy and Safety Steven M. Markowitz, M.D PII:
S0735-1097(13)02171-2
DOI:
10.1016/j.jacc.2013.04.072
Reference:
JAC 18956
To appear in:
Journal of the American College of Cardiology
Received Date: 26 April 2013 Accepted Date: 30 April 2013
Please cite this article as: Markowitz SM, Antithrombotic Regimens in Patients with Atrial Fibrillation and Coronary Disease: Optimizing Efficacy and Safety, Journal of the American College of Cardiology (2013), doi: 10.1016/j.jacc.2013.04.072. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Antithrombotic Regimens in Patients with Atrial Fibrillation and Coronary Disease: Optimizing Efficacy and Safety
SC
Steven M. Markowitz, M.D.
RI PT
Running Title: Anticoagulation for AF and coronary disease
M AN U
From the Department of Medicine, Division of Cardiology, Cornell University Medical Center, New York, NY 10065 Disclosures: none
Correspondence:
TE D
Word Count: 1781
AC C
EP
Steven M. Markowitz, MD Division of Cardiology, Starr 4 Cornell University Medical Center 525 East 68th Street New York, NY 10065 Tel: 212-746-2655 Fax: 212-746-6951 E-mail: [email protected]
Keywords: Atrial fibrillation, Coronary disease, Anticoagulation
ACCEPTED MANUSCRIPT 2
Clear evidence supports the value of oral anticoagulation (OAC) with vitamin K antagonists in preventing stroke and thromboembolism in patients with atrial fibrillation (AF) who have well
RI PT
established risk factors. For this indication, vitamin K antagonists have been shown to be
superior to single or dual antiplatelet agents in reducing thromboembolic complications. (1) Yet, up to 30% patients with AF also have indications for antiplatelet therapy because of coronary
SC
artery disease. (2) Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor (e.g., clopidogrel) is usually recommended after stent implantation or acute coronary syndrome. (3)
M AN U
Thus, patients with both AF and coronary events typically receive combination OAC and antiplatelet therapy. There has been concern that withholding antiplatelet therapy in these patients could expose them to higher rates of stent thrombosis and MI, and P2Y12 inhibitors appear to be particularly important in this regard. Yet, the combination of OAC with antiplatelet
TE D
drugs clearly increases the risk of major hemorrhages and fatal bleeding in both AF and coronary populations. (4-6) European guidelines from 2010 suggest triple therapy after stent implantation, with the duration depending on the type of stent implanted, the presence of an acute coronary
EP
syndrome, and the patient’s bleeding risk. (7) An earlier guideline document from the American College of Cardiology, American Heart Association, and European Society of Cardiology de-
AC C
emphasizes the use of aspirin and favors OAC + clopidogrel after stent implantation in AF patients, since “the addition of aspirin to the chronic anticoagulant regimen contributes more risk than benefit.” (8) For patients with both AF and coronary disease, there is a paucity of information to guide rational decisions and very little evidence to support intensive anticoagulation with triple therapy. In this issue of the Journal, Lamberts et al used national databanks and registries in Denmark to explore the safety and efficacy of different anticoagulation regimens in patients with
ACCEPTED MANUSCRIPT 3
AF who also had MI and/or PCI. (9) Since patients in Denmark have unique identifiers, the investigators could link national databases of hospitalizations, procedural treatments, drug prescriptions, and causes of death. This analysis has the advantage of studying outcomes in a
RI PT
large “real world” population, not one highly selected by rigorous inclusion criteria of a
randomized trial. It also illustrates the power of nationwide registries to explore clinically
important questions that might prove difficult to approach in randomized trials. As with any
SC
retrospective registry, some important data may not be available. For example, this study does not inform us how many PCI patients had drug eluting stents. Also, registry studies that use
M AN U
hospital diagnosis codes depend heavily on the accuracy of the coding. Fortunately, the codes employed in this study have been previously validated with relatively high specificities and predictive values.
