Letters
COMMENT & RESPONSE
ingly, the characteristics of the study population deserve careful examination. Only 21.8% of patients with atrial fibrillation were prescribed warfarin, despite more than 75% of patients having a CHADS2 score of 2 or higher, perhaps reflecting stringent selection of patients with low overall bleeding risk. The reasons for withholding warfarin were not detailed. Moreover, Scandinavian cohorts typically have a higher prevalence of time in therapeutic range while taking warfarin, perhaps further curtailing bleeding risk, compared with the general population. Furthermore, rates of percutaneous coronary intervention in this postmyocardial infarction population were low (approximately 30%), despite an incidence of ST-elevation myocardial infarction (STEMI) of roughly 22%. Rates of STEMI and percutaneous coronary intervention were lower in the warfarin cohort, and associated uptake of dual antiplatelet therapy and aspirin monotherapy was also reduced in this group. Thus, relatively few patients (approximately 17%) were discharged taking triple therapy (warfarin plus dual antiplatelet therapy) after myocardial infarction, which may underestimate the overall bleeding risk in patients who were treated with warfarin after a myocardial infarction in this study compared with the general population, despite multivariable modeling. These data stand in contrast to figures reported in contemporary US-based registries with 60% of patients treated with warfarin admitted for myocardial infarction requiring stenting and being discharged taking triple therapy.4 This study informs understanding of the prescribing patterns of warfarin in a relatively low-risk bleeding cohort, but specific ischemic and bleeding outcomes should be interpreted with caution. Limited data were provided regarding anticoagulation strategies in patients at higher risk of bleeding after myocardial infarction, including the large percentage of patients requiring dual antiplatelet therapy by current guidelines. As the armamentarium of available oral antiplatelet and anticoagulant agents grows, specific testing of this subgroup is required to optimize combination postmyocardial infarction therapies. On balance, major bleeding may be the single most important predictor of subsequent long-term mortality, potentially surpassing risk associated with early recurrent myocardial infarction.5 The study by Carrero et al1 may provide false reassurance that warfarin therapy following myocardial infarction is without significant risk of bleeding.
Influence of Chronic Kidney Disease on Warfarin Therapy for Atrial Fibrillation
Muthiah Vaduganathan, MD, MPH Stephen J. Greene, MD
Author Affiliations: Robert Wood Johnson Foundation Clinical Scholars Program, University of Michigan, Ann Arbor (Moniz); Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor (Davis); Department of Family Medicine, University of Michigan, Ann Arbor (Chang). Corresponding Author: Michelle H. Moniz, MD, Robert Wood Johnson Foundation Clinical Scholars Program, University of Michigan, 2800 Plymouth Rd, Bldg 10 G016, Ann Arbor, MI 48109 ([email protected]). Published Online: April 22, 2014. doi:10.1001/jama.2014.4766. Author Contributions: Drs Moniz and Davis had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All authors. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Moniz, Chang. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Moniz, Davis. Administrative, technical, or material support: Moniz, Davis. Study supervision: Davis, Chang. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Davis reported that he serves as chief medical executive for the Michigan Department of Community Health. No other disclosures were reported. Funding/Support: This study was funded by the Robert Wood Johnson Foundation Clinical Scholars program and the University of Michigan Health System. Role of the Sponsor: The Robert Wood Johnson Foundation Clinical Scholars program and the University of Michigan Health System had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The findings and statements included herein are those of the authors and do not necessarily represent the opinions of the Michigan Department of Community Health. 1. Butler AS, Clayton EW, eds. A Review of the HHS Family Planning Program: Mission, Management and Measurement of Results. Washington, DC: National Academies Press; 2009. 2. Gossett DR, Kiley JW, Hammond C. Contraception is a fundamental primary care service. JAMA. 2013;309(19):1997-1998. 3. Zimmer EA, Welie JV, Rendell MS. Contraceptives and the law: a view from a Catholic medical institution. JAMA. 2013;309(19):1999-2000. 4. Eckholm E. Poll finds wide support for birth control coverage [published online March 1, 2012]. New York Times. http://www.nytimes.com. Accessed March 18, 2014. 5. Eilperin J, Clement S. It's not the pill, it's the payment: what polling says about the contraception mandate [published online January 3, 2014]. Washington Post. http://www.washingtonpost.com. Accessed March 18, 2014. 6. Public Religion Research Institute. Survey: majority of Catholics think employers should be required to provide health care plans that cover birth control at no cost [published online February 7, 2012]. http://publicreligion.org. Accessed March 18, 2014.
