The number of patients supported with ventricular mechanical circulatory support devices (MSCDs) at the time of heart transplantation (HT) has steadily increased over the past decade.1 Patients supported with MCSDs are generally anticoagulated with warfarin and are on aspirin (81–325 mg) to prevent pump thrombosis, but this also increases the risk of bleeding at the time of HT.2 Reversal of anticoagulation can be utilized to reduce the risk of significant intraoperative and perioperative blood loss. Current guidelines endorse a variety of modalities to reverse anticoagulation before transplant, including administration of vitamin K, fresh frozen plasma (FFP), prothrombin complex concentrates (PCC), and recombinant factor VII (rFVIIa).3 However, limitations exist with their use, including time to normalization of international normalized ratio (INR) with vitamin K, time to thaw the FFP, and the volume burden associated with the amount of FFP required for adequate reversal. Proposed advantages to utilizing PCCs and rFVIIa include quicker time to reversal and a reduction in total volume administration.4 Studies have reported efficient reduction in INR and reduction in intraoperative blood product utilization with PCCs and rFVIIa5–14; however, concern exists about their thrombogenic potential.15–19 Data evaluating thrombogenic risk associated with use of anticoagulation reversal agents (ARAs) among MCSD-supported recipients of HT are further limited by sample size and unclear duration of follow-up.5,6 Therefore, in this single-center study of MCSD-supported patients undergoing HT, we evaluated the risk of thromboembolic (TE) events associated with the use of ARAs.
This retrospective study was approved by institutional review board at Vanderbilt University Medical Center. All consecutive adults (age ≥18 years) who were supported by durable MCSDs (HeartMate II [Abbott, Abbott Park, IL], HeartMate III [Abbott, Abbott Park, IL], or HeartWare [Medtronic, Minneapolis, Minnesota] left ventricular assist device) and underwent HT between May 1, 2013, and October 31, 2016, were included in this study; follow-up was available through January 7, 2017. We chose above timeline because 4F-PCC (KCentra [CSL Behring, Germany]) was approved by the Food and Drug Administration in May, 2013, for anticoagulation reversal among patients treated with warfarin who have acute major bleeding, or for emergent reversal before major surgery or an invasive procedure.20 We analyzed data until October 31, 2016, because of interim changes in posttransplant anticoagulation protocols at the institutional level. Data were collected on ARAs, patient characteristics at the time of HT, and perioperative and postoperative complications.
Anticoagulation Reversal Agents
Vitamin K was used on majority of the patients (93%) for anticoagulation reversal before undergoing HT. Intraoperatively, heparin effect was reversed with protamine, and FFP, platelets, and cryoprecipitate were utilized to correct for any residual coagulopathy and/or thrombocytopenia. If the patient continued to have bleeding, a decision was made to utilize ARAs and/or check a functional assay by obtaining a thromboelastogram. We examined use of the following ARAs: rFVIIa, 4F-PCC, or factor IX complex. Utilization of the above agents and their doses was at discretion of the implanting surgical team based on perceived bleeding risk.
Outcome of Interest
The primary outcome of interest was presence of either venous thrombus (deep vein thrombosis [DVT]) or TE event (pulmonary embolism [PE]), or systemic thrombus or TE event (embolic stroke, peripheral arterial occlusion, and acute myocardial infarction). TE events were recorded up to 3 months after use of ARAs. Various imaging modalities including venous Doppler ultrasound examination, computerized tomography scan, nuclear perfusion scan, magnetic resonance imaging, pulmonary angiogram, and invasive catheterization were used to diagnose various types of TE events. Autopsy findings were included whenever appropriate to diagnose PE or acute myocardial infarction. Imaging for thrombosis was prompted on clinical suspicion of a TE event. Of note, institutional protocols of DVT prophylaxis were followed during postoperative period using leg compression devices, subcutaneous heparin (unfractionated or low molecular weight), or both.
Baseline characteristics were analyzed by χ2 or Fisher’s exact test for categorical variables (presented as proportions [%]) whenever appropriate, or Student’s t-test for continuous variable (presented as mean ± standard deviation). Univariate logistic regression screening was performed for all potential independent variables; variables with univariate p value of <0.15 were included in the final multivariable analysis. Backward elimination (p value set at 0.20 for removal from model) and stepwise multivariable logistic regression analysis were performed to assess the relationship between use of ARAs and TE events. Data were analyzed using statistical software STATA version 13 (StataCorp LP, College Station, TX). For the purpose of these analyses, p value <0.05 was considered statistically significant.