Using this approach, 12,165 AF patients were identified who were hospitalized for MI
TE D
and/or PCI. Anticoagulation regimens were monotherapy in 38% (aspirin, clopidogrel, or OAC), dual therapy in 47% (dual antiplatelets or OAC + one antiplatelet), and triple therapy in 15%. Outcomes assessed after 1 year included MI, ischemic stroke, mortality, and bleeding, as judged
EP
from hospitalization and death records. In this analysis, OAC + clopidogrel emerged as the favored overall strategy. Compared to triple therapy, this dual combination showed no excess of
AC C
MI or coronary death, and there was no difference in ischemic stroke or overall mortality. In terms of bleeding, OAC + clopidogrel showed a nonsignificant benefit compared to triple therapy. Other regimens (OAC + aspirin; dual antiplatelet therapy without OAC) were associated with less bleeding, but at the cost of higher all-cause mortality rates. Not surprisingly, there were also more strokes among those treated with dual antiplatelets compared to any regimen that used an OAC. Those who had PCI without MI had a lower coronary event rate, but
ACCEPTED MANUSCRIPT 4
there was still a benefit for OAC + clopidogrel compared to the other regimens in these lower risk patients. Other interesting findings were high subsequent mortality, myocardial infarction, and stroke among those hospitalized for bleeding compared to those without. The higher rates of
RI PT
thrombotic events among those with nonfatal bleeding suggests that bleeding is dangerous not only because of the hemorrhage itself but also because it forces discontinuation of needed anticoagulation.
SC
A limitation of this study design is the possibility that treatment decisions were
confounded by many clinical features that cannot be captured from the national databases. The
M AN U
authors acknowledge this important limitation and report that baseline characteristics – such as CHADS2 and HAS-BLED scores – seem not to have influenced the choice of anticoagulation prescriptions. But it should be acknowledged that even this analysis does not control for other comorbidities that might lead physicians to choose a particular anticoagulation regimen
TE D
(clopidogrel alone versus the combination of aspirin + clopidogrel) after a new cardiac event. Finally, the number of patients who were initially prescribed the “optimal” regimen of OAC + clopidogrel was relatively small (548 of 12,615 subjects).
EP
The question of dual versus triple anticoagulation has recently been addressed in a prospective, randomized trial (What is the Optimal AntiplatElet and anticoagulant therapy in
AC C
patients with oral anticoagulation and coronary StenTing; WOEST). (10) This trial tested OAC + clopidogrel versus triple therapy in patients undergoing coronary stenting who also needed OAC (for AF in 69%). After 1 year of follow-up, OAC + clopidogrel was associated with significantly less overall bleeding, and there was no increase in stent thrombosis, although this relatively small study of 573 patients was underpowered to exclude excess stent thrombosis. In
ACCEPTED MANUSCRIPT 5
composite, these two studies suggest dual anticoagulation with OAC + clopidogrel as a safer and perhaps equally effective strategy compared to triple therapy. But a myriad of questions remain unanswered. Could there be even higher risk patients
RI PT
in whom coronary protection with triple therapy outweighs the bleeding risks? For example, patients with recurrent coronary events within 1 year would be considered at elevated risk, but patients with MI in the previous year were excluded from the Danish study. Also, this study
SC
does not address the time course of triple or even dual therapy after MI or PCI. Current
guidelines suggest that monotherapy with warfarin might be sufficient 1 year after stenting in
M AN U
lower risk patients, (7,8) an issue which is not addressed in the present study. Even more perplexing is how to treat patients with resistance to clopidogrel. These patients might be candidates for other P2Y12 inhibitors, but sparse data are available on the combination of OAC with newer P2Y12 receptor inhibitors (prasugrel, ticagrelor), which are shown to reduce coronary
TE D
endpoints but at the expense of more bleeding (11,12). Preliminary evidence suggests more bleeding occurs in triple therapy patients receiving prasugrel compared to clopidogrel. (13) Finally, these results cannot necessarily be extrapolated to the newer direct thrombin and factor
EP
Xa inhibitors, but it is probable that combining these new agents with dual antiplatelets would cause more bleeding than benefit. (14)
AC C
The implication here is that physicians should have confidence to curtail triple therapy
when OAC is needed for AF. One method to minimize the need for combination therapy is to use bare metal stents whenever possible in AF patients. New stent designs are likely reduce the need for triple therapy in the future. Ultimately, the clinician must exercise judgment and integrate bleeding and thrombotic risks in prescribing anticoagulation regimens in such situations.
ACCEPTED MANUSCRIPT 6
References 1.
Connolly S, Pogue J, Hart R et al. Clopidogrel plus aspirin versus oral anticoagulation for
RI PT
atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:190312.
