Traveling for heart transplantation and returning with COVID-19: a logistical, clinical, and pharmacotherapeutic challenge from the Middle East.

Heart transplantation (HT) has become a standard option for patients with end-stage heart failure (HF). However, the scarcity of donor availability remains a major hurdle for receiving this novel therapy, especially in the context of the rapidly spreading severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) pandemic. We report the case of a patient in the United Arab Emirates (UAE) with advanced HF who was glucose-6-phosphate dehydrogenase deficient and had a history of type 2 diabetes mellitus with diabetic retinopathy and nephropathy, chronic kidney disease stage II, and hyperlipidemia. He was referred for HT abroad and was subsequently caught in the midst of the COVID-19 pandemic in New York, the US state most affected by the crisis at the time. Despite limited experience with favipiravir, we judged it to be the most appropriate agent with this patient's complex history given the lower risk for QT prolongation, no need for renal-dose adjustment, and no reported drug-drug interactions. Given the limited clinical experience with this agent, particularly for our patient, we decided to adopt strategies to mitigate and monitor the potential for QT prolongation. We outline the logistical, clinical, and pharmacological challenges that the poly-morbid patient and our HT program in the Middle-East faced under those novel circumstances.

A per-protocol initiation of sacubitril/valsartan in an advanced heart failure disease management programme in the Middle East Gulf Region.

AIMS: The aim of this study is to evaluate the utilization and success in therapy intensification after initiation of sacubitril/valsartan using a specified protocol within an advanced heart failure and transplant programme in the Middle East Gulf Region. METHODS AND RESULTS: We studied a single-centre, retrospective cohort in a 364-bedded multi-speciality hospital located in the United Arab Emirates (February 2016 to July 2017). The advanced heart failure and transplant programme formulated an institutional protocol for initiation of sacubitril/valsartan with defined criteria for switching from angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB). Prescribing this drug is intended for patients with heart failure with reduced ejection fraction with left ventricular ejection fraction ≤40%. We excluded patients (i) with age below 18 years or (ii) initiated on sacubitril/valsartan from an outside hospital with or without follow-up in our outpatient clinic. We included 102 patients with an average initial dose of 78.9 ± 44.2 mg twice daily. Only 17 patients were on target doses of ACEI or ARB prior to switching to sacubitril/valsartan. Up-titration was successful in 55 patients during the follow-up period. In addition, 6.9% patients were hospitalized with heart failure exacerbation. In patients with elevated baseline serum potassium prior to initiating this medication, the serum potassium levels decreased post-initiation by 0.5 ± 0.3 mmol/L (P = 0.0008). CONCLUSIONS: Initiating sacubitril/valsartan through a defined protocol selects for appropriate candidates and guides starting dose and titration. Overall, significant success can be achieved in replacing ACEI or ARB by sacubitril/valsartan in symptomatic heart failure with reduced ejection fraction patients.

Permanent pacemaker implantation early and late after heart transplantation: clinical indication, risk factors and prognostic implications.

BACKGROUND: Permanent pacemaker implantation (PPM) early after cardiac transplantation has been shown not to predict a worse outcome. However, the requirement for pacing late after transplantation and its prognostic implications are not fully known. We describe the clinical indications, risk factors and long-term outcome in patients who required pacing early and late after transplantation. METHODS: The transplant database, medical records and pacing database/records were reviewed for all patients undergoing de novo orthotopic cardiac transplantation (n = 389) at our institution between January 1995 and May 2006. RESULTS: A total of 48 patients (12.3%) received a pacemaker after transplantation. Of these patients, 30 were paced early, pre-hospital discharge (25 ± 19 days post-transplantation), and 18 patients had late pacing (3.0 ± 3.3 years post-transplantation). There were no differences in clinical characteristics, use of anti-arrhythmic drugs or length-of-stay post-transplantation between early and late groups. Early indications for pacing were more often sino-atrial (SA) disease (24 of 30, 80%), whereas atrio-ventricular (AV) disease was more likely to occur later (p = 0.03). Risk factors for PPM included use of biatrial anastomosis (p = 0.001) and donor age (p = 0.002). Prior rejection was a univariate but not multivariate (p = 0.09) predictor of the need for PPM. Development of cardiac allograft vasculopathy was not predictive. There was no significant difference in mortality between late and early PPM patients or between late PPM patients and the non-paced patients who survived transplantation and initial stay. CONCLUSIONS: Patients who required PPM late after orthotopic cardiac transplantation had a prognosis comparable to those paced early and those who did not require PPM. The independent risk factors for PPM were biatrial anastomosis and increasing donor age. SA-nodal dysfunction as an indication for PPM was more prevalent early after transplantation, whereas atrioventricular (AV) disease more commonly presented late. The requirement for pacing late after transplantation was not associated with rejection or cardiac allograft vasculopathy.

