Intracranial hemorrhage (ICH) in patients with continuous flow left ventricular assist devices (CF-LVAD) can be a potentially devastating complication and has a reported incidence as high as 11%.1 As the number of patients with CF-LVAD implants grow worldwide, there will be an increasing prevalence of ICH in a population at a relatively high risk for this complication.2–4 Among the mainstays of treatment for patients who present with acute ICH on chronic vitamin K antagonist (VKA) therapy, is the reversal of the coagulopathy, which is critical, due to the substantial risk of hematoma expansion and subsequent mortality within the first 24 hours.4,5 When performed, commonly used VKA reversal strategies in patients with ICH involve either the administration of fresh frozen plasma (FFP) or prothrombin complex concentrates (PCC).
Fresh frozen plasma contains all components of the coagulation system and is associated with relatively large infusion volumes, transfusion-associated adverse events (infection, allergic reactions, lung injury, and volume overload), and a prolonged time to administration due to a requirement for ABO blood typing and thawing.6–9 In contrast, PCC’s are human plasma-derived concentrates of the vitamin K-dependent coagulation factors (II, VII, IX, and X) and its use has become an increasingly attractive alternative to many clinicians over FFP, as it avoids transfusion-associated adverse reactions, it requires shorter administration times, and it uses relatively small infusion volumes.8,10–12 However, despite the growing use of PCC’s in a variety of patient populations,4,8,13–17 its safety and efficacy for rapid VKA reversal in CF-LVAD patients on chronic VKA therapy is not well known.
In addition, it is unclear if rapid VKA reversal is necessary in all CF-LVAD patients who present with ICH, particularly in those with a history concerning for coexisting thromboembolic disease and in those with small bleeds who present after an interval from the onset of symptoms. An improved understanding of the factors that influenced the decision to forgo active reversal of anticoagulation therapy, and knowledge of the outcomes following such an approach, may help guide clinical decision making in instances where the risks of VKA reversal potentially outweigh its benefits. We present in this report our findings on the safety and efficacy of 4-factor (4F)-PCC assisted VKA reversal in a series of CF-LVAD patients presenting with acute ICH, and separately, describe the characteristics and outcomes of a subgroup of patients, on therapeutic anticoagulation, who were successfully managed with a no-reversal strategy.
An institution review board-approved review of all adult patients who underwent a CF-LVAD implant (HeartMate II VAD, Thoratec, Pleasanton, CA) at a quaternary care academic medical institution from May 2008 to 2015 was conducted. Patient data were obtained from a prospectively collected database and through a review of medical records. All eligible patients who were admitted for the treatment of ICH were included in the analysis. Patients were excluded if the baseline international normalized ratio (INR) on admission was ≤1.6 as these patients would not have been candidates for rapid VKA reversal and thus their outcomes would not have been applicable to the objectives of this study. Patient demographics, baseline characteristics, and clinical outcomes were collected and are reported. Variables relevant to the assessment of VKA reversal included 1) time to initiation of VKA reversal; 2) time to VKA reversal (defined as the time from initiation of VKA reversal to the INR time when no further VKA reversal agents are administered); 3) units FFP transfused; and 4) units/kg and total units of 4F-PCC transfused. Intracranial hemorrhage volumes were calculated for each patient based on previously published criteria,18 using the ABC/2 formula, where A was the greatest hemorrhage diameter by computed tomography (CT), B was the diameter 90° to A, and C was the approximate number of CT slides with hemorrhage multiplied by slice thickness.
The main objective of this study was to determine the safety and efficacy of 4F-PCC-assisted VKA reversal in CF-LVAD patients. The safety of 4F-PCC use was assessed by analyzing pre- and post reversal lactate acid dehydrogenase (LDH) levels and the rate of thromboembolic complications at 45 days following VKA reversal; thromboembolic complications that were investigated included VAD thrombosis, deep vein thrombosis (DVT), pulmonary embolism (PE), and new-onset ischemic cerebrovascular accidents (ICVA). The efficacy of 4F-PCC-assisted VKA reversal was assessed by determining if its use resulted in a difference in FFP requirements or a difference in time to VKA reversal, when compared with patients who were administered traditional agents alone (FFP and vitamin K). A secondary objective was to describe the characteristics of patients in whom rapid VKA reversal was not performed (no-reversal strategy), and to determine the clinical outcomes following that approach.