Nabauer M, Gerth A, Limbourg T et al. The Registry of the German Competence
SC
2.
NETwork on Atrial Fibrillation: patient characteristics and initial management. Europace
3.
M AN U
2009;11:423-34.
Jneid H, Anderson JL, Wright RS et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused
TE D
update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2012;60:645-81. 4.
Holmes DR, Jr., Kereiakes DJ, Kleiman NS, Moliterno DJ, Patti G, Grines CL.
5.
EP
Combining antiplatelet and anticoagulant therapies. J Am Coll Cardiol 2009;54:95-109. Sorensen R, Hansen ML, Abildstrom SZ et al. Risk of bleeding in patients with acute
AC C
myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009;374:1967-74.
6.
Hansen ML, Sorensen R, Clausen MT et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010;170:1433-41.
ACCEPTED MANUSCRIPT 7
7.
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). Eur Heart J 2010;31:2369-429. Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the
RI PT
8.
management of patients with atrial fibrillation--executive summary: a report of the
American College of Cardiology/American Heart Association Task Force on Practice
SC
Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With
9.
M AN U
Atrial Fibrillation). J Am Coll Cardiol 2006;48:854-906.
Lamberts M, Gislason GH, Olesen JB et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol 2013.
Dewilde WJ, Oirbans T, Verheugt FW et al. Use of clopidogrel with or without aspirin in
TE D
10.
patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107-15. Montalescot G, Wiviott SD, Braunwald E et al. Prasugrel compared with clopidogrel in
EP
11.
patients undergoing percutaneous coronary intervention for ST-elevation myocardial
AC C
infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009;373:723-31.
12.
Wallentin L, Becker RC, Budaj A et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57.
ACCEPTED MANUSCRIPT 8
13.
Sarafoff N, Martischnig A, Wealer J et al. Triple therapy with aspirin, prasugrel and vitamin K antagonists in patients with drug eluting stent implantation and an indication for oral anticoagulation. J Am Coll Cardiol 2013. doi: 10.1016/j.jacc.2013.02.036
RI PT
Dans AL, Connolly SJ, Wallentin L et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation
EP
TE D
M AN U
SC
Therapy (RE-LY) trial. Circulation 2013;127:634-40.
AC C
14.
S0735-1097(13)02171-2
DOI:
10.1016/j.jacc.2013.04.072
Reference:
JAC 18956
To appear in:
Journal of the American College of Cardiology
Received Date: 26 April 2013 Accepted Date: 30 April 2013
Please cite this article as: Markowitz SM, Antithrombotic Regimens in Patients with Atrial Fibrillation and Coronary Disease: Optimizing Efficacy and Safety, Journal of the American College of Cardiology (2013), doi: 10.1016/j.jacc.2013.04.072. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Antithrombotic Regimens in Patients with Atrial Fibrillation and Coronary Disease: Optimizing Efficacy and Safety
SC
Steven M. Markowitz, M.D.
RI PT
Running Title: Anticoagulation for AF and coronary disease
M AN U
From the Department of Medicine, Division of Cardiology, Cornell University Medical Center, New York, NY 10065 Disclosures: none
Correspondence:
TE D
Word Count: 1781
AC C
EP
Steven M. Markowitz, MD Division of Cardiology, Starr 4 Cornell University Medical Center 525 East 68th Street New York, NY 10065 Tel: 212-746-2655 Fax: 212-746-6951 E-mail: [email protected]
Keywords: Atrial fibrillation, Coronary disease, Anticoagulation
ACCEPTED MANUSCRIPT 2
Clear evidence supports the value of oral anticoagulation (OAC) with vitamin K antagonists in preventing stroke and thromboembolism in patients with atrial fibrillation (AF) who have well
RI PT
established risk factors. For this indication, vitamin K antagonists have been shown to be
superior to single or dual antiplatelet agents in reducing thromboembolic complications. (1) Yet, up to 30% patients with AF also have indications for antiplatelet therapy because of coronary
SC
artery disease. (2) Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor (e.g., clopidogrel) is usually recommended after stent implantation or acute coronary syndrome. (3)
M AN U
Thus, patients with both AF and coronary events typically receive combination OAC and antiplatelet therapy. There has been concern that withholding antiplatelet therapy in these patients could expose them to higher rates of stent thrombosis and MI, and P2Y12 inhibitors appear to be particularly important in this regard. Yet, the combination of OAC with antiplatelet
