revised April 27, 1998

An Overview of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH)

[Charache, et al., 1995. The effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 332:1317-1322]

Study Design

 The NHLBI organized the multicenter study of hydroxyurea in sickle cell anemia to answer the question of whether hydroxyurea was clinically useful to patients with sickle cell disease. The task of evaluating efficacy in sickle cell disease is difficult because of the inherent variability of the condition Further, some conditions genetically different from homozygous HbS disease have a similar phenotype (e.g., sickle ß-thalassemia and HbSC disease). In order to have a meaningful study, the design committee established strict entry criteria:

  1. Age 18 years or older.

  2. Homozygous Hb SS disease. Of note, patients with homozygous HbSS disease who also had alpha thalassemia were included in the study.

  3. Patients who had received transfusions could have no more than 15% HbA on hemoglobin electrophoresis at the start of the study.
    (Patients on long-term chronic transfusion programs were ineligible for the study.)

  4. The patient had to have reported at least three painful crises to the physician in the year before the study.

  5. Pregnant patients were ineligible.
    (hydroxyurea is teratogenic in rats.)

  6. Patients with known narcotic addiction or regularly consumed 30 or more oxycodone tablets (or equivalent other narcotic) in two weeks.

  7. No concurrent use of other potentially anti-sickling agents.

  8. No history of stroke in the preceding six years.

  9. No prior treatment with hydroxyurea.

  10. No antibody to the HIV virus.

  11. No pre-existing depression of blood counts that would obscure bone marrow suppression by the hydroxyurea.

 A total of 299 patients were enrolled in the study. Treatment with hydroxyurea was begun at a dose of 15 mg/kg/day, and was escalated in increments of 5 mg/kg every 12 weeks to the maximum tolerated does (MTD: platelet or reticulocyte count that falls to below 80,000/mm3.) If marrow depression occurred, the hydroxyurea was held until the counts normalized, and then was restarted at a dose less than that used previously by 2.5 mg/kg/day. One group of patients received placebo that was physically identical to the hydroxyurea tablets. Drug pauses and adjustments were made in this arm in order to maintain the double-blind nature of the investigation.

 The primary outcome variable was pain. A painful crisis was defined as a visit to a medical facility that lasted longer than four hours and required parenterally administered narcotics for pain control. Other primary outcome variables were acute chest syndrome, priapism and hepatic sequestration crisis.

Results

Characteristic
Hydroxyurea
(N=152)
Placebo
(N=147)
No. Crises in the year before before study entry (% patients)
3-5
44
44
6-9
26
21
> or = 10
30
35
Complications of sickle cell disease (% patients)
Chest syndrome
66
65
Ankle ulcer
31
33
Aseptic necrosis of bone
20
22
Hemoglobin (g/dl)
8.4
8.5
White cells (10-3/mm3)
12.6
12.3
Platelets(10-3/mm3)
468
457
Reticulocytes (10-3/mm3)
327
325
Fetal hemoglobin (%)
5.0
5.2
F-cells (%)
33
33
Dense cells (%)
14.3
14.0

 No significant difference existed between the two groups initially with respect to sex, age, race or ethnic group, number of alpha globin genes, or ß-globin haplotype. The blood counts were similar between the two groups prior to treatment. After treatment was begun, one patient in the hydroxyurea group was found to have sickle ß+-thalassemia (a small amount of HbA was present).

Graph of the effect of hydroxyurea on crises in sickle cell disease The median number of crises experienced by patients on hydroxyurea was approximately half that of the control group. In addition, hydroxyurea treatment reduced by more than half, the number of hospitalizations due to sickle cell crises. Further supporting the efficacy of hydroxyurea in preventing sickle cell crises, the median time to the first vaso-occlusive crisis was 3.0 months in the hydroxyurea group compared to 1.5 months in the placebo controls. The median time to the second crisis was likewise greater in the patients on hydroxyurea relative to the controls (8.8 versus 4.6 months.) At the end of the study, 51% of the patients on hydroxyurea were receiving maximal tolerated doses. The upper limit prescribed for any patient was 35 mg/kg/day.

 Acute chest syndrome is a leading cause of death of patients with sickle cell disease. The patients on hydroxyurea had 25 episodes of acute chest syndrome, while the placebo control patients experienced 51 episodes. The difference is significant with a P<0.001.

Graph of the effect of hydroxyurea on acute chest syndrome and blood transfusion Patients in the study were transfused at the discretion of their physicians (who were blinded to the treatment) as seemed medically appropriate. The number of patients who required transfusion was less in the hydroxyurea treated group compared to the controls. In addition, the patients on hydroxyurea received 336 transfusions while the patients in the control group received 586 (P=0.004). This apparently paradoxical effect of hydroxyurea is likely due diminished hemolysis in these patients relative to control. Some patients on hydroxyurea had dramatic rises in their hemoglobin levels, in some cases from the range of 7 gm/dl to as high as 13 gm/dl.

No death was related to treatment with hydroxyurea. Treatment was permanently stopped in 14 patients in the hydroxyurea group (two of whom showed myelotoxicity at a dose of 2.5 mg/kg/day). In the placebo group, treatment was discontinued in six patients. Treatment was stopped temporarily in nearly all the patients on hydroxyurea at some point because of myelosuppression.

Conclusion

 This controlled trial made hydroxyurea the first drug of proven benefit in the prevention of major problems caused by sickle cell disease. These are:
  1. Vaso-occlusive pain crisis

  2. Acute chest syndrome

 The study did not address the question of the ability of hydroxyurea to reverse chronic organ damage (such as skin ulcers) nor prevent stroke. Importantly, no significant side-effects of hydroxyurea therapy was noted. Long-term effects are being monitored in the MSH follow-up study. Of greatest concern in this regard is the possibility of neoplasic transformation by a drug that alters DNA synthesis.

Go to Guidelines for Use of Hydroxyurea

Go to Overview of Sickle Cell Management