mycophenolic-acid and Heart-Failure

Over the last 4 decades, cardiac transplantation has become the preferred therapy for select patients with end-stage heart disease. Heart transplantation is indicated in patients with heart failure despite optimal medical and device therapy, manifesting as intractable angina, refractory heart failure, or intractable ventricular arrhythmias. This article provides an overview of heart transplantation in the current era, focusing on the evaluation process for heart transplantation, the physiology of the transplanted heart, immunosuppressive regimens, and early and long-term complications.

Topics: Allografts; Azathioprine; Cardiotonic Agents; Contraindications; Graft Occlusion, Vascular; Graft Rejection; Heart; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Long-Term Care; Mycophenolic Acid; Neoplasms; Opportunistic Infections; Postoperative Care; Steroids

With an increasing number of heart transplants being performed around the world and the improvement in survival rates, more transplant recipients may present to the emergency department with comorbidities unique to the transplanted heart and related immunosuppression, including heart failure. This article is aimed at enabling the emergency department physician identify and better manage this unique group of patients for whom time is life.

Topics: Arrhythmias, Cardiac; Contraindications; Coronary Artery Disease; Diagnosis, Differential; Dyspnea; Electrocardiography; Emergency Service, Hospital; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Myocardium; Natriuretic Peptides; Postoperative Complications; Transplantation, Homologous; Ventricular Dysfunction, Left

Heart transplantation remains the best therapeutic option for the treatment of end-stage heart failure. However, good survival rates can be obtained only if patients are closely monitored, particularly for their immunosuppressive regimens. Currently, a triple-drug regimen usually based on calcineurin-inhibitors (cyclosporin A or tacrolimus), anti-proliferative agents and steroids is used in most recipients. New agents such as the mTOR inhibitors, a more recently developed class of immunosuppressive drugs, can also be used in some patients. The aim of this article is to review currently used immunosuppressive regimens after heart transplantation, and to propose some individualized options depending on specific patient characteristics and recent pharmacological developments in the field.

Topics: Chronic Disease; Clinical Trials as Topic; Cyclosporine; Drug Therapy, Combination; Glucocorticoids; Graft Rejection; Graft Survival; Heart Failure; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Meta-Analysis as Topic; Monitoring, Immunologic; Mycophenolic Acid; Protein Kinases; Randomized Controlled Trials as Topic; Sirolimus; Survival Analysis; T-Lymphocytes; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Pediatric heart transplantation is a surgical therapy for dilated cardiomyopathy and for complex congenital heart defects with low pulmonary artery resistance. However, it is still discussed as controversial because of uncertain long-term results. We report our experience with pediatric heart transplantation in a heterogeneous population.. Since 1988, 50 heart transplants were performed in 47 patients (30 with dilated cardiomyopathy, 17 with congenital heart disease). Mean age was 9.4 +/- 6.9 years (range, 4 days to 17.9 years). Twenty-three patients had a total of 36 previous operations. Clinical outcome was evaluated retrospectively.. Perioperative mortality was 6% due to primary graft failure. Late mortality (12%) was caused by acute rejection (n = 2), pneumonia (n = 2), intracranial hemorrhage (n = 1), and suicide (n = 1). Mean follow-up was 5.24 +/- 3.6 years. Actuarial 1, 5, and 10 year survival was 86%, 86%, and 80% and improved significantly after 1995 (92% [1 year]; 92% [5 years]). There was no significant difference between patients with dilated or congenital heart disease (1 year: 86% vs 82%; 5 years: 83% vs 74%; 10 years 83% vs 74%; p = 0.62). Three patients with therapy resistant acute or chronic rejection and assisted circulation underwent retransplantation and are alive. Freedom from acute rejection after 5 years was 40% with primary cyclosporine immunosuppression regime and 56% with tacrolimus. Since the introduction of mycophenolate mofetil, freedom from acute rejection increased to 62%. All survivors are at home and in good cardiac condition.. Pediatric heart transplantation is the treatment of choice for end-stage dilated cardiomyopathy as for congenital heart disease with excellent clinical midterm results. It is a valid alternative to reconstructive surgery in borderline patients. However, further follow-up is necessary to evaluate the long-term side effects of immunosuppressants.

