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 Rice University User on 05/19/2015
2543
Letters
The PEITHO study1 was not published when we wrote our review (although it has been published since), and we chose not to describe in detail data only available from an abstract. Furthermore, given the complexity and cost of thrombolytic therapy, we focused on mortality as the most likely outcome to affect practice. We acknowledge that the study was positive for the primary end point. In the MOPETT trial,2 the primary outcome was not clinically relevant (a reduction in pulmonary artery pressure) and therefore not likely to change practice; hence, we did not refer to it. With respect to thrombolysis for massive pulmonary embolism, there are no clinical trials that can be used as evidence to support it as a therapeutic mode. However, for patients with massive life-threatening pulmonary embolism, thrombolysis and surgery remain the only options available. Inferior vena cava filters are widely used in patients with acute venous thrombosis when anticoagulation is contraindicated, although there are no randomized trials that address this issue. Hence, it is correct that there is no strong evidence to support this practice. However, guidelines such as those from the American College of Chest Physicians 3 recommend this therapy when anticoagulation is contraindicated, but give it a grade 1B recommendation because there are no adequate data. The Prévention du Risque d’Embolie Pulmonaire par Interruption Cave 4 study did not address this issue but instead randomized patients with venous thromboembolism treated with anticoagulants to receive or not receive a filter. With respect to the use of aspirin for extended treatment of venous thromboembolism, we agree that the network meta-analysis5 showed a nonsignificant effect favoring the effectiveness of aspirin. In our opinion, at this time that is not enough to recommend aspirin as a treatment mode. Although it may be a reasonable option for secondary cardiovascular prevention, there are no data to support its use for a combined indication. Furthermore, although patients at high risk of bleeding with anticoagulation may bleed less with aspirin, there are no direct comparisons in patients with venous thromboembolism. In addition, there are currently no bleeding risk prediction tools that have been validated sufficiently in patients with venous thromboembolism. It is difficult to recommend aspirin when a high-risk bleeding group cannot be identified. Philip S. Wells, MD, FRCPC, MSc Melissa A. Forgie, MD, FRCPC, MSc Marc A. Rodger, MD, FRCPC, MSc Author Affiliations: Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada. Corresponding Author: Philip S. Wells, MD, FRCP(C), MSc, 501 Smyth Rd, PO Box 206, Ottawa, ON K1H 8L6, Canada ([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. 2544
1. 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. 2. 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. 3. Kearon C, Akl EA, Comerota AJ, et al. American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(suppl):e419Se494S. 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.
Legal and Ethical Challenges in Brain Death To the Editor Mr Gostin in his Viewpoint1 argued that “All states have followed the model act, although 2 states—New Jersey and New York—require hospitals to consider the family’s religious or moral views in determining a course of action after brain death.” However, the New Jersey statute and New York regulation require consideration of the individual’s belief, not the family’s. Furthermore, these states require determining death not by neurological criteria (and thus not after brain death) but solely upon the basis of cardiorespiratory criteria.2 Michael A. Grodin, MD Author Affiliation: Department of Health Law, Bioethics, and Human Rights, Boston University School of Public Health, Boston, Massachusetts. Corresponding Author: Michael A. Grodin, MD, Department of Health Law, Bioethics, and Human Rights, Boston University School of Public Health, 715 Albany St, Talbot W, Room 358, Boston, MA 02118 ([email protected]). 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. Gostin LO. Legal and ethical responsibilities following brain death: the McMath and Muñoz cases. JAMA. 2014;311(9):903-904. 2. Grodin MA. Religious exemptions: brain death and Jewish law. J Church State. 1994;36(2):357-372.
In Reply Dr Grodin is correct in his assertion that the laws of both New York1 and New Jersey2 refer to the religious beliefs of the individual rather than to those of the family. Both states, however, call upon the family or other close person to determine the individual’s beliefs when they are unknown.2,3 In the absence of an advance directive, it will thus often fall to the family to interpret and communicate the patient’s wishes. He also argues that, where an accommodation is granted, legal determination of death depends upon the cessation of cardiac and respiratory activity rather than upon measurement of neurological function. Such an accommodation could lead to an unfortunate situation in which a patient is medically brain dead but arguably not legally so.