TE D
drugs clearly increases the risk of major hemorrhages and fatal bleeding in both AF and coronary populations. (4-6) European guidelines from 2010 suggest triple therapy after stent implantation, with the duration depending on the type of stent implanted, the presence of an acute coronary
EP
syndrome, and the patient’s bleeding risk. (7) An earlier guideline document from the American College of Cardiology, American Heart Association, and European Society of Cardiology de-
AC C
emphasizes the use of aspirin and favors OAC + clopidogrel after stent implantation in AF patients, since “the addition of aspirin to the chronic anticoagulant regimen contributes more risk than benefit.” (8) For patients with both AF and coronary disease, there is a paucity of information to guide rational decisions and very little evidence to support intensive anticoagulation with triple therapy. In this issue of the Journal, Lamberts et al used national databanks and registries in Denmark to explore the safety and efficacy of different anticoagulation regimens in patients with
ACCEPTED MANUSCRIPT 3
AF who also had MI and/or PCI. (9) Since patients in Denmark have unique identifiers, the investigators could link national databases of hospitalizations, procedural treatments, drug prescriptions, and causes of death. This analysis has the advantage of studying outcomes in a
RI PT
large “real world” population, not one highly selected by rigorous inclusion criteria of a
randomized trial. It also illustrates the power of nationwide registries to explore clinically
important questions that might prove difficult to approach in randomized trials. As with any
SC
retrospective registry, some important data may not be available. For example, this study does not inform us how many PCI patients had drug eluting stents. Also, registry studies that use
M AN U
hospital diagnosis codes depend heavily on the accuracy of the coding. Fortunately, the codes employed in this study have been previously validated with relatively high specificities and predictive values.
Using this approach, 12,165 AF patients were identified who were hospitalized for MI
TE D
and/or PCI. Anticoagulation regimens were monotherapy in 38% (aspirin, clopidogrel, or OAC), dual therapy in 47% (dual antiplatelets or OAC + one antiplatelet), and triple therapy in 15%. Outcomes assessed after 1 year included MI, ischemic stroke, mortality, and bleeding, as judged
EP
from hospitalization and death records. In this analysis, OAC + clopidogrel emerged as the favored overall strategy. Compared to triple therapy, this dual combination showed no excess of
AC C
MI or coronary death, and there was no difference in ischemic stroke or overall mortality. In terms of bleeding, OAC + clopidogrel showed a nonsignificant benefit compared to triple therapy. Other regimens (OAC + aspirin; dual antiplatelet therapy without OAC) were associated with less bleeding, but at the cost of higher all-cause mortality rates. Not surprisingly, there were also more strokes among those treated with dual antiplatelets compared to any regimen that used an OAC. Those who had PCI without MI had a lower coronary event rate, but
ACCEPTED MANUSCRIPT 4
there was still a benefit for OAC + clopidogrel compared to the other regimens in these lower risk patients. Other interesting findings were high subsequent mortality, myocardial infarction, and stroke among those hospitalized for bleeding compared to those without. The higher rates of
RI PT
thrombotic events among those with nonfatal bleeding suggests that bleeding is dangerous not only because of the hemorrhage itself but also because it forces discontinuation of needed anticoagulation.
SC
A limitation of this study design is the possibility that treatment decisions were
confounded by many clinical features that cannot be captured from the national databases. The
M AN U
authors acknowledge this important limitation and report that baseline characteristics – such as CHADS2 and HAS-BLED scores – seem not to have influenced the choice of anticoagulation prescriptions. But it should be acknowledged that even this analysis does not control for other comorbidities that might lead physicians to choose a particular anticoagulation regimen
TE D
(clopidogrel alone versus the combination of aspirin + clopidogrel) after a new cardiac event. Finally, the number of patients who were initially prescribed the “optimal” regimen of OAC + clopidogrel was relatively small (548 of 12,615 subjects).
