Letters
with persistent postconcussion symptoms: a randomized clinical trial [published online November 17, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014 .5479. 4. Lacey DJ, Stolfi A, Pilati LE. Effects of hyperbaric oxygen on motor function in children with cerebral palsy. Ann Neurol. 2012;72(5):695-703. 5. Efrati S, Ben-Jacob E. How and why hyperbaric oxygen therapy can bring new hope for children suffering from cerebral palsy: an editorial perspective. Undersea Hyperb Med. 2014;41(2):71-76.
In Reply Advances in medical care depend on well-controlled randomized clinical trials to validate the safety and efficacy of new interventions and to ensure that clinicians understand the active components.1 Hyperbaric oxygen (HBO) treatment is a very time-consuming and costly procedure that is not without harmful effects. Nevertheless, HBO treatment is being promoted by clinicians who dispense the service as a treatment for a vast number of medical conditions for which there are no US Food and Drug Administration indications or even acceptance by respected organizations, such as the Undersea and Hyperbaric Medical Society.2 The field suffers from numerous studies, such as the one by Mukherjee et al,3 that involve observational, nonblinded, nonrandomized methodology. Foundational to the design of well-controlled clinical studies is the assessment of whether the intervention’s mechanism of action is biologically plausible, exhibits a meaningful dose response, and is potentially relevant for the condition being treated. Over decades of experience with HBO treatment, procedures for approved indications, such as wound healing, necrotizing infections, burns, radiation injury, or carbon monoxide poisoning, have been standardized, most commonly with 100% oxygen delivered between 1.5 and 3.0 atmospheres absolute (ATA). Although efficacy questions remain, even at these doses,4,5 experts would never consider room air (21% oxygen), delivered at 1.2 ATA, to be an acceptable therapeutic dose for any approved clinical indication. This is approximately equivalent to the pressure of 2 m of seawater, or oxygen delivered at 1 L per minute by nasal cannula, and thus has become a standard for sham control conditions in clinical trials owing to the small degree of middle ear pressure this induces (ensuring the scientific integrity of blinded conditions). It is illogical to think that this dose will have a biologically beneficial effect for any approved indication, much less for persistent symptoms attributed to distant combat-related concussions or for a chronic mental disorder like posttraumatic stress disorder. Even so, as mounting evidence accumulates for the lack of efficacy with doses ranging up to 2.4 ATA, HBO treatment proponents have modified their viewpoints on conventional dosing and taken to insisting that the sham-condition dose of 1.2 ATA room air is clinically meaningful, along a demonstrably flat dose response “curve.”6,7 A much more scientifically credible and clinically meaningful explanation for the aggregate data are that the act of engaging in daily HBO treatment sessions for more than 1 month results in powerful nonspecific placebo effects. Rather than conduct additional HBO clinical trials in combat veterans, the evidence strongly suggests the need for reassessing existing clinical approaches to postwar symptoms attributed to concussions. There are certainly many other ways to create safer, jamainternalmedicine.com
more cost-effective, and more readily accessible healing environments than HBO chambers for the tens of thousands of US veterans suffering from postwar health conditions. Charles W. Hoge, MD Wayne B. Jonas, MD Author Affiliations: Center for Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland (Hoge); Samueli Institute, Alexandria, Virginia (Jonas). Corresponding Author: Charles W. Hoge, MD, Center for Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910 ([email protected]). Conflict of Interest Disclosures: None reported. Disclaimer: This response reflects the views of the authors and is not an official US Army or Department of Defense position. 1. Miller RS, Weaver LK, Bahraina N, et al; HOOPS Trial Team. Effects of hyperbaric oxygen on symptoms and quality of life among service members with persistent postconcussion symptoms: a randomized clinical trial [published online November 17, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014 .5479. 2. US Food and Drug Administration Consumer Health Information. Hyperbaric oxygen therapy: don’t be misled. http://www.fda.gov/downloads /ForConsumers/ConsumerUpdates/UCM366015.pdf. Accessed February 19, 2015. 3. Mukherjee A, Raison M, Sahni T, et al. Intensive rehabilitation combined with HBO2 therapy in children with cerebral palsy: a controlled longitudinal study. Undersea Hyperb Med. 2014;41(2):77-85. 4. Kranke P, Bennett MH, Martyn-St JM, Schnabel A, Debus SE. Hyperbaric oxygen therapy for chronic wounds [review]. Cochrane Libr. 2012;(4):CD004123. doi:10.1002/14651858.CD004123.pub3. 5. Levett D, Bennett MH, Millar I. Adjunctive hyperbaric oxygen for necrotizing fasciitis [review]. Cochrane Libr. 2015;(1):CD007937. doi:10.1002/14651858 .CD007937.pub2. 6. Harch PG. Hyperbaric oxygen therapy for post-concussion syndrome: contradictory conclusions from a study mischaracterized as sham-controlled. J Neurotrauma. 2013;30(23):1995-1999. 7. Efrati S, Ben-Jacob E. How and why hyperbaric oxygen therapy can bring new hope for children suffering from cerebral palsy: an editorial perspective. Undersea Hyperb Med. 2014;41(2):71-76.
