Heart failure (HF) is the leading cause of death in the United States affecting more than 5 million Americans. Despite medical advances and an annual expenditure of $34.4 billion in the United States, 50% of diagnosed HF patients will succumb within 5 years.1 Continuous-flow left ventricular assist device (CF-LVAD) therapy has evolved into a standard therapy for patients with advanced HF2 either as destination therapy (DT), or as bridge to cardiac transplant, or as a platform for myocardial remodeling/recovery.3 However, device-related adverse events (bleeding, infection, and stroke) as well as right ventricular failure and multiorgan failure remain significantly clinical problems. The annual report from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) showed that major bleeding complication (MBC) is the most common postoperative complication in HF patients supported by CF-LVADs.4 Paradoxically concomitant to these bleeding complications, CF-LVAD implantation produces a prothrombotic environment due to the blood contact with titanium surface, increased shear stress, and activation of systemic inflammatory response.5,6 Anticoagulation and antiplatelet therapies are currently used to reduce the risks of thromboembolic events, particularly pump thrombosis and ischemic stroke. Hemorrhagic complications appear to be a multifactorial event, related to an acquired von Willebrand syndrome,7 alterations in platelet function,8,9 and arteriovenous malformation due to reduced pulsatility.10 International Society of Heart and Lung Transplantation provided specific international normalized ratio (INR) range for CF-LVAD device, but the optimal dose for aspirin (ASA) remains wide at 81–325 mg daily as dictated by local practice.11 The need to balance both arms of coagulation complications (thromboembolic and hemorrhagic) requires an antithrombotic therapy that is customized to the patient’s current hemostatic/clinical status. Common practice is to empirically reduce antithrombotic therapy after a hemorrhagic event or increase antithrombotic therapy after a thrombotic event to decrease the hazard of future thrombotic, hemorrhagic events. Aim of this study is to evaluate the safety and the freedom from recurrent thrombotic, hemorrhagic complications after changing antiplatelet therapy in response to a thrombotic or hemorrhagic event in patients supported with CF-LVAD.
We retrospectively reviewed all patients supported by CF-LVAD from July 2009 to February 2016, at our University hospital. Only patients with continuous flow pump were included: the Heart Mate II (HMII) (Abbott, Chicago, IL) and HeartWare (HVAD) (Medtronic, Minneapolis, MN) devices. Patients supported with a pulsatile LVAD were excluded from the analysis. Preoperative clinical information and baseline demographics were retrospectively collected from medical charts. Major adverse event requiring readmission during CF-LVAD support was also recorded, including hemorrhagic and thrombotic complications. Interagency Registry for Mechanically Assisted Circulatory Support adverse event definitions version 5.0 were used to define events. Epistaxis is not included in INTERMACS definition, and in our study, it was defined by necessitating an inpatient admission, a blood transfusion, or surgical cauterization.
Patients were categorized into three groups based on the different antiplatelet and antithrombotic regimens prescribed: (group 1, control group) ASA 325 mg daily (n = 115); (group 2) ASA 81 mg daily (n = 82); and (group 3) double antiplatelet therapy (DAPT) ASA and 75 mg clopidogrel daily (n = 34).
The decision to escalate or reduce antiplatelet therapy was based on the primary complication event by the multidisciplinary HF team. In group 1, not all patients with hematologic adverse events underwent changes in medication regimen and it was due to mortality after adverse events, pump exchange with normalization of LDH value, or resolution of gastrointestinal (GI) bleeding after it was hold anticoagulation and antiplatelet therapies. The study was approved by our institutional review board.
Anticoagulation-Antiplatelet Institution Strategy
After CF-LVAD implantation intravenous heparin or argatroban were initiated once the patient was clinically stable and in the \absence of active bleeding and coagulopathy. Heparin was the first choice, whereas argatroban was used in patients with low platelet count, hepatitis C infection, heparin-induced thrombocytopenia, or subtherapeutic partial thromboplastin time during heparin drip. Warfarin therapy was then bridged with an INR range between 2 and 3.12 Before discharge, ASA was started in all patients at 325 mg. Decision to switch antiplatelet therapy was based on the primary complication event, clinical, and laboratory status of the patient evaluated by the multidisciplinary HF team. After hemorrhagic complications, it was hold anticoagulation and antiplatelet therapies for at least 48–72 hours. Persistent hemorrhagic complications (GI bleeding, epistaxis, and hemorrhagic stroke) were used as indication to decrease ASA therapy to 81 mg. Thrombotic complications (ischemic stroke and pump thrombosis) or stent implantation was used as indication to DAPT adding clopidogrel 75 mg and decrease ASA therapy to 81 mg.
