mycophenolic-acid and Coronary-Disease

Topics: Coronary Disease; Cyclosporine; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppression Therapy; Immunosuppressive Agents; Isoxazoles; Leflunomide; Mycophenolic Acid; Polyenes; Postoperative Complications; Sirolimus; Tacrolimus

We investigated the potential of conversion to sirolimus (SRL) as a primary immunosuppressant in attenuating cardiac allograft vasculopathy progression.. Twenty-nine cardiac transplant recipients were converted to SRL 3.8+/-3.4 years after transplantation with complete calcineurin inhibitor (CNI) withdrawal. Secondary immunosuppressants (azathioprine or mycophenolate) and steroids remained unchanged. Forty patients (controls) 4.8+/-4.0 years from transplantation were maintained on CNIs. Three-dimensional intravascular ultrasound studies were performed at baseline and 12.1+/-2.6 months later. Mean plaque (media and intima) volume (PV) and plaque index (PI) (PV/vessel volume percent) increased significantly in the CNI group (1.28+/-2.86 mm(3)/mm, P=0.004; and 6+/-8%, P=0.0001) but not in the SRL group (0.1+/-1.13 mm(3)/mm, P=0.63; and 0.1+/-8%, P=0.94). In patients enrolled within 2 years after transplantation, the increases in PV (0.06+/-1.06 versus 1.77+/-1.65 mm(3)/mm; P=0.0081) and PI (0+/-9% versus 10+/-8%; P=0.0145) were smaller in the SRL group (n=11) than in the CNI (n=12) group. In patients enrolled >/=2 years after transplantation, the increase in PI was less in the SRL group compared with the CNI group (0.1+/-6.5% versus 5+/-8%; P=0.033), but changes in PV did not differ significantly. Treatment with azathioprine or mycophenolate did not affect PV or PI in either the SRL group (PV: 0.22+/-0.66 versus 0.05+/-1.45 mm(3)/mm, P=0.46; PI: 1.5+/-6% versus -1.6+/-8.5%, P=0.29) or the CNI group (PV: 1.42+/-1.39 versus 1.06+/-2.28 mm(3)/mm, P=0.49; PI: 7.8+/-8.7% versus 4.8+/-7.3%, P=0.23).. Substituting CNI with SRL as primary immunosuppression attenuates cardiac allograft vasculopathy progression.

Topics: Adrenal Cortex Hormones; Adult; Aged; Azathioprine; Coronary Disease; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Transplantation, Homologous

Both the proliferation signal inhibitor everolimus (1.5 mg/day) and mycophenolate mofetil (MMF) (3 g/day) have shown superior efficacy versus azathioprine in de novo heart transplantation. The cost-effectiveness of everolimus and MMF versus azathioprine was assessed to 6 months posttransplantation.. The evaluation was performed from the German health insurance payer perspective. The composite efficacy endpoint in the everolimus trial was death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR) grade>or=3A, rejection with hemodynamic compromise, and loss to follow-up. The composite endpoint in the MMF trial included only death, retransplantation, and BPAR with hemodynamic compromise. To mimic the everolimus endpoint, an estimated number of patients with BPAR>or=3A was added to the MMF trial results, using two mapping scenarios.. The incremental 6-month cost versus azathioprine was euro2535 for everolimus and euro3007 for MMF. The absolute reduction in efficacy failure versus azathioprine was 10.4% for everolimus and 9.8% and 10.1% for MMF, respectively, using scenarios 1 and 2. The incremental cost per efficacy failure avoided (ie, the incremental cost versus azathioprine divided by the reduction in efficacy failure) was euro24,457 for everolimus, and euro30,628 and euro29,912 for MMF in scenarios 1 and 2.. This analysis, based on findings from two clinical trials, suggested that everolimus was more cost-effective than MMF versus azathioprine in the first 6 months after heart transplantation. Data from a head-to-head trial are required to confirm these results.

