Case Report: tacrolimus toxicity in the setting of concurrent Paxlovid use in a heart-transplant recipient.

Background: Tacrolimus toxicity in patient's status post-orthotropic heart transplantation is not commonly reported. Given its narrow therapeutic window and drug-drug interactions, it must be closely monitored by providers who are experienced in transplant management. There are no case series of patients with tacrolimus toxicity in the setting of treatment for Sars-2-CoV-19 (COVID 19) for heart-transplant recipients. We present a case of tacrolimus toxicity in the setting of concurrent ritonavir-nirmatrelvir (Paxlovid) use. Case summary: The patient was a 74-year-old male with a prior significant history of heart transplantation and on maintenance immunosuppression with tacrolimus. He contracted COVID-19 and was prescribed antiviral therapy with Paxlovid by an outside provider prior to admission. The patient complained of severe headaches, dehydration, and tremors. After eliminating acute intracranial processes with imaging, laboratory investigation revealed a severely elevated tacrolimus level with acute renal injury. The patient was taken off tacrolimus and treated conservatively with intravenous hydration. The symptoms improved, particularly the headaches. He was discharged with instructions to resume his home dosing of tacrolimus and return to clinic in 1 week with a repeat trough level. The subsequent trough level was no longer supra-therapeutic. Discussion: Tacrolimus has a potent drug-drug interaction with Paxlovid (ritonavir-nirmatrelvir) and can be supra-therapeutic. Toxicity is associated with multiple adverse effects, including but not limited to, acute renal injury, neurotoxicity, and infections due to over-immunosuppression. As Paxlovid is effective in treating Sars-2-CoV-19 in heart-transplant recipients, knowledge and understanding of drug-drug interactions is crucial in preventing and mitigating toxicity.

Rehospitalization of Patients with Advanced Heart Failure Receiving Continuous, Palliative Dobutamine or Milrinone.

This study aims to determine the incidence of all-cause hospitalization in patients with advanced heart failure (AHF) receiving ambulatory continuous, intravenous dobutamine versus milrinone for palliative intent. Despite medical optimization, patients with AHF develop refractory symptoms, resulting in frequent hospitalizations. Previous trials precede modern care standards. Data regarding inotrope choice in palliation are limited. This retrospective analysis included 222 patients with AHF and reduced left ventricular ejection fraction discharged on palliative dobutamine (n = 135) or milrinone (n = 87). The primary outcome was incidence of all-cause rehospitalization compared by treatment type. Demographics between groups were similar. In the milrinone arm, more patients were discharged on ß blockers (62% vs 22%; p <0.001); fewer patients were discharged to hospice (6% vs 30%). More patients in the milrinone arm than in the dobutamine arm were rehospitalized within 180 days (80% vs 59%; p = 0.002); when patients discharged to hospice were excluded, this difference was no longer significant (83% vs 74%; p = 0.14). Overall mortality was lower in the milrinone arm (63% vs 80%; p = 0.006); survival was longer (median: 228 vs 52 days; p <0.001). Patients receiving milrinone spent more days alive and out of the hospital at 90 days after discharge (70 vs 37 days; p <0.001). In conclusion, in patients with AHF receiving palliative inotropes, there was no difference in rehospitalization when excluding patients discharged to hospice. Milrinone use was associated with decreased mortality and longer survival. Agent selection must closely align with the patient's disease trajectory.

Approaches and strategies to manage the hepatitis C virus-positive heart donor.

PURPOSE OF REVIEW: Cardiac transplantation remains the treatment of choice for patients with advanced heart failure, but is limited by a donor organ shortage. Utilization of hepatitis C virus (HCV)-positive donors has been recently adopted to expand access to heart transplantation. We review the history of HCV heart transplantation, modern drug therapy, and recent outcomes. RECENT FINDINGS: Since the advent of direct-acting antiviral (DAA) therapy, several single-center studies, and retrospective reviews have demonstrated good short-term outcomes, shorter waitlist times, and clearance of viremia with recipients of HCV-positive hearts. Two principle approaches to treatment of recipients of HCV viremic donors are utilized. In the prophylactic strategy, therapy is initiated before viremia is detected compared with the preemptive approach where initiation of DAA is delayed until after viremia is detected. Future studies are needed to address uncertainty about medium and long-term outcomes of using HCV-positive hearts and to determine the optimal treatment timing and duration. SUMMARY: Utilization of HCV-positive donors has expanded the heart donor pool and appears safe through the early posttransplant period. We suggest that prophylactic administration of the shortest effective course of a DAA pangenotypic agent should be the current standard of care.

