- Email: [email protected]
Fatal Association of Mechanical Valve Thrombosis With Dabigatran
2.
3. 4. 5. 6.
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developing world. Trans R Soc Trop Med Hyg. 2008;102(9): 843-851. Torres-Duque C, Maldonado D, Pérez-Padilla R, Ezzati M, Viegi G; Forum of International Respiratory Studies (FIRS) Task Force on Health Effects of Biomass Exposure. Biomass fuels and respiratory diseases: a review of the evidence. Proc Am Thorac Soc. 2008;5(5):577-590. Grobbelaar JP, Bateman ED. Hut lung: a domestically acquired pneumoconiosis of mixed etiology in rural women. Thorax. 1991;46(5):334-340. Gold JA, Jagirdar J, Hay JG, Addrizzo-Harris DJ, Naidich DP, Rom WN. Hut lung. A domestically acquired particulate lung disease. Medicine (Baltimore). 2000;79(5):310-317. Diaz JV, Koff J, Gotway MB, Nishimura S, Balmes JR. Case report: a case of wood-smoke-related pulmonary disease. Environ Health Perspect. 2006;114(5):759-762. Klaaver M, Kars AH, Maat AP, den Bakker MA. Pseudomediastinal fibrosis caused by massive lymphadenopathy in domestically acquired particulate lung disease. Ann Diagn Pathol. 2008;12(2):118-121. Nasr MR, Savici D, Tudor L, Abou Abdallah D, Newman N, Abraham JL. Inorganic dust exposure causes pulmonary fibrosis in smokers: analysis using light microscopy, scanning electron microscopy, and energy dispersive X-ray spectroscopy. Arch Environ Occup Health. 2006;61(2):53-60. Honma K, Abraham JL, Chiyotani K, et al. Proposed criteria for mixed-dust pneumoconiosis: definition, descriptions, and guidelines for pathologic diagnosis and clinical correlation. Hum Pathol. 2004;35(12):1515-1523.
for thromboembolism prevention in patients with nonvalvular atrial fibrillation (NVAF).1-3 They offer an ease of use for patients with NVAF, as well as a reduction in bleeding complications, as compared with the “old” oral anticoagulants (OACs). However, they are not yet approved for use in patients with prosthetic mechanical valves (PMVs), and no randomized data have been published so far on their safety and efficacy of use in these patients. Dabigatran etexilate is an oral direct thrombin inhibitor that has been approved recently in Israel under the 2012 “health basket” (national subsidized health care) for patients with NVAF who either (1) were treated with OACs and had uncontrolled international normalized ratio (INR) . 5 on one occasion in the recent year, (2) experienced stroke or transient ischemic attack in the last year while on OACs, or (3) have a CHADS2 (congestive heart failure, hypertension, age, diabetes mellitus, stroke) score ⱖ 4. The introduction of the NOACs has created confusion among cardiologists, general practitioners, and neurologists regarding their use in certain patient subsets. We present two cases of patients with PMVs who were switched from OACs to dabigatran and within 1 month experienced valve thrombosis leading eventually to their death. Both patients had an INR well within the therapeutic range prior to switching to dabigatran, had no comorbidities causing hypercoagulability, and were also highly compliant on dabigatran.