Topics: Acute Disease; Adult; Azathioprine; Belgium; Cardiomyopathy, Dilated; Coronary Disease; Cost of Illness; Double-Blind Method; Everolimus; Female; Graft Rejection; Heart Transplantation; Hemodynamics; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Survival Analysis; Treatment Failure

Cardiac allograft vasculopathy (CAV) is the major cause of late mortality in heart transplant recipients. Because immunosuppressive therapy has been convincingly shown to suppress cellular rejection and prolong cardiac allograft survival, we assessed the efficacy of advancing immunosuppressive therapy in reversing or delaying CAV by switching azathioprine to combination mycophenolate mofetil and prednisone (MMF-P).. Seventeen adult posttransplant patients, whose CAV was prospectively approached with the MMF-P protocol, were studied. The development of significant CAV was declared on the index coronary angiogram and the MMF-P protocol was instituted. The degree of occlusion for all coronary lesions was quantitated for the index angiogram, and for the angiograms performed 1 year before (baseline) the index angiogram and annually for 2 years after the index angiogram (MMF-P years 1 and 2). There was a significant change in percent occlusion over time (P < .001). Percent occlusion increased significantly from the baseline year to the index CAV year, but then decreased significantly from the index CAV year to the MMF-P treatment years 1 and 2.. Advancing immunosuppression with MMF-P can delay the progression of and partially reverse lumen narrowing of CAV in heart transplant recipients.

Topics: Azathioprine; Coronary Angiography; Coronary Disease; Cyclosporine; Drug Therapy, Combination; Female; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Prospective Studies

Topics: Adrenal Cortex Hormones; Adult; Aged; Azathioprine; Coronary Disease; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Transplantation, Homologous

It is unclear to what extent the "Glagov phenomenon" occurs in transplant coronary artery disease (TCAD). The objective of this study was to evaluate the relationship between intimal hyperplasia and compensatory enlargement in TCAD.. Intravascular ultrasound imaging was performed on 190 cardiac transplant recipients at (1.4 +/- 0.6) months and again (12.1 +/- 0.7) months after cardiac transplantation. Studies 1 year apart were matched at 625 sites. There were 345 coronary artery sites that had an increase in intimal area > 10% from baseline to one year, and this comprised the data set of the present study.. At the first year, 91% of coronary artery sites with intimal growth had a total cross-sectional area stenosis < or = 40%, but 38% of the sites showed a decrease of > 10% in lumen area. Receiver operating characteristic curve demonstrated that the change in cross-sectional area stenosis cut-off level at year 1 was 8% with a sensitivity of 75% and a specificity of 82% in predicting lumen loss. At a total cross-sectional area stenosis of 20%, sensitivity was 65% with a specificity of 81% in predicting lumen loss.. In TCAD, vessel enlargement as a compensatory mechanism for plaque growth is generally inadequate. Instead of continued vessel expansion, luminal narrowing develops when there is more than 8% cross-sectional area filled with intimal hyperplasia. In distinction to native coronary artery atherosclerotic disease, the transition point in transplant vasculopathy where the lumen is diminished by increasing intimal growth, occurs at a lower threshold, 20% vs 40% of vessel cross-sectional area.

Topics: Adult; Aged; Azathioprine; Coronary Disease; Coronary Vessels; Female; Heart Transplantation; Humans; Hyperplasia; Male; Middle Aged; Mycophenolic Acid; Tunica Intima; Ultrasonography, Interventional

The impact of long-term mycophenolate mofetil (MMF) treatment on the development of cardiac allograft vasculopathy (CAV) after heart transplantation is an area of much recent interest. This study analyzed the effects of various immunosuppressive combinations, including cyclosporine (CsA), azathioprine (Aza), tacrolimus (Tac) and MMF, on the time of onset, extent and progression of CAV.. Two hundred seventy-three consecutive heart transplant recipients (mean age: 51.2 +/- 12.2 years; mean follow-up: 6.8 +/- 1.9 years) were examined by coronary angiography on a yearly basis between 1995 and 2003. The extent of CAV was evaluated using a scoring system based on the severity of vessel stenosis. The onset of CAV was analyzed using Kaplan-Meier estimates and the log rank test for four treatment combinations, CsA/Aza (n = 47, 17.2%), CsA/MMF (n = 26, 9.5%), Tac/Aza (n = 62, 22.7%) and Tac/MMF (n = 138, 50.5%), and for the primary and the secondary immunosuppressants alone.. The rate of freedom from CAV at 5 years was 47% with CsA/Aza, 66% with CsA/MMF, 60% with Tac/Aza and 70% with Tac/MMF. After 5 years, the Tac/MMF group showed a significantly lower incidence of CAV than the CsA/Aza group (log rank 7.58, p = 0.0059). CsA (n = 73) was compared with Tac (n = 200) and MMF (n = 164) with Aza (n = 109): the rate of freedom from CAV was 51.2% in CsA patients vs 66.1% in Tac patients (log rank 5.7, p = 0.017), and 54.6% in Aza patients vs 67% in MMF patients (log rank 4.36, p = 0.037). Multivariate Cox regression analysis revealed that MMF decreased the incidence of CAV significantly (p = 0.041). In this patient cohort, Tac or CsA medication was not an independent risk factor for incidence of CAV nor for decreased survival.. The choice of immunosuppression has an impact on the incidence of CAV. In terms of prevention of CAV, MMF is superior to Aza in either combination. A trend toward improved survival in MMF patients was noted. The lower number of rejection episodes in the MMF groups may have contributed to these results.