Transfer from ciclosporin to mycophenolate-sirolimus immunosuppression for chronic renal disease after heart transplantation: safety and efficacy of two regimens.

BACKGROUND: Chronic kidney disease is common after heart transplantation, and is related to ciclosporin (CsA) therapy. We compared the safety and efficacy of two ciclosporin withdrawal regimens. METHODS: CsA was stopped and sirolimus (SRL) commenced immediately and the transfer was covered with prednisolone. Those on azathioprine (AZA) were transferred to MMF. In protocol A, the SRL target concentration was 16 (12-20) ng/ml; in protocol B, the target concentration was 7(5-10) ng/ml, but mycophenolate (MMF) and steroids were commenced prior to the transfer. RESULTS: Baseline characteristics were similar in both groups except that group B were switched later after transplantation. Renal function improved significantly in both groups; this was maintained up to 1 year. Two patients in group A experienced acute rejection (ISHLT grade 3A or 2R); none was seen in group B. Six patients (46%) remained on protocol A and 22 (85%) remained on protocol B at 1 year. CONCLUSIONS: MMF-SRL substitution resulted in a rapid but partial improvement in renal function; the lower dose SRL regimen was better tolerated.

A reevaluation of the role of IgM Non-HLA antibodies in cardiac transplantation.

BACKGROUND: Preexisting IgG antibodies to donor human leukocyte antigens (HLA) are a risk factor for rapid allograft rejection. However, non-HLA antibodies, of the IgM class, also called autoreactive antibodies, are not believed to affect graft survival. The aim of this study was to determine the incidence and clinical relevance of pretransplant lymphocytotoxic non-HLA IgM antibodies on long-term cardiac allograft survival. METHODS: A retrospective study of 616 adult recipients of cardiac allografts, transplanted at this center between 1991 and 2003, has been performed. Antibodies in pretransplant sera were initially defined using complement-dependent cytotoxicity assays, and subsequently analyzed for HLA specificities using solid phase assays. RESULTS: HLA antibodies were present in 69 of 616 heart recipients (58 IgG, 11 IgM); in 22 of these, the antibodies were donor-specific. Non-HLA IgM antibodies were detected in 59 of 616 recipients who did not have HLA-specific antibodies; these patients had a 1, 2, 5, and 10 year survival of 55.9%, 54.2%, 49.9%, and 43.3% compared with 75.8%, 73.7%, 66.6%, and 52.8% for those without antibodies (P=0.0085 log-rank test). Multivariate analysis demonstrated pretransplant non-HLA IgM antibodies to be an independent risk factor for mortality (P=0.0001). Myocardial histology of postmortem heart and cardiac biopsies suggested an association with ischemic damage and "primary" allograft failure. CONCLUSIONS: We propose the hypothesis that the presence of cytotoxic IgM antibodies to non-HLAs before heart transplantation maybe a risk factor for early allograft failure.

Chronic kidney disease after heart transplantation.

BACKGROUND: Chronic kidney disease (CKD) is a complication of heart transplantation related to calcineurin inhibitor nephrotoxicity. However, it is unclear whether early ciclosporin (CsA) exposure influences CKD in the long term. METHODS: We analysed risk factors for CKD in 352 patients who underwent orthotopic heart transplantation (1995-2005). In 2000, we reduced our target CsA levels in the first year after transplantation. RESULTS: Actuarial patient survival was 79% at 1 year and 62% at 10 years. Estimated median glomerular filtration rate (eGFR) by the four-variable Modification of Diet in Renal Disease formula was 64 ml/min/1.73 m2 before transplantation, inter-quartile range (IQR) 54-78. After transplantation, the eGFR was 48 (IQR 37-61) at Year 1, and 41(35-57) at Year 10. The cumulative probability of eGFR <45 ml/min/1.73 m2 was 45% at Year 1, 71% at Year 5 and 83% at Year 10. A multivariable logistic regression model was constructed for the development of eGFR <45 ml/min/1.73 m2 by 3 years. The risk factors were post-operative renal replacement therapy for acute renal failure (ARF), P < 0.001; pretransplant diabetes, P = 0.005; increasing recipient age, P < 0.001; female recipient, P = 0.029; female donor, P = 0.04, but not CsA regimen. The cumulative probability of developing stage 5 CKD (eGFR <15) was 3% at Year 5 and 12% at Year 10. Although lower ciclosporin initial levels were associated with less renal dysfunction at Year 1 (P = 0.008), there was no significant effect by Year 3 (P = 0.7). CONCLUSION: The incidence of CKD increased with time and was not influenced by the CsA regimen. Some risk factors are not modifiable but measures to reduce the incidence of post-operative ARF may help to reduce CKD.