4F-PCC Dosing and Administration
The administration of 4F-PCC’s used in this study (Kcentra, CSL Behring, King of Prussia, PA) was based on dosing recommendations outlined in the product insert (pre treatment INR 2.0–3.9: 25 units/kg 4F-PCC) but also factored the risk of thromboembolism in the determination of the appropriate dose. Lower doses, ≤20 units/kg, were considered in patients deemed at high risk for thromboembolism (history of concurrent or recent thromboembolic events or history of hypercoaguable disorders). Although manufacturer guidelines recommend a dose of 35 units/kg for patients with pre treatment INR’s ≥4, the maximum dose of 4F-PCC administered in this study did not exceed 28 units/kg. A repeat INR was performed approximately 30 minutes after infusion and repeat doses were administered if the appropriate degree of INR reversal was not initially achieved.
Patient demographics, baseline (admission) characteristics, and outcomes were reported using percentages for categorical variables and means ± standard deviation for continuous variables. Comparisons were performed using the χ2 or Fishers exact test for categorical variables where appropriate while the student’s t-test was used to compare continuous variables. A two-sided type I error rate of ≤0.05 was accepted as the criteria for statistical significance.
There were 42 ICH events that occurred in the 237 patients who underwent a CF-LVAD implant during the study period; 35 cases were due to hemorrhagic CVA’s (HCVA), while seven occurred after a traumatic fall. Two patients were excluded due to insufficient data for analysis and nine were excluded due to INR’s ≤1.6. Thirty-one patients with ICH met inclusion criteria for analysis; 4F-PCC assisted VKA reversal (4F-PCC group, n = 10), traditional agents alone (no-PCC group, n = 10), no reversal performed (no-reversal group, n = 11). The mean age and duration from CF-LVAD implant to ICH in the overall study population was 52 ± 13 years (range 31–70) and 578 ± 445 days, respectively. The two most common etiologies for ICH were traumatic falls (26%) and supratherapeutic INR’s (26%, mean INR on admission: 5.2 ± 1.1). There was a high proportion of isolated right-sided bleeds in the study population (52%), and the majority of ICH’s were either subarachnoid (48%) or intraparenchymal (42%). Other relevant baseline demographics and neurologic characteristics for all groups are presented in Table 1.
Safety and Efficacy of 4F-PCC in LVAD Patients with ICH
Thromboembolic complications at 45 days were investigated to determine the safety of 4F-PCC use in CF-LVAD patients. There were no DVT’s, PE’s, or newly diagnosed ICVA’s noted within that time period in 4F-PCC or no-PCC groups. However, one patient in the no-PCC group developed a VAD thrombus 19 days after VKA reversal was performed, resulting in the need for a VAD exchange (thromboembolic events: 4F-PCC vs. no-PCC, 0% vs. 10%, p = 1.0). This patient received 2 units of FFP but was administered an unknown dose of recombinant activated factor VII and IX at an outside hospital before admission to our institution. There was also no significant difference in the LDH values between the 4F-PCC and no-PCC groups, pre- and post VKA reversal (Table 2).
The mean baseline INR was not significantly different between both 4F-PCC (mean INR: 3.8 ± 1.5) and no-PCC (mean INR: 3.5 ± 1.5) patients. Other relevant hematologic variables are presented in Table 2. There was no difference in the time to initiate VKA reversal between both groups (4F-PCC vs. no-PCC, 135 vs. 214 minutes, p = 0.39); however, VKA reversal was completed significantly earlier in the 4F-PCC group (4F-PCC vs. n-PCC, 474 vs. 945 minutes, p = 0.02) to achieve a similar mean post reversal INR (Table 2). There was also a significant difference in the number of units of FFP administered, with 4F-PCC patients receiving on average 1.9 units and no-PCC patients receiving 3.6 units (p = 0.05). Three patients (30%) in the 4F-PCC group did not require FFP and all three had an INR of <1.5 within 60 minutes of administration. The mean INR before 4F-PCC administration in these three patients was 2.6 ± 0.6. There were no overall differences in the incidence of neurologic deficits at 30 days or in-hospital mortality between 4F-PCC and no-PCC groups (p = 1.0; Table 2).