Topics: Adolescent; Adult; Aged; Azathioprine; Coronary Disease; Disease Progression; Heart Transplantation; Humans; Immunosuppressive Agents; Middle Aged; Mycophenolic Acid; Retrospective Studies; Survival Analysis

A large Phase III clinical trial with the novel proliferation signal inhibitor, Certican (everolimus), has shown this agent to be associated with lower rates of acute rejection, cardiac allograft vasculopathy (CAV) and cytomegalovirus (CMV) infection when compared with azathioprine (AZA) at 12 months post-transplant. Given that CAV is the main risk factor for mortality after the first year post-transplant, and that acute rejection and CMV infection play a key role in the development of this disease, the findings suggest that everolimus has an important role as part of the primary immunosuppression of this population. Consideration of the presentation and outcome of patients from Stanford University who were enrolled in the pivotal trial with everolimus in heart transplantation has highlighted the efficacy of everolimus in this setting. Analysis of the angiographic outcome data of these patients demonstrates that the efficacy of everolimus observed in the large, multicenter trial involving heart transplant patients was replicated in the findings of a single center. This finding is important for the interpretation of clinical trial data, offering reassurance that data from large trials are applicable to an individual center. The results from Stanford also reveal an important difference between everolimus and AZA with regard to intimal thickening and the incidence of abnormal left ventricular ejection fraction (LVEF), suggesting that everolimus may improve left ventricular function. Because abnormal LVEF has been associated with greater risk of vascular rejection and allograft vascular disease, use of everolimus could well improve long-term outcomes in heart transplant recipients.

Topics: Adult; Angioplasty, Balloon, Coronary; Azathioprine; Clinical Trials, Phase III as Topic; Coronary Disease; Coronary Vessels; Everolimus; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Transplantation, Homologous; Tunica Intima; Ultrasonography, Interventional

In end-stage cardiomyopathy where concomitant chronic renal failure is a contraindication for cardiac transplantation (HTx), simultaneous heart and kidney transplantation (HKTx) may be the only feasible therapeutic option. Due to the increased donor shortage, the clinical outcome of combined HKTx patients on tacrolimus-based immunosuppression was assessed and compared with a group of HTx patients.. Three hundred forty-nine HTxs, including 13 (4%) combined HKTxs, were performed since 1995. Two hundred twenty-one HTx and all HKTx recipients received tacrolimus-based immunosuppression. Acute rejection episodes (AREs), infections, renal function and clinical outcome were evaluated. Pre-operative renal diagnoses for HKTx patients included cystic nephropathy (n = 4), glomerulonephritis (n = 4), cytostatica-induced nephropathy (n = 1), chronic rejection after renal transplant (n = 1), reflux nephropathy (n = 2) and chronic calcineurin-inhibitor -induced nephropathy after HTx (n = 1). Twelve patients (92%) were on hemodialysis pre-operatively, 1 underwent implantation of a left ventricular assist device (LVAD) before HKTx.. After 4.7 +/- 2 years, 92% of HKTx compared with 85% of HTx patients had survived (p = 0.42). Acute cardiac rejection episodes were more frequent in HTx than in HKTx patients (0.04 +/- 0.09 vs 0.02 +/- 0.04 ARE/100 patient-days; p = 0.07). Incidence of infection was comparable (0.3 +/- 0.2 vs 0.5 +/- 0.4 infection/100 patient-days). Freedom from transplant vasculopathy was 100% in the HKTx group compared with 71% in the HTx group after 4 years (p = 0.04).. Tacrolimus-based immunosuppression yields promising long-term results in HKTx and HTx. The incidence of transplant vasculopathy seems to be lower after HKTx than after HTx. If these results are secondary to a protective effect of tacrolimus-induced tolerance or of tolerance-associated co-transplantation they will need to be investigated in prospective multicenter trials.

Topics: Cardiomyopathy, Dilated; Comorbidity; Coronary Disease; Creatinine; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Azathioprine; Cardiomyopathy, Dilated; Coronary Disease; Cyclosporine; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Retrospective Studies

Topics: Animals; Coronary Disease; Graft Survival; Heart Transplantation; Immunosuppressive Agents; Isoantigens; Macaca fascicularis; Male; Mycophenolic Acid; Rats; Rats, Inbred Lew