Topics: Adolescent; Antiviral Agents; Bacterial Infections; Cardiomyopathy, Dilated; Child; Child, Preschool; Cyclosporine; Cytomegalovirus Infections; Extracorporeal Membrane Oxygenation; Female; Follow-Up Studies; Ganciclovir; Germany; Graft Rejection; Heart Defects, Congenital; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Immunosuppressive Agents; Life Tables; Lymphoma, Non-Hodgkin; Male; Mycophenolic Acid; Pneumonia, Pneumocystis; Postoperative Complications; Reoperation; Retrospective Studies; Survival Analysis; Survival Rate; Tacrolimus; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Vascular Resistance; Virus Diseases

In a randomized, open-label trial, everolimus was compared to cyclosporine in 115 de novo heart transplant recipients. Patients were assigned within 5 days posttransplant to low-exposure everolimus (3–6 ng/mL) with reduced-exposure cyclosporine (n = 56), or standard-exposure cyclosporine (n = 59), with both mycophenolate mofetil and corticosteroids. In the everolimus group, cyclosporine was withdrawn after 7–11 weeks and everolimus exposure increased (6–10 ng/mL). The primary efficacy end point, measured GFR at 12 months posttransplant, was significantly higher with everolimus versus cyclosporine (mean ± SD: 79.8 ± 17.7 mL/min/1.73 m2 vs. 61.5 ± 19.6 mL/min/1.73 m2; p < 0.001). Coronary intravascular ultrasound showed that the mean increase in maximal intimal thickness was smaller (0.03 mm [95% CI 0.01, 0.05 mm] vs. 0.08 mm [95% CI 0.05, 0.12 mm], p = 0.03), and the incidence of cardiac allograft vasculopathy (CAV) was lower (50.0% vs. 64.6%, p = 0.003), with everolimus versus cyclosporine at month 12. Biopsy-proven acute rejection after weeks 7–11 was more frequent with everolimus (p = 0.03). Left ventricular function was not inferior with everolimus versus cyclosporine. Cytomegalovirus infection was less common with everolimus (5.4% vs. 30.5%, p < 0.001); the incidence of bacterial infection was similar. In conclusion, everolimus-based immunosuppression with early elimination of cyclosporine markedly improved renal function after heart transplantation. Since postoperative safety was not jeopardized and development of CAV was attenuated, this strategy may benefit long-term outcome.

Topics: Adrenal Cortex Hormones; Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Drug Administration Schedule; Everolimus; Female; Glomerular Filtration Rate; Graft Rejection; Heart Failure; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Sirolimus; TOR Serine-Threonine Kinases; Ventricular Function, Left

Despite improvements in immunosuppressive therapy, chronic rejection, renal toxicity and malignancy are the major obstacles for long-term success after heart transplantation. We performed the worldwide first pilot-trial to evaluate the efficacy and safety of a de-novo calcineurin-inhibitor (CNI)-free immunosuppressive protocol. Between May 2003 and April 2005, 15 de-novo cardiac transplant recipients were assigned to receive sirolimus, mycophenolate mofetil and steroids. Antilymphocyte induction was given for 5 days; steroids were withdrawn after 6 months. A total of six of 15 patients received cytomegalovirus (CMV)-prophylaxis for high-risk CMV constellation (R-/D+).. Survival at 1 and 5 years was 87.5%. Freedom from biopsy-proven rejection was 71.3% at 1 year and 59.4% at 5 years. Freedom from angiographically detectable vasculopathy was 100% after 5 years and only one CMV infection occurred. Mean serum creatinine was 1.43 ± 0.31 mg/dl prior to heart transplantation (HTx), 1.29 ± 0.56 mg/dl at 1 year and 1.23 ± 0.53 mg/dl at 5 years. Cholesterol was 203 ± 32 mg/dl at 1 year and 199 ± 40 mg/dl at 5 years despite statins, and hypertriglyceridaemia (223 ± 97 mg/dl) persisted after 5 years. No new-onset diabetes occurred. Surgical interventions for pericardial effusions were necessary in five patients. Nine patients discontinued sirolimus treatment temporarily because of side-effects (four acute rejections, three delayed wound healing and two gastrointestinal toxicity), all nine patients were reintroduced to sirolimus after the side-effects resolved.. CNI-free immunosuppression is possible and long-term results are favourable for survival, malignancy, renal function, CMV infections and vasculopathy. On the other hand, de-novo CNI-free immunosuppression after HTx is less efficacious in preventing acute rejection and has an inferior side-effect profile.