Characteristics and Outcomes of No-Reversal Group Patients
Eleven CF-LVAD patients (35%), with a mean INR of 2.4 ± 0.4 (range: 1.8–3.1), did not undergo rapid VKA reversal with either FFP or PCC, and their INR’s were allowed to physiologically normalize after discontinuation of oral VKA agents. Of these, five cases developed after a traumatic fall (INR range: 2.1–3.1). All five patients had small bleeds on neuroimaging (mean ICH volume: 0.5 cm3), and were otherwise asymptomatic with no recognizable neurologic deficits. In three cases, ICH’s developed spontaneously (mean ICH volume: 0.3 cm3): two patients had minor symptoms (headache/lethargy) and no neurologic deficits, while one patient with a spontaneous subarachnoid bleed had right-sided hemianopsia and mild aphasia, and was not actively reversed due to concurrent cardioembolic left occipital and temporal lobe ICVA’s. Three patients developed ICH due to the hemorrhagic transformation of concurrent ischemic infarcts. All three patients had small bleeds on neuroimaging (mean ICH volume: 0.3 cm3); one patient, with an INR of 3.0, had a recent history of DVT’s, multiple embolic strokes, and a VAD thrombus, whereas another patient, with an INR of 2.5, had a history of factor V Leiden deficiency in addition to a concurrent ICVA. In both these patients, the risks associated with full VKA reversal was deemed to outweigh any potential benefits due to the small volume of hemorrhage, and was consequently not performed. The remaining patient, with an INR of 1.8 and a Glasgow coma score (GCS) of 3T on presentation, was not reversed due to an extremely poor prognosis as a result of large bilateral ischemic infarcts, and was the only mortality observed in the no-reversal group. Of the 10 patients who survived, all had normal GCS’s, none developed increasing hemorrhage, and only one required acute rehabilitation following discharge from the hospital. Other relevant characteristics of no-reversal CF-LVAD patients with ICH are presented in Table 3.
The Safety and Efficacy of PCC in CF-LVAD Patients
Historically, thromboembolic complications represented the biggest limitation to the general use of PCC’s; however, recent reviews have described low rates of this complication in patients who require reversal of chronic VKA therapy, likely as a result of newer, different formulations.11 In a meta-analysis on the safety of PCC’s, Dentali et al19 reported a thromboembolic event incidence of 1.4% in 1,032 patients who presented with bleeding or who required VKA reversal before surgery. Furthermore, other large multicenter studies comparing 4F-PCC to FFP in non-LVAD patients have reported a low 4F-PCC-related thromboembolic rate between 0.6% and 3.9%, which was not found to be significantly different when compared with a rate of 0.7–3.0% observed with the use of FFP, providing additional evidence as to its safety for use in the general population.8,10,20
There are few studies that describe the use of PCC’s in patients with CF-LVAD’s and the majority of research has been focused on its use for intraoperative coagulopathy or for pre-transplant VKA reversal. Bradford et al,13 in a review of 41 patients who received intraoperative 3F-PCC for coagulopathy during CF-LVAD implants, reported no difference in thromboembolic complications at 1 and 3 months post procedure when compared with a control group who did not receive PCC. In addition, case series of PCC use in CF-LVAD patients who require VKA reversal before heart transplantation report a significant reduction in intraoperative FFP use and no evidence of an increase in thromboembolic events post transplantation.14,15 However, as the authors in these studies note, it is difficult to ascertain the true incidence of adverse events related to use of PCC’s in the perioperative period for either CF-LVAD implantation or before heart transplantation, as the concomitant administration of other reversal agents and the presence of patient-related risk factors during surgery can contribute to the development of clots and confound the results. The only report to date on PCC use for VKA reversal due to bleeding events while on CF-LVAD support (in a non-operative setting) was by Jennings et al16 where they note the successful use of a 3F-PCC for VKA reversal in two CF-LVAD patients with ICH and report no thromboembolic events within 30 days of the event. In the largest series to date, our study reports no thromboembolic events or complications related to the use of 4F-PCC’s in 10 patients presenting with ICH while on CF-LVAD support, providing further evidence to support its safety for the reversal of non-surgical coagulopathy in patients with CF-LVAD’s.
Prothrombin complex concentrates have also been shown to be effective in rapidly reversing the INR and in reducing the rate of transfusion-associated adverse reactions when compared with FFP.8,10,17 Sarode et al,8 in a prospective randomized study of 4F-PCC versus FFP in 212 nonsurgical patients on oral VKA therapy presenting with major bleeding, demonstrated a rapid INR reduction (INR ≤ 1.3) at 1 and 24 hours in 69% and 88% of patients who received 4F-PCC versus 0% and 58% in the FFP group, respectively. This study also reported that adverse events related to VKA reversal were higher in patients receiving FFP (21% vs. 10%). Furthermore, a similar study investigating the use of factor IX-based PCC’s to supplement FFP for VKA reversal in patients presenting with ICH reported a significantly faster time to INR reversal and a reduced requirement for FFP, when compared with patients who received FFP alone.17 The results from our study in CF-LVAD patients presenting with ICH are similar to reports in the literature, in which the administration of 4F-PCC resulted in a faster INR reversal by an average of almost 8 hours and a reduction in FFP requirements by a factor of 2.
