ARTICLE IN PRESS doi:10.1510/icvts.2010.240747 Editorial
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Case report - Cardiac general
Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA b Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA c Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN, USA
a
Abstract
Best Evidence Topic Nomenclature Historical Pages Brief Case Report Communication
䊚 2010 Published by European Association for Cardio-Thoracic Surgery
State-of-the-art
夞 Grant support: This study was supported, in part by HL 84904 (Heart Failure Clinical Research Network), and NIH grants UL1RR24150 (N.L. Pereira). *Corresponding author. Tel.: q1 507-538-8151; fax: q1 507-266-0103. E-mail address:
[email protected] (N.L. Pereira).
A 74-year-old male with a history of ischemic cardiomyopathy underwent HeartMate XVE implantation. Approximately a month later, due to device failure, he underwent an exchange with HeartMate II implantation. His antithrombotic regimen consisted of warfarin and aspirin. He developed multi-drug resistant Pseudomonas aeruginosa bacteremia and was placed on chronic ceftazidime therapy. Approximately eight months after HeartMate II implantation, due to recurrent GI bleeding with no active bleeding sites identified, warfarin and aspirin were discontinued. Despite discontinuation, within a year the patient presented with recurrent melena and anemia on two separate occasions. The patient developed progressive debility, was bed-ridden and had difficulty in controlling ongoing bacteremia and infection. Approximately 21 months after HeartMate II device implantation, hemodialysis was withheld as per patient and family wishes, and the patient died. This patient had no thrombotic complications and had normal device function for a year after warfarin and aspirin were discontinued. His INR remained within normal limits; however, he had borderline thrombocytopenia (120,000–140,000yml). His D-dimer was elevated at 1010 (normal F250) suggestive of an acute phase reactant, and factor VIII coagulant activity was normal. The von Willebrand factor (VWF) multimer analysis revealed subtle loss
Follow-up Paper
Left ventricular assist devices (LVAD) are increasingly being used to bridge patients to cardiac transplantation and as permanent therapy for selected patients with endstage heart failure. Patient survival since the introduction of continuous-flow LVADs has improved considerably and is reported as 58% at two years w1x. The advantage of continuous-flow devices compared to the pulsatile-flow LVAD is that they are more durable, but a disadvantage is the suggested requirement for systemic anticoagulation. The recommended antithrombotic regimen is aspirin and warfarin with a targeted international normalized ratio (INR) of 2.0–3.0 w2x. However, there appears to be an increased risk of gastrointestinal (GI) bleeding after implantation that may necessitate discontinuation of antithrombotic therapy w3, 4x. The long-term follow-up of such patients has not been well described. We report two patients in whom despite discontinuation of antithrombotic therapy for a year or more, continued to have normal device function without thromboembolic complications.
2. Case 1
Negative Results
1. Introduction
Proposal for Bailout Procedure
Keywords: Heart failure; Ventricular assist device; Anticoagulation; Gastrointestinal bleeding
ESCVS Article
The recommended anticoagulation regimen during continuous-flow axial left ventricular assist device (LVAD) support is aspirin and warfarin with a targeted international normalized ratio of 2.0–3.0. We report two patients in whom recurrent gastrointestinal bleeding during LVAD support necessitated discontinuation of this anti-thrombotic regimen for a year or more. Despite this, neither patients developed thrombotic complications during 29 patient-months of follow-up. An acquired von Willebrand factor (VWF) abnormality reflected by the absence or decreased abundance of the highest molecular weight multimers was demonstrated in both patients. The gold standard test for platelet function, light transmission platelet aggregometry was measured in one patient and was normal, indicative that the predominant abnormality in the coagulation profile of these patients is an acquired VWF syndrome. Clinical trials are required to address the question whether it is safe to discontinue anticoagulation in LVAD patients with acquired VWF abnormalities. 䊚 2010 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.