Continuous variables are presented as mean ± standard deviation (SD) and categorical variables as frequencies and percentages. Statistical differences for the baseline demographic characteristics in different groups were determined by using χ2 test for categorical variables, and one-way analysis of variance (ANOVA; Wilcoxon rank sum test or Kruskal–Wallis test) for continuous variables as applicable. Hemorrhagic or thrombotic events are reported as the percentage of patients affected and as rate of events per patient-year (EPPY) during LVAD support. Kaplan–Meier curves were used to analyze differences in event-free survival from thrombotic or hemorrhagic complications by the log-rank test between the groups at the time of changing therapy. Multivariate logistic regression analysis for the detection of risk factor predictive to change in therapy was also performed after controlling potential confounders. In the multivariate model was included all the significant values at univariate analysis. All statistical analysis was performed using SPSS 21.0 (SPSS, Inc., Chicago, IL). Statistical significance was assigned at p < 0.05.
The study group included a total of 253 patients who were supported by a CF-LVAD (Table 1). Patients in group 2 were older (mean age was 58 ± 13 years) compared with group 1 (mean age was 54 ± 12 years) and group 3 (mean age was 50 ± 13 years) (p = 0.007). Indication for CF-LVAD as bridge to transplantation (BTT) and DT are equally distributed among the study groups (p = 0.13). HeartMate II was more common in group 2 (75%) and in group 3 (82%) (p = 0.005). Gender, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, diabetes mellitus, ischemic cardiomyopathy, chronic kidney disease, and atrial fibrillation were uniformly distributed among the study groups. Heparin-induced thrombocytopenia and blood groups were also similar between the groups. No difference was found for previous cardiac surgery (p = 0.18) among the groups, whereas patients in group 3 presented a significant higher number of previous stent (p = 0.003), higher number of previous smokers (p = 0.047), and a lower number of atrial fibrillation (p = 0.035). Incidence of INR out of therapeutic range during the entire support period was similar and no differences were present for low INR (p = 0.23) or high INR (p = 0.76).
Change in Aspirin Therapy and Subsequent Bleeding and Thrombosis
A schematic representation of overall population finding related to change in ASA therapy and subsequent clinical complications of bleeding and thrombosis is reported in Figure 1. In our single-center retrospective review of 253 HF patients, we report a 5.5% mortality at 30 days (14/253 patients). A total number of eight patients were excluded from the study because no antiplatelet therapy was started due to early bleeding complications (three presented severe coagulopathy, two were in ECMO, and three were on right ventricular assist device).
A total of 231 patients started ASA 325 after CF-LVAD implantation and then antiplatelet therapy was changed according to the primary complication event.
Patients with postoperative primary hemorrhagic complications were switched either to low dose of ASA (82 patients, 35%) or continued ASA 325 mg (40 patients, 17%). Among these patients reported overall hemorrhagic event where GI bleeding (83 patients, 36%), epistaxis (20 patients, 9%), and hemorrhagic stroke (19 patients, 8%). After decreasing ASA to 81 mg, GI bleeding recurrence was 40% (33 patients), epistaxis 1.2% (one patient), and hemorrhagic stroke 9% (eight patients), while ischemic stroke was 3.6% (three patients) and pump thrombosis 3% (two patients). A total of seven patients died as complication of the hemorrhagic stroke and in the remain patient that continued ASA 325 mg, GI bleeding was 30% (12 patients), and pump thrombosis was 5% (two patients).
During the follow-up, 64 patients (27%) did not develop any hemorrhagic or thrombotic complications.
Patients with postoperative primary thrombotic complications were switched either to DAPT (34 patients, 14%) or continued ASA 325 mg (11 patients, 4.7%). Among these patients reported overall thrombotic event where ischemic stroke (four patients, 2%), pump thrombosis (35 patients, 15%), and coronary stent treatment (six patients, 2.5%). A total of seven patients required LVAD exchange from axial to centrifugal technology,13 in the other patients the exchange was performed using the same pump design. After starting DAPT, ischemic stroke recurrence was 5% (two patients), pump thrombosis 8% (three patients), whereas hemorrhagic stroke was 5% (two patients), GI bleeding was 8% (three patients), and epistaxis 8% (three patients). In the group of patient who continued ASA 325 mg, pump thrombosis was 9% (one patient), GI bleeding was 18% (two patients), and hemorrhagic stroke was 18% (two patients).