Topics: Calcineurin; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Heart Failure; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Retrospective Studies; Sirolimus; Time Factors; Treatment Outcome

SLE patients have elevated cardiovascular disease (CVD) risk, but it is unclear whether this risk is affected by choice of immunosuppressive drug. We compared CVD risks among SLE patients starting MMF, CYC or AZA.. Using Medicaid Analytic eXtract (2000-2012), adult SLE patients starting MMF, CYC or AZA were identified and propensity scores (PS) were estimated for receipt of MMF vs CYC and MMF vs AZA. We examined rates of first CVD event (primary outcome), all-cause mortality, and a composite of first CVD event and all-cause mortality (secondary outcomes). After 1:1 PS-matching, Fine-Gray regression models estimated subdistribution hazard ratios (HRs.d.) for risk of CVD events. Cox regression models estimated HRs for all-cause mortality. The primary analysis was as-treated; 6- and 12-month intention-to-treat (ITT) analyses were secondary.. We studied 680 PS-matched pairs of patients with SLE initiating MMF vs CYC and 1871 pairs initiating MMF vs AZA. Risk of first CVD event was non-significantly reduced for MMF vs CYC [HRs.d 0.72 (95% CI: 0.37, 1.39)] and for MMF vs AZA [HRs.d 0.88 (95% CI: 0.59, 1.32)] groups. In the 12-month ITT, first CVD event risk was lower among MMF than AZA new users [HRs.d 0.68 (95% CI: 0.47, 0.98)].. In this head-to-head PS-matched analysis, CVD event risks among SLE patients starting MMF vs CYC or AZA were not statistically reduced except in one 12-month ITT analysis of MMF vs AZA, suggesting longer-term use may convey benefit. Further studies of potential cardioprotective benefit of MMF are necessary.

Topics: Adult; Azathioprine; Cardiovascular Diseases; Cause of Death; Coronary Artery Bypass; Cyclophosphamide; Female; Heart Disease Risk Factors; Heart Failure; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Mortality; Mycophenolic Acid; Myocardial Infarction; Percutaneous Coronary Intervention; Propensity Score; Proportional Hazards Models; Protective Factors; Risk Factors; Stroke; Young Adult

Cardiac sarcoidosis (CS) is a major cause of morbidity and mortality in patients with systemic sarcoidosis. Steroid-sparing agents are increasingly used, despite a lack of randomized trials or published guidelines to direct treatment.. This retrospective study included 77 patients with CS treated with prednisone monotherapy (n = 32) or a combination with mycophenolate mofetil (n = 45) between 2003 and 2018. Baseline characteristics and clinical outcomes were evaluated. The mean patient age was 53 ± 11 years at CS diagnosis, 66.2% were male, and 35.1% were Black. The total exposure to maximum prednisone dose (initial prednisone dose × days at dose) was lower in the combination therapy group (1440 mg [interquartile range (IQR), 1200-2760 mg] vs 2710 mg [IQR, 1200-5080 mg]; P = .06). On. Mycophenolate mofetil in combination with prednisone for the treatment of CS may minimize corticosteroid exposure and decrease cardiac inflammation without significant adverse effects.

Topics: Adult; Heart Failure; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prednisone; Retrospective Studies; Sarcoidosis

Simultaneous heart and kidney transplantation (SHKT) has become an accepted therapeutic option for patients with end-stage heart failure associated with end-stage renal disease. The immunosuppressive therapy is usually based upon a heart transplantation protocol using a calcineurin inhibitor (CNI). Sirolimus (SRL) is a potent nonnephrotoxic immunosuppressant with antiproliferative activity in nonimmune cells. Its use has recently been reported to show less nephrotoxicity among both heart and kidney transplants. However, the data for the SHKT are limited. We retrospectively examined the causes of 5 patients who received combined SRL-CNI immunosuppressive therapy with reduced CNI doses from 2003 to 2009. There was no mortality during follow-up. Two of the 3 patients who received a conversion regimen recovered renal function. One who suffered severe proteinuria after transplantation proceeded to hemodialysis at 3 years after conversion. Both of the patients who received the combined regimen de novo remained stable regarding their renal function. Cardiac function was stable in these patients; there was neither allograft rejection nor allograft coronary vasculopathy. We observed that patients without dyslipidemia or hyperuricemia before SHKT were less likely to develop these disorders under the combined regimen. Early medical intervention after close follow-up of lipid and uric acid values by dose adjustments resulted in a stable status of our patients.

Topics: Adolescent; Antilymphocyte Serum; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Female; Heart Failure; Heart Transplantation; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Retrospective Studies; Sirolimus; Tacrolimus; Young Adult

Topics: Abnormalities, Drug-Induced; Adult; Craniofacial Abnormalities; Female; Fetus; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Maternal Exposure; Mycophenolic Acid; Pregnancy