A total of 118 patients underwent HT during study period; average age at the time of HT was 54.6 years (standard deviation: 11.2; 79% men, 24.5% non-Caucasian Americans). We identified 71 patients (60%) who have received an ARA at the time of transplant; 23 received rFVIIa, 48 received 4F-PCC, and two received factor IX complex. Of the 71 patients, two received both rFVIIa and 4F-PCC at the time of HT. Patients receiving any ARAs were older (56 ± 11 vs. 52 ± 11 years), had lower body mass index (28.1 ± 3.9 vs. 30.1 ± 4), and a higher INR (2.4 ± 0.6 vs. 2.2 ± 0.5) compared with those who did not (p < 0.05 for all; Table 1). Upon examining perioperative characteristics, patients receiving any ARAs had higher amount of FFP, platelets and packed red blood cell transfusions (p < 0.05), indicating higher degree of intraoperative bleeding and thereby need for reversal agents (Table 1).
We identified a total of 32 patients with TE events during the study period. Ten patients had systemic TE events; median time to diagnosis was 5.5 days (interquartile range: 4–8 days). Of the patients with systemic TE, eight had an intracranial TE, one had a splenic infarct, and one had a left atrial clot. All the patients experiencing intracranial TE events had imaging evidence of acute ischemic stroke; two of the eight patients had both hemispheric involvement, whereas the remaining six had single hemispheric involvement. Three of the six patients with single hemispheric involvement had multilobar distribution of embolic stroke. Presence of bihemispheric or multilobar CVA (n = 5) was significantly associated with higher risk of overall mortality (prevalence of 40%) compared with those without (n = 113; prevalence of 9.7%; p = 0.034). A total of 25 patients experienced venous TE events; median time to diagnosis was 11.5 days (interquartile range: 9–31 days). Of the patients with venous TE, two had lower extremity and remaining had upper extremity DVT; none was diagnosed with PE. Of the venous TE events, 40% involved single vein, 32% involved ≥2 unilateral veins, 24% involved bilateral veins, and 4% involved right ventricular. Of the 32 patients, three had combined venous and systemic TE events (Appendix Table A, Supplemental Digital Content 1, http://links.lww.com/ASAIO/A316, describes baseline characteristics distribution according to presence of TE events).
Of those with use of any ARAs, 36.6% (n = 26) had TE events compared with 12.8% (n = 6) of those without (p = 0.004). Venous TE events were observed in 28.2% (n = 20), and systemic TE events were observed in 12.7% (n = 9) of the patients when any ARAs were used. Figure 1A shows prevalence of TE events during follow-up at various time points post-HT; majority of TE events (68.7%), including all of the systemic TE events, occurred within first 2 weeks post-HT. Multiple variables demonstrated univariate association (p < 0.15) with the risk of TE events, including use of ARA, admission INR, intraoperative number of units of FFP (>4 units) and packed red blood cells (≥5 units), amount of cryoprecipitate (>280 ml) and platelets (≥600 ml) volume, post-HT transfusion (>4 units), and infection. Upon backward stepwise multivariable logistic regression analysis, the use of any ARAs was associated with significantly higher risk of TE events at 3 months after adjustments (multivariable odds ratio [OR]: 3.05; 95% CI: 1.09–8.58; p = 0.034); Figure 2 shows ARA-associated risk of TE events captured at various follow-up points post-HT. Upon further sub-group analyses, 4F-PCC was observed to have significantly higher risk of TE events at 3 months (multivariable OR: 2.83; 95% CI: 1.14–7.06; p = 0.025), and rFVIIa was observed to have trend toward higher risk of TE events (multivariable OR: 1.42; 95% CI: 0.49–4.10; p = 0.514); Figure 1B shows prevalence of TE events across types of ARAs. Median dose of 4F-PCC was 1000 units (interquartile range: 1000–1500); we observed a trend toward higher risk of TE events with 4F-PCC dose of ≥2000 units (50% vs. 333%; p = 0.329). Median dose of rFVIIa was 2000 μg (interquartile range: 1000–5000); we observed a trend toward higher risk of TE events with rFVIIa total dose of ≥2000 μg (52.9% vs. 16.7%, p = 0.179). Prior history of TE events or hypercoagulable conditions may predispose patients to developing TE events when ARAs are used.21 We identified total of 25 patients with history of either pump thrombosis, previous TE events, heparin-induced thrombocytopenia, or hypercoagulable diseases; 17 of these patients (68%) had ARAs used at the time of HT (5 with rFVIIa, 11 with 4F-PCC, and 1 with 3F-PCC). Four (23.5%) of the above 17 patients developed TE events. Median dose of 4F-PCC was 1000 units (IQR: 1000–1500) for those with high-risk histories for TE events, which was similar to those without the high-risk histories for TE events. Median dose of rFVIIIa was 1000 μg (IQR: 1000–2000) for those with high-risk histories for TE events, which was lower compared with those without (median: 4000 μg; IQR: 2000–5000). Interestingly, none of the 5 patients who received rFVIIa at reduced dose developed TE events. In comparison, 4 of the 11 patients receiving 4F-PCC developed TE events compared with 1 of the remaining 14 patients who did not receive 4F-PCC (p = 0.133).
