Comparison of sirolimus with azathioprine in a tacrolimus-based immunosuppressive regimen in lung transplantation.

RATIONALE: Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of chronic rejection. Sirolimus is beneficial in preventing cardiac rejection and may decrease rejection after lung transplantation. OBJECTIVES: To determine the potential benefit versus risk of sirolimus in lung transplantation. METHODS: We conducted a multicenter randomized, open label controlled trial comparing sirolimus (SIR) with azathioprine (AZA) in a tacrolimus-based immunosuppressive regimen in lung transplantation. The primary end point was the incidence of acute rejection at 1 year after transplantation between the two study groups. MEASUREMENTS AND MAIN RESULTS: One hundred eighty-one patients were randomized to be included in this study. At 1 year after transplantation, there was no significant difference in the incidence of grade A acute rejection between the two study groups. Similarly, the incidence of chronic rejection and graft survival was no different between the two study groups. Cytomegalovirus infection was decreased in the SIR arm compared with the AZA arm (relative risk, 0.67 [95% confidence interval, 0.55, 0.82]; P < 0.01). There was a higher rate of adverse events leading to early discontinuation of SIR (64%) compared with AZA (49%) during the course of this study. CONCLUSIONS: Sirolimus, an mTOR inhibitor, did not decrease the incidence of acute rejection at 1 year compared with azathioprine in lung transplantation. These results differ from previous results in cardiac and renal transplantation and emphasize the need for multicenter randomized controlled trials in lung transplantation. Clinical trial registered with www.clinicaltrials.gov (NCT 00321906).

Cardiac Surgery Outcomes in Abdominal Solid Organ Transplant Recipients.

BACKGROUND: Cardiovascular disease is a cause of morbidity and mortality in organ transplant recipients. Cardiac surgery after organ transplantation is not uncommon in this population. We evaluated 30-day outcomes and long-term survival of abdominal transplant recipients undergoing cardiac surgery at our institution. METHODS: In all, 138 patients with previous kidney, kidney-pancreas, and liver transplants underwent cardiac surgery from 2000 to 2016. Propensity score (ratio 1:3) matched 115 abdominal transplant with 345 patients undergoing cardiac surgery without a history of abdominal transplant. They were matched for type and year of cardiac surgery, age, sex, body mass index, history of diabetes mellitus, and creatinine level before cardiac surgery. RESULTS: Median time from abdominal transplant to cardiac surgery was 7 years (interquartile range, 3 to 12 years). Perioperative variables, including surgery and cardiopulmonary bypass time, aortic cross-clamp and intubation time, and intensive care unit stay did not differ between the groups. Hospital length of stay and rate of 30-day hospital readmissions did not differ between the groups. Patients with abdominal transplants had more strokes (4% versus 0.6%; p = 0.005) within 30 days after surgery. There were no differences in renal failure, bleeding, site infections, atrial fibrillation, and pneumonia between the groups. Five patients (4%) died within 30 days after surgery in the abdominal transplant group (4 kidneys, 1 liver, 0 kidney-pancreas), and 7 patients (2%) died in the nontransplanted group (p = 0.24). CONCLUSIONS: Previous history of abdominal transplant is associated with an increased 30-day incidence of stroke after cardiac surgery. Abdominal transplant does not affect 30-day mortality after cardiac surgery, whereas long-term survival is significantly reduced. Regular patient follow-up and prevention and early treatment of postoperative complications are key to patient survival.

Short-term clinical outcomes after off-pump coronary artery bypass grafting at a single Veterans Affairs Medical Center.

BACKGROUND: We retrospectively assessed the outcomes after coronary revascularization at a single Veterans Affairs Medical Center when a strategy of assigning higher risk patients to off-pump coronary artery bypass grafting (CABG) was employed. METHODS: Over a 5 year period all consecutive patients that underwent CABG at our VA Medical Center were assigned to a surgeon who either performs the CABG exclusively off-pump or to one who performed the CABG on-pump. The higher risk patients were assigned preferentially for off-pump revascularization. VASQIP (VA Hospitals Surgical Quality Improvement Program) data between 10/2007 and 12/2012 were retrospectively reviewed at our VA Medical Center and the short term outcomes were assessed. RESULTS: A total of 252 consecutive patients underwent off-pump CABG (n = 170) and on-pump CABG (n = 82). There were significantly more patients with low LVEF (<45 %; p = 0.008) and cerebrovascular disease in the off-pump group (p = 0.024). The number of patients smoking at the time of surgery was significantly higher in the off-pump group (p = 0.002) as well. The 30-day composite morbidity and mortality was 6 % for all CABG patients and significantly lower with off-pump vs. on-pump CABG (3.5 % vs. 11 %; p = 0.019). There were no conversions from off-pump to on-pump surgery. CONCLUSIONS: A selective strategy to direct higher risk patients towards an off-pump revascularization yielded favorable outcomes in an unselected veteran population treated at a single VA Medical Center over a 5 year period.

