Despite chronic administration of antiplatelet and anticoagulant therapies, pump thrombosis in patients with continuous flow left ventricular assist devices (LVADs) remains a common and highly morbid event. In the initial and extended trials of the HeartMate II LVAD, the frequency of thrombosis was reported as 2–4%.1–3 Recent data from 837 patients implanted at three institutions revealed an increased rate of pump thrombosis with the HeartMate II LVAD from 2.2% (95%CI 1.5–3.4) in 2011 to 8.4% (95%CI 5.0–13.9) in 2013.4 Freedom from pump thrombus in the HeartWare bridge to transplant and subsequent continued access protocol at 12 months was 92%.5 Management strategies for LVAD thrombosis range from the initiation of antithrombotic, antiplatelet, or thrombolytic agents to the replacement or explantation of the pump. A step-wise approach to the diagnosis and management of LVAD thrombosis has been proposed.6 In this published algorithm, antithrombotic therapy with a direct thrombin inhibitor is considered a treatment option in the setting of persistent hemolysis, power spikes, and/or heart failure symptoms; however, this recommendation is based on anecdotal evidence.6 In 2011, the LVAD Thrombus Protocol for the Advanced Heart Failure Program at Tufts Medical Center was revised to include bivalirudin as a treatment option for patients with suspected pump thrombosis. In this series, we describe our experience with the use of bivalirudin as an alternative to heparin in six hemodynamically stable patients with ten hospital admissions for suspected LVAD thrombosis.
Between April and November 2012, we prospectively assessed the clinical responsiveness to bivalirudin in all patients treated with this agent for suspected LVAD thrombosis. To standardize therapy, an order set for dosing and monitoring of bivalirudin was developed (see Figure 1). As per our clinical protocols, lactate dehydrogenase (LDH) is monitored routinely at all clinic appointments. LVAD thrombosis was suspected in the setting of an LDH greater than 2.5 times the upper limit of normal (ULN) for our laboratory (>550 IU/L) in the absence of alternative etiologies, and/or LVAD dysfunction as evidenced by elevated pump power, new, regular opening of the aortic valve, and/or failure to decompress the left ventricle despite progressive rpm increase during echocardiographic interrogation. A clinical response was defined as a 50% or greater reduction in LDH and/or normalization of LVAD parameters. Rates of INTERMACS7 major bleeding constituted the safety assessment. All clinical parameters were extracted from the documented medical records.
Six patients admitted for a total of ten hospitalizations for suspected LVAD thrombosis received bivalirudin per our institution’s protocol. Baseline demographics are provided in Table 1. Patients were 53 to 65 years of age, four were men and all had a HeartMate II LVAD as a bridge to transplant. Three of the six patients had more than one admission for pump thrombosis. The time to presentation was a median of 150 days (range: 51–411 days) from the date of LVAD implantation. All patients were maintained as outpatients on warfarin and aspirin; three patients were additionally receiving clopidogrel 75 mg daily and two were receiving dipyridamole 75 mg orally three times a day. One patient had a subtherapeutic INR of 1.5 at the time of presentation.
At the time of presentation, all patients were hemodynamically stable and without evidence of neurologic or embolic events. Median admission and peak LDH levels were 1,132 IU/L (range: 621–2,043) and 1,541 IU/L (range: 928–2,453), respectively (Table 1). Median plasma-free hemoglobin concentration on admission was 13.55 mg/dl (range: 7.3–58.7); the value was greater than 40 mg/dl in only two cases. Hematuria was evident in 60% of the cases.
Bivalirudin was initiated per protocol at doses ranging from 0.03 to 0.15 mg/kg/hour based on renal function and baseline INR (Table 2). Median–estimated creatinine clearance was 61 ml/min (range: 53–141). Therapeutic activated partial thromboplastin times (aPTTs) were achieved in 100% of cases within 6 hours of bivalirudin administration and maintained at 12 hours. In seven of ten cases, frequent dose adjustments were required to maintain the target aPTT. Maintenance doses ranged from 0.04 to 0.23 mg/kg/hour.
Clinical response to bivalirudin occurred in nine of the ten hospital admissions for pump thrombosis (see Table 2). One course of bivalirudin therapy was deemed ineffective and changed to combination eptifibatide and heparin therapy on hospital day 3. In responders, the median time to a 50% reduction in LDH was 17 days (range: 5–44), median duration of bivalirudin therapy was 22 days (range: 11–237) and median cost of bivalirudin therapy was $79,800 (range: $31,359–$1,281,737). In seven of ten hospitalizations, the patient was successfully transitioned from bivalirudin to combination oral anticoagulant and antiplatelet therapy and subsequently discharged to home. Two patients were maintained on bivalirudin until transplantation due to recurrent LDH rises despite attempts to transition to oral therapies. There were no major bleeding events and one episode of minor bleeding (epistaxis) not requiring treatment.