Carotid Endarterectomy for Asymptomatic Stenosis To the Editor Brett and Levine1 recently discussed the case against identifying carotid stenosis in asymptomatic patients. We agree wholeheartedly that progress in medical therapy over the past 2 decades requires a reappraisal of whether carotid revascularization remains beneficial for such patients. In randomized trials, carotid endarterectomy (CEA) in asymptomatic patients was shown to be superior to medical management alone.2 At the time these trials were conducted, based on the observational studies available, many in the medical community had the opinion that CEA was not warranted because of the periprocedural risk; however, these trials proved that this view was incorrect. We have now entered a new period where many (including Brett and Levine) have the opinion based on observational studies that medical management has improved and revascularization in asymptomatic patients is no longer warranted. We suggest that CEA for asymptomatic stenosis not be discarded without the same rigor previously employed, that is, a high-quality randomized controlled trial to assess the relative efficacy and safety of intensive medical therapy alone, and intensive medical therapy plus CEA. (Reprinted) JAMA Internal Medicine July 2015 Volume 175, Number 7
Copyright 2015 American Medical Association. All rights reserved.
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1241
Letters
The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Study (CREST-2), funded by the National Institutes of Health, has recently been launched for exactly this purpose (NCT02089217). CREST-2 compares CEA or carotid artery stenting with intensive medical therapy. There are 2 parallel trials, one comparing CEA plus intensive medical therapy vs intensive medical therapy alone and the other comparing carotid artery stenting plus intensive medical therapy vs intensive medical therapy alone. Intensive medical therapy includes use of high-potency statins, targeted blood pressure reduction, targeted diabetes management, antiplatelet therapy, and lifestyle coaching (provided by INTERVENT; Savannah, Georgia). Patients with 70% to 99% asymptomatic carotid stenosis are eligible for enrollment. Further information is available on the study website3 and at clinicaltrials.gov. Physicians should consider referring patients with asymptomatic carotid stenosis for enrollment in CREST-2, so that highquality data can be collected to address this common clinical conundrum. Our patients deserve nothing less. Seemant Chaturvedi, MD George Howard, PhD James Meschia, MD Author Affiliations: Department of Neurology & Stroke Program, University of Miami Miller School of Medicine, Miami, Florida (Chaturvedi); Department of Biostatistics, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (Howard); Department of Neurology, Mayo ClinicFlorida, Jacksonville (Meschia). Corresponding Author: Seemant Chaturvedi, MD, Department of Neurology & Stroke Program, University of Miami, 1120 NW 14th St, Rm 1363, Miami, FL 33136 ([email protected]). Conflict of Interest Disclosures: Drs Howard and Meschia are two of the co-Principal Investigators for CREST-2. Dr Chaturvedi is an executive committee member of CREST-2. Editorial Note: This letter was shown to the corresponding author of the original article, who declined to reply on behalf of the authors. 1. Brett AS, Levine JD. The case against identifying carotid stenosis in asymptomatic patients. JAMA Intern Med. 2014;174(12):2004-2008. 2. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA. 1995;273(18): 1421-1428. 3. The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Study website. http://www.crest2trial.org. Accessed May 26, 2015.
