RESEARCH CORRESPONDENCE Safety of discontinuation of anticoagulation in patients with continuous-flow left ventricular assist devices Forum Kamdar, MD,a Peter Eckman, MD,a and Ranjit John, MDb From the aDivisions of Cardiology, University of Minnesota, Minneapolis, Minnesota; and the bCardiothoracic Surgery, University of Minnesota, Minneapolis, Minnesota
Continuous-flow left ventricular assist devices (CF-LVADs) are standard therapy for end-stage heart failure given their efficacy and durability. However, to prevent thrombotic device-related complications, these devices require systemic anti-coagulation and anti-platelet therapy. This can result in significant bleeding episodes, such as gastrointestinal bleeding and epistaxis, occurring in 15% to 45% of cases and occasionally warranting discontinuation of such therapy.1–3 The incidence of thrombotic complications, including pump thrombosis, neurologic complications and peripheral thromboembolic events, has been relatively low, ranging from 0% to 7% in large multicenter trials.1,2 Because bleeding complications predominate among the adverse events in patients with continuous-flow LVADs, major bleeding may occasionally warrant discontinuation of anti-coagulation therapy.3 The incidence of stopping anti-coagulation for prolonged periods and the safety profile with regard to thromboembolic complications in CF-LVAD patients has not been adequately described. We reviewed all patients receiving a CF-LVAD from June 2005 to October 2011 at the University of Minnesota. CF pumps included the HeartMate II (Thoratec, Pleasanton, CA), VentrAssist (Ventracor, Australia) and HVAD (HeartWare, Framingham, MA). Any patients whose anti-coagulation or anti-coagulation and anti-platelet therapy was discontinued for 430 days were included in the analysis. Patients with only temporary or biventricular mechanical circulatory support and patients who died within 30 days of LVAD placement were excluded from the analysis. We collected baseline and follow-up data, including patient characteristics, history of atrial fibrillation, history of heparin-induced thrombocytopenia, renal function at time of discontinuation, LVAD speed at time of discontinuation, and aortic valve opening on echocardiography within 3 months of discontinuation of anti-coagulation, anti-platelet and anti-coagulation use, and anti-coagulation hematologic parameters. After patients were discharged from the hospital, they
returned to our center for follow-up, device review and clinical assessment. Significant gastrointestinal bleeding (GI) bleeding was defined by major bleeding adverse event criteria according to INTERMACS: an episode of bleeding (in this case GI bleeding) that results in (a) death, (b) reoperation, (c) hospitalization and (d) transfusion of packed red blood cells (PRBCs) at 47 days post-implant. Initially (in our first 14 patients), we used intravenous infusion of unfractionated heparin as a bridge to warfarin therapy, titrating the dose to an international normalized ratio (INR) of 2 to 3. However, as reported previously, we changed our anti-coagulation therapy protocol to include only warfarin therapy starting on Days 2 or 3 postoperatively, titrating the dose to an INR of 1.5 to 2, in addition to anti-platelet therapy with aspirin.4 In 2010, we shifted to a goal INR of 2 to 2.5, in the absence of other indications for a higher goal, such as mechanical mitral valve. Thromboelastography or platelet function assay are not routinely used to guide anti-coagulation strategies in our practice. All data were prospectively collected and retrospectively analyzed. Continuous data are presented as mean ⫾ standard deviation. Categorical data are presented as a percent. Continuous data were compared by analysis of variance (ANOVA) or by t-test as indicated. The chi-square test or Fisher’s exact test was used for categorical variables. Results were considered statistically significant at p r 0.05. All analyses were done with SPSS, version 12.0 (SPSS, Inc., Chicago, IL). Two hundred thirteen patients received CF-LVADs between 2005 and 2011. Of these, 6.5% had discontinuation of either warfarin or both warfarin and aspirin: 10 patients had warfarin discontinued and 4 had both aspirin (ASA) and warfarin discontinued (Table 1). These patients had a mean age of 61 ⫾ 14 years, 64% were male, 76% had an etiology of ischemic cardiomyopathy, and 71% were implanted as bridge-to-transplant (BTT) patients. There was no overall significant difference between the anti-coagulated cohort and in the cohort in which anti-coagulation was discontinued (Table 2). Of the 14 patients in which anti-coagulation was discontinued, 36% had a history of atrial fibrillation, 7% with a history of heparin-induced thrombocytopenia, no patients had bacteremia in the 3 months preceding or subsequent to discontinuation of warfarin, 50% had aortic valve opening, and the average creatinine was 1.3 (Table 1). The indication for discontinuing anti-coagulation was significant GI bleeding in all patients. Discontinuation of warfarin occurred at a mean
