A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus

doi:10.1016/S1053-2498(98)00060-6

The Journal of Heart and Lung Transplantation

Volume 18, Issue 4, April 1999, Pages 336-345

Presented in part at the Annual Scientific Sessions of the International Society for Heart and Lung Transplantation, March 1997, London, UK.

https://doi.org/10.1016/S1053-2498(98)00060-6 Get rights and content

Abstract

Background

Tacrolimus-based immunosuppression seems safe and effective in liver and kidney transplantation. To assess the safety and efficacy of tacrolimus (TAC)-based immunosuppression after cardiac transplantation as well as the relative impact of tacrolimus on immunosuppression-related side effects such as hypertension and hyperlipidemia, we conducted a prospective, randomized, open-label, multicenter study of otherwise identical tacrolimus- and cyclosporine-based immunosuppressive regimens in adult patients undergoing cardiac transplantation.

Methods

Eighty-five adult patients (pts) at six United States cardiac transplant centers, undergoing their first cardiac transplant procedure, were prospectively randomized to receive either TAC-based (n = 39) or cyclosporine (CYA)-based (n = 46) immunosuppression. All pts received a triple-drug protocol with 15 pts (18%) receiving peri-operative OKT3 to delay TAC/CYA due to pre-transplant renal dysfunction. Endomyocardial biopsies were performed at Weeks 1, 2, 3, 4, 6, 8, 10, 12, 24, and 52. The study duration was 12 months.

Results

Patients were mostly male (87%) Caucasian (90%) with a mean age of 54 years and primary diagnoses of coronary artery disease (55%) and idiopathic dilated cardiomyopathy (41%). There were no significant demographic differences between groups. Patient and allograft survival were not different in the two groups. The probability and overall incidence of each grade of rejection, whether treated or not, and the types of treatment required did not differ between the groups. At baseline and through 12 months of follow-up, chemistry and hematology values were similar between the groups except serum cholesterol was higher in the CYA group at 3, 6, and 12 months (239 vs 205 mg/dL, 246 vs 191 mg/dL, 212 vs 186 mg/dL, respectively, p < 0.001). Likewise, LDL-cholesterol, HDL-cholesterol and triglycerides were significantly higher in the CYA group. More CYA patients received therapy for hypercholesterolemia (71% vs 41% at 12 months, p = 0.01). There were no significant differences in renal function, hyperglycemia, hypomagnesemia, or hyperkalemia during the first 12 months. More CYA patients developed new-onset hypertension requiring pharmacologic treatment (71% vs 48%, p = 0.05). The incidence of infection was the same for the two groups (2.6 episodes/pt/12 month follow-up).

Conclusion

Tacrolimus-based immunosuppression seems effective for rejection prophylaxis during the first year after cardiac transplantation and is associated with less hypertension and hyperlipidemia and no difference in renal function, hyperglycemia or infection incidence when compared to cyclosporine-based immunosuppression.

Section snippets

Study design

This study is a prospective, randomized, comparative, open-labeled multicenter trial of immunosuppressive therapy in patients undergoing cardiac transplantation. Patients received either tacrolimus or cyclosporine in addition to azathioprine and corticosteroids.

Study population

Eighty-eight patients undergoing primary orthotopic cardiac transplantation at six transplant centers were randomized into this 12-month study. Patients were excluded for the after: age less than 18 years, multiorgan or prior organ

Results

Of 85 patients, 39 were randomized to receive tacrolimus and 46 were randomized to receive cyclosporine. As shown in Table I , the groups were comparable. No significant baseline differences were observed in gender, age, etiology of heart disease, perioperative OKT3 use, panel reactive antibody (PRA), donor heart ischemic time or histocompatibility. A trend toward a higher proportion of UNOS status 1 patients being in the tacrolimus group was observed (p = 0.056). The doses of tacrolimus and

Discussion

Tacrolimus was first introduced into solid organ transplantation by Dr. Starzl and colleagues at the University of Pittsburgh in February 1989.2 The early single-center results in liver,2, 3, 4 heart8, 9 and kidney16 transplantation were encouraging, leading to multicenter, comparative trials in liver, renal, and heart transplantation.

Conclusion

Tacrolimus-based immunosuppression is effective and safe after cardiac transplantation. Additionally, in this prospectively, randomized trial, tacrolimus seems to be comparable to cyclosporine-based immunosuppression regarding cardiac allograft rejection prophylaxis. Tacrolimus use is associated with significantly less hyperlipidemia and systemic hypertension and enables decreased concomitant drug administration. The long-term impact of decreased propensities towards hyperlipidemia and