There are no guidelines to establish the indications and contraindications for a simultaneous heart and kidney transplantation. We report our single-institutional experience with simultaneous heart and kidney transplantation.. Retrospective chart review.. Between 1995 and 2006, 13 patients with co-existing end-stage heart and renal failure underwent simultaneous heart and kidney transplantation at the authors' hospital. Heart failure was secondary to dilated cardiomyopathy in five patients, ischemic cardiomyopathy in three, cardiac allograft vasculopathy in two, and congenital heart disease, cardiac allograft failure, and acute myocarditis each in one. Renal failure was secondary to glomerulonephritis in six patients, heart failure in two, cyclosporine nephropathy in three, hypertension in one, and systemic lupus erythematosus in one. Eight patients were in UNOS status IA and five patients in UNOS status II before transplantation. The 30-day mortality rate and in-hospital mortality rate were 15% and 38%. Of eight patients in UNOS status IA, seven patients have lived beyond 30 days and three (38%) beyond 1 year. Of five patients in UNOS status II, four patients have lived beyond 30 days and four (80%) beyond 1 year. Patients in UNOS status IA had high rates of previous cardiac surgery, cardiac allograft rejection, and major renal allograft complications.. Although simultaneous heart and kidney transplantation continues to be a viable option for patients with co-existing end-stage heart and renal failure, the results do not match those of isolated heart transplantation. The clinical outcomes were not satisfactory in UNOS status IA patients with previous cardiac surgery.

Topics: Adolescent; Adult; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Renal Insufficiency; Retrospective Studies; Survival Rate; Transplantation, Homologous

Anaemia is common following renal transplantation and is associated with the development of congestive heart failure (CHF). However the prevalence of anaemia in the first year following transplantation and the association between anaemia occurring early and the development of CHF have been understudied.. In this study, 132 incident patients undergoing tacrolimus and mycophenolate mofetil-based renal transplantation were studied for the prevalence of, and risk factors for, anaemia and CHF in the early period post transplantation.. Anaemia occurred in 94.5% and 53.1% of patients at 1 week and 12 months, respectively, and was associated with allograft dysfunction, hypoalbuminaemia, higher mycophenolic acid (MPA) levels, bacterial infection and hypoalbuminaemia. The association with hypoalbuminaemia may reflect the presence of chronic inflammation post-transplantation. Of patients displaying haemoglobin <11 g/dl, 41.1% and 29.4% were treated with erythropoiesis stimulating agents (ESAs) at 1 and 12 months respectively. CHF developed in 26 patients beyond 1 month post-transplantation, with echocardiographic left ventricular systolic function preserved in all but one. CHF was associated with anaemia and lower haemoglobin, allograft dysfunction, duration of dialysis and left ventricular hypertrophy on echocardiography prior to transplantation, suggesting the aetiology of CHF may involve the interplay of diastolic cardiac dysfunction, pre-load mismatch and after-load mismatch.. Modification of risk factors may improve anaemia management post transplantation. Reducing the prevalence of anaemia may in turn reduce the incidence of CHF-these observations support the need for clinical trials to determine how anaemia management may impact CHF incidence.

Topics: Adult; Anemia; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Hypoalbuminemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recombinant Proteins; Risk Factors; Tacrolimus; Time Factors

A 65-year-old male was admitted to our hospital for surgical treatment of congestive heart failure with aortic regurgitation. He had received renal transplantation 15 years before in the United States, and had been under immunosuppressive regimen with ciclosporin and mycophenolate mofetil. Although the renal allograft function had been gradually deteriorating, and preoperative serum creatinine level was 1.8 mg/dl, and it decreased to 1.5 mg/dl after aortic valve replacement. Cryopreserved aortic allograft was needed for the aortic valve replacement. The reasons are; the patient may need hemodialysis (HD) or retransplantation of the kidney in the future, and the immunosuppressive therapy for kidney will provide good immunologic environment for second allograft, i.e.--aortic valve. He tolerated the operation well and the immunosuppressive agents were continued in the perioperative period. He is now in New York Heart Association (NYHA) class I.

Topics: Aged; Aortic Valve; Aortic Valve Insufficiency; Cyclosporine; Heart Failure; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Mycophenolic Acid; Time Factors; Transplantation, Homologous

"Panel Reactive Antibody" (PRA) testing is commonly used to assess the pretransplant antibody status in order to estimate the risk of an adverse humoral response following transplantation. We report on a female patient with end-stage cardiac failure suffering from acute myocarditis who underwent implantation of a left-ventricular assist device (Novacor, Baxter Healthcare Corp. Oakland, CA). During evaluation for heart transplantation, a PRA level of 50-70% was detected. After treatment with mycophenolate mofetil at a dosage of 2 g daily, PRA levels declined within one week to 0-5%, and remained low after discontinuation of the immunosuppressive drug. We feel that pretreatment of patients with elevated PRA levels with mycophenolate mofetil is well justified.

Topics: Acute Disease; Adult; Antibodies, Monoclonal; Antibody Formation; Anticoagulants; Female; Follow-Up Studies; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Immunosuppressive Agents; Mycophenolic Acid; Myocarditis; Preoperative Care; Thrombophlebitis