Reduction of HLA donor specific antibodies in heart transplant patients treated with proteasome inhibitors for antibody mediated rejection.

In this project, we describe proteasome inhibitor (PI) treatment of antibody-mediated rejection (AMR) in heart transplantation (HTX). From January 2018 to September 2021, 10 patients were treated with PI for AMR: carfilzomib (CFZ) n = 8; bortezomib (BTZ) n = 2. Patients received 1-3 cycles of PI. All patients had ≥1 strong donor-specific antibody (DSA) (mean fluorescence intensity [MFI] > 8000) in undiluted serum. Most DSAs (20/21) had HLA class II specificity. The MFI of strong DSAs had a median reduction of 56% (IQR = 13%-89%) in undiluted serum and 92% (IQR = 53%-95%) at 1:16 dilution. Seventeen DSAs in seven patients were reduced > 50% at 1:16 dilution after treatment. Four DSAs from three patients did not respond. DSA with MFI > 8000 at 1:16 dilution was less responsive to treatment. 60% (6/10) patients presented with graft dysfunction; 4/6 recovered ejection fraction > 40% after treatment. Pathologic AMR was resolved in 5/7 (71.4%) of patients within 1 year after treatment. 9/10 (90%) patients survived to 1 year after AMR diagnosis. Using PI in AMR resulted in significant DSA reduction with some resolution of graft dysfunction. Larger studies are needed to evaluate PI for AMR.

Basiliximab induction versus no induction in adult heart transplantation.

BACKGROUND: Induction immunosuppression in heart transplant recipients varies greatly by center. Basiliximab (BAS) is the most commonly used induction immunosuppressant but has not been shown to reduce rejection or improve survival. The objective of this retrospective study was to compare rejection, infection, and mortality within the first 12 months following heart transplant in patients who received BAS or no induction. METHODS: This was a retrospective cohort study of adult heart transplant recipients given BAS or no induction from January 1, 2017 to May 31, 2021. The primary endpoint was incidence of treated acute cellular rejection (ACR) at 12-months post-transplant. Secondary endpoints included ACR at 90 days post-transplant, incidence of antibody-mediated rejection (AMR) at 90 days and 1 year, incidence of infection, and all-cause mortality at 1 year. RESULTS: A total of 108 patients received BAS, and 26 patients received no induction within the specified timeframe. There was a lower incidence of ACR within the first year in the BAS group compared to the no induction group (27.7 vs. 68.2%, p < .002). BAS was independently associated with a lower probability of having a rejection event during the first 12-months post-transplant (hazard ratio (HR) .285, 95% confidence interval [CI] .142-.571, p < .001). There was no difference in the rate of infection and in mortality after hospital discharge at 1-year post-transplant (6% vs. 0%, p = .20). CONCLUSION: BAS appears to be associated with greater freedom from rejection without an increase in infections. BAS may be a preferred to a no induction strategy in patients undergoing heart transplantation.

Outcomes of systemic bivalirudin and sodium bicarbonate purge solution for Impella 5.5.

BACKGROUND: Impella 5.5 (Abiomed; Danvers, MA) (IMP5) is a commonly used, surgically implanted, tMCS device that requires systemic anticoagulation and purge solution to avoid pump failure. To avoid heparin-induced thrombocytopenia (HIT) from unfractionated heparin (UFH) use, our program has explored the utility of bivalirudin (BIV) for systemic anticoagulation and sodium bicarbonate-dextrose purge solution (SBPS) in IMP5.5. METHODS: This single center, retrospective study included 34 patients supported on IMP5.5 with BIV based AC and SBPS between December 1st 2020 to December 1st 2021.The efficacy and safety end points were incidence of development of HIT, Tissue Plasminogen Activator (tPA) use for suspected pump thrombosis, stroke, and device failure as well as clinically significant bleeding. RESULTS: The median duration of IMP5.5 support was 9.8 days (IQR: 6-15). Most patients were bridged to HTX (58%) followed by recovery (27%) and LVAD implantation (15%). Patients were therapeutic on bivalirudin for 64% of their IMP5.5 support. One patient (2.9%) suffered from ischemic stroke and 26.5% (9) patients developed clinically significant bleeding. tPA was administered to 7(21%) patients. One patient in the entire cohort developed HIT. CONCLUSIONS: Our experience supports the use of systemic BIV and SBPS as a method to avoid heparin exposure in a patient population predisposed to the development of HIT.