One-Year Risk of Bleeding With Dabigatran in Patients With Atrial Fibrillation: Placing Real-World Results Into Perspective To the Editor The recent retrospective study by Hernandez et al1 reported that while dabigatran was associated with a lower rate of intracranial hemorrhage, the rate of major and gastrointestinal bleeding was higher relative to warfarin users in a Medicare cohort of patients with atrial fibrillation. To further substantiate these results, there are several aspects of this study that merit clarification. While the authors calculated the CHADS2 (congestive heart failure [1], hypertension [1], age ≥75 years [1], diabetes mellitus [1], prior stroke or transient ischemic attack or thromboembolism [2]) score to determine risk of stroke and 1242
thromboembolism,2 no validated tool is presented that offers predictive capability for bleeding risk. It would be worthwhile to assess the 1-year risk of major bleeding with dabigatran to determine if the benefit of anticoagulation indeed outweighed the risk. Whereas the bleeding results are consistent with the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, RE-LY demonstrated an increase in major bleeding only in patients older than 75 years. 3 Because the incidence of major bleeding was more pronounced in the dabigatran group, it would be valuable to report the number of patients who received an adjusted dose and the proportion of patients who experienced bleeding on 1 dosing regimen vs the other. Currently, there is no distinction between those who received dabigatran, 150 mg, twice daily, and those who received 75 mg, twice daily. Although the authors lacked access to detailed laboratory results, such as creatinine clearance, obtaining a list of patients with International Classification of Diseases, Ninth Revision (ICD-9), coding for chronic kidney disease could have sufficed. In addition, as an increasing number of antiplatelets augments bleeding risk, 4 it is worth noting the average number of antiplatelets used per patient. Owing to the proximity of this trial with dabigatran approval in the United States, the real-world results of bleeding rates seem to reflect clinician prescribing and lack of thorough patient assessment during the year following approval of a newly marketed anticoagulant. Owing to the numerous case reports of bleeding with dabigatran and heightened publicity to screen patients for candidacy, it is anticipated that a replica of this study in current time would result in decreased bleeding rates consistent with prescriber awareness to avoid or use caution in elderly patients, those with kidney disease, and those prescribed interacting medications. Notwithstanding, with subsequent approval of superior and equally effective albeit safer anticoagulants5 the question remains if the use of dabigatran should be relegated to second- or third-line therapy for atrial fibrillation. Marta A. Miyares, PharmD, BCPS (AQ Cardiology), CACP Author Affiliation: Pharmacy Department, Jackson Memorial Hospital, Miami, Florida. Corresponding Author: Marta A. Miyares, PharmD, BCPS (AQ Cardiology), CACP, Pharmacy Department, Jackson Memorial Hospital, 1611 NW 12th Ave, Miami, FL 33136 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Hernandez I, Baik SH, Piñera A, Zhang Y. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med. 2015;175(1):18-24. 2. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22): 2864-2870. 3. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151. 4. Hansen ML, Sørensen 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(16):1433-1441.
JAMA Internal Medicine July 2015 Volume 175, Number 7 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 07/07/2015
jamainternalmedicine.com
with persistent postconcussion symptoms: a randomized clinical trial [published online November 17, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014 .5479. 4. Lacey DJ, Stolfi A, Pilati LE. Effects of hyperbaric oxygen on motor function in children with cerebral palsy. Ann Neurol. 2012;72(5):695-703. 5. Efrati S, Ben-Jacob E. How and why hyperbaric oxygen therapy can bring new hope for children suffering from cerebral palsy: an editorial perspective. Undersea Hyperb Med. 2014;41(2):71-76.
In Reply Advances in medical care depend on well-controlled randomized clinical trials to validate the safety and efficacy of new interventions and to ensure that clinicians understand the active components.1 Hyperbaric oxygen (HBO) treatment is a very time-consuming and costly procedure that is not without harmful effects. Nevertheless, HBO treatment is being promoted by clinicians who dispense the service as a treatment for a vast number of medical conditions for which there are no US Food and Drug Administration indications or even acceptance by respected organizations, such as the Undersea and Hyperbaric Medical Society.2 The field suffers from numerous studies, such as the one by Mukherjee et al,3 that involve observational, nonblinded, nonrandomized methodology. Foundational to the design of well-controlled clinical studies is the assessment of whether the intervention’s mechanism of action is biologically plausible, exhibits a meaningful dose response, and is potentially relevant for the condition being treated. Over decades of experience with HBO treatment, procedures for approved indications, such as wound healing, necrotizing infections, burns, radiation injury, or carbon monoxide poisoning, have been standardized, most commonly with 100% oxygen delivered between 1.5 and 3.0 atmospheres absolute (ATA). Although efficacy questions remain, even at these doses,4,5 experts would never consider room air (21% oxygen), delivered at 1.2 ATA, to be an acceptable therapeutic dose for any approved clinical indication. This is approximately equivalent to the pressure of 2 m of seawater, or oxygen delivered at 1 L per minute by nasal cannula, and thus has become a standard for sham control conditions in clinical trials owing to the small degree of middle ear pressure this induces (ensuring the scientific integrity of blinded conditions). It is illogical to think that this dose will have a biologically beneficial effect for any approved indication, much less for persistent symptoms attributed to distant combat-related concussions or for a chronic mental disorder like posttraumatic stress disorder. Even so, as mounting evidence accumulates for the lack of efficacy with doses ranging up to 2.4 ATA, HBO treatment proponents have modified their viewpoints on conventional dosing and taken to insisting that the sham-condition dose of 1.2 ATA room air is clinically meaningful, along a demonstrably flat dose response “curve.”6,7 A much more scientifically credible and clinically meaningful explanation for the aggregate data are that the act of engaging in daily HBO treatment sessions for more than 1 month results in powerful nonspecific placebo effects. Rather than conduct additional HBO clinical trials in combat veterans, the evidence strongly suggests the need for reassessing existing clinical approaches to postwar symptoms attributed to concussions. There are certainly many other ways to create safer, jamainternalmedicine.com
more cost-effective, and more readily accessible healing environments than HBO chambers for the tens of thousands of US veterans suffering from postwar health conditions. Charles W. Hoge, MD Wayne B. Jonas, MD Author Affiliations: Center for Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland (Hoge); Samueli Institute, Alexandria, Virginia (Jonas). Corresponding Author: Charles W. Hoge, MD, Center for Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910 ([email protected]). Conflict of Interest Disclosures: None reported. Disclaimer: This response reflects the views of the authors and is not an official US Army or Department of Defense position. 1. Miller RS, Weaver LK, Bahraina N, et al; HOOPS Trial Team. Effects of hyperbaric oxygen on symptoms and quality of life among service members with persistent postconcussion symptoms: a randomized clinical trial [published online November 17, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014 .5479. 2. US Food and Drug Administration Consumer Health Information. Hyperbaric oxygen therapy: don’t be misled. http://www.fda.gov/downloads /ForConsumers/ConsumerUpdates/UCM366015.pdf. Accessed February 19, 2015. 3. Mukherjee A, Raison M, Sahni T, et al. Intensive rehabilitation combined with HBO2 therapy in children with cerebral palsy: a controlled longitudinal study. Undersea Hyperb Med. 2014;41(2):77-85. 4. Kranke P, Bennett MH, Martyn-St JM, Schnabel A, Debus SE. Hyperbaric oxygen therapy for chronic wounds [review]. Cochrane Libr. 2012;(4):CD004123. doi:10.1002/14651858.CD004123.pub3. 5. Levett D, Bennett MH, Millar I. Adjunctive hyperbaric oxygen for necrotizing fasciitis [review]. Cochrane Libr. 2015;(1):CD007937. doi:10.1002/14651858 .CD007937.pub2. 6. Harch PG. Hyperbaric oxygen therapy for post-concussion syndrome: contradictory conclusions from a study mischaracterized as sham-controlled. J Neurotrauma. 2013;30(23):1995-1999. 7. Efrati S, Ben-Jacob E. How and why hyperbaric oxygen therapy can bring new hope for children suffering from cerebral palsy: an editorial perspective. Undersea Hyperb Med. 2014;41(2):71-76.
Carotid Endarterectomy for Asymptomatic Stenosis To the Editor Brett and Levine1 recently discussed the case against identifying carotid stenosis in asymptomatic patients. We agree wholeheartedly that progress in medical therapy over the past 2 decades requires a reappraisal of whether carotid revascularization remains beneficial for such patients. In randomized trials, carotid endarterectomy (CEA) in asymptomatic patients was shown to be superior to medical management alone.2 At the time these trials were conducted, based on the observational studies available, many in the medical community had the opinion that CEA was not warranted because of the periprocedural risk; however, these trials proved that this view was incorrect. We have now entered a new period where many (including Brett and Levine) have the opinion based on observational studies that medical management has improved and revascularization in asymptomatic patients is no longer warranted. We suggest that CEA for asymptomatic stenosis not be discarded without the same rigor previously employed, that is, a high-quality randomized controlled trial to assess the relative efficacy and safety of intensive medical therapy alone, and intensive medical therapy plus CEA. (Reprinted) JAMA Internal Medicine July 2015 Volume 175, Number 7
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 07/07/2015
1241
Letters