During the index hospitalization, a higher prevalence of infection was observed among those with use of any ARAs (Table 2). Majority of posttransplant infections were respiratory in origin in our cohort (11 of 23; 4 of 11 were treated with empiric antibiotics); other infections observed were surgical wound infection (4 of 23), sepsis (3 of 23), urinary tract infection (1 of 23), Clostridium difficile (3 of 23), and empiric intravenous antibiotics in 1 of 23. Total of 13 patients died during follow-up (2 in-hospital and 11 post-discharge). There was trend toward higher prevalence of ARAs among those who died (10 of 71 [14.1%]) compared with those who did not (3 of 47 [6.4%]; p = 0.24). Prevalence of all TE events was found to be significantly higher among those who died (7 of 13 [53.9%]) compared with those who did not (25 of 105 [23.8%]; p = 0.022). Similarly, prevalence of systemic TE events was found to be significantly higher among those who died (4 of 13 [39.8%]) compared with those who did not (6 of 105 [5.7%]; p = 0.002)
In this study, we assessed risk of early TE events associated with use of ARAs among durable MCSD-supported patients undergoing HT; we observed that use of any ARAs was associated with a significantly higher risk of TE events.
The long-term incidence and prevalence of TE events is significantly higher among recipients of HT and is second only to those undergoing orthopedic surgery who are not receiving prophylactic anticoagulation.22–28 Various pathophysiological mechanisms have been proposed, including a hypercoagulable state, a role of immunosuppression agents, concurrent CMV infection, etc.25 Data, however, are limited when it comes to the risk of TE events in the early post-HT phase. Furthermore, the majority of patients examined in previous studies22–28 were transplanted before 200929 and had limited representation of those with durable MCSDs. In comparison, our study included patients transplanted after May 1, 2013, and were exclusively supported with durable MCSDs. We observed a high prevalence of venous (21.2%) and systemic (8.5%) TE events within first 3 months of HT (overall prevalence of 27.1%). We further observed high prevalence of ARAs’ usage at the time of HT among those who suffered TE events (36.6% vs. 12.8%; p = 0.004). Similarly high rates of TE events had been reported by other studies; for example, prevalence of TE events in randomized controlled trials (RCTs) of 4F-PCC and rFVIIa among non-MCSD patients ranged between 7% and ≈26%,7,19,30–32 and a retrospective single-center study of durable MCSD patients receiving rFVIIa reported 22.6% overall prevalence of TE events (Appendix Table B, Supplemental Digital Content 2, http://links.lww.com/ASAIO/A317).17 It is worth mentioning that above-mentioned RCTs varied in terms of follow-up (events recorded up to 45–90 days), and most of them excluded patients receiving nonstudy blood products like cryoprecipitates, platelets, vitamin K, etc. before ARA administration.
