title: Withdrawal of proliferation signal inhibitors due to adverse events in the maintenance phase of heart transplantation.
abstract: BACKGROUND
  The increasing use of proliferation signal inhibitors (PSIs) has raised the issue of their risk profile. We sought to determine the causes, incidence, risk factors, and consequences of withdrawal due to adverse events of PSIs in maintenance heart transplantation.
  
  
  METHODS
  This was a retrospective study from 9 centers of the Spanish Registry for Heart Transplantation. Demographic, clinical, analytic, and evolution data were obtained for patients in whom a PSI (sirolimus or everolimus) was used between October 2001 and March 2009.
  
  
  RESULTS
  In the first year, 16% of 548 patients could not tolerate PSIs. This incidence rate stabilized to 3% to 4% per year thereafter. The most frequent causes for discontinuation were edema (4.7%), gastrointestinal toxicity (3.8%), pneumonitis (3.3%), and hematologic toxicity (2.0%). In multivariate analysis, withdrawal of PSI was related to the absence of statin therapy (p = 0.006), concomitant treatment with anti-metabolites (p = 0.006), a poor baseline renal function (p = 0.026), and multiple indications for PSI use (p = 0.04). Drug discontinuation was associated with a decline in renal function (p = 0.045) but not with an excess in mortality (p = 0.42).
  
  
  CONCLUSIONS
  In this large cohort of maintenance heart transplant recipients taking a PSI, 16% withdrew treatment in the first year, and 25% had stopped PSI due to severe adverse events by the fourth year. This high rate of toxicity-related PSI withdrawal could limit the clinical utility of this otherwise novel class of immunosuppressive agents.
authors: Heart Failure and Cardiac Transplantation Unit, Cardiology Service of the University Hospital Marques de Valdecilla. Instituto de Formacion e Investigacion Marques de Valdecilla (IFIMAV), Santander, Spain. cargvf@humv.es
authors: Francisco
authors: F
authors: Gonzalez-Vilchez
authors: José Antonio
authors: JA
authors: Vazquez de Prada
authors: Luis
authors: L
authors: Almenar
authors: José María
authors: JM
authors: Arizon Del Prado
authors: Sonia
authors: S
authors: Mirabet
authors: Beatriz
authors: B
authors: Diaz-Molina
authors: Juan Francisco
authors: JF
authors: Delgado
authors: Manuel
authors: M
authors: Gomez-Bueno
authors: María Jesús
authors: MJ
authors: Paniagua
authors: Félix
authors: F
authors: Perez-Villa
authors: Eulalia
authors: E
authors: Roig
authors: Luis
authors: L
authors: Martínez-Dolz
authors: Vicens
authors: V
authors: Brossa
authors: José Luis
authors: JL
authors: Lambert
authors: Javier
authors: J
authors: Segovia
authors: María Generosa
authors: MG
authors: Crespo-Leiro
authors: María Jesús
authors: MJ
authors: Ruiz-Cano
mesh_terms: D000368:Aged; D004487:Edema / Q000139:chemically induced / Q000453:epidemiology; D000068338:Everolimus; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000453:epidemiology; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015994:Incidence; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011014:Pneumonia / Q000139:chemically induced / Q000453:epidemiology; D012042:Registries; D012189:Retrospective Studies; D012307:Risk Factors; D020123:Sirolimus / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013030:Spain; D028761:Withholding Treatment
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus