ASAIO Journal 2014
Case Series
Argatroban as Novel Therapy for Suspected Thrombosis in Patients With Continuous-Flow Left Ventricle Assist Device and Hemolysis Amit Badiye,* Gabriel A. Hernandez,† and Sandra Chaparro*
The growing use of left ventricular assist devices as a bridge to transplant and their increased duration as destination therapy in patients successfully treated for advance heart failure unwrap a new spectrum of complications seen in long-term use of the devices. Device thrombosis remains a therapeutic dilemma, and limited data are available for the use of direct thrombin inhibitors as a treatment option. We performed a review of literature and present a series of four patients with suspected left ventricular assist device–associated thrombosis, manifesting as hemolysis, who were treated empirically with argotraban, a direct thrombin inhibitor with the ability to interact with both free and clot-bound thrombin. In this case series, we treated four patients with argatroban for suspected device thrombosis. All showed significant improvement of hemolysis according to lactate dehydrogenase measurements, and device removal was prevented in three. Bleeding complications occurred when therapy was used closer to the operative period. Argatroban can be a viable option to treat patients with hemolysis from suspected device thrombosis in patients with HeartMate II continuous-flow left ventricular assist device. Prompt attention is needed to monitor any bleeding complications. ASAIO Journal 2014; 60:361–365.
Despite the bleeding risk, anticoagulation is indicated within the first 24 hours post-LVAD implantation2 because of the overwhelming occurrence of embolic events, hemolysis, and pump failure. Left ventricular assist device thrombus is the fourth most common cause of readmission after LVAD implantation (13.9% of readmissions)3 and is the second most common cause of pump replacement after percutaneous lead damage4; however, an abrupt increase in its incidence has been noted during the last couple of years.5 Pump thrombosis implies the formation of a clot within the flow path of the device, including the inflow cannula, the outflow graft, and the housing that contains the rotor.6 Recently described by Goldstein et al.,6 risk factors that contribute to pump thrombosis are related to the pump itself (i.e., heat, shearing forces, and malposition), to the patient (i.e., atrial fibrillation, preexistent thrombus, and hypercoagulable state), and to the management (i.e., suboptimal anticoagulation). They presented an algorithm for the diagnosis of pump thrombus as well as current management options favoring pump exchange or urgent transplantation. Other nonsurgical approaches have been attempted to treat LVAD-related thrombosis with resultant conflicting data regarding the use of different thrombolytic agents.7,8
Key Words: anticoagulation, heart failure, ventricle assist device, thrombosis, heart
Methods
The growing use of the left ventricular assist device (LVAD)
We performed a review of literature and presented a case series of four patients exhibiting hemolysis caused by HeartMate II (HMII) (Thoratec Corporation, Pleasanton, CA) LVAD-related thrombosis who were treated with argatroban, a direct thrombin inhibitor with a unique pharmacological profile and ability to interact with both free and clot-bound thrombin.9 The diagnosis of hemolysis was made with symptoms, hemoglobin, and lactate dehydrogenase (LDH) levels. Because of the retrospective nature of the study, plasma-free hemoglobin levels were not uniformly collected. Lactate dehydrogenase levels greater than three times the upper limit of normal should raise concern for possible thrombus.6 In our institution, values less than 600 IU/L are considered normal. The overall strategy of initial anticoagulation to prevent thrombosis was made according to the current literature at the time of treatment.1,2 We use aspirin 81 mg within the first 24 hours after device implantation followed by heparin as bridge to warfarin (target international normalized ratio [INR] of 2–3 per manufacturer recommendations and the addition of dipyridamole was optional as per implanting surgeon’s discretion).
as a bridge to transplant and their increased duration as destination therapy in patients with end-stage cardiomyopathy unwrap a new spectrum of complications seen in long-term use of the devices. The most common complications are disorders of coagulation, ranging from bleeding to thrombosis.1 From the *Division of Cardiology, Department of Medicine, University of Miami, Jackson Memorial Hospital, Miami, Florida; and †Department of Medicine, University of Miami, Jackson Memorial Hospital, Miami, Florida. Submitted for consideration September 9, 2013; accepted for publication in revised form February 20, 2014. Disclosure: The authors have no conflicts of interest to report. Reprint Requests: Sandra Chaparro, MD, Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Clinical Research Building, Room 1110, 1120 NW 14th Street, Miami, FL 33136. Email: [email protected]. Copyright © 2014 by the American Society for Artificial Internal Organs DOI: 10.1097/MAT.0000000000000067
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362 BADIYE et al. Case 1 A 48-year-old male with nonischemic cardiomyopathy secondary to left ventricle noncompaction and a left ventricle ejection fraction (LVEF) of 10% was referred to our institution for advanced heart failure therapies. He had multiple admissions because of acute decompensated heart failure (ADHF) despite optimal medical management. He became inotrope dependent, decompensated because of a catheter-related sepsis, and required intraaortic balloon pump for stabilization. He underwent HMII LVAD implantation with mitral valve repair as a bridge to transplant with an INTERMACS profile of 1. Postoperatively, he developed right ventricular failure requiring inotropic support for 2 weeks. He recovered and was discharged home on postoperative day 28 on warfarin, dipyridamole 75 mg three times a day, and aspirin 81 mg. Almost 7 months later, he reported having dark-colored urine and dyspnea and was admitted for further evaluation. His laboratory workup showed an increased blood urea nitrogen and creatinine with a significant drop of his hemoglobin from a baseline of 10 to 7.6 g/dl; LDH was found to be greater than 12,900 from a baseline of 1,500 u/L. International normalized ratio was subtherapeutic at 1.44 despite the patient being on a stable dose for a long time. Interestingly, neither his LVAD nor the log files sent to the company showed any alarms or power spikes on interrogation. Transthoracic and transesophageal echocardiograms were done and no thrombus or aortic valve abnormalities were seen. Gated cardiac computed tomography (CT) revealed a circumferential low-density chronic thrombus in the inflow and outflow of the LVAD, without significant luminal narrowing. The patient was hydrated and empirically started on argatroban, because of its clot-bound properties, with significant improvement of symptoms and normalization of urine color. However, after initial trending down of LDH, he had a milder but persistent hemolysis requiring multiple transfusions. His status was upgraded to 1A on the heart transplant list because of LVAD thrombosis, and device exchange was planned. He successfully underwent orthotopic heart transplant on postoperative day 264. Explanted device revealed a thrombus encircling the impeller, but inflow and outflow cannulae were normal (Figure 1). Case 2 A 30-year-old female with a history of acute lymphocytic leukemia at the age of 3 years who received chemotherapy with doxorubicin and radiation was diagnosed with heart failure at the age of 11 years. She was stable on optimal medical therapy until the age of 30 years when she became inotrope dependent and was listed as status 1B for heart transplant. Her echocardiographic evaluation demonstrated severe mitral regurgitation and an LVEF of 15%. After 6 months of inotropic support, she deteriorated and was admitted for optimization and started sliding on inotropes with an INTERMACS profile of 2. She successfully underwent implantation of HMII LVAD as bridge to transplant. She also underwent repair of her mitral valve and patent foramen of ovale. Postoperatively, she was anticoagulated with heparin and bridged to warfarin per protocol. Aspirin 81 mg was started on postoperative day 1 and increased to 325 mg by day 5. She developed right ventricular failure requiring inotrope support for 12 days postoperatively and recuperated well until it was noted that her LDH began to rise up to 5,787 u/L alongside the
plasma-free hemoglobin requiring several transfusions. Left ventricular assist device showed persistently increased power spikes and high flows. Given that she was being bridged with heparin and was therapeutic with warfarin, she was started on argatroban and dipyridamole 75 mg three times a day for suspected thrombus in the LVAD and listed as 1A on transplant list for devicerelated complications. Gated CT scan and echocardiogram showed no evidence of thrombus or conduit abnormalities. Lactate dehydrogenase started to trend down, but unfortunately after 7 days of argatroban therapy, she sustained a fall, had seizures, and developed right side hemiparesis. Computed tomography scan of the brain revealed a subdural hematoma which progressively worsened, requiring evacuation. All anticoagulants were held and aspirin 81 mg was reintroduced 24 hours postprocedure. Once cleared by neurosurgery, she was restarted on heparin and warfarin, with a lower activated partial thromboplastin time and INR goal. This regimen was started instead of argatroban because the hemolysis had resolved and LDH had normalized. Follow-up echocardiogram and chest x-ray showed slight septal positioning of the inflow cannula, but no other abnormalities were detected. She was discharged on postoperative day 54 and is currently stable 14 months postintervention. Her INTERMACS level is 6 and she is awaiting transplant. Case 3 A 69-year-old male with a 4-year history of nonischemic cardiomyopathy treated with optimal medical therapy presented with automatic implantable cardioverter defibrillator (AICD) shocks. He had a gradual deterioration in his clinical status and had multiple admissions because of ADHF with an LVEF of 15% and INTERMACS 3 and underwent elective HMII LVAD implantation as bridge to transplant. Within the first 24 hours, he was anticoagulated with heparin, dipyridamole 75 mg three times a day, and aspirin 81 mg. Warfarin was introduced on day 2 and he was weaned off inotropes by postoperative day 3; there were no postoperative complications and he was discharged on postoperative day 14 with aspirin 81 mg and warfarin with a therapeutic INR of 2–3. The patient had a stable clinical course but was readmitted on postoperative day 53 with tea-colored urine and suspected melena. Hemoglobin dropped to 8.4 from a baseline of 10 g/dl and LDH was found to be significantly increased up to 5,525 u/L from a baseline below a thousand. It was decided to empirically start him on argatroban, as his INR was therapeutic on warfarin, and aspirin was continued. Upper and lower gastrointestinal endoscopy was normal and his melena resolved. Computed tomography angiography revealed a focal kink in the LVAD efferent cannula causing 50% diameter stenosis, but there was no luminal compromise as the kink was actually a smaller caliber Teflon graft extension used for anastomosis in this very tall patient. He was listed as 1A on transplant list because of LVAD-related complications. After a week of treatment, his LDH improved significantly. Warfarin and dipyridamole 75 mg three times a day were restarted on admission day 4, and the patient was kept on argatroban for a total of 17 days until the INR reached a determined goal of 4. He was discharged on aspirin and warfarin with an LDH at baseline. The patient is currently doing well 14 months postintervention, INTERMACS 7 and is on the transplant waiting list status 1B (Figure 2).
ARGATROBAN IN LVAD SUSPECTED THROMBOSIS
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Figure 1. Explanted device revealed a thrombus encircling the impeller, but inflow and outflow cannulae were normal.
Case 4 A 52-year-old male with nonischemic cardiomyopathy, a history of ventricular tachycardia, and an LVEF of 10% was admitted after multiple episodes of ADHF, hepatic and renal failure, and AICD shocks. He became inotrope dependent and was optimized on his heart failure therapies. His clinical course was complicated by sustained ventricular tachycardia with AICD shocks. He was not a candidate for heart transplant at our institution because of chronic persistent hepatitis B; therefore, he underwent HMII LVAD implantation as destination therapy and mitral valve repaired with Alfieri stitch. He was started on anticoagulation per protocol, but unfortunately his immediate postoperative period was complicated by expanding mediastinal hematoma requiring re-exploration. Once stabilized, dipyridamole 75 mg three times a day and aspirin 325 mg were started on postoperative day 1, heparin on day 2, and warfarin on day 3. He was successfully extubated, chest tubes were pulled and he was weaned off inotropes. By postoperative day 7, the LVAD controller showed high
power and flow alarms, LDH was slightly increased to 1,566 from baseline of 700 and hemolysis was diagnosed, possibly because of suspected clot. Echocardiogram showed adequate emptying of left ventricular cavity with optimal revolutions per minutes on the device. He was being bridged to warfarin and had therapeutic partial thromboplastin time of 60–80 seconds while on heparin therapy but given the persistent hemolysis, he was switched to argatroban. Lactate dehydrogenase started trending down and the LVAD controller’s alarms resolved. Unfortunately, after 9 days of argatroban therapy, he developed worsening of dyspnea. A repeat echocardiogram showed moderate pericardial effusion and all anticoagulants were held. A pericardial window was done which had to be extended to sternotomy and there were clots compressing the left atrium which were evacuated. Anticoagulation with heparin, clopidogrel, and aspirin was resumed 24 hours after the procedure at the discretion of the surgical team. Lactate dehydrogenase continued to remain at baseline without any further evidence of hemolysis. He was
Figure 2. A: Axial computed tomography view of the focal kink in the left ventricular assist device efferent cannula, proximal to the anastomosis into the ascending aorta, which causing 50% diameter stenosis. The anastomosis itself with the ascending aorta is patent measuring 12.2 mm in diameter. B: Reconstruction image, kink is marked with the large arrow.
364 BADIYE et al.
Figure 3. Argatroban use and lactate dehydrogenase (LDH) tendency in our case series in respect to time. X-axis represents the days since hemolysis was diagnosed. Asterisks Indicate the initiation of argatroban.
discharged home on postoperative day 28 on warfarin and aspirin 81 mg. He is currently stable 13 months postintervention (Figure 3). Discussion Left ventricular assist device complications are more commonly seen with the increased frequency and duration of their use. The high incidence of bleeding as a postoperative complication, requiring re-intervention in up to 60% of recipients,10 delays the initiation of anticoagulation and leads to clot formation.11 Risk of bleeding continues even past the first year1 and is due to the high prevalence of acquired Von Willebrand factor deficiency as well as the relation of arteriovenous malformations in patients with the continuous-flow HMII. Management thus always involves the fine balance between bleeding and thrombosis. Aspirin within the first 24 hours after device implantation followed by heparin as bridge to warfarin, to achieve a therapeutic INR goal of 2–3, is the usual guideline-driven anticoagulation therapy in patients with centrifugal pumps recommended by the International Society of Heart and Lung Transplantation2 and supported by the American Heart Association.12 Perioperative anticoagulation in patients with LVAD is still evolving and our center shared the same concern published in recent article about early device thrombosis5; therefore, we added antiplatelet therapy in some patients. Hemolysis is a known adverse event of LVAD.3 Destruction of red blood cells is the result of wall shear stress, flow acceleration, and interaction with artificial surfaces. Factors that generate changes in flow rate and power demand, such as conduit kinks or wall thrombosis, lead to a higher rate of hemolysis.6 Diagnosis of hemolysis secondary to red blood cells destruction is made in the setting of anemia, absence of blood loss, increased lactate dehydrogenase, unconjugated bilirubin, and decreased haptoglobin levels. The use of heparin for patients suspected of having a thrombus leading to hemolysis is challenging because of its immunogenicity and inability to inhibit clot-bound fibrin.13 In our case series, we empirically used an alternate therapeutic approach with argatroban, a direct thrombin inhibitor derived from L-arginine, in patients presenting with hemolysis due to suspected thrombosis after excluding other causes.6 More so, argatroban has been successfully used in patients with LVADs and heparin-induced thrombocytopenia as initial postoperative anticoagulant.14
Argatroban reversely inhibits thrombin by inhibiting thrombin-induced reactions and activation of coagulation factors V, VIII, and XIII, and protein C.9 It is also effective at inhibiting platelet aggregation and thromboxane generation in the presence of both free and clot-bound thrombin. These pharmacologic properties are different from those of hirudin and heparin, for which markedly higher concentrations are required to inhibit clot-bound thrombin in contrast to free thrombin.13 Argatroban has a linear pharmacokinetic property and reaches its steady-state level within 1–3 hours after the initiation of infusion. After cessation, the anticoagulant effect is lost within 2–4 hours.9 It has been previously used in patients with LVADs, and several data show its safety and efficacy as initial postoperative anticoagulant in patients with heparin-induced thrombocytopenia.14 All patients undergoing LVAD implant are screened for hypercoagulable states and the screen was negative in our series. The drawback of argatroban is that, in the event of bleeding, there is no reversal agent and it is difficult to monitor given its effects on both prothrombin time/INR and partial thromboplastin time (PTT). The goal for argatroban therapy is a PTT of 1.5–3 times the baseline (not exceeding 100 seconds) and monitoring the INR is only useful when switching to warfarin. Because of the rapid steady state of argatroban and its short half-life, the variation of the INR will be brisk when used in combination of warfarin, which has a longer half-life. This is of significance when transitioning from argotraban to warfarin or vice versa. This was studied by Sheth et al., who found that the INR will roughly double when argatroban is added to warfarin at different INR levels. From these data, it can be extrapolated that an INR of 4 might be ideal for stopping argatroban. The INR should then be repeated 4–6 hours later, when the anticoagulant effects of argatroban would be expected to be negligible, to ensure a therapeutic value on warfarin alone. Although INR levels of 4–5 are known not to increase bleeding when co-therapy is used,15 we recommend extreme caution when starting argatroban with a baseline INR close to 4 because it will overshoot. Whether argatroban carries an increased risk of bleeding in patients with LVADs has not been proven in previous studies performed on heparin-induced thrombocytopenia14; in our patients, we noticed that the presence of hemolysis in the perioperative period correlated with bleeding problems as seen in two of our patients, as opposed to those who were further away from the date of implant. This is not necessarily due to our intervention, as previously mentioned bleeding in the postoperative time is the most common complication.10 Extreme caution should be taken when argatroban is used in patients with liver dysfunction because the clearance is delayed and they have a higher risk for bleeding,8 but there is no contraindication in patients with renal dysfunction as it is not renally excreted. Avoid the use of argatroban in patients at risk of bleeding, in severe hypertension, and if major surgery is planned. An average 60 kg patient will use 170 mg/day (2 μg/ kg/min) at a price of $272.40 for 50 mg/50 ml. In comparison with bivalirudin (both direct thrombin inhibitors), argatroban has different affinity for thrombin. Higher concentrations of bivalirudin are required to inhibit clot-bound thrombin in contrast to free thrombin, hence requiring greater doses with higher risk of bleeding. To our knowledge, no other intravenous administered anticoagulant has a clot-bounded thrombin properties (hirudin is no longer available). Dabigatran (direct thrombin inhibitor)
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ARGATROBAN IN LVAD SUSPECTED THROMBOSIS
and rivaroxaban (clot-bound factor Xa properties) are both orally administered and have not been studied in patients with ventricular assist devices. Although current guidelines and a recent algorithm6 recommend prompt admission for optimization of anticoagulation and possible pump exchange in the presence of hemolysis,2 different approaches have been attempted to medically treat LVADrelated thrombosis with conflicting data regarding the use of thrombolytic agents.7,8 Attempts to understand mortality risks in these patients have been made. Ballew et al.8 classified them according to their LDH levels and found that patients with levels greater than 1000 U/L treated medically with anticoagulants other than argatroban had a mortality of 50% compared with patients who had surgical intervention with survival of 100%. Our series also highlights how imaging can be misleading and one has to consider the entire clinical scenario before making surgical decisions such as LVAD exchange. Although device exchange is safe, it carries the risk of i ntervention-related complications and increases cost.4,8 Case 1 had a delay in seeking medical attention and remained on argotraban until he was transplanted. Although symptoms improved alongside LDH levels, he was still hemolysing and a pump replacement was considered. It was suspected to have a thrombus layering the inside of the inflow cannula on CT scan, but the explanted device showed thrombus layering the impeller only. Given the significant improvement of LDH and hemolysis rate, it can be presumed that argatroban had an effect decreasing the thrombus burden. Case 3 had a suspected kink at the outflow graft connection to the aorta, but in reality, there was no luminal compromise as the kink was just a small caliber Teflon graft extension used for anastomosis. As seen in the Figure 3, it is important to note that early initiation of anticoagulation leads to higher chances of resolution of thrombus and hemolysis. Only one patient persistently had hemolysis leading to pump explant and heart transplantation; particularly, this patient had low INR as an outpatient. Notably, the remaining three patients were therapeutic with either warfarin or heparin at the onset of hemolysis. This also promotes the hypothesis that the chances of thrombus and hemolysis resolution with argatroban may be higher if patients are therapeutic while having this complication. This case series is unique and to our knowledge the first one to use argatroban for suspected device thrombosis–related hemolysis in patients with HMII LVAD. Devices with less space around the impellers may need a more proactive and aggressive approach for hemolysis. Early diagnosis and prompt treatment of suspected device thrombosis presenting with hemolysis is thus imperative. Comment To our knowledge, this is the first series showing the use of argatroban to treat hemolysis from suspected device thrombosis in patients with HMII continuous-flow LVAD. We acknowledge our limitations and further investigation on use of direct thrombin inhibitors with larger patient dataset and randomized control trials will be needed to justify our approach. Although bleeding was observed in half of our patients, our survival remained 100%. In addition, further evaluation of explanted pumps, when the time comes, will give us a better idea of thrombus resolution. We did not consider treatment with thrombolytics because of a high risk of cerebrovascular events, bleeding, and reduced
comfort level with these medications in perioperative period. The use of GP2B3A inhibitors was considered, but we selected argatroban, given the properties of interacting with both free and clot-bound thrombin. Our therapy was effective when given for as short as 7 days, and three of our patients treated medically are currently free of hemolysis 13 months or more postintervention. Prompt attention is needed to monitor any bleeding complication, especially in the postoperative period, when bleeding is the most common complication.10 References 1. Rossi M, Serraino GF, Jiritano F, Renzulli A: What is the optimal anticoagulation in patients with a left ventricular assist device? Interact Cardiovasc Thorac Surg 15: 733–740, 2012. 2. Feldman D, Pamboukian SV, Teuteberg JJ, et al; International Society for Heart and Lung Transplantation: The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: Executive summary. J Heart Lung Transplant 32: 157–187, 2013. 3. Hasin T, Marmor Y, Kremers W, et al: Readmissions after implantation of axial flow left ventricular assist device. J Am Coll Cardiol 61: 153–163, 2013. 4. Moazami N, Milano CA, John R, et al; HeartMate II Investigators: Pump replacement for left ventricular assist device failure can be done safely and is associated with low mortality. Ann Thorac Surg 95: 500–505, 2013. 5. Starling RC, Moazami N, Silvestry SC, et al: Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med 370: 33–40, 2014. 6. Goldstein DJ, John R, Salerno C, et al: Algorithm for the diagnosis and management of suspected pump thrombus. J Heart Lung Transplant 32: 667–670, 2013. 7. Hayes H, Dembo L, Larbalestier R, O’Driscoll G: Successful treatment of ventricular assist device associated ventricular thrombus with systemic tenecteplase. Heart Lung Circ 17: 253–255, 2008. 8. Ballew CC, Benton EM, Groves DS, et al: Comparing survival of HMII patients with elevated LDH: Implications for medical and surgical management. J Heart Lung Transplant 32: s38, 2013. 9. Swan SK, Hursting MJ: The pharmacokinetics and pharmacodynamics of argatroban: Effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 20: 318–329, 2000. 10. Goldstein DJ, Beauford RB: Left ventricular assist devices and bleeding: Adding insult to injury. Ann Thorac Surg 75(6 suppl): S42–S47, 2003. 11. Reilly MP, Wiegers SE, Cucchiara AJ, et al: Frequency, risk factors, and clinical outcomes of left ventricular assist d evice-associated ventricular thrombus. Am J Cardiol 86: 1156–1159, A10, 2000. 12. Peura JL, Colvin-Adams M, Francis GS, et al; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia: Recommendations for the use of mechanical circulatory support: Device strategies and patient selection: A scientific statement from the American Heart Association. Circulation 126: 2648–2667, 2012. 13. Berry CN, Girardot C, Lecoffre C, Lunven C: Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: Comparison with heparin and recombinant Hirudin. Thromb Haemost 72: 381–386, 1994. 14. Pappalardo F, Scandroglio AM, Potapov E, et al: Argatroban anticoagulation for heparin induced thrombocytopenia in patients with ventricular assist devices. Minerva Anestesiol 78: 330– 335, 2012. 15. Sheth SB, DiCicco RA, Hursting MJ, Montague T, Jorkasky DK: Interpreting the International Normalized Ratio (INR) in individuals receiving argatroban and warfarin. Thromb Haemost 85: 435–440, 2001.
Case Series
Argatroban as Novel Therapy for Suspected Thrombosis in Patients With Continuous-Flow Left Ventricle Assist Device and Hemolysis Amit Badiye,* Gabriel A. Hernandez,† and Sandra Chaparro*
The growing use of left ventricular assist devices as a bridge to transplant and their increased duration as destination therapy in patients successfully treated for advance heart failure unwrap a new spectrum of complications seen in long-term use of the devices. Device thrombosis remains a therapeutic dilemma, and limited data are available for the use of direct thrombin inhibitors as a treatment option. We performed a review of literature and present a series of four patients with suspected left ventricular assist device–associated thrombosis, manifesting as hemolysis, who were treated empirically with argotraban, a direct thrombin inhibitor with the ability to interact with both free and clot-bound thrombin. In this case series, we treated four patients with argatroban for suspected device thrombosis. All showed significant improvement of hemolysis according to lactate dehydrogenase measurements, and device removal was prevented in three. Bleeding complications occurred when therapy was used closer to the operative period. Argatroban can be a viable option to treat patients with hemolysis from suspected device thrombosis in patients with HeartMate II continuous-flow left ventricular assist device. Prompt attention is needed to monitor any bleeding complications. ASAIO Journal 2014; 60:361–365.
Despite the bleeding risk, anticoagulation is indicated within the first 24 hours post-LVAD implantation2 because of the overwhelming occurrence of embolic events, hemolysis, and pump failure. Left ventricular assist device thrombus is the fourth most common cause of readmission after LVAD implantation (13.9% of readmissions)3 and is the second most common cause of pump replacement after percutaneous lead damage4; however, an abrupt increase in its incidence has been noted during the last couple of years.5 Pump thrombosis implies the formation of a clot within the flow path of the device, including the inflow cannula, the outflow graft, and the housing that contains the rotor.6 Recently described by Goldstein et al.,6 risk factors that contribute to pump thrombosis are related to the pump itself (i.e., heat, shearing forces, and malposition), to the patient (i.e., atrial fibrillation, preexistent thrombus, and hypercoagulable state), and to the management (i.e., suboptimal anticoagulation). They presented an algorithm for the diagnosis of pump thrombus as well as current management options favoring pump exchange or urgent transplantation. Other nonsurgical approaches have been attempted to treat LVAD-related thrombosis with resultant conflicting data regarding the use of different thrombolytic agents.7,8
Key Words: anticoagulation, heart failure, ventricle assist device, thrombosis, heart
Methods
The growing use of the left ventricular assist device (LVAD)
We performed a review of literature and presented a case series of four patients exhibiting hemolysis caused by HeartMate II (HMII) (Thoratec Corporation, Pleasanton, CA) LVAD-related thrombosis who were treated with argatroban, a direct thrombin inhibitor with a unique pharmacological profile and ability to interact with both free and clot-bound thrombin.9 The diagnosis of hemolysis was made with symptoms, hemoglobin, and lactate dehydrogenase (LDH) levels. Because of the retrospective nature of the study, plasma-free hemoglobin levels were not uniformly collected. Lactate dehydrogenase levels greater than three times the upper limit of normal should raise concern for possible thrombus.6 In our institution, values less than 600 IU/L are considered normal. The overall strategy of initial anticoagulation to prevent thrombosis was made according to the current literature at the time of treatment.1,2 We use aspirin 81 mg within the first 24 hours after device implantation followed by heparin as bridge to warfarin (target international normalized ratio [INR] of 2–3 per manufacturer recommendations and the addition of dipyridamole was optional as per implanting surgeon’s discretion).
as a bridge to transplant and their increased duration as destination therapy in patients with end-stage cardiomyopathy unwrap a new spectrum of complications seen in long-term use of the devices. The most common complications are disorders of coagulation, ranging from bleeding to thrombosis.1 From the *Division of Cardiology, Department of Medicine, University of Miami, Jackson Memorial Hospital, Miami, Florida; and †Department of Medicine, University of Miami, Jackson Memorial Hospital, Miami, Florida. Submitted for consideration September 9, 2013; accepted for publication in revised form February 20, 2014. Disclosure: The authors have no conflicts of interest to report. Reprint Requests: Sandra Chaparro, MD, Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Clinical Research Building, Room 1110, 1120 NW 14th Street, Miami, FL 33136. Email: [email protected]. Copyright © 2014 by the American Society for Artificial Internal Organs DOI: 10.1097/MAT.0000000000000067
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362 BADIYE et al. Case 1 A 48-year-old male with nonischemic cardiomyopathy secondary to left ventricle noncompaction and a left ventricle ejection fraction (LVEF) of 10% was referred to our institution for advanced heart failure therapies. He had multiple admissions because of acute decompensated heart failure (ADHF) despite optimal medical management. He became inotrope dependent, decompensated because of a catheter-related sepsis, and required intraaortic balloon pump for stabilization. He underwent HMII LVAD implantation with mitral valve repair as a bridge to transplant with an INTERMACS profile of 1. Postoperatively, he developed right ventricular failure requiring inotropic support for 2 weeks. He recovered and was discharged home on postoperative day 28 on warfarin, dipyridamole 75 mg three times a day, and aspirin 81 mg. Almost 7 months later, he reported having dark-colored urine and dyspnea and was admitted for further evaluation. His laboratory workup showed an increased blood urea nitrogen and creatinine with a significant drop of his hemoglobin from a baseline of 10 to 7.6 g/dl; LDH was found to be greater than 12,900 from a baseline of 1,500 u/L. International normalized ratio was subtherapeutic at 1.44 despite the patient being on a stable dose for a long time. Interestingly, neither his LVAD nor the log files sent to the company showed any alarms or power spikes on interrogation. Transthoracic and transesophageal echocardiograms were done and no thrombus or aortic valve abnormalities were seen. Gated cardiac computed tomography (CT) revealed a circumferential low-density chronic thrombus in the inflow and outflow of the LVAD, without significant luminal narrowing. The patient was hydrated and empirically started on argatroban, because of its clot-bound properties, with significant improvement of symptoms and normalization of urine color. However, after initial trending down of LDH, he had a milder but persistent hemolysis requiring multiple transfusions. His status was upgraded to 1A on the heart transplant list because of LVAD thrombosis, and device exchange was planned. He successfully underwent orthotopic heart transplant on postoperative day 264. Explanted device revealed a thrombus encircling the impeller, but inflow and outflow cannulae were normal (Figure 1). Case 2 A 30-year-old female with a history of acute lymphocytic leukemia at the age of 3 years who received chemotherapy with doxorubicin and radiation was diagnosed with heart failure at the age of 11 years. She was stable on optimal medical therapy until the age of 30 years when she became inotrope dependent and was listed as status 1B for heart transplant. Her echocardiographic evaluation demonstrated severe mitral regurgitation and an LVEF of 15%. After 6 months of inotropic support, she deteriorated and was admitted for optimization and started sliding on inotropes with an INTERMACS profile of 2. She successfully underwent implantation of HMII LVAD as bridge to transplant. She also underwent repair of her mitral valve and patent foramen of ovale. Postoperatively, she was anticoagulated with heparin and bridged to warfarin per protocol. Aspirin 81 mg was started on postoperative day 1 and increased to 325 mg by day 5. She developed right ventricular failure requiring inotrope support for 12 days postoperatively and recuperated well until it was noted that her LDH began to rise up to 5,787 u/L alongside the
plasma-free hemoglobin requiring several transfusions. Left ventricular assist device showed persistently increased power spikes and high flows. Given that she was being bridged with heparin and was therapeutic with warfarin, she was started on argatroban and dipyridamole 75 mg three times a day for suspected thrombus in the LVAD and listed as 1A on transplant list for devicerelated complications. Gated CT scan and echocardiogram showed no evidence of thrombus or conduit abnormalities. Lactate dehydrogenase started to trend down, but unfortunately after 7 days of argatroban therapy, she sustained a fall, had seizures, and developed right side hemiparesis. Computed tomography scan of the brain revealed a subdural hematoma which progressively worsened, requiring evacuation. All anticoagulants were held and aspirin 81 mg was reintroduced 24 hours postprocedure. Once cleared by neurosurgery, she was restarted on heparin and warfarin, with a lower activated partial thromboplastin time and INR goal. This regimen was started instead of argatroban because the hemolysis had resolved and LDH had normalized. Follow-up echocardiogram and chest x-ray showed slight septal positioning of the inflow cannula, but no other abnormalities were detected. She was discharged on postoperative day 54 and is currently stable 14 months postintervention. Her INTERMACS level is 6 and she is awaiting transplant. Case 3 A 69-year-old male with a 4-year history of nonischemic cardiomyopathy treated with optimal medical therapy presented with automatic implantable cardioverter defibrillator (AICD) shocks. He had a gradual deterioration in his clinical status and had multiple admissions because of ADHF with an LVEF of 15% and INTERMACS 3 and underwent elective HMII LVAD implantation as bridge to transplant. Within the first 24 hours, he was anticoagulated with heparin, dipyridamole 75 mg three times a day, and aspirin 81 mg. Warfarin was introduced on day 2 and he was weaned off inotropes by postoperative day 3; there were no postoperative complications and he was discharged on postoperative day 14 with aspirin 81 mg and warfarin with a therapeutic INR of 2–3. The patient had a stable clinical course but was readmitted on postoperative day 53 with tea-colored urine and suspected melena. Hemoglobin dropped to 8.4 from a baseline of 10 g/dl and LDH was found to be significantly increased up to 5,525 u/L from a baseline below a thousand. It was decided to empirically start him on argatroban, as his INR was therapeutic on warfarin, and aspirin was continued. Upper and lower gastrointestinal endoscopy was normal and his melena resolved. Computed tomography angiography revealed a focal kink in the LVAD efferent cannula causing 50% diameter stenosis, but there was no luminal compromise as the kink was actually a smaller caliber Teflon graft extension used for anastomosis in this very tall patient. He was listed as 1A on transplant list because of LVAD-related complications. After a week of treatment, his LDH improved significantly. Warfarin and dipyridamole 75 mg three times a day were restarted on admission day 4, and the patient was kept on argatroban for a total of 17 days until the INR reached a determined goal of 4. He was discharged on aspirin and warfarin with an LDH at baseline. The patient is currently doing well 14 months postintervention, INTERMACS 7 and is on the transplant waiting list status 1B (Figure 2).
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Figure 1. Explanted device revealed a thrombus encircling the impeller, but inflow and outflow cannulae were normal.
Case 4 A 52-year-old male with nonischemic cardiomyopathy, a history of ventricular tachycardia, and an LVEF of 10% was admitted after multiple episodes of ADHF, hepatic and renal failure, and AICD shocks. He became inotrope dependent and was optimized on his heart failure therapies. His clinical course was complicated by sustained ventricular tachycardia with AICD shocks. He was not a candidate for heart transplant at our institution because of chronic persistent hepatitis B; therefore, he underwent HMII LVAD implantation as destination therapy and mitral valve repaired with Alfieri stitch. He was started on anticoagulation per protocol, but unfortunately his immediate postoperative period was complicated by expanding mediastinal hematoma requiring re-exploration. Once stabilized, dipyridamole 75 mg three times a day and aspirin 325 mg were started on postoperative day 1, heparin on day 2, and warfarin on day 3. He was successfully extubated, chest tubes were pulled and he was weaned off inotropes. By postoperative day 7, the LVAD controller showed high
power and flow alarms, LDH was slightly increased to 1,566 from baseline of 700 and hemolysis was diagnosed, possibly because of suspected clot. Echocardiogram showed adequate emptying of left ventricular cavity with optimal revolutions per minutes on the device. He was being bridged to warfarin and had therapeutic partial thromboplastin time of 60–80 seconds while on heparin therapy but given the persistent hemolysis, he was switched to argatroban. Lactate dehydrogenase started trending down and the LVAD controller’s alarms resolved. Unfortunately, after 9 days of argatroban therapy, he developed worsening of dyspnea. A repeat echocardiogram showed moderate pericardial effusion and all anticoagulants were held. A pericardial window was done which had to be extended to sternotomy and there were clots compressing the left atrium which were evacuated. Anticoagulation with heparin, clopidogrel, and aspirin was resumed 24 hours after the procedure at the discretion of the surgical team. Lactate dehydrogenase continued to remain at baseline without any further evidence of hemolysis. He was
Figure 2. A: Axial computed tomography view of the focal kink in the left ventricular assist device efferent cannula, proximal to the anastomosis into the ascending aorta, which causing 50% diameter stenosis. The anastomosis itself with the ascending aorta is patent measuring 12.2 mm in diameter. B: Reconstruction image, kink is marked with the large arrow.