JAMA June 25, 2014 Volume 311, Number 24
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Rice University User on 05/19/2015
jama.com
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 Rice University User on 05/19/2015
2543
Letters
The PEITHO study1 was not published when we wrote our review (although it has been published since), and we chose not to describe in detail data only available from an abstract. Furthermore, given the complexity and cost of thrombolytic therapy, we focused on mortality as the most likely outcome to affect practice. We acknowledge that the study was positive for the primary end point. In the MOPETT trial,2 the primary outcome was not clinically relevant (a reduction in pulmonary artery pressure) and therefore not likely to change practice; hence, we did not refer to it. With respect to thrombolysis for massive pulmonary embolism, there are no clinical trials that can be used as evidence to support it as a therapeutic mode. However, for patients with massive life-threatening pulmonary embolism, thrombolysis and surgery remain the only options available. Inferior vena cava filters are widely used in patients with acute venous thrombosis when anticoagulation is contraindicated, although there are no randomized trials that address this issue. Hence, it is correct that there is no strong evidence to support this practice. However, guidelines such as those from the American College of Chest Physicians 3 recommend this therapy when anticoagulation is contraindicated, but give it a grade 1B recommendation because there are no adequate data. The Prévention du Risque d’Embolie Pulmonaire par Interruption Cave 4 study did not address this issue but instead randomized patients with venous thromboembolism treated with anticoagulants to receive or not receive a filter. With respect to the use of aspirin for extended treatment of venous thromboembolism, we agree that the network meta-analysis5 showed a nonsignificant effect favoring the effectiveness of aspirin. In our opinion, at this time that is not enough to recommend aspirin as a treatment mode. Although it may be a reasonable option for secondary cardiovascular prevention, there are no data to support its use for a combined indication. Furthermore, although patients at high risk of bleeding with anticoagulation may bleed less with aspirin, there are no direct comparisons in patients with venous thromboembolism. In addition, there are currently no bleeding risk prediction tools that have been validated sufficiently in patients with venous thromboembolism. It is difficult to recommend aspirin when a high-risk bleeding group cannot be identified. Philip S. Wells, MD, FRCPC, MSc Melissa A. Forgie, MD, FRCPC, MSc Marc A. Rodger, MD, FRCPC, MSc Author Affiliations: Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada. Corresponding Author: Philip S. Wells, MD, FRCP(C), MSc, 501 Smyth Rd, PO Box 206, Ottawa, ON K1H 8L6, Canada ([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. 2544
1. 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. 2. 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. 3. Kearon C, Akl EA, Comerota AJ, et al. American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(suppl):e419Se494S. 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.
Legal and Ethical Challenges in Brain Death To the Editor Mr Gostin in his Viewpoint1 argued that “All states have followed the model act, although 2 states—New Jersey and New York—require hospitals to consider the family’s religious or moral views in determining a course of action after brain death.” However, the New Jersey statute and New York regulation require consideration of the individual’s belief, not the family’s. Furthermore, these states require determining death not by neurological criteria (and thus not after brain death) but solely upon the basis of cardiorespiratory criteria.2 Michael A. Grodin, MD Author Affiliation: Department of Health Law, Bioethics, and Human Rights, Boston University School of Public Health, Boston, Massachusetts. Corresponding Author: Michael A. Grodin, MD, Department of Health Law, Bioethics, and Human Rights, Boston University School of Public Health, 715 Albany St, Talbot W, Room 358, Boston, MA 02118 ([email protected]). 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. Gostin LO. Legal and ethical responsibilities following brain death: the McMath and Muñoz cases. JAMA. 2014;311(9):903-904. 2. Grodin MA. Religious exemptions: brain death and Jewish law. J Church State. 1994;36(2):357-372.
In Reply Dr Grodin is correct in his assertion that the laws of both New York1 and New Jersey2 refer to the religious beliefs of the individual rather than to those of the family. Both states, however, call upon the family or other close person to determine the individual’s beliefs when they are unknown.2,3 In the absence of an advance directive, it will thus often fall to the family to interpret and communicate the patient’s wishes. He also argues that, where an accommodation is granted, legal determination of death depends upon the cessation of cardiac and respiratory activity rather than upon measurement of neurological function. Such an accommodation could lead to an unfortunate situation in which a patient is medically brain dead but arguably not legally so.
JAMA June 25, 2014 Volume 311, Number 24
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Rice University User on 05/19/2015
jama.com
