Reducing Mortality in Sickle Cell Disease with Hydroxyurea

Abstract & Commentary

Synopsis: Participants in the initial Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) interventional trial were followed, upon completion of that trial for up to 9 years, to determine the long-term effects of treatment. In this publication of the observational phase of the MSH trial, there is noted a 40% reduction in mortality for those who had received a year or more of the drug.

Source: Steinberg MH, et al. JAMA. 2003;289; 1645-1651.

Hydroxyurea increases the level of fetal hemoglobin (HbF)1 and decreases morbidity from vaso-oclusive complications in patients with sickle cell anemia (SCA).2,3 In fact, epidemiological studies have shown that HbF concentration is the strongest determinant of clinical severity of sickle cell disease.4-6 Thus, a large, multicenter, placebo-controlled trial was conducted between the years 1992-1995 (The Multicenter Study of Hydroxyurea in Sickle Cell Anemia [MSH]), which confirmed a reduction in morbidity (particularly veno-occlusive events) in patients with SCA. In the hydroxyurea treatment group (n = 152), there was a 44% reduction in the annual number of painful episodes and a 58% decrease in the number of cases for which hospitalization was required.7 That trial was the basis for the Food and Drug Administration’s approval of hydroxyurea for patients with recurrent moderate-to-severe painful crises associated with SCA.

The objective of the current research was to determine whether hydroxyurea treatment attenuates mortality in SCA patients. For this, survival of the participants in the MSH trial was recorded. These participants, upon completion of the formal trial, either chose to stay on hydroxyurea, be switched on to hydroxyurea (if they had received placebo during the interventional trial), or be treated with supportive measures alone, without hydroxyurea.

Of the original 299 patients who had participated in the MSH trial (hydroxyurea treated, n = 152; placebo, n = 147), follow-up data were available for up to 9 years on 233 (77.9%). Ninety-six (32%) of the patients never received hydroxyurea; 48 (16%) received hydroxyurea for less than 1 year, and 156 (52%) received hydroxyurea for 1 or more years.

Twenty-five percent of patients (n = 75) who were originally enrolled in the MSH trial have died. The most common cause of death (28%) was pulmonary disease. The 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 = 0.03). Individuals who had acute chest syndrome during the trial had 32% mortality compared with 18% of individuals without acute chest syndrome (P = 0.02). Taking hydroxyurea was associated with a 40% reduction in mortality (P = 0.04) in this observational follow-up.

Comment by William B. Ershler, MD

Since the publication of the MSH trial results, hematologists have been aware of the therapeutic benefit of hydroxyurea for those sickle cell patients with moderate or severe disease, particularly in reducing the frequency of painful crises and hospitalizations. The current follow-up provides the first data on survival, and the results are encouraging. Adult SCA patients (who had moderate-to-severe disease at the time of entry into trial, as defined by 3 or more painful crises/year) were shown to have reduced mortality after 9 years of follow-up. Furthermore, patients appeared to tolerate hydroxyurea well and not have increased long-term adverse consequences. There were 3 cancers observed in those receiving hydroxyurea, and only 1 proved fatal.

The questions remain, however, as to just who should receive hydroxyurea (those with mild, moderate, or only those with severe SCA?), at what age should treatment be started, and will this somewhat expensive medicine be available for all those who could benefit from it? Additional clinical trials and health services research will be paramount to addressing these questions.


1. Eaton WA, et al. Adv Protein Chem. 1990;40:63-279.

2. Charache S, et al. Blood. 1992;79:2555-2565.

3. Bridges KR, et al. Blood. 1996;88:4701-4710.

4 Castro O, et al. Blood. 1994;84:643-649.

5. Platt OS, et al. N Engl J Med. 1991;325:11-16.

6. Platt OS, et al. N Engl J Med. 1994;330:1639-1644.

7. Charache S, et al. N Engl J Med. 1995;332:1317-1322.