Case Reports
Fatal Association of Mechanical Valve Thrombosis With Dabigatran A Report of Two Cases Shaul Atar, MD; Alice Wishniak, MD; Alexander Shturman, MD; Sewaed Shtiwi, MD; and Marc Brezins, MD
Several new oral anticoagulants have been approved for thromboembolism prevention in patients with nonvalvular atrial fibrillation. However, they are not yet approved for anticoagulation use in patients with prosthetic mechanical valves, and no randomized data have been published so far on their safety of use in these patients. We present two cases of patients with prosthetic mechanical mitral valves who were switched from warfarin and acenocoumarol to dabigatran and within 1 month experienced severe valve complications resulting in death. One patient experienced stroke and later cardiogenic shock and death, and the other experienced pulmonary edema, cardiogenic shock, and subsequent death. CHEST 2013; 144(1):327–328 Abbreviations: AF 5 atrial fibrillation; INR 5 international normalized ratio; NOAC 5 new oral anticoagulant; NVAF 5 nonvalvular atrial fibrillation; OAC 5 oral anticoagulant; PMV 5 prosthetic mechanical valve
S
everal new oral anticoagulants (NOACs) (dabigatran etexilate, rivaroxaban, apixaban) have been approved
Case 1 A 72-year-old woman presented with pulmonary edema. She had undergone mitral valve open commissurotomy 39 years earlier and a mechanical bileaflet mitral valve replacement 21 years later, and since then was treated with acenocoumarol. She had permanent AF, was highly compliant with her medications, and never had thrombotic or bleeding complications. Five months prior to her admission, her general practitioner switched her from acenocoumarol to dabigatran (110 mg bid) because of a single measurement of an INR above 5. One month later, she was admitted with dysarthria and mild hemiparesis and received a diagnosis of stroke, yet dabigatran was continued on discharge, and no cardiology consultation was requested. Three months later, she was admitted with severe pulmonary edema and shock. Cinefluoroscopy revealed a stuck anterior mitral leaflet, and transesophageal echocardiography revealed a large thrombus obstructing the mitral valve. She was sent to undergo immediate mitral valve replacement. A large occluding organized thrombus lining the atrial aspect of the prosthetic valve was discovered, and the valve was replaced with a biologic valve. Unfortunately, the patient died 3 days later of cardiogenic shock.
Case 2 A 73-year-old woman with a prior mechanical bileaflet mitral valve replacement 12 years earlier, paroxysmal AF, and a history of gastrointestinal bleeding, was switched from warfarin to dabigatran (150 mg bid) by the family
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practitioner 2 months prior to her admission. She was reportedly highly compliant with warfarin and also received aspirin 100 mg daily. She now presented with pulmonary edema and cardiogenic shock. Cinefluoroscopy revealed a stuck anterior mitral leaflet, and the patient was referred for urgent surgery. A large organized thrombus obstructing both leaflets was discovered during operation, and the valve was replaced with a biologic valve. Despite all possible measurements taken, including the insertion of an intraaortic balloon pump, the patient died a few hours postsurgery.
Discussion We present two tragic cases of patients admitted to a cardiology department of a single community hospital. These two patients had their valves implanted 12 and 18 years earlier, had never experienced any valve complication, were highly compliant with OAC therapy, and had no previous signs or symptoms of valve failure. One to 2 months after being switched from OACs to dabigatran, both patients became severely symptomatic (one developed stroke and the other cardiogenic shock) and were subsequently diagnosed with valve thrombosis. Thus, in both cases, a temporal association with the discontinuation of OACs and the initiation of dabigatran is highly suggestive. Although there is a risk of rebound hypercoagulability after stopping OACs, the time interval (few weeks to months) to death, as well as the presence of well-organized, large thrombi found on surgery suggests a failure of dabigatran to prevent valve thrombosis. There are currently three case reports of mechanical valve thrombosis in association with the NOACs: one of an aortic valve thrombosis resulting in stroke4 and two other cases of aortic and mitral valve thrombosis in patients who survived the repeat surgery.5 Both of these patients, however, did not survive the repeat surgery, suggestive of a fatal association of the use of NOACs with mechanical valve thrombosis. The time interval from discontinuation of OACs and the switch to the NOACs in all five cases is as early as 1 to 2 months. The use of dabigatran for anticoagulation with mechanical valves has been previously studied in vitro.6,7 These studies suggest that dabigatran in very high doses (20 mg/kg po bid)7 or in doses 15 to 20 times higher than those used in clinical practice6 was equal to low-molecular-weight heparin, Manuscript received October 8, 2012; revision accepted January 26, 2013. Affiliations: From the Department of Cardiovascular Medicine (Drs Atar, Wishniak, Shturman, and Brezins), The Western Galilee Hospital in Nahariya, Nahariya; Faculty of Medicine of the Galilee (Drs Atar, Shturman, and Brezins), Bar Ilan University, Safed; and Department of Cardiothoracic Surgery (Dr Shtiwi), Lady Davis Carmel Medical Center, Haifa, Israel. Correspondence to: Shaul Atar, MD, The Western Galilee Hospital of Nahariya, Nahariya 22100, Israel; e-mail: shaul.atar@ gmail.com © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-2486
and, thus, may have a future potential use for anticoagulation in patients with PMV. Rivaroxaban was also studied in vitro and has been suggested as a bridge for temporary discontinuation of OACs.8 RE-ALIGN, a phase 2 trial evaluating the safety and pharmacokinetics of dabigatran in 400 patients with PMV, is currently ongoing.9 This 12-week study will compare three doses of dabigatran (150 mg bid, 220 mg bid, and 300 mg bid) to warfarin. A RE-ALIGN extension study will evaluate the safety of dabigatran in this patient population for up to 84 months, and the dose of long-term dabigatran treatment will be determined according to individual minimal dabigatran plasma level.9 However, until further phase 3 large clinical studies are published, the off-label use of NOACs in patients with PMV or in patients at much higher thrombotic risk than those with NVAF should strongly be discouraged.