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Liver transplantation has led to great improvements in long-term survival in patients with decompensated liver disease and hepatocellular carcinoma. Cardiovascular disease is the leading cause of non-graft-related deaths and has increased prevalence in liver allograft recipients. This is partly secondary to higher post-transplant rates of metabolic risk factors—notably obesity, hypertension, dyslipidemia, and diabetes mellitus, which comprise metabolic syndrome. Post-transplantation metabolic syndrome is expected to be a growing factor in morbidity and mortality as transplant candidates trend older, the rates of metabolic risk factors in the general population increase, non-alcoholic steatohepatitis grows disproportionally as an indication for transplantation, and post-transplantation survival lengthens.
This review discusses the incidence and contributory factors for post-transplant increases in metabolic disease, as well as the burden of cardiovascular disease in the liver allograft recipient. Patients with pre-transplant diabetes or obesity are at particularly high risk for post-transplant metabolic syndrome, and would likely benefit from closer surveillance and more aggressive medical management of risk factors. In metabolic disease resistant to initial medical therapies, tailoring of immunosuppressive regimens may further assist in minimizing long-term cardiovascular disease, although this must be done with caution to avoid worsening the risk of graft failure.
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Compared to tacrolimus, cyclosporine increases cardiovascular risk. Furthermore, tacrolimus has a negative effect on glucose metabolism compared to cyclosporine. This study investigated the effect of the conversion from cyclosporine to tacrolimus for immunosuppressive therapy on glucose metabolism and cardiovascular risk profiles in long-term stable kidney transplant recipients (KTRs).
In this prospective, open-label, single-arm study, 36 KTRs were enrolled; 3 were excluded. Patients were evaluated for glucose metabolism and cardiovascular risk factors at baseline, 3, and 6 months after conversion of medication. Serial changes were analyzed by repeated analysis of variance.
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Citation Excerpt :
However, in one study, this effect was not seen when tacrolimus and sirolimus were coprescribed.42 Although tacrolimus produces effects on lipoprotein metabolism comparable to those of cyclosporine, the resulting dyslipidemia is less pronounced with peak increases in TC 7% to 30%, LDL-C 3% to 40%, triglycerides 5% to 44%, and HDL-C 12% to 34%.24,26,28–30,33,38,43 This was further highlighted in direct comparator studies evaluating cyclosporine vs tacrolimus, revealing a 14% to 30% and 15% to 46% greater mean TC and LDL-C, respectively, and a 5% lower to 21% higher mean triglyceride values with cyclosporine compared to tacrolimus, despite higher lipid-lowering drug use in the cyclosporine arm.33,44–50
Solid organ transplantation (SOT) has revolutionized treatment of end-stage disease. Improvements in the SOT continuum of care have unmasked a significant burden of cardiovascular disease, manifesting as a leading cause of morbidity and mortality. Although several risk factors for development of post-transplant cardiovascular disease exist, dyslipidemia remains one of the most frequent and modifiable risks. An important contributor to dyslipidemia in SOT recipients is the off-target metabolic effects of immunosuppressive medications, which may alter lipoproteins and their metabolism. Dyslipidemia management is paramount as lipid-lowering therapy with statins has demonstrated reductions in graft vasculopathy, decreased rejection rates, and improved survival. Several nonstatin medication options are available, but data supporting their benefit in the SOT population are minimal, typically extrapolated from studies in the general population. Further compounding dyslipidemia management is the complex interplay of drug interactions between lipid-lowering and immunosuppressant medications, which can result in serious toxicity and/or therapeutic failure.
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¹: This study was sponsored by a grant from Fujisawa USA, Deerfield, Illinois.

²: The authors were working on behalf of the Tacrolimus US Heart Transplant Multicenter Study Group. Other members of the Study Group included (principal investigator listed first): UTAH Cardiac Transplant Program, Salt Lake City, Utah: David O. Taylor, MD, Dale G. Renlund, MD, Abdallah G. Kfoury, MD; St. Luke’s Episcopal Hospital/Texas Heart Institute, Houston, Texas: O. H. Frazier, MD, Branislav Radovancevic, MD, Edward K. Massin, MD; University of Wisconsin Hospitals and Clinics, Madison, Wisconsin: Robert M. Mentzer, Jr., MD, Charles C. Canver, MD, Robert B. Love, MD; Ochsner Medical Foundation, New Orleans, Louisiana: Frank W. Smart, MD, Hector O. Ventura, MD, Dwight D. Stapleton, MD, Mandeep Mehra, MD; University of Southern California, Los Angeles, California: Mark L. Barr, MD, Vaugh A. Starnes, MD; Medical College of Virginia, Richmond, Virginia: David E. Tolman, MD, Albert Guerraty, MD, David Salter, MD; Cleveland Clinic Foundation, Cleveland, Ohio: James B. Young, MD; Data Management and Statistical Coordinating Center-The EMMES Corporation, Potomac, Maryland: Paul VanVeldhuisen, MS, Anne Lindblad, PhD, Anita Yaffe, MSN, MPH.

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Immunosuppression<195>Clinical and Animal StudiesA randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus12

Abstract

Background

Methods

Results

Conclusion

Section snippets

Study design

Study population

Results

Discussion

Conclusion

Lancet

Ann Thorac Surg

J Thorac Cardiovasc Surg

Liver Transplant Surg

The Registry of the International Society for Heart and Lung TransplantationFourteenth official report-1997

J Heart Lung Transplant

Conversion from cyclosporine to FK 506 in liver allograft recipients with cyclosporine-related complications

Transplant Proc

Early trials with FK506 as primary treatment in liver transplantation

Transplant Proc

A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation

N Engl J Med

Randomized trial comparing tacrolimus (FK506) and cyclosporin in the prevention of liver allograft rejection

Lancet

A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation

Transplantation

Immunosuppression<195>Clinical and Animal Studies
A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus1 2