1053-2498/$ - see front matter r 2014 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2013.12.008
Research Correspondence
Table 1
Patient number 1 2 3 4 5a 6b 7 8 9 10 11c 12c 13c 14c
Profiles of Patients off Anti-coagulation During CF-LVAD Support
Age Gender Etiology
Implant strategy
History of atrial History fibrillation of HIT
Baseline platelet count
Baseline creatinine
Time to discontinuation of anticoagulation (days)
79 44 63 65 66 71 66 72 51 65 70 63 48 24
DT BTT BTT BTT BTT DT BTT DT BTT BTT DT BTT BTT BTT
Yes No No No No No Yes Yes Yes No No Yes No No
225 246 272 101 290 473 109 165 313 99 142 101 424 191
1.8 0.99 1.53 1.37 1.17 0.9 1.5 1.62 1.12 0.92 1.12 2.4 1.18 1.12
494 157 9 185 189 626 676 31 322 51 1,607 180 120 469
M F M M M F M M F M F M M F
Ischemic Non-ischemic Ischemic Ischemic Ischemic Ischemic Ischemic Ischemic Ischemic Ischemic Ischemic Ischemic Non-ischemic Non-ischemic
No No No No No No No No No No No No No Yes
Time off anticoagulation (days)
Platelet count at of discontinuation of anticoagulation
Positive blood culture ⫾3 LVAD speed Aortic valve months (RPM) opens
1,980 382 137 31 68 473 1,252 99 45 61 38 55 494 220
176 224 252 126 150 290 98 304 184 181 191 126 402 360
No No No No No No No No No No No No No No
9,400 9,600 8,800 9,400 2,000 8,600 9,200 8,800 9,000 9,200 9,000 8,800 9,000 10,000
No No Yes Yes Yes Yes Yes No No No Yes Yes No Yes
a This b This c
patient had VentrAssist LVAD. patient had device exchange due to pump thrombus after being off warfarin for 1.3 years. These patients had discontinuation of both anti-coagulation and aspirin.
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The Journal of Heart and Lung Transplantation, Vol 33, No 3, March 2014
Table 2 Baseline Characteristics of No Anti-coagulation Patient Cohort and Anti-coagulated Patient Cohort
Age Male gender (%) Ischemic etiology Bridge to transplant
No anti-coagulation Anti-coagulated (n ¼ 14) (n ¼ 199)
p-value
60 ⫾ 14 64%
55 ⫾ 14 78%
0.97 0.2
76%
56%
0.16
71%
79%
0.50
duration of 381 days of LVAD support (range 9 to 1,670 days). The mean duration off warfarin was 392 days (range 31 to 1,980 days). The total cumulative time off warfarin was 15 patient-years. Of the 14 patients, 5 (35.7%) have been off warfarin for at least 1 year. One patient had a pump thrombus due to device malpositioning that required a device exchange after being off warfarin for 1.3 years. After discontinuing warfarin, there were no additional adverse thromboembolic, hemolytic or neurologic events in these patients. There were 4 patients who were rechallenged with warfarin, without rebleeding. The time to restart warfarin ranged from 38 to 636 days with a mean of 194 ⫾ 294 days. Standard anti-coagulation recommendations for CF-LVADs have included warfarin as well as ASA therapy. Although initial attention with CF-LVADs focused on risk of thrombosis and thromboembolic events, it soon became clear that bleeding events became most relevant.1–3 A trend toward a less aggressive INR goal, especially for the HeartMate II LVAD, was observed after findings demonstrating low thromboembolic risk.4,5 As the frequency of thrombosis and thromboembolic events is low in patients with an INR o2, the risk of further reducing anti-coagulant therapy and even discontinuing it in patients who have been shown to have recurrent bleeding episodes has been speculated to be low. Despite the successes of CF-LVADs, adverse events such as GI bleeding may necessitate the discontinuation of anticoagulation therapy. However, many of these patients may tolerate discontinuation of anti-coagulation therapy without an increased risk of adverse thromboembolic events, as shown in this report on a select group of patients. The data reported thus far on the ability to discontinue anticoagulation therapy for prolonged periods are very limited.6 In this report we have presented the largest number of patients who have had discontinued anti-coagulant therapy after CF-LVAD for recurrent GI bleeding.