Prevalence and Events Per Patient-Year of Thrombotic Hemorrhagic Complications After Changing Therapy
Prevalence and EPPY of adverse events after changing therapy are summarized in Table 2 and EPPY of adverse events for all patients during study group are reported in Table 3: A total of 115 patients in group 1 were treated with high ASA during the 197.07 patient-years time. In group 1, 25 (21%; 0.26 EPPY) patients had a GI bleeding, eight (7%, 0.04 EPPY) had epistaxis, seven (6%, 0.035 EPPY) patients experienced a hemorrhagic stroke, one (0.8%, 0.005 EPPY) had ischemic stroke, and 10 (8%, 0.05 EPPY) had pump thrombosis requiring device exchange.
A total of 82 patients in group 2 were treated with low ASA after hemorrhagic complications. Gastrointestinal bleeding after reducing ASA therapy persisted in 27 patients (40%; 0.2 EPPY). Epistaxis after reducing ASA therapy was present only in one patient (1.2%; 0.004 EPPY). Hemorrhagic stroke after reducing ASA therapy occurred in eight patients (9%; 0.032 EPPY). Ischemic stroke after reducing ASA therapy happened in three patients (3.6%; 0.012 EPPY). After reducing ASA therapy pump thrombosis happened in two patients (3%; 0.008 EPPY).
A total of 34 patients in group 3 were treated with DAPT after a thrombotic complication. Coronary stent treatment was required in six patients (17%; 0.17 EPPY) and it was an indication to start DAPT. Gastrointestinal bleeding after starting DAPT therapy persisted in three patients (8%; 0.18 EPPY). Epistaxis after starting DAPT therapy continued in three patients (8%; 0.010 EPPY). No hemorrhagic stroke was reported before changing therapy, but after starting DAPT therapy occurred in two patients (5%; 0.05 EPPY). Ischemic stroke after starting DAPT therapy happened in two patients (5%; 0.06 EPPY). Pump thrombosis recurrence after starting DAPT therapy happened in three patients (8%; 0.008 EPPY).
Device-Related Thrombotic Hemorrhagic Complications
Thrombotic and hemorrhagic complications after changing antiplatelet therapy are reported in Table 4 for patient with HeartMate II and HeartWare (HW). Pump thrombosis with device exchange was significantly higher in HeartMate II patients during high dose antiplatelet therapy compared with HW patients (p = 0.027).
After performing a multivariate analysis on significant univariate factors, only the type of device was significant as predictor to change therapy. Heart Mate II required more antiplatelet therapy changes during CF-LVAD support compared with HVAD (odds ratio [OR]: 3.611, confidence interval [CI]: 1.8–6.9; p = 0.0001). Antiplatelet therapy changes in HMII were mainly due to GI bleeding and pump thrombosis. Age was not associated to changing antiplatelet therapy (OR: 0.9, CI: 0.8–1.0; p = 0.84). Atrial fibrillation (OR: 1.4, 95% CI: 0.5–4.2; p = 0.482), previous smoker (OR: 0.9, 95% CI: 0.4–2.0; p = 0.979), and previous stent placement (OR: 1.3, 95% CI: 0.5–3.2; p = 0.446) were also not associated to changing antiplatelet therapy.
Freedom from Thrombotic Hemorrhagic Events
After changing therapy, survival free from thrombotic events at 1 year was comparable for groups 1, 2, and 3, respectively, 97%, 98%, and 91% (log rank = 0.317) (Figure 2). After changing therapy, survival free from major hemorrhagic bleeding event at 1 year was comparable for groups 1, 2, and 3, respectively, 96%, 97%, and 91% (log rank = 0.421) (Figure 2).
Management of anticoagulation during CF-LVAD support is crucial to reduce thromboembolic complications. In our populations of 253 patients with CF-LVAD support, ASA therapy was started at a standard dose of 325 mg and then it was modulated accordingly to clinical events complications in patients supported with CF-LVAD. Our study supports the strategy to reduce or increase antithrombotic therapies in response to major thrombotic or hemorrhagic events to try to avoid recurrences.
In this study, patients who develop hemorrhagic complications during CF-LVAD support were switched to a low antiplatelet therapy. This group was older (p = 0.007) and in 78% supported with Heartmate II (p = 0.0005). The antiplatelet therapy was decreased in patients presenting hemorrhagic complications and after the medication change the freedom event survival was similar both on control group and patient on DAPT (log rank = 0.421).