Institutional Report
Received 10 May 2010; received in revised form 21 June 2010; accepted 29 June 2010
Protocol
Naveen L. Pereiraa,*, Dong Chenb, Sudhir S. Kushwahaa, Soon J. Parkc
Work in Progress Report
Discontinuation of antithrombotic therapy for a year or more in patients with continuous-flow left ventricular assist devices夞
New Ideas
Interactive CardioVascular and Thoracic Surgery 11 (2010) 503–506
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of the highest molecular weight multimers, but no increased abundance of lower molecular weight VWF multimers suggesting an acquired VWF abnormality. 3. Case 2 A 59-year-old female with idiopathic dilated cardiomyopathy underwent implantation of a HeartMate II device with a bioprosthetic tricuspid valve replacement. She had significant renal dysfunction preoperatively and became dialysis dependent postoperatively. She developed recurrent GI bleeding on warfarin and aspirin therapy after LVAD implantation. Despite undergoing extensive endoscopy no source of active bleeding was found and was presumed to be due to vascular ectasia in the small bowel. Approximately seven weeks after implantation, warfarin and aspirin therapy was therefore discontinued. She was admitted several times for recurrent GI bleeding despite discontinuation of antithrombotic therapy. Her INR has been within normal limits; however, she too had a mild thrombocytopenia (120,000–140,000yml) and elevated D-dimer (1600 ngyml). Platelet function was assessed by PFA-100 and light transmission aggregometry. She had prolonged PFA-100 epinephrine and adenosine diphosphate (ADP) cartridge closure times. Her platelet aggregation responses to arachidonic acid, ADP, epinephrine, collagen, and ristocetin were all within normal range. Therefore, the prolonged PFA-100 closure times were most likely attributed to acquired VWS. Her fibrinogen was normal at 296 mgydl (200–430), and soluble fibrin monomers were negative. Coagulation factors II, V, VII, VIII, and XIII were all normal. Activated factor X was mildly reduced at 45% (60–140) likely related to recent warfarin use. The VWF multimer analysis revealed marked decrease in abundance of the highest molecular weight multimers (Fig. 1). She had no thrombotic complications and the device functions normally, 18 months after antithrombotic therapy has been discontinued. The VWF profile of both patients is outlined in the Table 1. 4. Discussion The recommendations for continuous-flow devices include warfarin and aspirin therapy to prevent thrombotic complications. However, as the durability of LVADs and survival of these patients improve; complications, such as GI bleeding are becoming increasingly recognized. Bleeding complications were a major cause of death in the recently reported
Fig. 1. VWF multimer analysis. Patients’ plasma samples were analyzed by VWF multimer electrophoresis. Patient 2, who had significant loss of VWF multimer as compared to control and indicated by the arrow head, is displayed. VWF, von Willebrand factor.
Table 1. The von Willebrand factor (VWF) profile in two patients with continuous axial flow left ventricular assist devices VWF ristocetin cofactor Normal values (55–200%)
VWF antigen Normal values (55–200%)
VWF ristocetin activityyantigen ratio Normal values G0.7
Patient 1: 177% Patient 2: 210%
169% 247%
1.1 0.8
HeartMate II destination therapy trial w1x. Non-fatal hemorrhagic complications have been reported in single center experiences describing GI bleeding occurring in 15–40% of HeartMate II patients w3, 4x. The occurrence of bleeding complications may require discontinuation of anticoagulation therapy. The proposed risk incurred by patients who have had anticoagulation discontinued is device thrombosis. Patients with HeartMate II devices despite being maintained with a lower INR seem to have an acceptable thromboembolic risk during a mean follow-up period of 7.2"5.2 months w4x. However, longterm follow-up of patients with HeartMate II in whom warfarin and aspirin have been discontinued has not been reported. Our experience describes two patients who had significant, recurrent GI bleeds with no thrombotic complications, a year or more following discontinuation of antithrombotic therapy. The most likely explanation for the patient’s bleeding risk and favorable thrombotic profile is the acquired VWF abnormality. Patients with chronic renal failure are also at an increased risk for both GI and procedure related bleeding complications w5x primarily due to platelet dysfunction w6x. However, dialysis which was being done in both patients does partially correct this bleeding tendency w6x and platelet dysfunction alone would not explain the lack of thrombosis due to warfarin being discontinued. Furthermore, light transmission platelet aggregometry performed in patient 2 was normal providing no conclusive laboratory evidence of acquired – platelet dysfunction. Coagulation abnormalities due to acquired – VW syndrome have been described with the HeartMate II device w7x. Both the cases reported had absent or reduced VWF high molecular weight multimers. This reduction may be due to accelerated proteolysis caused by shear stress with the HeartMate II device, similar to the mechanism for VWF abnormalities in severe aortic stenosis w8x. The VWF ristocetin activityy antigen ratios of both cases were normal as shown in the Table 1, indicating that the current VWF activity test by ristocetin may not be sensitive enough to identify such an acquired – VWF abnormality. These cases therefore raise the possibility that anticoagulation may not be required for selected patients with HeartMate II devices who have acquired VWS. The textured inner surface of the inflow conduit and outflow graft and the polished surfaces of the pump rotor, duct, inlet and outlet stator may also help reduce the thrombogenicity of the HeartMate II device. However, clinical trials will be required to address the use of an altered anticoagulation regimen in these patients.
ARTICLE IN PRESS N.L. Pereira et al. / Interactive CardioVascular and Thoracic Surgery 11 (2010) 503–506
Negative Results Follow-up Paper State-of-the-art Best Evidence Topic Nomenclature Historical Pages Brief Case Report Communication
Authors: Naveen L. Pereira, Mayo Clinic, 200 First Street SW, Rochester, MN, USA; Dong Chen, Sudhir S. Kushwaha, Soon J. Park doi:10.1510/icvts.2010.240747A1 We would like to thank Charitos and Sievers w1x for their comments regarding our case report w2x on two patients who had no clinical thrombotic complications despite antithrombotic therapy being discontinued for a year or more with HeartMate II devices. These cases were not part of a research protocol or study and hence written, informed consent was unnecessary. However, as with all routine or difficult clinical decisions we ensured that patients fully understood the risks and benefits of stopping antithrombotic therapy while being supported on these continuous axial flow devices, hence this strategy was adopted only after full informed consent of the patients. Charitos and Sievers propose that the lack of thrombotic complications can be explained by the short period of follow-up. First of all, no valid conclusions can be reached or a statistical analysis performed with two patients. Secondly, the thrombotic complication rate cited by Charitos and Sievers of 5–35%/patient-year is based on patients who have followed standard guidelines of anticoagulation with warfarin and aspirin while being supported with HeartMate II devices, hence a comparison cannot be made to our case series. Theoretically, the thrombotic rate should be much higher
Proposal for Bailout Procedure
eResponse: Discontinuation of antithrombotic therapy for a year or more in patients with continuous-flow left ventricular assist devices: a time for reappraisal
ESCVS Article
Authors: Efstratios I. Charitos, Cardiac and Thoracic Vascular Surgery Clinic, University of Luebeck, Luebeck, Germany; Hans-Hinrich Sievers doi:10.1510/icvts.2010.240747A Pereira et al. report on two HeartMate II patients in whom the authors decided to stop anticoagulation with warfarin and aspirin because of recurrent gastrointestinal bleeding w1x. It is unclear if the authors obtained informed consent for this. This report outlines a significant problem that left ventricular assist device (LVAD) physicians face, weighing the risks of thrombosis when lowering or stopping anticoagulation therapy and the risks of bleeding while on anticoagulation. The authors present data on the coagulation and thrombocyte function of the patients and postulate that the ‘most likely’ explanation for this ‘favorable thrombotic profile of these patients is the acquired von Willebrand (vW) factor abnormality’ in patients implanted with the HeartMate II device and suggest that ‘these cases raise the possibility that anticoagulation may not be required for selected patients with HeartMate II devices who have acquired vW syndrome’. However, the most probable explanation for the lack of thrombotic events in this cohort is the extremely short observation time (2.42 patient-years). An analog can be seen in studies of mechanical valves (MV). Patients with MV under the recommended anticoagulation regime have a risk for thrombotic events between 0.3% and 2.3%/patient-year. However, small studies conducted in the past show that stopping anticoagulation in MV patients does not have immediate adverse effects, with some reports describing no dramatic increase of thrombotic events in patients receiving only aspirin. There are also anecdotal reports of patients with mechanical valves receiving no anticoagulation over many years (even decades), without complications w2x. These small studies are seriously flawed and their results should not be generalized because of the insufficient power they have to detect such events, especially if the incidence of number events/patient-year is per se low. Therefore, the guidelines remain unchanged, recommending the use of warfarin in MV patients.
w1x Pereira NL, Chen D, Kushwaha SS, Park SJ. Discontinuation of antithrombotic therapy for a year or more in patients with continuous-flow left ventricular assist devices. Interact CardioVasc Thorac Surg 2010; 11:503–506. w2x Sharma S, McMurty K, Chalapathy N, Ameen A. Mechanical aortic valve without anticoagulation for twenty-three years. Interact CardioVasc Thorac Surg 2009;8:263–264. w3x Boyle AJ, Russell SD, Teuteberg JJ, Slaughter MS, Moazami N, Pagani FD, Frazier OH, Heatley G, Farrar DJ, John R. Low thromboembolism and pump thrombosis with the HeartMate II left ventricular assist device: analysis of outpatient anti-coagulation. J Heart Lung Transplant 2009;28:881–887. w4x Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D, Sun B, Tatooles AJ, Delgado RM 3rd, Long JW, Wozniak TC, Ghumman W, Farrar DJ, Frazier OH. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009;361:2241– 2251. w5x Pagani FD, Miller LW, Russell SD, Aaronson KD, John R, Boyle AJ, Conte JV, Bogaev RC, MacGillivray TE, Naka Y, Mancini D, Massey HT, Chen L, Klodell CT, Aranda JM, Moazami N, Ewald GA, Farrar DJ, Frazier OH. Extended mechanical circulatory support with a continuous-flow rotary left ventricular assist device. J Am Coll Cardiol 2009;54:312–321.