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: The authors obtained patient permission to publish this information.
References 1. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11): 981-992. 2. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. 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. Stewart RA, Astell H, Young L, White HD. Thrombosis on a mechanical aortic valve whilst anti-coagulated with dabigatran. Heart Lung Circ. 2012;21(1):53-55. 5. Price J, Hynes M, Labinaz M, Ruel M, Boodhwani M. Mechanical valve thrombosis on dabigatran. J Am Coll Cardiol. 2012;60(17):1710-1711. 6. Maegdefessel L, Linde T, Krapiec F, et al. In vitro comparison of dabigatran, unfractionated heparin, and low-molecularweight heparin in preventing thrombus formation on mechanical heart valves. Thromb Res. 2010;126(3):e196-e200. 7. McKellar SH, Abel S, Camp CL, Suri RM, Ereth MH, Schaff HV. Effectiveness of dabigatran etexilate for thromboprophylaxis of mechanical heart valves. J Thorac Cardiovasc Surg. 2011;141(6):1410-1416. 8. Kaeberich A, Reindl I, Raaz U, et al. Comparison of unfractionated heparin, low-molecular-weight heparin, low-dose and high-dose rivaroxaban in preventing thrombus formation on mechanical heart valves: results of an in vitro study. J Thromb Thrombolysis. 2011;32(4):417-425. 9. Van de Werf F, Brueckmann M, Connolly SJ, et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: the randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). Am Heart J. 2012;163(6):931-937.
328
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 07/08/2013
Selected Reports
3. 4. 5. 6.
7.
8.
developing world. Trans R Soc Trop Med Hyg. 2008;102(9): 843-851. Torres-Duque C, Maldonado D, Pérez-Padilla R, Ezzati M, Viegi G; Forum of International Respiratory Studies (FIRS) Task Force on Health Effects of Biomass Exposure. Biomass fuels and respiratory diseases: a review of the evidence. Proc Am Thorac Soc. 2008;5(5):577-590. Grobbelaar JP, Bateman ED. Hut lung: a domestically acquired pneumoconiosis of mixed etiology in rural women. Thorax. 1991;46(5):334-340. Gold JA, Jagirdar J, Hay JG, Addrizzo-Harris DJ, Naidich DP, Rom WN. Hut lung. A domestically acquired particulate lung disease. Medicine (Baltimore). 2000;79(5):310-317. Diaz JV, Koff J, Gotway MB, Nishimura S, Balmes JR. Case report: a case of wood-smoke-related pulmonary disease. Environ Health Perspect. 2006;114(5):759-762. Klaaver M, Kars AH, Maat AP, den Bakker MA. Pseudomediastinal fibrosis caused by massive lymphadenopathy in domestically acquired particulate lung disease. Ann Diagn Pathol. 2008;12(2):118-121. Nasr MR, Savici D, Tudor L, Abou Abdallah D, Newman N, Abraham JL. Inorganic dust exposure causes pulmonary fibrosis in smokers: analysis using light microscopy, scanning electron microscopy, and energy dispersive X-ray spectroscopy. Arch Environ Occup Health. 2006;61(2):53-60. Honma K, Abraham JL, Chiyotani K, et al. Proposed criteria for mixed-dust pneumoconiosis: definition, descriptions, and guidelines for pathologic diagnosis and clinical correlation. Hum Pathol. 2004;35(12):1515-1523.