Moreover, patient after reducing antiplatelet therapy does not increase thrombotic complications compared with control group (ASA 325 mg) and patient on DAPT (log = rank 0.317). Our results correlate with the findings of the observational European study of reduced anti-coagulation/anti-platelet therapy in patients with the heartmate (TRACE), where HMII patients received only vitamin K antagonist without antiplatelet therapy.14 This anticoagulation regimen showed a reduced incidence of major bleeding without increasing the risk of thromboembolic events, including ischemic stroke and pump thrombosis.14 Otherwise the American TRACE study shows that reducing antithrombotic therapies in response to bleeding was feasible but may be associated with an increased risk for device thrombosis.15 Furthermore, despite a reduced antiplatelet strategy, bleeding complications often will persist15 and this finding is found consistent in our study, where patients presenting GI bleeding have high recurrence.
In this study, patients who develop thrombotic complications during CF-LVAD support were switched to a DAPT. This group was younger (p = 0.007), 82% supported with Heartmate II (p = 0.0003), 58% were previous smoker, 44% had previous stent, and a 17% present atrial fibrillation.
The antiplatelet therapy was increased in patients presenting thrombotic complications and after the medication change the freedom event survival was similar both on control group and patient on reduced ASA (log rank = 0.317). A total of six patients develop during CF-LVAD support symptomatic coronary stenosis requiring percutaneous coronary interventions (PCI) and then DAPT due to stent placement. Actual experience with PCI during CF-LVAD is limited. Anyanwu et al.16 reported that a case series of six patients underwent PCI post-CF-LVAD implantation, reporting two early deaths due to fatal GI bleeding while on DAPT and warfarin. Double antiplatelet therapy does not significantly increase bleeding complications after changing therapy when compared with the other study groups (log rank = 0.421).
Multivariate analysis was used to find risk factors predictive of changing antiplatelet therapy during CF-LVAD support. Only the type of CF-LVAD device was significant to predict a change in antiplatelet therapy. The analysis shows that HeartMate II required more antiplatelet therapy adjustment during support compared with HW HVAD. Previous clinical evidences support this finding: the ADVANCE study confirmed that ASA at 325 mg in HVAD reduces the annualized rate of pump exchange for suspected thrombus (from 0.063 to 0.027) and the ischemic strokes declined from 5.1% (0.089 EPPY) to 2.8% (0.047 EPPY).17 Otherwise, ASA at 325 mg in Heart Mate II patients treated concomitantly with warfarin was associated with an increased hazard of bleeding but does not reduce thrombotic events.18 A coagulation study profile also shows that activation of coagulation is different between HeartMate II and HW: Birschmann et al.19 show that HeartMate II patient develops more hemolysis during support, as measured by lactate dehydrogenase levels, while HW patient presented an increased D-dimer value.
Limitations of the Study
Our study presents limitations that should be addressed. First, our study was an observational study without randomization or blinding and data were collected retrospectively. Thus, the presence of possible bias and unmeasured confounders may have influenced outcomes, as the differences in the comparison groups. Patients on DAPT represent also a small cohort of patients. Longer follow-up will provide more information on the effect of antiplatelet therapy and thrombotic or hemorrhagic complications. The use of operative interventions for bleeding complications was not included in our analysis and clearly warrants further investigation. Our data were limited to a small sample size of 231 patients, but it may not be representative of the overall population. Indication to reduce antiplatelet therapy or to start DAPT was based on individual cases by the bedside multidisciplinary heart team and makes it difficult to assess which unmeasured factors led to the decision to change therapy in some patients and whether such factors led to occurrence of similar outcomes. Moreover, we used low or high INR events over the time as surrogate of warfarin therapy, but we were unable to determine the time in therapeutic range as a measure of the overall quality of anticoagulation.
Decreasing antiplatelet therapy in response to hemorrhagic events during CF-LVAD reduces subsequent bleeding complications, without increasing thrombotic complications. Likewise increasing antiplatelet therapy in response to thrombotic events may reduce thrombotic complications, without increasing hemorrhagic complications. Furthermore, a distinct footprint in antiplatelet management can be attributed to different CF-LVAD technology and in instance HeartMate II required more adjustment of antiplatelet therapy during follow-up compared with HW HVAD. Future prospective, randomized studies are needed to confirm these findings and future studies have to characterize the coagulation rheology between patient-CF-LVAD interaction to better manage the antiplatelet therapy.
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