To the Editor Dr Carrero and colleagues1 evaluated the influence of chronic kidney disease (CKD) on the efficacy and safety of warfarin therapy in a population with atrial fibrillation and recent myocardial infarction. Previous studies have found that warfarin, when added to aspirin or dual antiplatelet therapy, is associated with increased risk of major bleeding.2,3 We thus find it surprising that, in this registrybased Swedish investigation, no excess bleeding risk was observed in warfarin users across stages of CKD. Accord-
Author Affiliations: Department of Medicine, Massachusetts General Hospital, Boston (Vaduganathan); Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois (Greene). Corresponding Author: Muthiah Vaduganathan, MD, MPH, Department of Medicine, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
jama.com
JAMA June 25, 2014 Volume 311, Number 24
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Otterbein University User on 05/31/2015
2541
Letters
1. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA. 2014;311(9):919-928.
Corresponding Author: Rahman Shah, MD, Section of Cardiovascular Medicine, University of Tennessee School of Medicine, 1030 Jefferson Ave, Memphis, TN 38104 ([email protected]).
2. Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation. 2012;126(10):1185-1193.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
3. Sørensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding in patients with acute 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(9706):1967-1974. 4. Wang TY, Robinson LA, Ou FS, et al. Discharge antithrombotic strategies among patients with acute coronary syndrome previously on warfarin anticoagulation: physician practice in the CRUSADE registry. Am Heart J. 2008; 155(2):361-368. 5. Mehran R, Pocock SJ, Nikolsky E, et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol. 2010;55(23):25562566.
To the Editor Several randomized trials and meta-analyses have shown that the risk of bleeding is significantly higher for warfarin anticoagulation therapy than for treatment with aspirin.1,2 However, in the study by Dr Carrero and colleagues,3 the authors concluded that warfarin use was not associated with an increased risk of bleeding, compared with no warfarin, in patients with CKD. This result is contrary to conventional wisdom and the current literature.1,2 Information bias, misclassification, and unmeasured confounding are major issues complicating the interpretation of observational studies4 and may have led to the conclusion that warfarin use did not increase the risk of bleeding in patients with CKD. Furthermore, clinical trials1,2 have shown that one of the major safety issues associated with warfarin therapy is intracranial hemorrhage, but Carrero et al3 did not provide any data on intracranial hemorrhage. In addition, the safety and efficacy of warfarin in patients with mild-to-moderate CKD are well established by randomized trials; the safety and efficacy of warfarin are unclear only in patients with stage 5 CKD.1 In the study by Carrero et al,3 the better outcome of warfarin therapy for stage 5 CKD is predominantly driven by a decreased risk of recurrent myocardial infarction, as the individual hazard ratio for mortality and ischemic stroke was not significant. However, in randomized trials, warfarin, in combination with aspirin or given alone, has been shown to be superior to aspirin alone in reducing the incidence of myocardial infarction in patients with, but not without, acute coronary syndrome.1,2 Thus, the findings of Carrero et al3 may not be generalizable to patients without acute coronary syndrome because all patients in the study had acute coronary syndrome. Rahman Shah, MD Kirsten M. Roberts, PharmD Kodangudi B. Ramanathan, MD Author Affiliations: Section of Cardiovascular Medicine, University of Tennessee School of Medicine, Memphis (Shah, Ramanathan); Veterans Affairs Medical Center, Memphis, Tennessee (Roberts). 2542
1. Aguilar MI, Hart R, Pearce LA. Oral anticoagulants vs antiplatelet therapy for preventing stroke in patients with nonvalvular atrial fibrillation and no history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2007;3(3): CD006186. 2. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347(13):969-974. 3. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA. 2014;311(9):919-928. 4. Jepsen P, Johnsen SP, Gillman MW, Sørensen HT. Interpretation of observational studies. Heart. 2004;90(8):956-960.