Primary Graft Dysfunction in Heart Transplant Recipients-Risk Factors and Longitudinal Outcomes.

Before the 33rd Annual International Society for Heart and Lung Transplantation conference, there was significant intercenter variability in definitions of primary graft dysfunction (PGD). The incidence, risk factors, and outcomes of consensus-defined PGD warrant further investigation. We retrospectively examined 448 adult cardiac transplant recipients at our institution from 2005 to 2017. Patient and procedural characteristics were compared between PGD cases and controls. Multivariable logistic regression was used to model PGD and immediate postoperative high-inotrope requirement for hypothesized risk factors. Patients were followed for a mean 5.3 years to determine longitudinal mortality. The incidence of PGD was 16.5%. No significant differences were found with respect to age, sex, race, body mass index, predicted heart mass mismatch, pretransplant amiodarone therapy, or pretransplant mechanical circulatory support (MCS) between recipients with PGD versus no PGD. Each 10 minute increase in ischemic time was associated with 5% greater odds of PGD (OR = 1.05 [95% CI, 1.00-1.10]; p = 0.049). Pretransplant MCS, predicted heart mass mismatch ≥30%, and pretransplant amiodarone therapy were associated with high-immediate postoperative inotropic requirement. The 30 day, 1 year, and 5 year mortality for patients with PGD were 28.4%, 38.0%, and 45.8%, respectively, compared with 1.9%, 7.1%, and 21.5% for those without PGD (log-rank, p < 0.0001). PGD heralded high 30 day, 1 year, and 5 year mortality. Pretransplant MCS, predicted heart mass mismatch, and amiodarone exposure were associated with high-inotrope requirement, while prolonged ischemic time and multiple perioperative transfusions were associated with consensus-defined PGD, which may have important clinical implications under the revised United Network for Organ Sharing allocation system.

Outcomes of systemic anticoagulation with bivalirudin for Impella 5.0.

Temporary mechanical circulatory support (tMCS) devices are used for the management of cardiogenic shock. The Impella 5.0 (Abiomed; Danvers, MA) (IMP5) is a commonly used, surgically implanted, tMCS device that requires systemic anticoagulation and purge solution to avoid pump failure. To avoid heparin-induced thrombocytopenia (HIT) from unfractionated heparin (UFH) use, our program has explored the utility of bivalirudin (BIV) for systemic anticoagulation in IMP5. This single center, retrospective study included patients supported on IMP5 with BIV based AC. The efficacy and safety end points were recovery, bridge to left ventricular assist device (LVAD), cardiac transplant (HTX), or death as well as clinically significant bleeding, incidence of Tissue Plasminogen Activator (tPA) use for suspected pump thrombosis, stroke, and device failure. There were 31 patients included, and 26 (84%) received BIV purge solutions. The median duration of IMP5 was 6 (IQR 4-10) days. Most patients were bridged to LVAD (39%, 12); 16% (5) were bridged to HTX, 16% (5) recovered, and 29% (9) died. One patient (3%) suffered from ischemic stroke and 12% (4) patients developed clinically significant bleeding. tPA was administered to 8 (26%) patients. Logistic regression analysis demonstrated that duration of IMP5 was a significant predictor of tPA use (OR 1.28; 95% Confidence Interval 1.04-1.56). There were no cases of pump failure. Our experience highlights the feasibility of utilizing BIV for routine AC use in IMP5.

Impact of carfilzomib-based desensitization on heart transplantation of sensitized candidates.

