title: Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment.
abstract: BACKGROUND
  Hydroxyurea increases levels of fetal hemoglobin (HbF) and decreases morbidity from vaso-occlusive complications in patients with sickle cell anemia (SCA). High HbF levels reduce morbidity and mortality.
  
  
  OBJECTIVE
  To determine whether hydroxyurea attenuates mortality in patients with SCA.
  
  
  METHODS
  Long-term observational follow-up study of mortality in patients with SCA who originally participated in the randomized, double-blind, placebo-controlled Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), conducted in 1992-1995, to determine if hydroxyurea reduces vaso-occlusive events. In the MSH Patients' Follow-up, conducted in 1996-2001, patients could continue, stop, or start hydroxyurea. Data were collected during the trial and in the follow-up period.
  
  
  METHODS
  Inpatients and outpatients in 21 sickle cell referral centers in the United States and Canada.
  
  
  METHODS
  Two-hundred ninety-nine adult patients with frequent painful episodes enrolled in the follow-up. Follow-up data through May 2001 were complete for 233 patients.
  
  
  METHODS
  In the MSH, patients were randomly assigned to receive hydroxyurea (n = 152) or placebo (n = 147).
  
  
  METHODS
  Mortality, HbF levels, painful episodes, acute chest syndrome, and blood cell counts. The randomized trial was not designed to detect specified differences in mortality.
  
  
  RESULTS
  Seventy-five of the original 299 patients died, 28% from pulmonary disease. Patients with reticulocyte counts less than 250 000/mm3 and hemoglobin levels lower than 9 g/dL had increased mortality (P =.002). Cumulative mortality at 9 years was 28% when HbF levels were lower than 0.5 g/dL after the trial was completed compared with 15% when HbF levels were 0.5 g/dL or higher (P =.03 ). Individuals who had acute chest syndrome during the trial had 32% mortality compared with 18% of individuals without acute chest syndrome (P =.02). Patients with 3 or more painful episodes per year during the trial had 27% mortality compared with 17% of patients with less frequent episodes (P =.06). Taking hydroxyurea was associated with a 40% reduction in mortality (P =.04) in this observational follow-up with self-selected treatment. There were 3 cases of cancer, 1 fatal.
  
  
  CONCLUSIONS
  Adult patients taking hydroxyurea for frequent painful sickle cell episodes appear to have reduced mortality after 9 of years follow-up. Survival was related to HbF levels and frequency of vaso-occlusive events. Whether indications for hydroxyurea treatment should be expanded is unknown.
authors.affiliation: Boston University School of Medicine, Center of Excellence in Sickle Cell Disease, Boston Medical Center, Boston, Mass 02118, USA. msteinberg@medicine.bu.edu
authors.forename: Martin H
authors.initials: MH
authors.lastname: Steinberg
authors.forename: Franca
authors.initials: F
authors.lastname: Barton
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Castro
authors.forename: Charles H
authors.initials: CH
authors.lastname: Pegelow
authors.forename: Samir K
authors.initials: SK
authors.lastname: Ballas
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
authors.forename: Eugene
authors.initials: E
authors.lastname: Orringer
authors.forename: Rita
authors.initials: R
authors.lastname: Bellevue
authors.forename: Nancy
authors.initials: N
authors.lastname: Olivieri
authors.forename: James
authors.initials: J
authors.lastname: Eckman
authors.forename: Mala
authors.initials: M
authors.lastname: Varma
authors.forename: Gloria
authors.initials: G
authors.lastname: Ramirez
authors.forename: Brian
authors.initials: B
authors.lastname: Adler
authors.forename: Wally
authors.initials: W
authors.lastname: Smith
authors.forename: Timothy
authors.initials: T
authors.lastname: Carlos
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ataga
authors.forename: Laura
authors.initials: L
authors.lastname: DeCastro
authors.forename: Carolyn
authors.initials: C
authors.lastname: Bigelow
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.forename: Margaret
authors.initials: M
authors.lastname: Telfer
authors.forename: Elliott
authors.initials: E
authors.lastname: Vichinsky
authors.forename: Susan
authors.initials: S
authors.lastname: Claster
authors.forename: Susan
authors.initials: S
authors.lastname: Shurin
authors.forename: Kenneth
authors.initials: K
authors.lastname: Bridges
authors.forename: Myron
authors.initials: M
authors.lastname: Waclawiw
authors.forename: Duane
authors.initials: D
authors.lastname: Bonds
authors.forename: Michael
authors.initials: M
authors.lastname: Terrin
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000401:mortality* / Q000503:physiopathology; D000986:Antisickling Agents / Q000627:therapeutic use*; D001772:Blood Cell Count; D002423:Cause of Death; D004311:Double-Blind Method; D005319:Fetal Hemoglobin / Q000378:metabolism; D005500:Follow-Up Studies; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D009017:Morbidity; D018570:Risk Assessment; D016019:Survival Analysis
chemical_list: D000986:Antisickling Agents; D005319:Fetal Hemoglobin; D006918:Hydroxyurea