In Reply In our observational analysis, we reported outcomes associated with warfarin exposure in consecutive patients with atrial fibrillation surviving a myocardial infarction index event. Our data reflect Swedish clinical practice patterns in 2003 to 2010, which may not be the same as those in other parts of the world, other periods, or other populations. Drs Vaduganathan and Greene were surprised by the low percentage of patients with atrial fibrillation who were prescribed warfarin in our study. There may have been an underuse of warfarin in patients with atrial fibrillation during this period, as previously documented.1,2 However, the proportion of patients with a CHADS2 score of 2 and higher or with bleeding risk factors (age, hypertension, CKD, or previous stroke) was similar between groups, arguing against patient selection. The proportion of patients with myocardial infarction undergoing percutaneous coronary intervention in our study and the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry-Get With the Guidelines (GWTG) in the United States are similar for this period.3 The specific inclusion criteria of our study, together with an older patient age, possibly explain our low percutaneous coronary intervention rates. The low rates and the wellknown increased bleeding risk of triple therapy may explain the low prescription of dual antiplatelet therapy in warfarinexposed individuals. It is reassuring, however, that results remained robust in propensity-matched analyses balancing for dual antiplatelet therapy. Because a placebo-controlled study would be unethical, large-scale observational studies are substitutes but have to be interpreted with caution due to confounding by indication. Dr Shah and colleagues are concerned that our results disagree with some previous observational studies on warfarin safety in stage 4 and 5 CKD. As highlighted in the Editorial,4 explanations for this divergence may include our national coverage with universal health care access, adequate time in the therapeutic range while taking warfarin, and the richness of information to address confounding. The safety of warfarin use in patients receiving dialysis should, however, not be inferred from our study; although no
JAMA June 25, 2014 Volume 311, Number 24
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Otterbein University User on 05/31/2015
jama.com
Letters
linear deviations were observed, our study was underpowered for us to make definitive statements regarding warfarin outcomes in patients with stage 5 CKD. We did not report hemorrhagic stroke as a separate outcome, but given our short follow-up period, the number of registered events was too low to provide conclusive results. We believe that the most relevant outcome to consider is the aggregated composite as a surrogate for the net clinical benefit of warfarin use. The possible harm associated with warfarin use in CKD is of great concern, but our report suggests that such harm is not a universal finding. Our observational study does not solve this clinical dilemma, but adds alternative views to consider when balancing treatment options for a patient population in need of anticoagulant therapy. Juan Jesús Carrero, PhD(Pharm and Med) Karolina Szummer, MD, PhD Tomas Jernberg, MD, PhD Author Affiliations: Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden (Carrero); Division of Cardiology, Karolinska Institutet, Stockholm, Sweden (Szummer, Jernberg). Corresponding Author: Juan Jesús Carrero, PhD (Pharm and Med), Division of Renal Medicine, Karolinska Institutet, SE-14186 Stockholm, Sweden (juan.jesus [email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Carrero reported receiving grant funding from the Swedish Medical Research Council and the Westman Foundation. Dr Szummer reported receiving grant funding from ALF Medicin. Dr Jernberg reported receiving grant funding from the Swedish Heart and Lung Foundation and ALF Medicin. 1. Friberg L, Hammar N, Ringh M, Pettersson H, Rosenqvist M. Stroke prophylaxis in atrial fibrillation: who gets it and who does not? report from the Stockholm Cohort-study on Atrial Fibrillation (SCAF-study). Eur Heart J. 2006;27(16):1954-1964. 2. Waldo AL, Becker RC, Tapson VF, Colgan KJ; NABOR Steering Committee. Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation. J Am Coll Cardiol. 2005;46(9): 1729-1736. 3. Masoudi FA, Ponirakis A, Yeh RW, et al. Cardiovascular care facts: a report from the national cardiovascular data registry: 2011. J Am Coll Cardiol. 2013;62 (21):1931-1947. 4. Winkelmayer WC, Turakhia MP. Warfarin treatment in patients with atrial fibrillation and advanced chronic kidney disease: sins of omission or commission? JAMA. 2014;311(9):913-915.