BACKGROUND: Allosensitization in heart transplant candidates is associated with longer transplant wait times and post-transplant complications. We summarize our experience with desensitization using carfilzomib, an irreversible proteasome inhibitor that causes plasma cell apoptosis. METHODS: One cycle of desensitization consisted of plasmapheresis and carfilzomib 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 with intravenous immune globulin 2 g/kg after carfilzomib on day 16. Patients underwent repeat cycles as indicated. We compare calculated panel-reactive antibody (cPRA) for neat combined Class I and II IgG and C1q pre- and post-treatment using a cutoff for cPRA entry of ≥ 4000 and 500 MFI, respectively. RESULTS: From June 2013 to October 2019, 9 patients underwent 20 cycles of carfilzomib-based desensitization. Each cycle resulted in an average cPRA decrease of 24% (95% CI: 6-42) for IgG and 36% (95% CI: 17-55) for C1q. From treatment start to finish, mean cPRA fell from 76% to 40% (p = 0.01) for IgG and 56% to 4% (p = 0.017) for C1q. Six of 9 patients have been transplanted with 5 of the transplanted hearts crossing preoperative donor-specific antibodies. During a median follow-up of 35.1 months, all transplanted patients have survived with only 1 occurrence of treated rejection. Side effects of desensitization included acute kidney injury (67%) and thrombocytopenia (33%) with all episodes self-resolving. CONCLUSIONS: A carfilzomib-based desensitization strategy among heart transplant candidates reduces the level of HLA antibodies and complement binding, facilitates successful transplantation, and is associated with excellent outcomes at 3 years.

Bloodstream Infections in Continuous Flow Left Ventricular Assist Device Recipients: Diagnostic and Clinical Implications.

Bloodstream infection (BSI) is a common complication of left ventricular assist device (LVAD) support and particularly difficult to treat. The presentation is often variable because of altered physiology and augmentation of cardiac output by the device. We studied LVAD recipients at a single institution. Multivariate logistic and Cox (with time-varying parameters) regression were implemented. Of 212 patients, 58% experienced infections. Driveline infection (DLI) affected 31%, with 60% of them having deep-tissue involvement. Sixty-six patients (31%) suffered from 135 BSIs. Systemic inflammatory response syndrome (SIRS) was present in 47% of BSIs at presentation and associated with increased mortality. Right heart failure, destination therapy, Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile, morbid obesity, and deep-DLI were independent risk factors for BSI. The BSI was independently associated with mortality. Bridge-to-transplantation (BTT) patients were more likely to receive transplant if they did not have BSIs. Among 104 BTT patients who received heart transplantation, development of BSI was associated with shorter time-to-transplantation. Diagnosis of BSI poses diagnostic and prognostic challenges because of the hemodynamic profile of LVAD patients who may not mount the expected physiologic response to sepsis. Although SIRS criteria lack sensitivity in the LVAD population, SIRS signifies increased risk for death. Deep DLI was the strongest predictor of BSI. Despite the upgrade in listing status of BTT-LVADs with BSIs and shorter time-to-transplantation, BSI remain a major cause of mortality. BSIs are associated with significant mortality and should be regarded as a serious complication, similar to pump thrombosis and stroke.

Assessing Anticoagulation Practice Patterns in Patients on Durable Mechanical Circulatory Support Devices: An International Survey.

Anticoagulation in mechanical circulatory support (MCS) patients dictated by local practice, and therefore uniform standards for management are lacking. To characterize the worldwide variance in anticoagulation and antiplatelet therapy in patients with MCS devices, a 42 item survey was created and distributed electronically in August 2014. The survey assessed the center-perceived thromboembolic risk (minimal, low, moderate, or high) and characterized the antiplatelet and anticoagulant strategies for the Thoratec HeartMate II (HMII) and HeartWare HVAD (HVAD). A total of 83/214 centers (39%) responded: North America (60/152), Europe (18/50), Australia (2/4), and Asia (3/8). Although the most common target international normalized ratio (INR) was 2-3 for both devices, significant variability exists. Anticoagulation intensity tended to be lower with the HMII, with more centers targeting INR values of less than 2.5. Aspirin monotherapy was the most common antiplatelet regimen; however, the HVAD patients were more likely to be on daily aspirin doses over 100 mg. In addition, parenteral bridging was more frequent with the HVAD device. While 43.8% of respondents indicated an increase in the perceived risk of HMII device thrombosis in 2014, intensification of anticoagulation (22%) or antiplatelet (11%) therapy was infrequent. Our findings verify the wide variety of anticoagulation practice patterns between MCS centers.

Pharmacotherapy of sepsis.