Institutional Report
eComment: Antithrombotic therapy in patients with left ventricular assist devices: a critical view of the data and lessons from the past
References
Protocol
w1x HeartMate II Investigators. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009;361:2241– 2251. w2x HeartMate II Clinical Investigators. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007;357:885– 896. w3x Stern DR, Kazam J, Shariff S, Edwards P, McAllister N, Maybaum S, Bello R, D’Allessandro D, Goldstein D. Increased incidence of gastrointestinal bleeding following implantation of the HeartMate II LVAD. J Card Surg 2009;25:352–356. w4x John R, Lee S. The biological basis of thrombosis and bleeding in patients with ventricular assist devices. J Cardiovasc Trans Res 2009; 2:63–70. w5x Gangji AS, Shoal AS, Treleaven D, Crowther MA. Bleeding in patients with renal insufficiency: a practical guide to clinical management. Thromb Res 2006;118:423–428. w6x Remuzzi G. Bleeding in renal failure. Lancet 1988;331:1205–1208. w7x Geisen U, Heilmann C, Beyersdorf F, Benk C, Berchtold-Herz M, Schlensak C, Budde U, Zieger B. Non-surgical bleeding in patients with ventricular assist devices could be explained by acquired von Willebrand disease. Eur J Cardiothorac Surg 2008;33:679–684. w8x Vincentelli A, Susen S, Le Tourneau T, Six I, Fabre O, Juthier F, Bauters A, Decoene C, Goudemand J, Prat A, Jude B. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 2003;349:343–349.
Work in Progress Report
References
New Ideas
We thank Kasey L. Muetzel for her assistance with the preparation of this manuscript.
Large studies indicate that thrombotic complications in HeartMate II patients under the recommended anticoagulation regime with warfarin and aspirin present with an incidence of 7–44% (5–35%/patient-year, depending on definition, inclusion of transient ischemic attacks) w3–5x. While we agree that these patients present with various degrees of acquired vW factor defects, we are not surprised that the authors could not detect any thrombotic complication. In fact, assuming a Poisson process for the incidence of thrombotic events, the authors would have required 40 patientyears of follow-up with a thrombotic incidence of just 5%/patient-year, or a thrombotic incidence of 80%/patient-year with a follow-up of 2.42 patientyears in order to have a )85% probability to be able to detect at least one event! Therefore, while we agree that a vW factor defect might play some role, the duration of follow-up prohibits any viable conclusion from this patient cohort. Longer term studies with sufficient number of patient-years are needed to draw any conclusions regarding the feasibility and safety of maintaining HeartMate II patients with no anticoagulation. Until then however, we believe that the decision to withdraw anticoagulation in these patients should be made with extreme caution after carefully weighing the expected benefits and risks from such action, and only after obtaining the patients informed consent.
Editorial
Acknowledgements
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if anticoagulation was discontinued making our observation even more pertinent. This case report is meant to draw attention to the fact that despite standard guidelines regarding systemic anticoagulation in HeartMate II recipients, many patients do develop an acquired von Willebrand factor (vWF) syndrome and there has been no long-term follow-up reported to date on these patients in whom antithrombotic therapy has been discontinued. We have clearly acknowledged in our case report that clinical trials are needed to address this issue and this observation will hopefully prompt a more systematic study in this patient population.
References w1x Charitos EI, Sievers HH. eComment. Antithrombotic therapy in patients with left ventricular assist devices: a critical view of the data and lessons from the past. Interact CardioVasc Thorac Surg 2010;11:505. w2x Pereira NL, Chen D, Kushwaha SS, Park SJ. Discontinuation of antithrombotic therapy for a year or more in patients with continuous-flow left ventricular assist devices. Interact CardioVasc Thorac Surg 2010; 11:503–506.