Therapies for Venous Thromboembolism To the Editor The review by Dr Wells and colleagues1 on the treatment of venous thromboembolism requires some clarifications. Table 1 in the article summarized new oral anticoagulants as treatment options for venous thromboembolism. However, only rivaroxaban is currently approved in both the United States and Europe, dabigatran was recently approved by the US Food and Drug Administration (FDA), and apixaban awaits approval by both the FDA and the European Medicines Agency. For thrombolysis for submassive pulmonary embolism, Wells et al1 mentioned that the Pulmonary Embolism Thrombolysis (PEITHO) trial2 did not show a mortality reduction, but they did not mention that the PEITHO trial was not designed for that purpose. It was in fact positive for its primary end point,
a composite of death or hemodynamic collapse within 7 days (odds ratio, 0.44). Furthermore, 23 patients in the placebo group vs 4 in the intervention group received rescue thrombolysis (P < .001). In addition, Wells et al1 did not discuss the recent Moderate Pulmonary Embolism Treated With Thrombolysis (MOPETT) trial, which suggested low-dose thrombolysis as a potentially safe and beneficial option for less severe pulmonary embolism.3 In the text of the article, the authors also made no comments about massive pulmonary embolism, the clearest indication for thrombolysis. Wells et al1 stated that “inferior vena cava filters, ideally the retrievable variety, should be used when anticoagulation is contraindicated.” Although clinically reasonable, there is no strong evidence to support such practice. Filter placement is expensive, is not devoid of risk, and in the single existing randomized trial was not associated with reduced mortality.4 Last, citing a recent network meta-analysis,5 Wells et al1 argued against use of aspirin for extended treatment of venous thromboembolism. However, the reported nonsignificant effect was in the same direction as the significant reduction seen in other analyses. Aspirin could be a reasonable option for extended venous thromboembolism treatment, especially among those receiving it for secondary cardiovascular prevention and patients at high risk of bleeding with anticoagulants. Behnood Bikdeli, MD Author Affiliation: Yale University School of Medicine, New Haven, Connecticut. Corresponding Author: Behnood Bikdeli, MD, Yale University School of Medicine, One Church St, Ste 200, New Haven, CT 06510 (behnood.bikdeli @yale.edu). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Wells PS, Forgie MA, Rodger MA. Treatment of venous thromboembolism. JAMA. 2014;311(7):717-728. 2. Meyer G, Vicaut E, Danays T, et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370 (15):1402-1411. 3. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M; MOPETT Investigators. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273-277. 4. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis: Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7):409-415. 5. Castellucci LA, Cameron C, Le Gal G, et al. Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis. BMJ. 2013;347:f5133.
In Reply We are aware that the FDA and other agencies may not have approved all of the new oral anticoagulants for the treatment of venous thromboembolism; however, many jurisdictions have. The purpose of Table 1 was not to list drugs that have received agency approval but rather to list drugs that have evidence behind their use.
jama.com
JAMA June 25, 2014 Volume 311, Number 24
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Otterbein University User on 05/31/2015
2543
COMMENT & RESPONSE
ingly, the characteristics of the study population deserve careful examination. Only 21.8% of patients with atrial fibrillation were prescribed warfarin, despite more than 75% of patients having a CHADS2 score of 2 or higher, perhaps reflecting stringent selection of patients with low overall bleeding risk. The reasons for withholding warfarin were not detailed. Moreover, Scandinavian cohorts typically have a higher prevalence of time in therapeutic range while taking warfarin, perhaps further curtailing bleeding risk, compared with the general population. Furthermore, rates of percutaneous coronary intervention in this postmyocardial infarction population were low (approximately 30%), despite an incidence of ST-elevation myocardial infarction (STEMI) of roughly 22%. Rates of STEMI and percutaneous coronary intervention were lower in the warfarin cohort, and associated uptake of dual antiplatelet therapy and aspirin monotherapy was also reduced in this group. Thus, relatively few patients (approximately 17%) were discharged taking triple therapy (warfarin plus dual antiplatelet therapy) after myocardial infarction, which may underestimate the overall bleeding risk in patients who were treated with warfarin after a myocardial infarction in this study compared with the general population, despite multivariable modeling. These data stand in contrast to figures reported in contemporary US-based registries with 60% of patients treated with warfarin admitted for myocardial infarction requiring stenting and being discharged taking triple therapy.4 This study informs understanding of the prescribing patterns of warfarin in a relatively low-risk bleeding cohort, but specific ischemic and bleeding outcomes should be interpreted with caution. Limited data were provided regarding anticoagulation strategies in patients at higher risk of bleeding after myocardial infarction, including the large percentage of patients requiring dual antiplatelet therapy by current guidelines. As the armamentarium of available oral antiplatelet and anticoagulant agents grows, specific testing of this subgroup is required to optimize combination postmyocardial infarction therapies. On balance, major bleeding may be the single most important predictor of subsequent long-term mortality, potentially surpassing risk associated with early recurrent myocardial infarction.5 The study by Carrero et al1 may provide false reassurance that warfarin therapy following myocardial infarction is without significant risk of bleeding.
Influence of Chronic Kidney Disease on Warfarin Therapy for Atrial Fibrillation
Muthiah Vaduganathan, MD, MPH Stephen J. Greene, MD
Author Affiliations: Robert Wood Johnson Foundation Clinical Scholars Program, University of Michigan, Ann Arbor (Moniz); Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor (Davis); Department of Family Medicine, University of Michigan, Ann Arbor (Chang). Corresponding Author: Michelle H. Moniz, MD, Robert Wood Johnson Foundation Clinical Scholars Program, University of Michigan, 2800 Plymouth Rd, Bldg 10 G016, Ann Arbor, MI 48109 ([email protected]). Published Online: April 22, 2014. doi:10.1001/jama.2014.4766. Author Contributions: Drs Moniz and Davis had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All authors. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Moniz, Chang. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Moniz, Davis. Administrative, technical, or material support: Moniz, Davis. Study supervision: Davis, Chang. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Davis reported that he serves as chief medical executive for the Michigan Department of Community Health. No other disclosures were reported. Funding/Support: This study was funded by the Robert Wood Johnson Foundation Clinical Scholars program and the University of Michigan Health System. Role of the Sponsor: The Robert Wood Johnson Foundation Clinical Scholars program and the University of Michigan Health System had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The findings and statements included herein are those of the authors and do not necessarily represent the opinions of the Michigan Department of Community Health. 1. Butler AS, Clayton EW, eds. A Review of the HHS Family Planning Program: Mission, Management and Measurement of Results. Washington, DC: National Academies Press; 2009. 2. Gossett DR, Kiley JW, Hammond C. Contraception is a fundamental primary care service. JAMA. 2013;309(19):1997-1998. 3. Zimmer EA, Welie JV, Rendell MS. Contraceptives and the law: a view from a Catholic medical institution. JAMA. 2013;309(19):1999-2000. 4. Eckholm E. Poll finds wide support for birth control coverage [published online March 1, 2012]. New York Times. http://www.nytimes.com. Accessed March 18, 2014. 5. Eilperin J, Clement S. It's not the pill, it's the payment: what polling says about the contraception mandate [published online January 3, 2014]. Washington Post. http://www.washingtonpost.com. Accessed March 18, 2014. 6. Public Religion Research Institute. Survey: majority of Catholics think employers should be required to provide health care plans that cover birth control at no cost [published online February 7, 2012]. http://publicreligion.org. Accessed March 18, 2014.
To the Editor Dr Carrero and colleagues1 evaluated the influence of chronic kidney disease (CKD) on the efficacy and safety of warfarin therapy in a population with atrial fibrillation and recent myocardial infarction. Previous studies have found that warfarin, when added to aspirin or dual antiplatelet therapy, is associated with increased risk of major bleeding.2,3 We thus find it surprising that, in this registrybased Swedish investigation, no excess bleeding risk was observed in warfarin users across stages of CKD. Accord-
Author Affiliations: Department of Medicine, Massachusetts General Hospital, Boston (Vaduganathan); Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois (Greene). Corresponding Author: Muthiah Vaduganathan, MD, MPH, Department of Medicine, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
jama.com
JAMA June 25, 2014 Volume 311, Number 24
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Otterbein University User on 05/31/2015
2541
Letters
1. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA. 2014;311(9):919-928.
Corresponding Author: Rahman Shah, MD, Section of Cardiovascular Medicine, University of Tennessee School of Medicine, 1030 Jefferson Ave, Memphis, TN 38104 ([email protected]).
2. Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation. 2012;126(10):1185-1193.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
3. Sørensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding in patients with acute 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(9706):1967-1974. 4. Wang TY, Robinson LA, Ou FS, et al. Discharge antithrombotic strategies among patients with acute coronary syndrome previously on warfarin anticoagulation: physician practice in the CRUSADE registry. Am Heart J. 2008; 155(2):361-368. 5. Mehran R, Pocock SJ, Nikolsky E, et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol. 2010;55(23):25562566.
To the Editor Several randomized trials and meta-analyses have shown that the risk of bleeding is significantly higher for warfarin anticoagulation therapy than for treatment with aspirin.1,2 However, in the study by Dr Carrero and colleagues,3 the authors concluded that warfarin use was not associated with an increased risk of bleeding, compared with no warfarin, in patients with CKD. This result is contrary to conventional wisdom and the current literature.1,2 Information bias, misclassification, and unmeasured confounding are major issues complicating the interpretation of observational studies4 and may have led to the conclusion that warfarin use did not increase the risk of bleeding in patients with CKD. Furthermore, clinical trials1,2 have shown that one of the major safety issues associated with warfarin therapy is intracranial hemorrhage, but Carrero et al3 did not provide any data on intracranial hemorrhage. In addition, the safety and efficacy of warfarin in patients with mild-to-moderate CKD are well established by randomized trials; the safety and efficacy of warfarin are unclear only in patients with stage 5 CKD.1 In the study by Carrero et al,3 the better outcome of warfarin therapy for stage 5 CKD is predominantly driven by a decreased risk of recurrent myocardial infarction, as the individual hazard ratio for mortality and ischemic stroke was not significant. However, in randomized trials, warfarin, in combination with aspirin or given alone, has been shown to be superior to aspirin alone in reducing the incidence of myocardial infarction in patients with, but not without, acute coronary syndrome.1,2 Thus, the findings of Carrero et al3 may not be generalizable to patients without acute coronary syndrome because all patients in the study had acute coronary syndrome. Rahman Shah, MD Kirsten M. Roberts, PharmD Kodangudi B. Ramanathan, MD Author Affiliations: Section of Cardiovascular Medicine, University of Tennessee School of Medicine, Memphis (Shah, Ramanathan); Veterans Affairs Medical Center, Memphis, Tennessee (Roberts). 2542
1. Aguilar MI, Hart R, Pearce LA. Oral anticoagulants vs antiplatelet therapy for preventing stroke in patients with nonvalvular atrial fibrillation and no history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2007;3(3): CD006186. 2. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347(13):969-974. 3. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA. 2014;311(9):919-928. 4. Jepsen P, Johnsen SP, Gillman MW, Sørensen HT. Interpretation of observational studies. Heart. 2004;90(8):956-960.