Treatment of sepsis involves prompt recognition and treatment to optimize outcome. Several medication considerations are pertinent to patients with sepsis, severe sepsis, and septic shock. Medications play a crucial role in providing resuscitation, hemodynamic support, resolution of infection, and reduction of complications of the disease. Over the past 20 years, significant focus has been devoted to the pharmacologic treatment of septic shock, resulting in significant advances and controversies. Ongoing research will continue to focus on this disease process and will continue to shape treatment in the future. The use of medication therapies directed at treatment of sepsis will be reviewed in this article.

The pathophysiology of endothelin in complications after solid organ transplantation: a potential novel therapeutic role for endothelin receptor antagonists.

Although short-term allograft survival after solid organ transplantation has improved during the past two decades, improvement in long-term graft survival has been less pronounced. Common complications after transplantation include chronic allograft rejection, nephrotoxicity from calcineurin inhibitors (CNIs), and systemic hypertension, which all impact posttransplantation morbidity and mortality. Endothelin (ET)-1, a potent endogenous vasoconstrictor, inducer of fibrosis, and vascular smooth muscle cell proliferation, may play a key role in both the development of CNI-induced nephrotoxicity and endothelial vasculopathy in chronic allograft rejection. ET-1 levels increase after isograft implantation, and ET-1 plays a key role in CNI-induced renal vasoconstriction, sodium retention, and hypertension. Preclinical studies have demonstrated that endothelin receptor antagonists (ERAs) can reduce or prevent CNI-induced hypertension after renal transplantation. In addition, ERAs can ameliorate CNI-induced renal vasoconstriction and improve proteinuria and preserve renal function in animal models of renal transplantation. ET-1 may also play a significant role in cardiac allograft vasculopathy, and in animal models, ERAs improve pulmonary function and ischemic-reperfusion injury in lung transplantation and hepatic function and structure in liver transplantation. Emerging pharmacokinetic data suggest that the selective ERA ambrisentan may be used safely in conjunction with the most commonly used immunosuppressive agents tacrolimus and mycophenolate, albeit with appropriate dose adjustment. The weight of available evidence pointing toward a potential beneficial role of ERAs in ameliorating common complications after solid organ transplantation must be balanced with potential toxicities of ERAs but suggests that a randomized clinical trial of ERAs in transplant patients is warranted.

Safe use of hemodialysis for dabigatran removal before cardiac surgery.

OBJECTIVE: To describe a case in which hemodialysis was performed before cardiac transplantation in an attempt to reverse the effects of dabigatran and reduce the risk of bleeding associated with surgery. CASE SUMMARY: A 59-year-old female with heart failure and atrial fibrillation was admitted for orthotropic heart transplant. She had been stable at home with continuous milrinone therapy 0.25 µg/kg/min, amiodarone 200 mg twice daily, and dabigatran 150 mg twice daily for stroke prevention secondary to atrial fibrillation. Upon notification of organ availability, the patient was admitted to the hospital for transplant surgery, with her last dose of dabigatran taken approximately 36 hours before admission. Coagulation studies indicated normal activated partial thromboplastin time, slightly elevated international normalized ratio of 1.2, and elevated thrombin time (TT) of 90.6 seconds (upper limit of normal 19.9 seconds). A hemodialysis catheter was emergently placed and dialysis was initiated. One hour after initiation, TT decreased to 65.5 seconds. After 2.5 hours of dialysis, TT further decreased to 60.2 seconds; at that time, the patient underwent transplantation with no abnormal bleeding during or following surgery. DISCUSSION: Minimal data exist on techniques to reverse the effects of dabigatran in cases of bleeding or emergent surgery. This case examines the efficacy of hemodialysis to decrease dabigatran's effect on clotting assays prior to surgery to reduce the risk of bleeding. In this case, a TT of 60.2 seconds with recent dabigatran administration did not result in abnormal bleeding associated with cardiac surgery. CONCLUSIONS: To our knowledge, this case report represents the first published data on the effects of hemodialysis on dabigatran removal and reversal of anticoagulation associated with dabigatran before surgery. The routine use of preoperative hemodialysis in patients on dabigatran is not recommended; however, the potential efficacy in such circumstances is supported by the successful results in this case.