Further studies are needed to understand the mechanisms of hemorrhage and thrombosis after CF-LVAD, and may permit characterization of an individual’s relative risks of thrombosis or hemorrhage. This critical step may permit implementation of more “personalized” anti-coagulation in CF-LVAD patients. Comparison of patients, such as those observed in this series, to others with thrombosis may also present an opportunity to improve our understanding of the impact of CF-LVAD on the mechanisms of hemostasis. Such work may be particularly relevant in light of the limited enthusiasm for prospective clinical trials to test the safety of reduced anti-coagulation. Until then, based on this series, carefully selected patients who have recurrent bleeding episodes may have anti-coagulation therapy discontinued while close surveillance and monitoring for thrombosis and thromboembolic events is maintained with an acceptable safety profile.
Disclosure statement P.E. received honoraria and grant support from Thoratec and HeartWare. R.J. was a consultant and received grant support from Thoratec. The remaining authors have no conflicts of interest to disclose. These findings were presented at the annual meeting of the International Society for Heart and Lung Transplantation, Prague, Czech Republic, April 2012.
References 1. Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007;357:885-96. 2. Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009;361:2241-51. 3. Stern DR, Kazam J, Shariff S, et al. Increased incidence of gastrointestinal bleeding following implantation of the HeartMate II LVAD. J Card Surg 2009;25:352-6. 4. John R, Kamdar F, Liao K, et al. Low thromboembolic risk with the HeartMate II left ventricular assist device. J Thorac Cardiovasc Surg 2008;136:1318-23. 5. Boyle AJ, Russell SD, Teuteberg JJ, et al. Low thromboembolism and pump thrombosis with the HeartMate II left ventricular assist device: analysis of outpatient anti-coagulation. J Heart Lung Transplant 2009;28:881-7. 6. Pereira NL, Chen D, Kushwaha SS, et al. Discontinuation of antithrombotic therapy for a year or more in patients with continuousflow left ventricular assist devices. Interact Cardiovasc Thorac Surg 2010;11:503-5.
C. Starling, MD, MPH, W.H. Wilson Tang, MD, and Bruce L. Wilkoff, MD
Low cardiac output associated with ventricular tachyarrhythmias in continuous-flow LVAD recipients with a concomitant ICD (LoCo VT Study)
From the Sydell and Arnold Miller Family Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.
Daniel J. Cantillon, MD, Walid I. Saliba, MD, Oussama M. Wazni, MD, Mohamed Kanj, MD, Randall
A survival benefit has been demonstrated for implantable cardioverter-defibrillator (ICD) use during left ventricular assist device (LVAD) support, with appropriate therapy
Continuous-flow left ventricular assist devices (CF-LVADs) are standard therapy for end-stage heart failure given their efficacy and durability. However, to prevent thrombotic device-related complications, these devices require systemic anti-coagulation and anti-platelet therapy. This can result in significant bleeding episodes, such as gastrointestinal bleeding and epistaxis, occurring in 15% to 45% of cases and occasionally warranting discontinuation of such therapy.1–3 The incidence of thrombotic complications, including pump thrombosis, neurologic complications and peripheral thromboembolic events, has been relatively low, ranging from 0% to 7% in large multicenter trials.1,2 Because bleeding complications predominate among the adverse events in patients with continuous-flow LVADs, major bleeding may occasionally warrant discontinuation of anti-coagulation therapy.3 The incidence of stopping anti-coagulation for prolonged periods and the safety profile with regard to thromboembolic complications in CF-LVAD patients has not been adequately described. We reviewed all patients receiving a CF-LVAD from June 2005 to October 2011 at the University of Minnesota. CF pumps included the HeartMate II (Thoratec, Pleasanton, CA), VentrAssist (Ventracor, Australia) and HVAD (HeartWare, Framingham, MA). Any patients whose anti-coagulation or anti-coagulation and anti-platelet therapy was discontinued for 430 days were included in the analysis. Patients with only temporary or biventricular mechanical circulatory support and patients who died within 30 days of LVAD placement were excluded from the analysis. We collected baseline and follow-up data, including patient characteristics, history of atrial fibrillation, history of heparin-induced thrombocytopenia, renal function at time of discontinuation, LVAD speed at time of discontinuation, and aortic valve opening on echocardiography within 3 months of discontinuation of anti-coagulation, anti-platelet and anti-coagulation use, and anti-coagulation hematologic parameters. After patients were discharged from the hospital, they
returned to our center for follow-up, device review and clinical assessment. Significant gastrointestinal bleeding (GI) bleeding was defined by major bleeding adverse event criteria according to INTERMACS: an episode of bleeding (in this case GI bleeding) that results in (a) death, (b) reoperation, (c) hospitalization and (d) transfusion of packed red blood cells (PRBCs) at 47 days post-implant. Initially (in our first 14 patients), we used intravenous infusion of unfractionated heparin as a bridge to warfarin therapy, titrating the dose to an international normalized ratio (INR) of 2 to 3. However, as reported previously, we changed our anti-coagulation therapy protocol to include only warfarin therapy starting on Days 2 or 3 postoperatively, titrating the dose to an INR of 1.5 to 2, in addition to anti-platelet therapy with aspirin.4 In 2010, we shifted to a goal INR of 2 to 2.5, in the absence of other indications for a higher goal, such as mechanical mitral valve. Thromboelastography or platelet function assay are not routinely used to guide anti-coagulation strategies in our practice. All data were prospectively collected and retrospectively analyzed. Continuous data are presented as mean ⫾ standard deviation. Categorical data are presented as a percent. Continuous data were compared by analysis of variance (ANOVA) or by t-test as indicated. The chi-square test or Fisher’s exact test was used for categorical variables. Results were considered statistically significant at p r 0.05. All analyses were done with SPSS, version 12.0 (SPSS, Inc., Chicago, IL). Two hundred thirteen patients received CF-LVADs between 2005 and 2011. Of these, 6.5% had discontinuation of either warfarin or both warfarin and aspirin: 10 patients had warfarin discontinued and 4 had both aspirin (ASA) and warfarin discontinued (Table 1). These patients had a mean age of 61 ⫾ 14 years, 64% were male, 76% had an etiology of ischemic cardiomyopathy, and 71% were implanted as bridge-to-transplant (BTT) patients. There was no overall significant difference between the anti-coagulated cohort and in the cohort in which anti-coagulation was discontinued (Table 2). Of the 14 patients in which anti-coagulation was discontinued, 36% had a history of atrial fibrillation, 7% with a history of heparin-induced thrombocytopenia, no patients had bacteremia in the 3 months preceding or subsequent to discontinuation of warfarin, 50% had aortic valve opening, and the average creatinine was 1.3 (Table 1). The indication for discontinuing anti-coagulation was significant GI bleeding in all patients. Discontinuation of warfarin occurred at a mean
1053-2498/$ - see front matter r 2014 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2013.12.008
Research Correspondence
Table 1
Patient number 1 2 3 4 5a 6b 7 8 9 10 11c 12c 13c 14c
Profiles of Patients off Anti-coagulation During CF-LVAD Support
Age Gender Etiology
Implant strategy
History of atrial History fibrillation of HIT
Baseline platelet count
Baseline creatinine
Time to discontinuation of anticoagulation (days)
79 44 63 65 66 71 66 72 51 65 70 63 48 24
DT BTT BTT BTT BTT DT BTT DT BTT BTT DT BTT BTT BTT
Yes No No No No No Yes Yes Yes No No Yes No No
225 246 272 101 290 473 109 165 313 99 142 101 424 191
1.8 0.99 1.53 1.37 1.17 0.9 1.5 1.62 1.12 0.92 1.12 2.4 1.18 1.12
494 157 9 185 189 626 676 31 322 51 1,607 180 120 469
M F M M M F M M F M F M M F
Ischemic Non-ischemic Ischemic Ischemic Ischemic Ischemic Ischemic Ischemic Ischemic Ischemic Ischemic Ischemic Non-ischemic Non-ischemic
No No No No No No No No No No No No No Yes
Time off anticoagulation (days)
Platelet count at of discontinuation of anticoagulation
Positive blood culture ⫾3 LVAD speed Aortic valve months (RPM) opens
1,980 382 137 31 68 473 1,252 99 45 61 38 55 494 220
176 224 252 126 150 290 98 304 184 181 191 126 402 360
No No No No No No No No No No No No No No
9,400 9,600 8,800 9,400 2,000 8,600 9,200 8,800 9,000 9,200 9,000 8,800 9,000 10,000
No No Yes Yes Yes Yes Yes No No No Yes Yes No Yes
a This b This c
patient had VentrAssist LVAD. patient had device exchange due to pump thrombus after being off warfarin for 1.3 years. These patients had discontinuation of both anti-coagulation and aspirin.
