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Risks and Benefits Up to 9 Years of Treatment

Martin H. Steinberg, MD; Franca Barton, MS; Oswaldo Castro, MD; Charles H. Pegelow, MD; Samir K. Ballas, MD; Abdullah Kutlar, MD; Eugene Orringer, MD; Rita Bellevue, MD; Nancy Olivieri, MD; James Eckman, MD; Mala Varma, MD; Gloria Ramirez, MD; Brian Adler, MD; Wally Smith, MD; Timothy Carlos, MD; Kenneth Ataga, MD; Laura DeCastro, MD; Carolyn Bigelow, MD; Yogen Saunthararajah, MD; Margaret Telfer, MD; Elliott Vichinsky, MD; Susan Claster, MD; Susan Shurin, MD; Kenneth Bridges, MD; Myron Waclawiw, PhD; Duane Bonds, MD; Michael Terrin, MD, MPH

JAMA. 2003;289:1645-1651.

Context  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.

Design  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.

Setting  Inpatients and outpatients in 21 sickle cell referral centers in the United States and Canada.

Patients  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.

Intervention  In the MSH, patients were randomly assigned to receive hydroxyurea (n = 152) or placebo (n = 147).

Main Outcome Measure  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.

Author Affiliations: Boston University School of Medicine, Center of Excellence in Sickle Cell Disease, Boston Medical Center, Boston, Mass (Dr Steinberg); University of Mississippi School of Medicine, Jackson (Drs Steinberg, and Bigelow); Maryland Medical Research Institute, Baltimore (Ms Barton, Dr Terrin); Center for Sickle Cell Disease, Howard University School of Medicine, Washington, DC (Dr Castro); University of Miami School of Medicine, Miami, Fla (Dr Pegelow); Thomas Jefferson University, Philadelphia, Pa (Dr Ballas); Medical College of Georgia, Augusta (Dr Kutlar); University of North Carolina, Chapel Hill (Drs Orringer and Ataga); New York Methodist Hospital, Brooklyn (Dr Bellevue); Hospital for Sick Children, Toronto, Ontario (Dr Olivieri); Sickle Cell Center, Emory University, Atlanta, Ga (Dr Eckman); University of Medicine and Dentistry of New Jersey, Newark (Dr Varma); Roosevelt Medical Center, New York, NY (Dr Ramirez); University of Alabama at Birmingham (Dr Adler); Virginia Commonwealth University, Richmond (Dr Smith); University of Pittsburgh, Pittsburgh, Pa (Dr Carlos); Duke University School of Medicine, Durham, NC (Dr DeCastro); University of Illinois at Chicago (Dr Saunthararajah); Michael Reese Medical Center, Chicago, Ill (Dr Telfer); Children's Hospital and Research Center at Oakland, Oakland, Calif (Dr Vichinsky); University of California at San Francisco (Dr Claster); Rainbow Babies and Children's Hospital, Cleveland, Ohio (Dr Shurin); Brigham and Women's Hospital, Boston (Dr Bridges); National Heart, Lung, and Blood Institute, Bethesda, Md (Drs Bonds and Waclawiw). Dr Pegelow is deceased.

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