It is worth noting that despite the demonstration of a significant improvement in the ability of PCC’s to reverse the INR effectively and quickly, and to reduce the requirement for large volumes of FFP transfusions, the use of PCC’s have not been shown to improve the survival of patients who require VKA reversal for major bleeding, surgery, or for ICH, compared with the use of traditional VKA reversal agents alone.6,8,10 Our study demonstrate similar findings, where we note no significant difference in the rate of hemorrhagic expansion on repeat imaging, the presence of significant neurologic deficits at 30 days, or overall survival between PCC and no-PCC groups. However, this study was not designed nor adequately powered to determine such a difference and further research in larger, prospective studies will be required to determine the effect of PCC’s on survival.
Reversal of Anticoagulation in CF-LVAD Patients Presenting with ICH
Guidelines for the management of ICH in non-LVAD patients on chronic VKA therapy clearly state the need for rapid reversal of anticoagulation, which is essential to the prevention of continued bleeding in the brain and progressive neurologic injury. In patients with VKA-associated major bleeding, the 2012 ACCP (American College of Chest Physicians) guidelines recommend the use of 4F-PCC rather than plasma for the rapid reversal of anticoagulation,7 while the 2015 AHA/ASA (American Heart Association/American Stroke Association) guidelines on the management of ICH also suggest that PCC’s might be considered over FFP due to earlier correction of INR’s and fewer complications.6 These guidelines, however, do not address the unique situation faced by CF-LVAD patients with ICH, where rapid VKA reversal is critical to preventing worsening hemorrhage but can also expose these patients to the risk of adverse thromboembolic events. We consider the presence of ICH a life-threatening medical emergency, and in accordance with published guidelines,6,7 will reverse VKA therapy in the majority of CF-LVAD patients who present with this complication. Using this approach, we observed one thromboembolic event (5%) in 20 VKA reversal attempts, and an in-hospital mortality rate of 20%. Similar reports in the literature describe mortality rates that range between 33% and 60%,1,16 while one study described a 30 day thromboembolic incidence of 3% in 38 CF-LVAD patients undergoing rapid VKA reversal for major bleeding or invasive procedures.16
Despite this, a decision was made to forgo active reversal of anticoagulation with either 4F-PCC or FFP in 11 patients that were reviewed in this study (no-reversal group). It was difficult to retrospectively determine the individual factors that influenced this decision, but it is notable that seven of the 11 patients had small subarachnoid bleeds with minimal symptoms and no apparent neurologic deficits at presentation. In addition, of these seven patients, four presented with prior neuroimaging from an outside hospital and were noted to have a stable bleed on repeat scans at the time of admission to our institution. The remaining four patients were not reversed due to a high suspicion for ongoing cardioembolic phenomena and none were noted to have increased hemorrhage on repeat neuroimaging. Although the rapid reversal of VKA therapy should remain the standard of care for the management of CF-LVAD patients presenting with ICH, our data suggest that allowing the INR to physiologically normalize by discontinuing oral VKA agents can be a safe alternative in select patients with either concurrent cardioembolic disease or a favorable clinical presentation. To the best of our knowledge, there is no report in the literature that provides such data, which may prove useful in instances where the risks of rapid VKA reversal in CF-LVAD patients with ICH outweigh its potential benefits. More research is clearly needed to investigate and characterize the subgroup of patients who may benefit from such an approach.
One limitation of this study was the retrospective nature of the analysis. It was difficult to determine the National Institute of Health Stroke Score (NIHSS) in many cases due to a lack of documentation in the medical record. Although the NIHSS would have provided more detail on the neurologic status at presentation, GCS scores were available, and these scores provided some objective assessment of neurologic morbidity. This is also a relatively small study and thus it may be underpowered to demonstrate significant differences in thromboembolic complications or survival. Nonetheless, experience in use of PCC’s in postoperative patients with CF-LVAD’s remain limited to a few centers and is not well described in the literature. Finally, off-label dosing of 4F-PCC was used in this study, with lower-than-recommended doses utilized in patients with concurrent (or a recent history of) thromboembolic events, or in those with INR’s ≥4. The off-label dosing of 4F-PCC was necessary at the time due to our early experience with its use and the uncertainty regarding its potential adverse effects in our LVAD population.
