Everolimus Versus Mycophenolate Mofetil De Novo After Lung Transplantation: A Prospective, Randomized, Open-Label Trial.
The role of mammalian target of rapamycin (mTOR) inhibitors in de novo immunosuppression after lung transplantation is not well defined. We compared Everolimus versus mycophenolate mofetil in an investigator-initiated single-center trial in Hannover, Germany. A total of 190 patients were randomly assigned 1:1 on day 28 posttransplantation to mycophenolate mofetil (MMF) or Everolimus combined with cyclosporine A (CsA) and steroids. Patients were followed up for 2 years. The primary endpoint was freedom from bronchiolitis obliterans syndrome (BOS). The secondary endpoints were incidence of acute rejections, infections, treatment failure and kidney function. BOS-free survival in intention-to-treat (ITT) analysis was similar in both groups (p = 0.174). The study protocol was completed by 51% of enrolled patients. The per-protocol analysis shows incidence of bronchiolitis obliterans syndrome (BOS): 1/43 in the Everolimus group and 8/54 in the MMF group (p = 0.041). Less biopsy-proven acute rejection (AR) (p = 0.005), cytomegalovirus (CMV) antigenemia (p = 0.005) and lower respiratory tract infection (p = 0.003) and no leucopenia were seen in the Everolimus group. The glomerular filtration rate (GFR) decreased in both groups about 50% within 6 months. Due to a high withdrawal rate, the study was underpowered to prove a difference in BOS-free survival. The dropout rate was more pronounced in the Everolimus group. Secondary endpoints indicate potential advantages of Everolimus-based protocols but also a potentially higher rate of drug-related serious adverse events.
Richard DeVos Heart & Lung Transplant Program, Frederik Meijer Heart & Vascular Institute, Grand Rapids, MI. strueber@msu.edu.
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M
Strueber
Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.|German Centre of Lung Research (DZL/BREATH), Hannover Medical School, Hannover, Germany.
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G
Warnecke
Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.
J
J
Fuge
Department of Heart and Lung Transplantation/VAD, Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom.
A R
AR
Simon
Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
R
R
Zhang
German Centre of Lung Research (DZL/BREATH), Hannover Medical School, Hannover, Germany.|Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.
T
T
Welte
Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.|German Centre of Lung Research (DZL/BREATH), Hannover Medical School, Hannover, Germany.
A
A
Haverich
German Centre of Lung Research (DZL/BREATH), Hannover Medical School, Hannover, Germany.|Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.
J
J
Gottlieb
D000293:Adolescent; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000068338:Everolimus / Q000494:pharmacology*; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008171:Lung Diseases / Q000601:surgery*; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000494:pharmacology*; D011183:Postoperative Complications / Q000188:drug therapy*; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D055815:Young Adult
D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D000068338:Everolimus; D009173:Mycophenolic Acid
antiproliferative agent: mycophenolate mofetil (MMF); bronchiolitis obliterans (BOS); calcineurin inhibitor: cyclosporine A (CsA); clinical research/practice; clinical trial; immunosuppressant; immunosuppression/immune modulation; lung transplantation/pulmonology; mechanistic target of rapamycin (mTOR); pharmacology