Limited utility of endomyocardial biopsy in the first year after heart transplantation.

BACKGROUND: Surveillance endomyocardial biopsies (EMBs) are used for the early diagnosis of acute cardiac allograft rejection. Protocols became standardized in an earlier era and their utility with contemporary immunosuppression has not been investigated. METHODS: We studied 258 patients after orthotopic heart transplantation comparing 135 patients immunosuppressed by mycophenolate mofetil (MMF) with 123 patients treated by azathioprine (AZA); both with cyclosporine and corticosteroids after induction therapy with rabbit antithymocyte globulin. Fifteen EMBs were scheduled in the first year. Additional EMBs were performed for suspected rejection, after treatment, or for inadequate samples. The MMF group had 1875 EMBs vs. 1854 in the AZA group. RESULTS: The yield of International Society for Heart and Lung Transplantation (ISHLT) grade> or =3A biopsy-proven acute rejection (BPAR) was 1.87% per biopsy (35 of 1875) with MMF vs. 3.13% (58 of 1854) with AZA P=0.024. The number of clinically silent BPAR ISHLT grade > or =3A (the true yield of surveillance EMBs) was 1.39% (26 of 1875) of biopsies MMF vs. 2.1% (39 of 1854) AZA, P=0.48. There were five serious complications requiring intervention or causing long-term sequelae; 0.13% (5 of 3729) per biopsy and 1.94% (5 of 258) per patient. The incidence of all definite and potential complications was 1.42% (53 of 3729) per biopsy and 20.5% (53 of 258) per patient. There was no biopsy-related mortality. CONCLUSION: The yield of BPAR was low in the AZA group and very low in the MMF group. The incidence of complications was also low, but repeated biopsies led to a higher rate per patient. Routine surveillance EMBs and the frequency of such biopsies should be reevaluated in the light of their low yield with current immunosuppression.

Mycophenolate mofetil may allow cyclosporine and steroid sparing in de novo heart transplant patients.

BACKGROUND: Mycophenolate mofetil (MMF) provides superior prophylaxis against acute rejection when compared with azathioprine (AZA) in heart and renal transplantation. However, it remains unclear whether this results in improved survival or reduced morbidity after heart transplantation. METHOD: In a sequential study, 240 cardiac transplant patients were treated with either MMF (n=119) or AZA (n=121) both in combination with cyclosporine and corticosteroids after rabbit antithymocyte globulin induction. RESULTS: By protocol lower cyclosporine levels were targeted in the MMF group during the first year (e.g. 203+/-52 ng/mL MMF vs. 236+/-59 ng/mL AZA, P=0.0006 at 6 months). Patient survival at 1 year (82% MMF vs. 79% AZA, P=0.55) and at 3 years was similar in both groups. The cumulative probability of receiving antirejection treatment within 1 year was lower in the MMF group, as was biopsy-proven acute rejection with International Society of Heart and Lung Transplantation grade > or =3A (24% vs. 35%, P=0.03). The MMF group also had fewer episodes requiring cytolytic therapy (6% vs. 13%, P=0.04) and more patients had steroids withdrawn by 1 year (66% vs. 32%, P<0.001). Renal function was better in the MMF group with lower creatinine levels at 1 year (133+/-45 vs. 155+/-46 micromol/L, P=0.0004). Calculated creatinine clearance (Cockcroft and Gault formula) at 1 year was also better (MMF 74+/-32 mL/min vs. AZA 62+/-24 mL/min, P=0.004). CONCLUSION: Our results suggest that immunosuppression with MMF rather than AZA may allow lower cyclosporine levels, better renal function, and increased steroid weaning at 1 year while also achieving better control of acute rejection.

Reversible sirolimus-associated pneumonitis after heart transplantation.

Sirolimus (rapamycin) and everolimus are immunosuppressive agents that inhibit cardiac allograft vasculopathy. Sirolimus has been widely used in renal transplantation, and its use in heart transplantation is increasing. Sirolimus-associated pneumonitis has been described in renal transplant patients. Two cases of sirolimus-associated pneumonitis have been reported after cardiac transplantation. Only 1 case has been described in detail, and this had a fatal outcome. Here, we present a case of sirolimus-associated interstitial pneumonitis in a cardiac transplant recipient that resolved completely with withdrawal of the drug and treatment with corticosteroids.