Timing and Frequency of Unplanned Readmissions After Lung Transplantation Impact Long-Term Survival.

BACKGROUND: Adverse events that require hospital readmission frequently occur long after lung transplantation (LT) that has been successfully performed. We sought to identify the causes and rate of unplanned readmissions after LT and to determine whether unplanned readmissions have a significant impact on post-LT survival. METHODS: We retrospectively reviewed the outcomes in 174 LT recipients who underwent LT at our center from June 2005 to May 2014. The median follow-up period was 38 months (range, 17 to 72 months). RESULTS: One hundred sixty (92%) of the 174 recipients were readmitted 854 times (5.3 times per patient). The median time to first readmission was 71 days (interquartile range [IQR], 28 to 240 days), and the median hospital length of stay at readmission was 3 days (IQR, 2 to 6 days). Freedom from first readmission was observed for 65% of patients at 1 month, 48% at 3 months, 43% at 6 months, and 26% at 12 months. Gender, lung allocation score, body surface area, year of transplantation, air leak longer than 5 days after operation, and allograft function were risk factors for readmission. The causes of readmission included infections (33%), respiratory adverse events (18%), rejection (15%), gastrointestinal events (15%), renal dysfunction (5%), and cardiac events (4%). Patients who died were found to have had early readmissions (p = 0.04) and more frequent readmissions (p = 0.001). CONCLUSIONS: The first year after LT remains a high-risk period for unplanned readmissions regardless of pretransplantation diagnosis. Readmissions soon after discharge at index hospitalization and multiple readmissions are associated with an increased risk of mortality.

Interobserver variability in grading transbronchial lung biopsy specimens after lung transplantation.

BACKGROUND: Acute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to standardize the diagnosis of acute lung-allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies. METHODS: We examined the level of agreement in grading transbronchial biopsy specimens obtained from a large multicenter study (AIRSAC [Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen vs Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation] trial). Biopsy specimens were initially graded for acute rejection and lymphocytic bronchiolitis by the site pathologist and subsequently graded by a central pathologist. Reliability of interobserver grading was evaluated using Cohen κ coefficients. RESULTS: A total of 481 transbronchial biopsy specimens were graded by both the site and central pathologists. The overall concordance rates were 74% and 89% for grade A and grade B biopsy specimens, respectively. When samples from biopsies performed at different time points after transplantation were assessed, there was a higher level of agreement early (≤ 6 weeks) after transplant compared with later time points for acute rejection. However, there was still only moderate agreement for both grade A (κ score 0.479; 95% CI, 0.29-0.67) and grade B (κ score 0.465; 95% CI, 0.08-0.85) rejection. CONCLUSIONS: These results expand upon previous reports of interobserver variability in grading transbronchial biopsy specimens after lung transplantation. Given the variability in grading these specimens, we advocate further education of the histopathologic findings in lung transplant biopsy specimens, as well as revisiting the current criteria for grading transbronchial biopsy specimens to improve concordance among lung transplant pathologists. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT00321906; URL: www.clinicaltrials.gov.

Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation.

BACKGROUND: Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database. METHODS: The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution. RESULTS: The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis. CONCLUSIONS: These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events.

Increased risk of venous thromboembolism with a sirolimus-based immunosuppression regimen in lung transplantation.

BACKGROUND: Sirolimus (rapamycin) is a potent anti-proliferative agent with immunosuppressive properties that is increasingly being used in solid-organ and hematopoietic stem cell transplantation. In addition, this drug is being investigated for treatment of a broad range of disorders, including cardiovascular disease, malignancies, tuberous sclerosis, and lymphangeioleiomyomatosis. In this study, we found an increased risk of venous thromboembolism (VTE) in lung transplant recipients treated with a sirolimus (SIR)-based immunosuppressive regimen. METHODS: One hundred eighty-one lung transplant recipients were enrolled in a prospective, multicenter, randomized, open-label trial comparing a tacrolimus (TAC)/SIR/prednisone immunosuppression regimen with a TAC/azathioprine (AZA)/prednisone immunosuppressive regimen. The differences in rates of VTE were examined. RESULTS: There was a significantly higher occurrence of VTE in the SIR cohort [15 of 87 (17.2%)] compared with the AZA cohort [3 of 94 (3.2%)] (stratified log-rank statistic = 7.44, p < 0.01). When adjusted for pre-transplant diagnosis and stratified by transplant center, this difference remained essentially unchanged (hazard ratio for SIR vs AZA = 5.2, 95% confidence interval 1.4 to 19.5, p = 0.01). CONCLUSION: Clinicians prescribing SIR should maintain a high level of vigilance for VTE, particularly among patients with other risk factors for this complication.