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Long-Term Outcomes of Sirolimus in Maintenance Heart Transplant Recipients
Study Questions:
What is the long-term safety and efficacy of conversion from calcineurin inhibition (CNI) to sirolimus (SRL), an inhibitor of the mammalian target of rapamycin (mTOR), as maintenance therapy on cardiac allograft vasculopathy (CAV) progression and outcomes after heart transplantation (HT)?
Methods:
This was a nonrandomized, retrospective, single-center study with a cohort comprised of 402 patients who underwent HT and were treated either with CNI alone (n = 134) or converted from CNI to SRL (n = 268) as primary immunosuppression. All HT recipients received induction therapy with low-dose OKT3 or ATG as part of a standard induction protocol and a three-drug maintenance immunosuppressive regimen consisting of a CNI (cyclosporine A or tacrolimus), an antimetabolite agent (mycophenolate mofetil or azathioprine), and tapering doses of prednisone post-HT. The study authors assessed progression of CAV by serial coronary intravascular ultrasound (IVUS) while treated with CNI (n = 99) and after conversion to SRL (n = 235) in patients who had at least two IVUS studies. The primary outcome endpoints of this study were: 1) Progression of CAV by volumetric assessment of vascular geometry using repeated IVUS measurements during follow-up; 2) all-cause mortality; 3) CAV-related death, defined as death as a result of myocardial infarction confirmed by pathological examination and/or an increase in cardiac enzymes or sudden death in the setting of progressive CAV; and 4) CAV-related events including one of the following: allograft failure associated with known CAV in the absence of significant rejection or significant organic tricuspid valve regurgitation, myocardial infarction, or coronary angioplasty due to advanced CAV. The secondary endpoints included: 1) composite endpoint of fatal and nonfatal CAV events, and 2) composite endpoint of all-cause mortality, fatal, and nonfatal CAV events. All patients who had at least one IVUS exam were included for analysis, and thus, they left survival data censored.
Results:
The mean follow-up time from baseline to last IVUS examination was 4.5 ± 3.3 years in the CNI group and 5.0 ± 3.2 years in the SRL group (p = 0.19). The study authors found that progression in plaque volume (2.8 ± 2.3 vs. 0.46 ± 1.8; p < 0.0001) and plaque index (plaque volume to vessel volume ratio) (12.2 ± 9.6% vs. 1.1 ± 7.9%; p < 0.0001) was significantly attenuated when treated with SRL compared with CNI. Over a mean follow-up of 8.9 years from time of HT, all-cause mortality occurred in 25.6% of the patients and was lower while treated with SRL compared with CNI (adjusted hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.31–0.70; p = 0.0002), and CAV-associated death was also significantly decreased in patients taking SRL as compared to those continuing on CNI in the unadjusted (HR, 0.22; 95% CI, 0.09–0.47; p = 0.0003) and adjusted model (HR, 0.27; 95% CI, 0.11–0.61; p = 0.003). CAV-related events were also lower while treated with SRL (adjusted HR, 0.35; 95% CI, 0.21–0.59; p < 0.0001). The use of SRL as primary immunosuppressant was also associated with significantly decreased secondary composite endpoints of fatal and nonfatal CAV-related events as well as all-cause mortality and all CAV-related events (p < 0.0001 for both adjusted models). There was more attenuation of CAV and more favorable clinical outcomes with earlier conversion to SRL (≤2 years) compared with late conversion (>2 years) after HT. Among patients converted to SRL, the study authors found that patients with baseline advanced renal failure (estimated glomerular filtration rate [eGFR] <30 ml/min) had a higher risk of all-cause mortality (HR, 2.5; 95% CI, 1.10-4.90; p = 0.03) as compared to those with more preserved renal function (eGFR ≥30 ml/min), but the risk for CAV-related events was similar (p = 0.89). Moreover, patients with baseline established CAV prior to SRL conversion had a trend towards an increased risk of CAV-related events (HR, 2.0; 95% CI, 0.94-4.4; p = 0.070) and all-cause mortality (HR, 1.7; 95% CI, 0.96-3.14; p = 0.068), and a significantly higher composite risk of CAV-related events and all-cause mortality (HR, 1.9; 95% CI, 1.15-3.22; p = 0.012). The authors reported that SRL-associated dyslipidemia is typically amenable to statin therapy. Compared with the anticipated median survival of 13 years post-HT presented by the International Society for Heart and Lung Transplantation registry, these data showed that patients converted to SRL had strikingly increased survival with median survival of about 18 years.
Conclusions:
The authors concluded that early conversion to SRL is associated with attenuated CAV progression as well as with lower long-term mortality and CAV-related events compared with continued CNI usage.
Perspective:
This is an important study because its findings suggest that early conversion to SRL (within 6 months to 2 years) attenuates CAV progression and increases survival (by ~5 years). Until more data are available, every center performing HT should consider switching HT recipients to SRL, particularly in those whose eGFR is >30 ml/min.
Keywords: Allografts, Angioplasty, Azathioprine, Cyclosporine, Death, Sudden, Dyslipidemias, Glomerular Filtration Rate, Heart Failure, Heart Transplantation, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Immunosuppression, Immunosuppressive Agents, Lung Transplantation, Myocardial Infarction, Prednisone, Sirolimus, Tacrolimus, Tricuspid Valve Insufficiency, Ultrasonography
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