Cardiovascular Outcomes in De Novo Kidney Transplant Recipients Receiving Everolimus and Reduced Calcineurin Inhibitor or Standard Triple Therapy: 24-month Post Hoc Analysis From TRANSFORM Study.
Journal
Transplantation
ISSN: 1534-6080
Titre abrégé: Transplantation
Pays: United States
ID NLM: 0132144
Informations de publication
Date de publication:
01 07 2023
01 07 2023
Historique:
medline:
23
6
2023
pubmed:
25
3
2023
entrez:
24
3
2023
Statut:
ppublish
Résumé
The comparative impact of everolimus (EVR)-based regimens versus standard of care (mycophenolic acid+standard calcineurin inhibitor [MPA+sCNI]) on cardiovascular outcomes in de novo kidney transplant recipients (KTRs) is poorly understood. The incidence of major adverse cardiac events (MACEs) in KTRs receiving EVR+reduced CNI (rCNI) or MPA+sCNI from the TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen study was evaluated. The incidence of MACE was determined for all randomized patients receiving at least 1 dose of the study drug. Factors associated with MACEs were determined by logistic regression. Risk of MACE out to 3 y post-study was calculated using the Patient Outcome in Renal Transplantation equation. MACE occurred in 81 of 1014 (8.0%; EVR+rCNI) versus 89 of 1012 (8.8%; MPA+sCNI) KTRs (risk ratio, 0.91 [95% confidence interval [CI], 0.68-1.21]). The incidence of circulatory death, myocardial infarction, revascularization, or angina was similar between the arms. Incidence of MACE was similar between EVR+rCNI and MPA+sCNI arms with a higher incidence in prespecified risk groups: older age, pretransplant diabetes (15.1% versus 15.9%), statin use (8.5% versus 10.8%), and low estimated glomerular filtration rate (Month 2 estimated glomerular filtration rate <30 versus >60 mL/min/1.73 m 2 ; odds ratio, 2.23 [95% CI, 1.02-4.86]; P = 0.044), respectively. Predicted risk of MACE within 3 y of follow-up did not differ between the treatment arms. Cardiovascular morbidity and mortality were similar between de novo KTRs receiving EVR+rCNI and MPA+sCNI. EVR+rCNI is a viable alternative to the current standard of care in KTRs.
Sections du résumé
BACKGROUND
The comparative impact of everolimus (EVR)-based regimens versus standard of care (mycophenolic acid+standard calcineurin inhibitor [MPA+sCNI]) on cardiovascular outcomes in de novo kidney transplant recipients (KTRs) is poorly understood. The incidence of major adverse cardiac events (MACEs) in KTRs receiving EVR+reduced CNI (rCNI) or MPA+sCNI from the TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen study was evaluated.
METHODS
The incidence of MACE was determined for all randomized patients receiving at least 1 dose of the study drug. Factors associated with MACEs were determined by logistic regression. Risk of MACE out to 3 y post-study was calculated using the Patient Outcome in Renal Transplantation equation.
RESULTS
MACE occurred in 81 of 1014 (8.0%; EVR+rCNI) versus 89 of 1012 (8.8%; MPA+sCNI) KTRs (risk ratio, 0.91 [95% confidence interval [CI], 0.68-1.21]). The incidence of circulatory death, myocardial infarction, revascularization, or angina was similar between the arms. Incidence of MACE was similar between EVR+rCNI and MPA+sCNI arms with a higher incidence in prespecified risk groups: older age, pretransplant diabetes (15.1% versus 15.9%), statin use (8.5% versus 10.8%), and low estimated glomerular filtration rate (Month 2 estimated glomerular filtration rate <30 versus >60 mL/min/1.73 m 2 ; odds ratio, 2.23 [95% CI, 1.02-4.86]; P = 0.044), respectively. Predicted risk of MACE within 3 y of follow-up did not differ between the treatment arms.
CONCLUSIONS
Cardiovascular morbidity and mortality were similar between de novo KTRs receiving EVR+rCNI and MPA+sCNI. EVR+rCNI is a viable alternative to the current standard of care in KTRs.
Identifiants
pubmed: 36959121
doi: 10.1097/TP.0000000000004555
pii: 00007890-202307000-00025
doi:
Substances chimiques
Everolimus
9HW64Q8G6G
Calcineurin Inhibitors
0
Immunosuppressive Agents
0
Mycophenolic Acid
HU9DX48N0T
Tacrolimus
WM0HAQ4WNM
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1593-1604Informations de copyright
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
Déclaration de conflit d'intérêts
C.S. declares no personal conflicts; the hospital received patients' fees and research grants from Novartis. F.C. received consulting honoraria and travel grants from Novartis. J.H. is an employee of Novartis Pharmaceuticals. A.G. is an employee of Novartis Healthcare Pvt. Ltd. P.B. is an employee of Novartis Pharma AG. S.C. received funding from Novartis, Astra Zeneca, Bayer, and CSL for research, travel, or speakers’ honoraria. The other authors declare no conflicts of interest.