317
318
The Journal of Heart and Lung Transplantation, Vol 33, No 3, March 2014
Table 2 Baseline Characteristics of No Anti-coagulation Patient Cohort and Anti-coagulated Patient Cohort
Age Male gender (%) Ischemic etiology Bridge to transplant
No anti-coagulation Anti-coagulated (n ¼ 14) (n ¼ 199)
p-value
60 ⫾ 14 64%
55 ⫾ 14 78%
0.97 0.2
76%
56%
0.16
71%
79%
0.50
duration of 381 days of LVAD support (range 9 to 1,670 days). The mean duration off warfarin was 392 days (range 31 to 1,980 days). The total cumulative time off warfarin was 15 patient-years. Of the 14 patients, 5 (35.7%) have been off warfarin for at least 1 year. One patient had a pump thrombus due to device malpositioning that required a device exchange after being off warfarin for 1.3 years. After discontinuing warfarin, there were no additional adverse thromboembolic, hemolytic or neurologic events in these patients. There were 4 patients who were rechallenged with warfarin, without rebleeding. The time to restart warfarin ranged from 38 to 636 days with a mean of 194 ⫾ 294 days. Standard anti-coagulation recommendations for CF-LVADs have included warfarin as well as ASA therapy. Although initial attention with CF-LVADs focused on risk of thrombosis and thromboembolic events, it soon became clear that bleeding events became most relevant.1–3 A trend toward a less aggressive INR goal, especially for the HeartMate II LVAD, was observed after findings demonstrating low thromboembolic risk.4,5 As the frequency of thrombosis and thromboembolic events is low in patients with an INR o2, the risk of further reducing anti-coagulant therapy and even discontinuing it in patients who have been shown to have recurrent bleeding episodes has been speculated to be low. Despite the successes of CF-LVADs, adverse events such as GI bleeding may necessitate the discontinuation of anticoagulation therapy. However, many of these patients may tolerate discontinuation of anti-coagulation therapy without an increased risk of adverse thromboembolic events, as shown in this report on a select group of patients. The data reported thus far on the ability to discontinue anticoagulation therapy for prolonged periods are very limited.6 In this report we have presented the largest number of patients who have had discontinued anti-coagulant therapy after CF-LVAD for recurrent GI bleeding.
Further studies are needed to understand the mechanisms of hemorrhage and thrombosis after CF-LVAD, and may permit characterization of an individual’s relative risks of thrombosis or hemorrhage. This critical step may permit implementation of more “personalized” anti-coagulation in CF-LVAD patients. Comparison of patients, such as those observed in this series, to others with thrombosis may also present an opportunity to improve our understanding of the impact of CF-LVAD on the mechanisms of hemostasis. Such work may be particularly relevant in light of the limited enthusiasm for prospective clinical trials to test the safety of reduced anti-coagulation. Until then, based on this series, carefully selected patients who have recurrent bleeding episodes may have anti-coagulation therapy discontinued while close surveillance and monitoring for thrombosis and thromboembolic events is maintained with an acceptable safety profile.
Disclosure statement P.E. received honoraria and grant support from Thoratec and HeartWare. R.J. was a consultant and received grant support from Thoratec. The remaining authors have no conflicts of interest to disclose. These findings were presented at the annual meeting of the International Society for Heart and Lung Transplantation, Prague, Czech Republic, April 2012.
References 1. Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007;357:885-96. 2. Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009;361:2241-51. 3. Stern DR, Kazam J, Shariff S, et al. Increased incidence of gastrointestinal bleeding following implantation of the HeartMate II LVAD. J Card Surg 2009;25:352-6. 4. John R, Kamdar F, Liao K, et al. Low thromboembolic risk with the HeartMate II left ventricular assist device. J Thorac Cardiovasc Surg 2008;136:1318-23. 5. Boyle AJ, Russell SD, Teuteberg JJ, et al. Low thromboembolism and pump thrombosis with the HeartMate II left ventricular assist device: analysis of outpatient anti-coagulation. J Heart Lung Transplant 2009;28:881-7. 6. Pereira NL, Chen D, Kushwaha SS, et al. Discontinuation of antithrombotic therapy for a year or more in patients with continuousflow left ventricular assist devices. Interact Cardiovasc Thorac Surg 2010;11:503-5.
C. Starling, MD, MPH, W.H. Wilson Tang, MD, and Bruce L. Wilkoff, MD
Low cardiac output associated with ventricular tachyarrhythmias in continuous-flow LVAD recipients with a concomitant ICD (LoCo VT Study)
From the Sydell and Arnold Miller Family Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.
Daniel J. Cantillon, MD, Walid I. Saliba, MD, Oussama M. Wazni, MD, Mohamed Kanj, MD, Randall
A survival benefit has been demonstrated for implantable cardioverter-defibrillator (ICD) use during left ventricular assist device (LVAD) support, with appropriate therapy