for thromboembolism prevention in patients with nonvalvular atrial fibrillation (NVAF).1-3 They offer an ease of use for patients with NVAF, as well as a reduction in bleeding complications, as compared with the “old” oral anticoagulants (OACs). However, they are not yet approved for use in patients with prosthetic mechanical valves (PMVs), and no randomized data have been published so far on their safety and efficacy of use in these patients. Dabigatran etexilate is an oral direct thrombin inhibitor that has been approved recently in Israel under the 2012 “health basket” (national subsidized health care) for patients with NVAF who either (1) were treated with OACs and had uncontrolled international normalized ratio (INR) . 5 on one occasion in the recent year, (2) experienced stroke or transient ischemic attack in the last year while on OACs, or (3) have a CHADS2 (congestive heart failure, hypertension, age, diabetes mellitus, stroke) score ⱖ 4. The introduction of the NOACs has created confusion among cardiologists, general practitioners, and neurologists regarding their use in certain patient subsets. We present two cases of patients with PMVs who were switched from OACs to dabigatran and within 1 month experienced valve thrombosis leading eventually to their death. Both patients had an INR well within the therapeutic range prior to switching to dabigatran, had no comorbidities causing hypercoagulability, and were also highly compliant on dabigatran.
Case Reports
Fatal Association of Mechanical Valve Thrombosis With Dabigatran A Report of Two Cases Shaul Atar, MD; Alice Wishniak, MD; Alexander Shturman, MD; Sewaed Shtiwi, MD; and Marc Brezins, MD
Several new oral anticoagulants have been approved for thromboembolism prevention in patients with nonvalvular atrial fibrillation. However, they are not yet approved for anticoagulation use in patients with prosthetic mechanical valves, and no randomized data have been published so far on their safety of use in these patients. We present two cases of patients with prosthetic mechanical mitral valves who were switched from warfarin and acenocoumarol to dabigatran and within 1 month experienced severe valve complications resulting in death. One patient experienced stroke and later cardiogenic shock and death, and the other experienced pulmonary edema, cardiogenic shock, and subsequent death. CHEST 2013; 144(1):327–328 Abbreviations: AF 5 atrial fibrillation; INR 5 international normalized ratio; NOAC 5 new oral anticoagulant; NVAF 5 nonvalvular atrial fibrillation; OAC 5 oral anticoagulant; PMV 5 prosthetic mechanical valve
S
everal new oral anticoagulants (NOACs) (dabigatran etexilate, rivaroxaban, apixaban) have been approved
Case 1 A 72-year-old woman presented with pulmonary edema. She had undergone mitral valve open commissurotomy 39 years earlier and a mechanical bileaflet mitral valve replacement 21 years later, and since then was treated with acenocoumarol. She had permanent AF, was highly compliant with her medications, and never had thrombotic or bleeding complications. Five months prior to her admission, her general practitioner switched her from acenocoumarol to dabigatran (110 mg bid) because of a single measurement of an INR above 5. One month later, she was admitted with dysarthria and mild hemiparesis and received a diagnosis of stroke, yet dabigatran was continued on discharge, and no cardiology consultation was requested. Three months later, she was admitted with severe pulmonary edema and shock. Cinefluoroscopy revealed a stuck anterior mitral leaflet, and transesophageal echocardiography revealed a large thrombus obstructing the mitral valve. She was sent to undergo immediate mitral valve replacement. A large occluding organized thrombus lining the atrial aspect of the prosthetic valve was discovered, and the valve was replaced with a biologic valve. Unfortunately, the patient died 3 days later of cardiogenic shock.
Case 2 A 73-year-old woman with a prior mechanical bileaflet mitral valve replacement 12 years earlier, paroxysmal AF, and a history of gastrointestinal bleeding, was switched from warfarin to dabigatran (150 mg bid) by the family
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 07/08/2013
CHEST / 144 / 1 / JULY 2013
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practitioner 2 months prior to her admission. She was reportedly highly compliant with warfarin and also received aspirin 100 mg daily. She now presented with pulmonary edema and cardiogenic shock. Cinefluoroscopy revealed a stuck anterior mitral leaflet, and the patient was referred for urgent surgery. A large organized thrombus obstructing both leaflets was discovered during operation, and the valve was replaced with a biologic valve. Despite all possible measurements taken, including the insertion of an intraaortic balloon pump, the patient died a few hours postsurgery.