In Reply In our observational analysis, we reported outcomes associated with warfarin exposure in consecutive patients with atrial fibrillation surviving a myocardial infarction index event. Our data reflect Swedish clinical practice patterns in 2003 to 2010, which may not be the same as those in other parts of the world, other periods, or other populations. Drs Vaduganathan and Greene were surprised by the low percentage of patients with atrial fibrillation who were prescribed warfarin in our study. There may have been an underuse of warfarin in patients with atrial fibrillation during this period, as previously documented.1,2 However, the proportion of patients with a CHADS2 score of 2 and higher or with bleeding risk factors (age, hypertension, CKD, or previous stroke) was similar between groups, arguing against patient selection. The proportion of patients with myocardial infarction undergoing percutaneous coronary intervention in our study and the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry-Get With the Guidelines (GWTG) in the United States are similar for this period.3 The specific inclusion criteria of our study, together with an older patient age, possibly explain our low percutaneous coronary intervention rates. The low rates and the wellknown increased bleeding risk of triple therapy may explain the low prescription of dual antiplatelet therapy in warfarinexposed individuals. It is reassuring, however, that results remained robust in propensity-matched analyses balancing for dual antiplatelet therapy. Because a placebo-controlled study would be unethical, large-scale observational studies are substitutes but have to be interpreted with caution due to confounding by indication. Dr Shah and colleagues are concerned that our results disagree with some previous observational studies on warfarin safety in stage 4 and 5 CKD. As highlighted in the Editorial,4 explanations for this divergence may include our national coverage with universal health care access, adequate time in the therapeutic range while taking warfarin, and the richness of information to address confounding. The safety of warfarin use in patients receiving dialysis should, however, not be inferred from our study; although no
JAMA June 25, 2014 Volume 311, Number 24
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Otterbein University User on 05/31/2015
jama.com
Letters
linear deviations were observed, our study was underpowered for us to make definitive statements regarding warfarin outcomes in patients with stage 5 CKD. We did not report hemorrhagic stroke as a separate outcome, but given our short follow-up period, the number of registered events was too low to provide conclusive results. We believe that the most relevant outcome to consider is the aggregated composite as a surrogate for the net clinical benefit of warfarin use. The possible harm associated with warfarin use in CKD is of great concern, but our report suggests that such harm is not a universal finding. Our observational study does not solve this clinical dilemma, but adds alternative views to consider when balancing treatment options for a patient population in need of anticoagulant therapy. Juan Jesús Carrero, PhD(Pharm and Med) Karolina Szummer, MD, PhD Tomas Jernberg, MD, PhD Author Affiliations: Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden (Carrero); Division of Cardiology, Karolinska Institutet, Stockholm, Sweden (Szummer, Jernberg). Corresponding Author: Juan Jesús Carrero, PhD (Pharm and Med), Division of Renal Medicine, Karolinska Institutet, SE-14186 Stockholm, Sweden (juan.jesus [email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Carrero reported receiving grant funding from the Swedish Medical Research Council and the Westman Foundation. Dr Szummer reported receiving grant funding from ALF Medicin. Dr Jernberg reported receiving grant funding from the Swedish Heart and Lung Foundation and ALF Medicin. 1. Friberg L, Hammar N, Ringh M, Pettersson H, Rosenqvist M. Stroke prophylaxis in atrial fibrillation: who gets it and who does not? report from the Stockholm Cohort-study on Atrial Fibrillation (SCAF-study). Eur Heart J. 2006;27(16):1954-1964. 2. Waldo AL, Becker RC, Tapson VF, Colgan KJ; NABOR Steering Committee. Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation. J Am Coll Cardiol. 2005;46(9): 1729-1736. 3. Masoudi FA, Ponirakis A, Yeh RW, et al. Cardiovascular care facts: a report from the national cardiovascular data registry: 2011. J Am Coll Cardiol. 2013;62 (21):1931-1947. 4. Winkelmayer WC, Turakhia MP. Warfarin treatment in patients with atrial fibrillation and advanced chronic kidney disease: sins of omission or commission? JAMA. 2014;311(9):913-915.