Références
Rao NN, Coates PT. Cardiovascular disease after kidney transplant. Semin Nephrol. 2018;38:291–297.
Ying T, Shi B, Kelly PJ, et al. Death after kidney transplantation: an analysis by era and time post-transplant. J Am Soc Nephrol. 2020;31:2887–2899.
Jardine AG, Gaston RS, Fellstrom BC, et al. Prevention of cardiovascular disease in adult recipients of kidney transplants. Lancet. 2011;378:1419–1427.
Wyld MLR, De La Mata NL, Masson P, et al. Cardiac mortality in kidney transplant patients: a population-based cohort study 1988-2013 in Australia and New Zealand. Transplantation. 2021;105:413–422.
Porrini E, Diaz JM, Moreso F, et al. Prediabetes is a risk factor for cardiovascular disease following renal transplantation. Kidney Int. 2019;96:1374–1380.
Devine PA, Courtney AE, Maxwell AP. Cardiovascular risk in renal transplant recipients. J Nephrol. 2019;32:389–399.
Meier-Kriesche HU, Baliga R, Kaplan B. Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation. Transplantation. 2003;75:1291–1295.
Weiner DE, Carpenter MA, Levey AS, et al. Kidney function and risk of cardiovascular disease and mortality in kidney transplant recipients: the FAVORIT trial. Am J Transplant. 2012;12:2437–2445.
Miller LW. Cardiovascular toxicities of immunosuppressive agents. Am J Transplant. 2002;2:807–818.
Chakkera HA, Mandarino LJ. Calcineurin inhibition and new-onset diabetes mellitus after transplantation. Transplantation. 2013;95:647–652.
Shihab FS, Cibrik D, Chan L, et al. Association of clinical events with everolimus exposure in kidney transplant patients receiving reduced cyclosporine. Clin Transplant. 2013;27:217–226.
Shihab F, Qazi Y, Mulgaonkar S, et al. Association of clinical events with everolimus exposure in kidney transplant patients receiving low doses of tacrolimus. Am J Transplant. 2017;17:2363–2371.
Qazi Y, Shaffer D, Kaplan B, et al. Efficacy and safety of everolimus plus low-dose tacrolimus versus mycophenolate mofetil plus standard-dose tacrolimus in de novo renal transplant recipients: 12-month data. Am J Transplant. 2017;17:1358–1369.
Cibrik D, Silva HT Jr, Vathsala A, et al. Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation. Transplantation. 2013;95:933–942.
Warden BA, Duell PB. Management of dyslipidemia in adult solid organ transplant recipients. J Clin Lipidol. 2019;13:231–245.
Pascual J, Berger SP, Chadban SJ, et al. Evidence-based practice: guidance for using everolimus in combination with low-exposure calcineurin inhibitors as initial immunosuppression in kidney transplant patients. Transplant Rev (Orlando). 2019;33:191–199.
Kobashigawa JA, Pauly DF, Starling RC, et al. Cardiac allograft vasculopathy by intravascular ultrasound in heart transplant patients: substudy from the everolimus versus mycophenolate mofetil randomized, multicenter trial. JACC Heart Fail. 2013;1:389–399.
Arora S, Andreassen AK, Karason K, et al. Effect of everolimus initiation and calcineurin inhibitor elimination on cardiac allograft vasculopathy in de novo heart transplant recipients. Circ Heart Fail. 2018;11:e004050.
Holdaas H, de Fijter JW, Cruzado JM, et al. Cardiovascular parameters to 2 years after kidney transplantation following early switch to everolimus without calcineurin inhibitor therapy: an analysis of the randomized ELEVATE study. Transplantation. 2017;101:2612–2620.
Paoletti E. mTOR inhibition and cardiovascular diseases: cardiac hypertrophy. Transplantation. 2018;102:S41–S43.
Pascual J, Berger SP, Witzke O, et al. Everolimus with reduced calcineurin inhibitor exposure in renal transplantation. J Am Soc Nephrol. 2018;29:1979–1991.
Berger SP, Sommerer C, Witzke O, et al. Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from the TRANSFORM study. Am J Transplant. 2019;19:3018–3034.
Currie G, Delles C. Proteinuria and its relation to cardiovascular disease. Int J Nephrol Renovasc Dis. 2014;7:13–24.
Israni AK, Snyder JJ, Skeans MA, et al. Predicting coronary heart disease after kidney transplantation: patient outcomes in renal transplantation (PORT) study. Am J Transplant. 2010;10:338–353.
Holdaas H, Fellstrom B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet. 2003;361:2024–2031.
Asberg A, Holdaas H, Jardine AG, et al. Fluvastatin reduces atherogenic lipids without any effect on native endothelial function early after kidney transplantation. Clin Transplant. 2003;17:385–390.
Herrington WG, Emberson J, et al. Cholesterol Treatment Trialists Collaboration. Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials. Lancet Diabetes Endocrinol. 2016;4:829–839.
Messow CM, Isles C. Meta-analysis of statins in chronic kidney disease: who benefits? QJM. 2017;110:493–500.
Clayton PA, McDonald SP, Russ GR, et al. Long-term outcomes after acute rejection in kidney transplant recipients: an ANZDATA analysis. J Am Soc Nephrol. 2019;30:1697–1707.
Jeon JY, Kim SJ, Ha KH, et al. Trends in the effects of pre-transplant diabetes on mortality and cardiovascular events after kidney transplantation. J Diabetes Investig. 2021;12:811–818.
Cosio FG, Hickson LJ, Griffin MD, et al. Patient survival and cardiovascular risk after kidney transplantation: the challenge of diabetes. Am J Transplant. 2008;8:593–599.
Taber DJ, Meadows HB, Pilch NA, et al. Pre-existing diabetes significantly increases the risk of graft failure and mortality following renal transplantation. Clin Transplant. 2013;27:274–282.
Lim WH, Wong G, Pilmore HL, et al. Long-term outcomes of kidney transplantation in people with type 2 diabetes: a population cohort study. Lancet Diabetes Endocrinol. 2017;5:26–33.
Rocha A, Malheiro J, Martins LS, et al. Kidney transplantation in type 2 diabetic patients: a matched survival analysis. Transplant Proc. 2013;45:2141–2146.
Wyld MLR, et al. Sex-based differences in risk factors and complications of CKD. Semin Nephrol. 2022;42:153–169.
Foster MC, Weiner DE, Bostom AG, et al. Filtration markers, cardiovascular disease, mortality, and kidney outcomes in stable kidney transplant recipients: the FAVORIT trial. Am J Transplant. 2017;17:2390–2399.
McMullen JR, Sherwood MC, Tarnavski O, et al. Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation. 2004;109:3050–3055.
Shioi T, McMullen JR, Tarnavski O, et al. Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation. 2003;107:1664–1670.
Gao XM, Wong G, Wang B, et al. Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis. J Hypertens. 2006;24:1663–1670.
Buss SJ, Muenz S, Riffel JH, et al. Beneficial effects of mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction. J Am Coll Cardiol. 2009;54:2435–2446.
Topilsky Y, Hasin T, Raichlin E, et al. Sirolimus as primary immunosuppression attenuates allograft vasculopathy with improved late survival and decreased cardiac events after cardiac transplantation. Circulation. 2012;125:708–720.
Kushwaha SS, Raichlin E, Sheinin Y, et al. Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients. Eur Heart J. 2008;29:2742–2750.
Raichlin E, Chandrasekaran K, Kremers WK, et al. Sirolimus as primary immunosuppressant reduces left ventricular mass and improves diastolic function of the cardiac allograft. Transplantation. 2008;86:1395–1400.
Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med. 2003;349:847–858.
Eisen HJ, Kobashigawa J, Starling RC, et al. Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. Am J Transplant. 2013;13:1203–1216.
Seckinger J, Sommerer C, Hinkel UP, et al. Switch of immunosuppression from cyclosporine a to everolimus: impact on pulse wave velocity in stable de-novo renal allograft recipients. J Hypertens. 2008;26:2213–2219.
Joannides R, Monteil C, de Ligny BH, et al. Immunosuppressant regimen based on sirolimus decreases aortic stiffness in renal transplant recipients in comparison to cyclosporine. Am J Transplant. 2011;11:2414–2422.
Paoletti E, Amidone M, Cassottana P, et al. Effect of sirolimus on left ventricular hypertrophy in kidney transplant recipients: a 1-year nonrandomized controlled trial. Am J Kidney Dis. 2008;52:324–330.
Cruzado JM, Pascual J, Sanchez-Fructuoso A, et al. Controlled randomized study comparing the cardiovascular profile of everolimus with tacrolimus in renal transplantation. Transpl Int. 2016;29:1317–1328.
Ying T, Wong G, Lim W, et al. De novo or early conversion to everolimus and long-term cancer outcomes in kidney transplant recipients: a trial-based linkage study. Am J Transplant. 2018;18:2977–2986.
Lim WH, Russ GR, Wong G, et al. The risk of cancer in kidney transplant recipients may be reduced in those maintained on everolimus and reduced cyclosporine. Kidney Int. 2017;91:954–963.