The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Study (CREST-2), funded by the National Institutes of Health, has recently been launched for exactly this purpose (NCT02089217). CREST-2 compares CEA or carotid artery stenting with intensive medical therapy. There are 2 parallel trials, one comparing CEA plus intensive medical therapy vs intensive medical therapy alone and the other comparing carotid artery stenting plus intensive medical therapy vs intensive medical therapy alone. Intensive medical therapy includes use of high-potency statins, targeted blood pressure reduction, targeted diabetes management, antiplatelet therapy, and lifestyle coaching (provided by INTERVENT; Savannah, Georgia). Patients with 70% to 99% asymptomatic carotid stenosis are eligible for enrollment. Further information is available on the study website3 and at clinicaltrials.gov. Physicians should consider referring patients with asymptomatic carotid stenosis for enrollment in CREST-2, so that highquality data can be collected to address this common clinical conundrum. Our patients deserve nothing less. Seemant Chaturvedi, MD George Howard, PhD James Meschia, MD Author Affiliations: Department of Neurology & Stroke Program, University of Miami Miller School of Medicine, Miami, Florida (Chaturvedi); Department of Biostatistics, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (Howard); Department of Neurology, Mayo ClinicFlorida, Jacksonville (Meschia). Corresponding Author: Seemant Chaturvedi, MD, Department of Neurology & Stroke Program, University of Miami, 1120 NW 14th St, Rm 1363, Miami, FL 33136 ([email protected]). Conflict of Interest Disclosures: Drs Howard and Meschia are two of the co-Principal Investigators for CREST-2. Dr Chaturvedi is an executive committee member of CREST-2. Editorial Note: This letter was shown to the corresponding author of the original article, who declined to reply on behalf of the authors. 1. Brett AS, Levine JD. The case against identifying carotid stenosis in asymptomatic patients. JAMA Intern Med. 2014;174(12):2004-2008. 2. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA. 1995;273(18): 1421-1428. 3. The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Study website. http://www.crest2trial.org. Accessed May 26, 2015.
One-Year Risk of Bleeding With Dabigatran in Patients With Atrial Fibrillation: Placing Real-World Results Into Perspective To the Editor The recent retrospective study by Hernandez et al1 reported that while dabigatran was associated with a lower rate of intracranial hemorrhage, the rate of major and gastrointestinal bleeding was higher relative to warfarin users in a Medicare cohort of patients with atrial fibrillation. To further substantiate these results, there are several aspects of this study that merit clarification. While the authors calculated the CHADS2 (congestive heart failure [1], hypertension [1], age ≥75 years [1], diabetes mellitus [1], prior stroke or transient ischemic attack or thromboembolism [2]) score to determine risk of stroke and 1242
thromboembolism,2 no validated tool is presented that offers predictive capability for bleeding risk. It would be worthwhile to assess the 1-year risk of major bleeding with dabigatran to determine if the benefit of anticoagulation indeed outweighed the risk. Whereas the bleeding results are consistent with the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, RE-LY demonstrated an increase in major bleeding only in patients older than 75 years. 3 Because the incidence of major bleeding was more pronounced in the dabigatran group, it would be valuable to report the number of patients who received an adjusted dose and the proportion of patients who experienced bleeding on 1 dosing regimen vs the other. Currently, there is no distinction between those who received dabigatran, 150 mg, twice daily, and those who received 75 mg, twice daily. Although the authors lacked access to detailed laboratory results, such as creatinine clearance, obtaining a list of patients with International Classification of Diseases, Ninth Revision (ICD-9), coding for chronic kidney disease could have sufficed. In addition, as an increasing number of antiplatelets augments bleeding risk, 4 it is worth noting the average number of antiplatelets used per patient. Owing to the proximity of this trial with dabigatran approval in the United States, the real-world results of bleeding rates seem to reflect clinician prescribing and lack of thorough patient assessment during the year following approval of a newly marketed anticoagulant. Owing to the numerous case reports of bleeding with dabigatran and heightened publicity to screen patients for candidacy, it is anticipated that a replica of this study in current time would result in decreased bleeding rates consistent with prescriber awareness to avoid or use caution in elderly patients, those with kidney disease, and those prescribed interacting medications. Notwithstanding, with subsequent approval of superior and equally effective albeit safer anticoagulants5 the question remains if the use of dabigatran should be relegated to second- or third-line therapy for atrial fibrillation. Marta A. Miyares, PharmD, BCPS (AQ Cardiology), CACP Author Affiliation: Pharmacy Department, Jackson Memorial Hospital, Miami, Florida. Corresponding Author: Marta A. Miyares, PharmD, BCPS (AQ Cardiology), CACP, Pharmacy Department, Jackson Memorial Hospital, 1611 NW 12th Ave, Miami, FL 33136 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Hernandez I, Baik SH, Piñera A, Zhang Y. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med. 2015;175(1):18-24. 2. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22): 2864-2870. 3. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151. 4. Hansen ML, Sørensen 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(16):1433-1441.
JAMA Internal Medicine July 2015 Volume 175, Number 7 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 07/07/2015
jamainternalmedicine.com