Therapies for Venous Thromboembolism To the Editor The review by Dr Wells and colleagues1 on the treatment of venous thromboembolism requires some clarifications. Table 1 in the article summarized new oral anticoagulants as treatment options for venous thromboembolism. However, only rivaroxaban is currently approved in both the United States and Europe, dabigatran was recently approved by the US Food and Drug Administration (FDA), and apixaban awaits approval by both the FDA and the European Medicines Agency. For thrombolysis for submassive pulmonary embolism, Wells et al1 mentioned that the Pulmonary Embolism Thrombolysis (PEITHO) trial2 did not show a mortality reduction, but they did not mention that the PEITHO trial was not designed for that purpose. It was in fact positive for its primary end point,
a composite of death or hemodynamic collapse within 7 days (odds ratio, 0.44). Furthermore, 23 patients in the placebo group vs 4 in the intervention group received rescue thrombolysis (P < .001). In addition, Wells et al1 did not discuss the recent Moderate Pulmonary Embolism Treated With Thrombolysis (MOPETT) trial, which suggested low-dose thrombolysis as a potentially safe and beneficial option for less severe pulmonary embolism.3 In the text of the article, the authors also made no comments about massive pulmonary embolism, the clearest indication for thrombolysis. Wells et al1 stated that “inferior vena cava filters, ideally the retrievable variety, should be used when anticoagulation is contraindicated.” Although clinically reasonable, there is no strong evidence to support such practice. Filter placement is expensive, is not devoid of risk, and in the single existing randomized trial was not associated with reduced mortality.4 Last, citing a recent network meta-analysis,5 Wells et al1 argued against use of aspirin for extended treatment of venous thromboembolism. However, the reported nonsignificant effect was in the same direction as the significant reduction seen in other analyses. Aspirin could be a reasonable option for extended venous thromboembolism treatment, especially among those receiving it for secondary cardiovascular prevention and patients at high risk of bleeding with anticoagulants. Behnood Bikdeli, MD Author Affiliation: Yale University School of Medicine, New Haven, Connecticut. Corresponding Author: Behnood Bikdeli, MD, Yale University School of Medicine, One Church St, Ste 200, New Haven, CT 06510 (behnood.bikdeli @yale.edu). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Wells PS, Forgie MA, Rodger MA. Treatment of venous thromboembolism. JAMA. 2014;311(7):717-728. 2. Meyer G, Vicaut E, Danays T, et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370 (15):1402-1411. 3. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M; MOPETT Investigators. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273-277. 4. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis: Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7):409-415. 5. Castellucci LA, Cameron C, Le Gal G, et al. Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis. BMJ. 2013;347:f5133.
In Reply We are aware that the FDA and other agencies may not have approved all of the new oral anticoagulants for the treatment of venous thromboembolism; however, many jurisdictions have. The purpose of Table 1 was not to list drugs that have received agency approval but rather to list drugs that have evidence behind their use.
jama.com
JAMA June 25, 2014 Volume 311, Number 24
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Otterbein University User on 05/31/2015
2543
