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Low-Dose Prothrombin Complex Concentrate in Patients with Left Ventricular Assist Devices

Brown, Caitlin S.*; Zemrak, Wesley R.; Dyer, Kaitlin J.; Rolfe, Stephen

doi: 10.1097/MAT.0000000000000783
Case Reports
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Left ventricular assist devices (LVADs) have become an important advancement for patients with end-stage heart failure. Left ventricular assist devices come with the risk of stroke and pump thrombosis, and to mitigate these risks, anticoagulation is given to these patients. With anticoagulation comes increased bleeding risk, and urgent reversal may be necessary. Reports have shown that the risk of thrombosis with prothrombin complex concentrate (PCC) does exist, especially in patients with baseline risk factors for thrombosis. We describe two cases of warfarin reversal with low-dose 4-factor PCC (4F-PCC) in two different LVAD patient scenarios. Low-dose 4F-PCC was administered to one patient with a Heart Mate II (HM II) LVAD, international normalized ratio (INR) of 4.7 on admission and in need of an urgent procedure. He received approximately 16 units/kg of 4F-PCC with reversal of his INR to 2.3 within 45 minutes. The second patient also had a HM II LVAD and presented with a right occipital intraparenchymal hemorrhage and subdural hematoma with an INR of 3.7. He received approximately 11 units/kg of 4F-PCC with INR reversal to 1.6 within 1 hour. Both of these patients had no thrombotic complications and successful reversal of their INR with low-dose 4F-PCC. Further investigation into low-dose 4F-PCC dosing strategies is warranted.

From the *Department of Pharmacy, Mayo Clinic, Rochester, Minnesota

Department of Pharmacy, Maine Medical Center, Portland, Maine

Department of Cardiology/Heart Failure, Maine Medical Center, Portland, Maine.

Submitted for consideration October 2017; accepted for publication in revised form February 2018.

Disclosure: The authors have no conflicts of interest to report.

Correspondence: Wesley R. Zemrak, Department of Pharmacy, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102. Email: zemraw@mmc.org.

Left ventricular assist devices (LVADs) have emerged as an important technologic and therapeutic advancement for the care of patients with end-stage heart failure. Over 5 million people in the United States are affected by heart failure, and LVADs have become firmly placed as a therapeutic option in patients as a bridge to transplant or as destination therapy.1 Patients with LVADs require anticoagulation to reduce the risk of thrombosis; however, anticoagulation with warfarin has a narrow therapeutic window and anticoagulation management in these patients must be balanced between bleeding and thrombosis.

Each commercially available LVAD carries an increased risk for the development of stroke and pump thrombosis, and their necessary anticoagulation increases their risk of bleeding. The Eighth Interagency registry for mechanically assisted circulatory support (INTERMACS) report for adverse event rates in the first 12 months postimplant from 2008 to 2016 reports a bleeding rate of 16.24/100 patient months in the first 3 months after implant and 4.08/100 patient months in the subsequent 3–12 months. This report also provides data for adverse thromboembolic outcomes reporting a stroke rate of 2.42/100 patient months during the first 3 months of device implant and 1.12/100 patient months for the subsequent 3–12 months.2 Given these high rates of complications, patients often require urgent reversal for bleeding episodes or for complications arising from suspected or confirmed pump thrombosis.

In patients treated with warfarin for indications other than LVADs, reversal guidelines recommend the use of prothrombin complex concentrate (PCC) in conjunction with vitamin K over the use of fresh frozen plasma (FFP).3 , 4 Four-factor PCC (4-F PCC) has been compared with FFP for both patients with major bleeding and need for reversal for urgent procedures. It has been shown to be noninferior to FFP for international normalized ratio (INR) correction and 24 hour hemostatic efficacy.5 , 6 It has been recently reported that the risk of thrombosis in randomized trials of 4F-PCC versus FFP is not higher in either group, occurring at a rate of approximately 8%.7 Despite these findings, other reports have shown that the risks of thrombosis with PCC are present, especially in patients with high baseline risk factors and potentially with higher doses of PCC.8–10 Patients with LVADs certainly are at a high risk of thrombosis, thus the desire to minimize this risk with the lowest effective dose of PCC is paramount.