Three of six patients subsequently received a LVAD exchange due to recurrent hemolysis and power spikes at 111, 130, and 259 days following completion of the bivalirudin protocol.
To the best of our knowledge, this is the first series of LVAD patients treated for pump thrombosis with bivalirudin per an institutional protocol. A MEDLINE search from 1996 to December 2013 did not reveal any reports describing the use of a direct thrombin inhibitor (i.e., bivalirudin, argatroban, or lepirudin) for management of LVAD thrombosis. One report described the use of bivalirudin for treatment of aortic valve thrombosis after LVAD implantation.8 The authors suggest the potential role of bivalirudin in LVAD patients who develop a thrombus despite anticoagulation with unfractionated heparin, including patients who develop a thrombus in the LVAD or on the inflow or outflow cannula.8
This series documents clinical responsiveness as determined by laboratory markers of hemolysis in nine of ten cases. The cohort represents a clinically stable group of patients with probable, sub-acute LVAD thrombosis who, while hemodynamically stable, had evidence of either hemolysis and/or abnormal LVAD function. Clinical response was achieved in the majority of treated patients, allowing for successful conversion to an oral anticoagulant/antiplatelet regimen with discharge to home. However, despite initial clinical response, the risk of recurrence in this small cohort was high; 50% of patients eventually underwent LVAD exchange during a subsequent admission while two patients were maintained on bivalirudin until the time of transplantation.
Suboptimal responses to heparin for treatment of pump thrombosis led to the inclusion of bivalirudin in our LVAD Thrombus Protocol. There are multiple potential advantages of bivalirudin as compared to heparin. Bivalirudin inhibits both circulating and fibrin-bound thrombin, is less immunogenic than heparin, and inhibits platelet adhesion.9,10 The pharmacology and pharmacokinetics of this hirudin analog contribute to its safety profile. As a bivalent direct thrombin inhibitor, bivalirudin initially binds independently and concurrently to both the active site (exosite III) and the fibrinogen-activation site, exosite 1, of thrombin.9 Proteases including thrombin subsequently cleave the arginine–proline bond of the bivalirudin molecule, causing dissociation of the drug from the active site of thrombin and weakened affinity of the drug for binding at exosite 1. The remaining bivalirudin fragment transforms into a competitive inhibitor of thrombin, accounting for the drug’s transient and reversible effect. Bivalirudin is primarily removed via proteolysis (80%) with renal elimination contributing to 20% of drug clearance.10 The short serum half-life of 25 minutes in patients with normal renal function coupled by bivalirudin’s transient reversible effects on thrombin support a relatively wide safety margin. Compared to heparin, bivalirudin has been associated with a lower risk of major bleeding. A meta-analysis of 14 trials revealed a 45% relative decrease in major bleeding (OR 0.55, 95%CI 0.43–0.72) with bivalirudin compared to unfractionated heparin among patients undergoing transfemoral percutaneous coronary intervention.11
Drawbacks to the use of bivalirudin in our series included the need for frequent dosage adjustments to maintain the target aPTT as well as the cost of therapy. Daily fluctuations in the aPTT could not be explained by changes in the renal clearance of bivalirudin as estimated by indices of patient renal function. The majority of the dose adjustments were up-titrations within the first five days of drug initiation. One possible explanation for the required, frequent, early dose titrations to maintain a therapeutic aPTT in the setting of LVAD support may be accelerated proteolytic cleavage of bivalirudin due to intraventricular flow stasis. In addition to the need for frequent monitoring, additional consideration should be given to the cost of bivalirudin therapy. The reported median cost of approximately $80,000 in our series reflects the cost of the drug product only.
This case series is the first to describe the successful use of bivalirudin in patients with suspected pump thrombosis associated with the HeartMate II LVAD. In this limited series of hemodynamically stable patients, bivalirudin was relatively safe and effective for the medical management of LVAD thrombosis; however, the risk of recurrence was high. These findings suggest that, with careful monitoring, bivalirudin may be considered as part of an initially conservative strategy for treatment of VAD thrombosis or used as a bridge to a longer term strategy including VAD exchange or cardiac transplantation.
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bivalirudin; direct thrombin inhibitor; LVAD; thrombosis