The results from this study suggest that 4F-PCC-assisted VKA reversal in CF-LVAD patients presenting with ICH is safe and does not result in an increased risk of thromboembolic events compared with the use of FFP alone. Furthermore, this approach may also improve the efficacy of INR reversal in this population while reducing the volume of FFP required to achieve hemostasis. In patients where the risks of rapid VKA reversal outweigh any potential benefits, the discontinuation of oral anticoagulants may be sufficient; however, until such patients are better characterized in larger prospective studies, early and rapid reversal of the coagulopathy should be the standard of care in all CF-LVAD patients presenting with acute ICH.
1. Wilson TJ, Stetler WR Jr, Al-Holou WN, Sullivan SE, Fletcher JJ: Management of intracranial hemorrhage in patients with left ventricular assist devices. J Neurosurg 2013.118: 1063–1068.
2. Kirklin JK, Naftel DC, Pagani FD, et al. Seventh INTERMACS annual report: 15,000 patients and counting. J Heart Lung Transplant 2015.34: 1495–1504.
3. Harvey L, Holley C, Roy SS, et al: Stroke after left ventricular assist device implantation: Outcomes in the continuous-flow era. Ann Thorac Surg 2015.100: 535–541.
4. Willey JZ, Demmer RT, Takayama H, Colombo PC, Lazar RM: Cerebrovascular disease in the era of left ventricular assist devices with continuous flow: risk factors, diagnosis, and treatment. J Heart Lung Transplant 2014.33: 878–887.
5. Brouwers HB, Chang Y, Falcone GJ, et al: Predicting hematoma expansion after primary intracerebral hemorrhage. JAMA Neurol 2014.71: 158–164.
6. Hemphill JC 3rd, Greenberg SM, Anderson CS, et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology: Guidelines for the management of spontaneous intracerebral hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2015.46: 2032–2060.
7. Holbrook A, Schulman S, Witt DM, et al; American College of Chest Physicians: Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th
ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012.141(2 suppl): e152S–e184S.
8. Sarode R, Milling TJ Jr, Refaai MA, et al: Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013.128: 1234–1243.
9. Goldstein JN, Thomas SH, Frontiero V, et al: Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 2006.37: 151–155.
10. Hickey M, Gatien M, Taljaard M, Aujnarain A, Giulivi A, Perry JJ: Outcomes of urgent warfarin reversal with frozen plasma versus prothrombin complex concentrate in the emergency department. Circulation 2013.128: 360–364.
11. Sørensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R: Clinical review: Prothrombin complex concentrates–evaluation of safety and thrombogenicity. Crit Care 2011.15: 201.
12. Klein L, Peters J, Miner J, Gorlin J: Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med 2015.33: 1213–1218.
13. Bradford CD, Stahovich MJ, Dembitsky WP, Adamson RM, Engelbert JJ, Perreiter AS: Safety of prothombin complex concentrate to control excess bleeding during continuous flow LVAD insertion. ASAIO J 2015.61: 509–513.
14. Nuckles KB, Pratt JH, Cameron CM, Ingemi AI: Case series of four-factor prothrombin complex concentrate for warfarin reversal before heart transplantation. Transplant Proc 2015.47: 841–843.
15. Kantorovich A, Fink JM, Militello MA, et al: Low-dose 3-factor prothrombin complex concentrate for warfarin reversal prior to heart transplant. Ann Pharmacother 2015.49: 876–882.
16. Jennings DL, Jacob M, Chopra A, Nemerovski CW, Morgan JA, Lanfear DE: Safety of anticoagulation reversal in patients supported with continuous-flow left ventricular assist devices. ASAIO J 2014.60: 381–384.
17. Boulis NM, Bobek MP, Schmaier A, Hoff JT: Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999.45: 1113–8; discussion 1118.
18. Kothari RU, Brott T, Broderick JP, et al: The ABCs of measuring intracerebral hemorrhage volumes. Stroke 1996.27: 1304–1305.
19. Dentali F, Marchesi C, Giorgi Pierfranceschi M, et al: Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 2011.106: 429–438.
20. Milling TJ Jr, Refaai MA, Goldstein JN, et al: Thromboembolic events after vitamin K antagonist reversal with 4-factor prothrombin complex concentrate: Exploratory analyses of two randomized, plasma-controlled studies. Ann Emerg Med 2016.67: 96–105.e5.
4-factor prothrombin complex concentrates; intracranial hemorrhage; left ventricular assist device; anticoagulation reversal