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Figure 3. Argatroban use and lactate dehydrogenase (LDH) tendency in our case series in respect to time. X-axis represents the days since hemolysis was diagnosed. Asterisks Indicate the initiation of argatroban.
discharged home on postoperative day 28 on warfarin and aspirin 81 mg. He is currently stable 13 months postintervention (Figure 3). Discussion Left ventricular assist device complications are more commonly seen with the increased frequency and duration of their use. The high incidence of bleeding as a postoperative complication, requiring re-intervention in up to 60% of recipients,10 delays the initiation of anticoagulation and leads to clot formation.11 Risk of bleeding continues even past the first year1 and is due to the high prevalence of acquired Von Willebrand factor deficiency as well as the relation of arteriovenous malformations in patients with the continuous-flow HMII. Management thus always involves the fine balance between bleeding and thrombosis. Aspirin within the first 24 hours after device implantation followed by heparin as bridge to warfarin, to achieve a therapeutic INR goal of 2–3, is the usual guideline-driven anticoagulation therapy in patients with centrifugal pumps recommended by the International Society of Heart and Lung Transplantation2 and supported by the American Heart Association.12 Perioperative anticoagulation in patients with LVAD is still evolving and our center shared the same concern published in recent article about early device thrombosis5; therefore, we added antiplatelet therapy in some patients. Hemolysis is a known adverse event of LVAD.3 Destruction of red blood cells is the result of wall shear stress, flow acceleration, and interaction with artificial surfaces. Factors that generate changes in flow rate and power demand, such as conduit kinks or wall thrombosis, lead to a higher rate of hemolysis.6 Diagnosis of hemolysis secondary to red blood cells destruction is made in the setting of anemia, absence of blood loss, increased lactate dehydrogenase, unconjugated bilirubin, and decreased haptoglobin levels. The use of heparin for patients suspected of having a thrombus leading to hemolysis is challenging because of its immunogenicity and inability to inhibit clot-bound fibrin.13 In our case series, we empirically used an alternate therapeutic approach with argatroban, a direct thrombin inhibitor derived from L-arginine, in patients presenting with hemolysis due to suspected thrombosis after excluding other causes.6 More so, argatroban has been successfully used in patients with LVADs and heparin-induced thrombocytopenia as initial postoperative anticoagulant.14
Argatroban reversely inhibits thrombin by inhibiting thrombin-induced reactions and activation of coagulation factors V, VIII, and XIII, and protein C.9 It is also effective at inhibiting platelet aggregation and thromboxane generation in the presence of both free and clot-bound thrombin. These pharmacologic properties are different from those of hirudin and heparin, for which markedly higher concentrations are required to inhibit clot-bound thrombin in contrast to free thrombin.13 Argatroban has a linear pharmacokinetic property and reaches its steady-state level within 1–3 hours after the initiation of infusion. After cessation, the anticoagulant effect is lost within 2–4 hours.9 It has been previously used in patients with LVADs, and several data show its safety and efficacy as initial postoperative anticoagulant in patients with heparin-induced thrombocytopenia.14 All patients undergoing LVAD implant are screened for hypercoagulable states and the screen was negative in our series. The drawback of argatroban is that, in the event of bleeding, there is no reversal agent and it is difficult to monitor given its effects on both prothrombin time/INR and partial thromboplastin time (PTT). The goal for argatroban therapy is a PTT of 1.5–3 times the baseline (not exceeding 100 seconds) and monitoring the INR is only useful when switching to warfarin. Because of the rapid steady state of argatroban and its short half-life, the variation of the INR will be brisk when used in combination of warfarin, which has a longer half-life. This is of significance when transitioning from argotraban to warfarin or vice versa. This was studied by Sheth et al., who found that the INR will roughly double when argatroban is added to warfarin at different INR levels. From these data, it can be extrapolated that an INR of 4 might be ideal for stopping argatroban. The INR should then be repeated 4–6 hours later, when the anticoagulant effects of argatroban would be expected to be negligible, to ensure a therapeutic value on warfarin alone. Although INR levels of 4–5 are known not to increase bleeding when co-therapy is used,15 we recommend extreme caution when starting argatroban with a baseline INR close to 4 because it will overshoot. Whether argatroban carries an increased risk of bleeding in patients with LVADs has not been proven in previous studies performed on heparin-induced thrombocytopenia14; in our patients, we noticed that the presence of hemolysis in the perioperative period correlated with bleeding problems as seen in two of our patients, as opposed to those who were further away from the date of implant. This is not necessarily due to our intervention, as previously mentioned bleeding in the postoperative time is the most common complication.10 Extreme caution should be taken when argatroban is used in patients with liver dysfunction because the clearance is delayed and they have a higher risk for bleeding,8 but there is no contraindication in patients with renal dysfunction as it is not renally excreted. Avoid the use of argatroban in patients at risk of bleeding, in severe hypertension, and if major surgery is planned. An average 60 kg patient will use 170 mg/day (2 μg/ kg/min) at a price of $272.40 for 50 mg/50 ml. In comparison with bivalirudin (both direct thrombin inhibitors), argatroban has different affinity for thrombin. Higher concentrations of bivalirudin are required to inhibit clot-bound thrombin in contrast to free thrombin, hence requiring greater doses with higher risk of bleeding. To our knowledge, no other intravenous administered anticoagulant has a clot-bounded thrombin properties (hirudin is no longer available). Dabigatran (direct thrombin inhibitor)
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and rivaroxaban (clot-bound factor Xa properties) are both orally administered and have not been studied in patients with ventricular assist devices. Although current guidelines and a recent algorithm6 recommend prompt admission for optimization of anticoagulation and possible pump exchange in the presence of hemolysis,2 different approaches have been attempted to medically treat LVADrelated thrombosis with conflicting data regarding the use of thrombolytic agents.7,8 Attempts to understand mortality risks in these patients have been made. Ballew et al.8 classified them according to their LDH levels and found that patients with levels greater than 1000 U/L treated medically with anticoagulants other than argatroban had a mortality of 50% compared with patients who had surgical intervention with survival of 100%. Our series also highlights how imaging can be misleading and one has to consider the entire clinical scenario before making surgical decisions such as LVAD exchange. Although device exchange is safe, it carries the risk of i ntervention-related complications and increases cost.4,8 Case 1 had a delay in seeking medical attention and remained on argotraban until he was transplanted. Although symptoms improved alongside LDH levels, he was still hemolysing and a pump replacement was considered. It was suspected to have a thrombus layering the inside of the inflow cannula on CT scan, but the explanted device showed thrombus layering the impeller only. Given the significant improvement of LDH and hemolysis rate, it can be presumed that argatroban had an effect decreasing the thrombus burden. Case 3 had a suspected kink at the outflow graft connection to the aorta, but in reality, there was no luminal compromise as the kink was just a small caliber Teflon graft extension used for anastomosis. As seen in the Figure 3, it is important to note that early initiation of anticoagulation leads to higher chances of resolution of thrombus and hemolysis. Only one patient persistently had hemolysis leading to pump explant and heart transplantation; particularly, this patient had low INR as an outpatient. Notably, the remaining three patients were therapeutic with either warfarin or heparin at the onset of hemolysis. This also promotes the hypothesis that the chances of thrombus and hemolysis resolution with argatroban may be higher if patients are therapeutic while having this complication. This case series is unique and to our knowledge the first one to use argatroban for suspected device thrombosis–related hemolysis in patients with HMII LVAD. Devices with less space around the impellers may need a more proactive and aggressive approach for hemolysis. Early diagnosis and prompt treatment of suspected device thrombosis presenting with hemolysis is thus imperative. Comment To our knowledge, this is the first series showing the use of argatroban to treat hemolysis from suspected device thrombosis in patients with HMII continuous-flow LVAD. We acknowledge our limitations and further investigation on use of direct thrombin inhibitors with larger patient dataset and randomized control trials will be needed to justify our approach. Although bleeding was observed in half of our patients, our survival remained 100%. In addition, further evaluation of explanted pumps, when the time comes, will give us a better idea of thrombus resolution. We did not consider treatment with thrombolytics because of a high risk of cerebrovascular events, bleeding, and reduced
comfort level with these medications in perioperative period. The use of GP2B3A inhibitors was considered, but we selected argatroban, given the properties of interacting with both free and clot-bound thrombin. Our therapy was effective when given for as short as 7 days, and three of our patients treated medically are currently free of hemolysis 13 months or more postintervention. Prompt attention is needed to monitor any bleeding complication, especially in the postoperative period, when bleeding is the most common complication.10 References 1. Rossi M, Serraino GF, Jiritano F, Renzulli A: What is the optimal anticoagulation in patients with a left ventricular assist device? Interact Cardiovasc Thorac Surg 15: 733–740, 2012. 2. Feldman D, Pamboukian SV, Teuteberg JJ, et al; International Society for Heart and Lung Transplantation: The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: Executive summary. J Heart Lung Transplant 32: 157–187, 2013. 3. Hasin T, Marmor Y, Kremers W, et al: Readmissions after implantation of axial flow left ventricular assist device. J Am Coll Cardiol 61: 153–163, 2013. 4. Moazami N, Milano CA, John R, et al; HeartMate II Investigators: Pump replacement for left ventricular assist device failure can be done safely and is associated with low mortality. Ann Thorac Surg 95: 500–505, 2013. 5. Starling RC, Moazami N, Silvestry SC, et al: Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med 370: 33–40, 2014. 6. Goldstein DJ, John R, Salerno C, et al: Algorithm for the diagnosis and management of suspected pump thrombus. J Heart Lung Transplant 32: 667–670, 2013. 7. Hayes H, Dembo L, Larbalestier R, O’Driscoll G: Successful treatment of ventricular assist device associated ventricular thrombus with systemic tenecteplase. Heart Lung Circ 17: 253–255, 2008. 8. Ballew CC, Benton EM, Groves DS, et al: Comparing survival of HMII patients with elevated LDH: Implications for medical and surgical management. J Heart Lung Transplant 32: s38, 2013. 9. Swan SK, Hursting MJ: The pharmacokinetics and pharmacodynamics of argatroban: Effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 20: 318–329, 2000. 10. Goldstein DJ, Beauford RB: Left ventricular assist devices and bleeding: Adding insult to injury. Ann Thorac Surg 75(6 suppl): S42–S47, 2003. 11. Reilly MP, Wiegers SE, Cucchiara AJ, et al: Frequency, risk factors, and clinical outcomes of left ventricular assist d evice-associated ventricular thrombus. Am J Cardiol 86: 1156–1159, A10, 2000. 12. Peura JL, Colvin-Adams M, Francis GS, et al; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia: Recommendations for the use of mechanical circulatory support: Device strategies and patient selection: A scientific statement from the American Heart Association. Circulation 126: 2648–2667, 2012. 13. Berry CN, Girardot C, Lecoffre C, Lunven C: Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: Comparison with heparin and recombinant Hirudin. Thromb Haemost 72: 381–386, 1994. 14. Pappalardo F, Scandroglio AM, Potapov E, et al: Argatroban anticoagulation for heparin induced thrombocytopenia in patients with ventricular assist devices. Minerva Anestesiol 78: 330– 335, 2012. 15. Sheth SB, DiCicco RA, Hursting MJ, Montague T, Jorkasky DK: Interpreting the International Normalized Ratio (INR) in individuals receiving argatroban and warfarin. Thromb Haemost 85: 435–440, 2001.