We report two cases of LVAD patients receiving low-dose 4F-PCC for acute warfarin reversal in two different clinical settings.

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Case 1

A 68 year old Caucasian male (height 183 cm, weight during admission 102.06 kg) presented to the emergency department for complaints of nausea and right upper quadrant pain and was diagnosed by with perforated acute cholecystitis and splenic infarct. The patient had a HM II LVAD placed approximately 21 months earlier secondary to stage D systolic heart failure, INTERMACS level 3. Other medical history included cardiac and lung sarcoidosis, chronic kidney disease stage 3, gout, and atrial fibrillation. Of note he also presented to the emergency department 2 weeks earlier with a gastrointestinal bleed with no clear source, and was discharged home. On presentation to the emergency department, his INR was 4.7, hemoglobin 8.1 g/dl, and hematocrit 25.7%. Two days before emergency department presentation, his INR was 6.7, and he was instructed to hold his warfarin (Table 1). Surgery and interventional radiology (IR) were consulted, and IR planned for placement of a percutaneous cholecystostomy tube when the INR was approximately 2.0. He was given 2.5 mg intravenous vitamin K and approximately 16 units/kg (1,648 units) of 4F-PCC based on institutional policy. Forty-two minutes after administration of PCC, his INR was 2.3, and approximately 6 hours after 4F-PCC administration, his INR was 2.2 (Table 1). Interventional radiology proceeded with percutaneous cholecystostomy placement approximately 2 hours after 4F-PCC administration without complication. The patient was found to have Klebsiella pneumoniae bacteremia and was treated for 2 weeks with ceftriaxone. Anticoagulation with a heparin infusion was initiated 2 days after drain placement, and warfarin was initiated 3 days after drain placement. The patient was discharged after a 7 day hospital stay with the cholecystostomy tube to remain in place for approximately 6 weeks. The patient’s LVAD was stable throughout his stay with no signs of pump thrombosis, flow (L/min) between 5.2 and 6.8, speed (rpm) at 8,800, pulsatility index (PI) between 5.3 and 5.9, and power (W) between 3.8 and 6.6. There were no bleeding or thrombotic complications throughout the hospital course or for several weeks after the administration of 4F-PCC.

Table 1

Table 1

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Case 2

A 67 year old Caucasian male (height 180 cm, weight during admission 92.2 kg) presented with confusion, headache, and a fall on the way to the emergency department. The patient has a history of nonischemic cardiomyopathy and had a HM II LVAD placed approximately 10 months before. His other medical history included diet-controlled diabetes, hypertension, hyperlipidemia, sleep apnea on continuous positive airway pressure (CPAP), and gout. His home medications were significant for warfarin and aspirin. On admission, his INR was 3.7, hemoglobin 10.9 g/dl, and hematocrit 32.5% (Table 2). A computed tomography (CT) without contrast was obtained, which showed right occipital intraparenchymal hemorrhage and subdural hematoma (Figure 1, image 1). His intracerebral hemorrhage (ICH) score on admission was 0. The patient was given 5 mg of intravenous vitamin K, and approximately 11 units/kg (1,058 units) of 4F-PCC. One hour after PCC administration, the INR was 1.6, and a repeat INR 6 hours after 4F-PCC administration was 1.6 (Table 2). A CT angiogram showed no vascular malformation or aneurysm, and no large vessel occlusion.