Discussion We present two tragic cases of patients admitted to a cardiology department of a single community hospital. These two patients had their valves implanted 12 and 18 years earlier, had never experienced any valve complication, were highly compliant with OAC therapy, and had no previous signs or symptoms of valve failure. One to 2 months after being switched from OACs to dabigatran, both patients became severely symptomatic (one developed stroke and the other cardiogenic shock) and were subsequently diagnosed with valve thrombosis. Thus, in both cases, a temporal association with the discontinuation of OACs and the initiation of dabigatran is highly suggestive. Although there is a risk of rebound hypercoagulability after stopping OACs, the time interval (few weeks to months) to death, as well as the presence of well-organized, large thrombi found on surgery suggests a failure of dabigatran to prevent valve thrombosis. There are currently three case reports of mechanical valve thrombosis in association with the NOACs: one of an aortic valve thrombosis resulting in stroke4 and two other cases of aortic and mitral valve thrombosis in patients who survived the repeat surgery.5 Both of these patients, however, did not survive the repeat surgery, suggestive of a fatal association of the use of NOACs with mechanical valve thrombosis. The time interval from discontinuation of OACs and the switch to the NOACs in all five cases is as early as 1 to 2 months. The use of dabigatran for anticoagulation with mechanical valves has been previously studied in vitro.6,7 These studies suggest that dabigatran in very high doses (20 mg/kg po bid)7 or in doses 15 to 20 times higher than those used in clinical practice6 was equal to low-molecular-weight heparin, Manuscript received October 8, 2012; revision accepted January 26, 2013. Affiliations: From the Department of Cardiovascular Medicine (Drs Atar, Wishniak, Shturman, and Brezins), The Western Galilee Hospital in Nahariya, Nahariya; Faculty of Medicine of the Galilee (Drs Atar, Shturman, and Brezins), Bar Ilan University, Safed; and Department of Cardiothoracic Surgery (Dr Shtiwi), Lady Davis Carmel Medical Center, Haifa, Israel. Correspondence to: Shaul Atar, MD, The Western Galilee Hospital of Nahariya, Nahariya 22100, Israel; e-mail: shaul.atar@ gmail.com © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-2486
and, thus, may have a future potential use for anticoagulation in patients with PMV. Rivaroxaban was also studied in vitro and has been suggested as a bridge for temporary discontinuation of OACs.8 RE-ALIGN, a phase 2 trial evaluating the safety and pharmacokinetics of dabigatran in 400 patients with PMV, is currently ongoing.9 This 12-week study will compare three doses of dabigatran (150 mg bid, 220 mg bid, and 300 mg bid) to warfarin. A RE-ALIGN extension study will evaluate the safety of dabigatran in this patient population for up to 84 months, and the dose of long-term dabigatran treatment will be determined according to individual minimal dabigatran plasma level.9 However, until further phase 3 large clinical studies are published, the off-label use of NOACs in patients with PMV or in patients at much higher thrombotic risk than those with NVAF should strongly be discouraged.
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: The authors obtained patient permission to publish this information.
References 1. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11): 981-992. 2. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. 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. Stewart RA, Astell H, Young L, White HD. Thrombosis on a mechanical aortic valve whilst anti-coagulated with dabigatran. Heart Lung Circ. 2012;21(1):53-55. 5. Price J, Hynes M, Labinaz M, Ruel M, Boodhwani M. Mechanical valve thrombosis on dabigatran. J Am Coll Cardiol. 2012;60(17):1710-1711. 6. Maegdefessel L, Linde T, Krapiec F, et al. In vitro comparison of dabigatran, unfractionated heparin, and low-molecularweight heparin in preventing thrombus formation on mechanical heart valves. Thromb Res. 2010;126(3):e196-e200. 7. McKellar SH, Abel S, Camp CL, Suri RM, Ereth MH, Schaff HV. Effectiveness of dabigatran etexilate for thromboprophylaxis of mechanical heart valves. J Thorac Cardiovasc Surg. 2011;141(6):1410-1416. 8. Kaeberich A, Reindl I, Raaz U, et al. Comparison of unfractionated heparin, low-molecular-weight heparin, low-dose and high-dose rivaroxaban in preventing thrombus formation on mechanical heart valves: results of an in vitro study. J Thromb Thrombolysis. 2011;32(4):417-425. 9. Van de Werf F, Brueckmann M, Connolly SJ, et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: the randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). Am Heart J. 2012;163(6):931-937.
328
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 07/08/2013
Selected Reports