The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) showed that hydroxyurea reduced the incidence of painful episodes and acute chest syndrome by nearly one half over 2.5 years. After completion of the randomized controlled MSH, patients were followed in an observational study undertaken by Steinberg and colleagues to determine the effects of hydroxyurea on mortality rates.
In the observational portion of this study, previously randomized patients were free to continue, stop, or start hydroxyurea treatment. Fetal hemoglobin (HbF) levels had been measured at the beginning of the trial and at two years.
Data were collected and completed for up to nine years in 233 of 299 patients. During the trial and its follow-up, 75 (25 percent) of the MSH patients died. When data were analyzed according to the original assignment in the randomized portion of the trial, no mortality difference was found between the two groups. Cumulative mortality over nine years in patients with HbF levels lower than 0.5 g per dL was 28 percent compared with 15 percent in patients with HbF levels higher than 0.5 g per dL. Of the patients with low HbF levels before the trial, those receiving hydroxyurea were more likely to have increased HbF levels at the trial's completion than those without treatment. Total months of exposure to hydroxyurea were related to original treatment assignment, durations of survival in follow-up, and choice of treatment in follow-up. Mortality rates were reduced by 40 percent during three-month intervals when patients were taking hydroxyurea (2.6 versus 1.5 deaths per three months).
Steinberg and colleagues note that patients with reduced crises, reduced chest syndrome, and good bone marrow reserve after two years of receiving hydroxyurea in the randomized portion of the trial were the ones with reduced mortality in follow-up. This observation, coupled with a 40 percent reduction in mortality at three-month follow-up intervals, leads the authors to conclude that hydroxyurea has a positive impact on mortality in sickle cell anemia. Increased HbF is a possible mediator of this mortality benefit.