Table 2

Table 2

Figure 1

Figure 1

The patient’s neurologic examination was closely monitored throughout his stay, and a repeat CT at 24 hours was stable (Figure 1, image 2). Seventy-two hours after presentation, a repeat CT was performed which showed an unchanged intracranial hemorrhage (Figure 1, image 3). At this time, anticoagulation with a low-intensity heparin infusion (8 units/kg/hr, maximum weight of 83 kg) was initiated and titrated per institutional protocol for a goal-activated partial thromboplastin time (aPTT) of 50–60. A CT was repeated 24 hours after heparin initiation, which again showed a stable hemorrhage (Figure 1, image 4). Warfarin was initiated on hospital day 6, and on hospital day 10, a repeat CT was performed due the patient experiencing an increasing headache. The CT showed no new hemorrhage, and expected evolution of the right intraparenchymal hemorrhage with associated persistent edema surrounding the area of the hemorrhage (Figure 1, image 5). Another repeat CT was performed on hospital day 11 due to altered mental status. The INR at this time was therapeutic at 2.0, and the CT was again stable (Figure 1, image 6).

The patient’s LVAD remained stable throughout his stay with no signs of pump thrombosis, flow (L/min) between 3.5 and 6.8, speed (rpm) at 9,000, PI between 5.9 and 8.1, and power (W) between 4.1 and 6.1. The patient was discharged to an acute rehab facility on hospital day 12 with some noted left-sided neglect and impulsiveness, but otherwise back to baseline neurological status. He was subsequently discharged home with home physical and occupational therapy 14 days later.

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Discussion

The cases above illustrate the use of a low-dose strategy of 4F-PCC (approximately 15 units/kg) to facilitate the need for an urgent procedure and urgent reversal for a warfarin-associated intracranial hemorrhage. In both situations, this low-dose strategy was selected given the high thrombotic risk of the presence of a LVAD in both patients. In the first case, the INR was reduced from 6.7 to 2.3, which allowed the procedure to occur and no complications were seen. Under package insert dosing recommendations, this patient would have received 50 units/kg of 4F-PCC for this INR value and likely would have been put at risk of INR over correction and potential thrombosis. The second case showed an INR reduction from 3.7 to 1.6 immediately after the administration of an even lower dose (11 units/kg) than what is typically recommended, even in our institutional low-dose guideline. We opted to administer this even lower dose of 4F-PCC in this situation given his stable neurologic examination and his high thrombotic risk status given the presence of his LVAD.

Optimal dosing of PCC has not been fully investigated in randomized clinical trials; however, data with alternative PCC products in Europe have demonstrated that low fixed-dose strategies provide reliable and complete reversal of warfarin in most clinical situations.11–13 On approval by the Food and Drug Administration (FDA) and the beginning of 4F-PCC use at our institution, we implemented a low-dose 4F-PCC strategy (15 units/kg) for patients presenting with central nervous system (CNS)-related hemorrhage with INR values 1.6–1.9, for procedural reversal where INR goal is ≤2, and for select cases where the patient is deemed to have a very high risk for thrombosis. In patients presented with CNS-related hemorrhage, this strategy has shown promising effectiveness with minimal risk of thrombotic complications.14

In conclusion, the use of a low-dose 4F-PCC strategy of 16 and 11 units/kg facilitated warfarin reversal for an urgent procedure and ICH in two patients with LVADs. Given the lack of clinical data supporting current dosing recommendations for 4F-PCC dosing, evidence of success with lower doses of alternative 4F-PCC products, and the high complications rates including thrombosis and hemorrhage in patients with LVADs, utilization of a low-dose 4F-PCC strategy for warfarin reversal may be promising. Further investigation into lower dose 4F-PCC strategies is warranted.

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References

1. Baumann Kreuziger LM, Kim B, Wieselthaler GM. Antithrombotic therapy for left ventricular assist devices in adults: A systematic review. J Thromb Haemost 2015.13: 946–955.
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14. Zemrak WR, Smith KE, Rolfe SS, et al. Low-dose prothrombin complex concentrate for warfarin-associated intracranial hemorrhage with INR less than 2.0. Neurocrit Care 2017.27: 334–340.
Keywords:

warfarin; prothrombin complex concentrate; PCC; LVAD; reversal

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