Incidence of cytomegalovirus in cardiac transplant recipients receiving induction immunosuppression with antithymocyte globulin.

BACKGROUND: Cytomegalovirus (CMV) is a major cause of morbidity and mortality in cardiac transplant recipients. Use of induction immunosuppression in cardiac transplantation may have an impact on the incidence of CMV, but literature is limited. METHODS: Single-center, retrospective cohort study comparing the risk of CMV infection and disease in cardiac transplant patients receiving antithymocyte globulin (ATG) induction therapy to those receiving no antibody induction. RESULTS: A total of 75 patients were included in our analysis, 50 who received ATG induction and 25 who did not. CMV infection occurred in 10 (20%) and 5 (20%) patients in the ATG and No ATG groups, respectively (P > 0.99). CMV disease occurred in 10 (20%) and 4 (16%) patients in the ATG and No ATG groups, respectively (P = 0.763). The median time from transplant to CMV infection was 200.0 [142.5, 364.5] days in the ATG group vs 221.0 [192.0, 299.0] days in the No ATG group (P = 0.723). The median time from end of CMV prophylaxis to CMV infection was 94.5 [66.5, 151.0] days in the ATG group vs 53.0 [41.0,149.5] days in the No ATG group (P = 0.202). Freedom from CMV infection was highest in the D+/R+ group and lowest in the D+/R- group. CONCLUSION: In cardiac transplant recipients, ATG induction was not associated with an increased incidence of CMV infection or disease in the setting of valganciclovir prophylaxis and an initial maintenance immunosuppression regimen of primarily steroids, mycophenolate mofetil, and tacrolimus.

Comparison of the effects of combination diuretic therapy with oral hydrochlorothiazide or intravenous chlorothiazide in patients receiving intravenous furosemide therapy for the treatment of heart failure.

STUDY OBJECTIVE: To compare the effects of combination diuretic therapy with oral hydrochlorothiazide or intravenous chlorothiazide added to background intravenous loop diuretic therapy among patients hospitalized with heart failure. DESIGN: Single-center, retrospective review. SETTING: Cardiovascular hospital within a university-affiliated teaching institution. PATIENTS: Eighty-two patients hospitalized for heart failure between September 1, 2009, and August 31, 2011, who were receiving background intravenous furosemide therapy (total daily dose ≥ 160 mg); of those patients, 28 patients also received oral hydrochlorothiazide (median dose 25 mg [interquartile range 25-50 mg]), and 54 patients also received intravenous chlorothiazide (median dose 500 mg [interquartile range 250-750 mg]). MEASUREMENTS AND MAIN RESULTS: The primary outcome was change in 24-hour urine output. Urine output was recorded from the 24 hours before and after the first administration of either oral hydrochlorothiazide or intravenous chlorothiazide. Baseline characteristics, with the exception of female sex (p=0.01) and home loop diuretic dose (p=0.03), were similar between groups. Twenty-four-hour urine output before administration of the thiazide diuretic was not significantly different between groups. After treatment, 24-hour urine output increased in both groups; however, urine output increased to a lesser extent with oral hydrochlorothiazide (from mean ± SD 2104 ± 830 ml to 3038 ± 917 ml) than with intravenous chlorothiazide (from 2342 ± 978 ml to 4128 ± 1755 ml) (p=0.005). Hypokalemia occurred frequently in both groups: 71.4% and 83.3% in the oral hydrochlorothiazide and intravenous chlorothiazide groups, respectively (p=0.21). CONCLUSION: Among hospitalized patients with heart failure receiving intravenous loop diuretics, the addition of either oral hydrochlorothiazide or intravenous chlorothiazide augmented diuresis. Urine output increased to a greater extent with intravenous chlorothiazide compared with oral hydrochlorothiazide. However, given the positive response observed, ease of administration, and lower drug cost, oral hydrochlorothiazide should still be considered as an option for combination diuretic therapy in this patient population.