Current guidelines recommend reversal of anticoagulation at the time of HT in order to prevent bleeding complications and reduce perioperative blood product consumption3; variety of agents, including PCC, rFVIIa, vitamin K, and FFP, are proposed to achieve anticoagulation reversal. Historically, PCCs were used as a source of factor IX for hemophilia B patients.33 Over the past several decades, PCCs have gained popularity as a method of urgent reversal of vitamin K antagonists and have demonstrated efficacy when compared with vitamin K and FFP.7,8,30,34 The principal concern of 4F-PCC, however, has been the risk of TE events; higher levels of factor II and prothrombin have been postulated to explain the risk.18 Newer generations of PCC have heparin, antithrombin, and protein C and S in varying concentrations to counter-balance the TE risk, with studies reporting nonsignificant risk of TE events associated with them; however, data are limited by sample size and power to detect the differences in TE events between comparison groups.5–8,10,18,30,34 Additionally, as mentioned earlier, RCTs of 4F-PCCs further excluded those receiving vitamin K,7 antiplatelets,31 or other nonstudy blood products7,19,30 before drug administration. In our study, we observed that prevalence of TE events was 37.5% among those receiving 4F-PCC compared with 20.0% among those who did not (p = 0.036; multivariable OR: 2.84; 95% CI: 1.14–7.06; p = 0.025). Our results are in contrast to those reported by Pratt Cleary et al.,5 who showed no risk of TE events with protocolized preemptive use of 4F-PCC; however, this study was limited by relatively smaller sample size and unclear duration of follow-up to diagnose TE events. Recipients of solid organ transplants have been reported to have impaired fibrinolysis and protein C activation, higher levels of fibrinogen, and overactivation of extrinsic coagulation pathway, which may explain higher risk of TE events.25,35,36 It is plausible that inherently higher risk of TE events among HT recipients is accentuated by use of ARAs; future RCTs are required to confirm this hypothesis.
The rFVIIa is also Food and Drug Administration approved for treating refractory bleeding in hemophilia patients with presence of inhibitors to factor VIII or factor IX.16 Several retrospective studies have also shown rFVIIa to be effective in achieving hemostasis and control of refractory bleeding as well, particularly among patients undergoing cardiac surgeries11–14; however, concerns for TE events in general population persist with its use.14,32,37 Increased thrombin generation38 and possibility of rFVIIa acting on locations beyond the surface of activated platelets at the bleeding site39 are proposed to explain its association with increased risk of TE events. Among patients undergoing durable MCSD implantation, Bruckner et al.,17 observed an incidence rate for TEs of 36.7% with higher doses of rFVIIa compared with 9.4% with lower doses. Similarly higher risk of TE events with rFVIIa was reported by Gandhi et al.40 for patient undergoing MCSD or HT. In our study, 43.5% of rFVIIa recipients developed TE event compared with 23.2% of those who did not (p = 0.049; multivariable OR: 1.42; 95% CI: 0.49–4.10; p = 0.514).
Several important limitations of our study need mentioning. First, this was a single-center retrospective analysis; effects of unmeasured confounders and effect modifiers cannot be excluded. However, it is worth mentioning that this is one of the largest study reported to date assessing role of ARAs on the risk of TE events among durable MCSD-bridged HT recipients. Second, ARAs were used at the discretion of implanting surgical team, and no prespecified protocol was used to guide their choice, timing, and dosing. Third, we examined a relatively liberal window of up to 3 months post-HT to capture clinically suspected TE events. Although, it is important to note that 68.7% of all TE events (including 100% of all systemic TE events) were recorded within first 2 weeks with significantly higher prevalence of ARAs (25.4%) among those who developed TE events versus those who did not (8.5%; p = 0.021). Fourth, because diagnosis of TE events was prompted by occurrence of clinical events, it is possible that venous TE events were underdiagnosed because of sampling error given the lack of uniform surveillance protocols. Although severity of illness at the time of HT may play a role in occurrence of TE events, statistically nonsignificant differences were observed in patient characteristics such as renal dysfunction, hospitalization or status upgrade status, home inotropic support use, degree of anemia, or level of anticoagulation among those with and without TE events (Appendix Table, Supplemental Digital Content 1, http://links.lww.com/ASAIO/A316). Role of early postoperative complications, such as degree of vasoplegia, anticoagulation strategies, duration of central line or pulmonary artery catheter placement, and level of ambulation, need further exploration for their association with TE events independent of ARAs. Despite of these limitations, our study highlights an important issue of TE risk associated with use of ARAs for HT recipients bridged with MCSDs and highlights the need for further studies with prospective designs to confirm our findings.
Use of ARAs at the time of HT among patients supported with MCSDs was associated with significantly higher risk of TE events. Randomized controlled studies are needed to establish safety and efficacy of ARAs for MCSD-supported patients undergoing HT.
The authors acknowledge the Vanderbilt Advanced Heart Failure Registry & Bio-repository (IRB No. 131978).
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