EP
The question of dual versus triple anticoagulation has recently been addressed in a prospective, randomized trial (What is the Optimal AntiplatElet and anticoagulant therapy in
AC C
patients with oral anticoagulation and coronary StenTing; WOEST). (10) This trial tested OAC + clopidogrel versus triple therapy in patients undergoing coronary stenting who also needed OAC (for AF in 69%). After 1 year of follow-up, OAC + clopidogrel was associated with significantly less overall bleeding, and there was no increase in stent thrombosis, although this relatively small study of 573 patients was underpowered to exclude excess stent thrombosis. In
ACCEPTED MANUSCRIPT 5
composite, these two studies suggest dual anticoagulation with OAC + clopidogrel as a safer and perhaps equally effective strategy compared to triple therapy. But a myriad of questions remain unanswered. Could there be even higher risk patients
RI PT
in whom coronary protection with triple therapy outweighs the bleeding risks? For example, patients with recurrent coronary events within 1 year would be considered at elevated risk, but patients with MI in the previous year were excluded from the Danish study. Also, this study
SC
does not address the time course of triple or even dual therapy after MI or PCI. Current
guidelines suggest that monotherapy with warfarin might be sufficient 1 year after stenting in
M AN U
lower risk patients, (7,8) an issue which is not addressed in the present study. Even more perplexing is how to treat patients with resistance to clopidogrel. These patients might be candidates for other P2Y12 inhibitors, but sparse data are available on the combination of OAC with newer P2Y12 receptor inhibitors (prasugrel, ticagrelor), which are shown to reduce coronary
TE D
endpoints but at the expense of more bleeding (11,12). Preliminary evidence suggests more bleeding occurs in triple therapy patients receiving prasugrel compared to clopidogrel. (13) Finally, these results cannot necessarily be extrapolated to the newer direct thrombin and factor
EP
Xa inhibitors, but it is probable that combining these new agents with dual antiplatelets would cause more bleeding than benefit. (14)
AC C
The implication here is that physicians should have confidence to curtail triple therapy
when OAC is needed for AF. One method to minimize the need for combination therapy is to use bare metal stents whenever possible in AF patients. New stent designs are likely reduce the need for triple therapy in the future. Ultimately, the clinician must exercise judgment and integrate bleeding and thrombotic risks in prescribing anticoagulation regimens in such situations.
ACCEPTED MANUSCRIPT 6
References 1.
Connolly S, Pogue J, Hart R et al. Clopidogrel plus aspirin versus oral anticoagulation for
RI PT
atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:190312.
Nabauer M, Gerth A, Limbourg T et al. The Registry of the German Competence
SC
2.
NETwork on Atrial Fibrillation: patient characteristics and initial management. Europace
3.
M AN U
2009;11:423-34.
Jneid H, Anderson JL, Wright RS et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused
TE D
update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2012;60:645-81. 4.
Holmes DR, Jr., Kereiakes DJ, Kleiman NS, Moliterno DJ, Patti G, Grines CL.
5.
EP
Combining antiplatelet and anticoagulant therapies. J Am Coll Cardiol 2009;54:95-109. Sorensen R, Hansen ML, Abildstrom SZ et al. Risk of bleeding in patients with acute
AC C
myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009;374:1967-74.
6.
Hansen ML, Sorensen R, Clausen MT et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010;170:1433-41.
ACCEPTED MANUSCRIPT 7
7.
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). Eur Heart J 2010;31:2369-429. Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the
RI PT
8.
management of patients with atrial fibrillation--executive summary: a report of the
American College of Cardiology/American Heart Association Task Force on Practice
SC
Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With
9.
M AN U
Atrial Fibrillation). J Am Coll Cardiol 2006;48:854-906.
Lamberts M, Gislason GH, Olesen JB et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol 2013.
Dewilde WJ, Oirbans T, Verheugt FW et al. Use of clopidogrel with or without aspirin in
TE D
10.
patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107-15. Montalescot G, Wiviott SD, Braunwald E et al. Prasugrel compared with clopidogrel in
EP
11.
patients undergoing percutaneous coronary intervention for ST-elevation myocardial
AC C
infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009;373:723-31.
12.
Wallentin L, Becker RC, Budaj A et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57.
ACCEPTED MANUSCRIPT 8
13.
Sarafoff N, Martischnig A, Wealer J et al. Triple therapy with aspirin, prasugrel and vitamin K antagonists in patients with drug eluting stent implantation and an indication for oral anticoagulation. J Am Coll Cardiol 2013. doi: 10.1016/j.jacc.2013.02.036
RI PT
Dans AL, Connolly SJ, Wallentin L et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation
EP
TE D
M AN U
SC
Therapy (RE-LY) trial. Circulation 2013;127:634-40.
AC C
14.