Since its approval for the treatment of sickle cell disease in 1998, hydroxyurea has been under intense study. On the basis of 1 high-quality randomized trial in adults and many observational studies, we conclude that hydroxyurea increases fetal hemoglobin in adults with sickle cell disease, reduces the frequency of pain crises, reduces the frequency or duration of hospitalization, and reduces transfusions (). Although the data convincingly demonstrate an increase in fetal hemoglobin percentage with use of this drug, far less evidence is available regarding the clinically relevant outcomes of hospitalization, stroke, pain crises, the acute chest syndrome, and death.
Summary of the Evidence in Sickle Cell Disease*
Although the evidence is sparse, it suggests that hydroxyurea treatment in adults is not associated with leukemia. In addition, hydroxyurea is not associated with leg ulcers in patients with sickle cell disease, although it is in patients with other conditions. We hypothesize that the improvement in rheology offsets any increase in leg ulcer risk associated with the drug. We cannot draw conclusions from the evidence about whether hydroxyurea contributes to skin neoplasms in sickle cell disease, although it convincingly does in other conditions. The other populations studied were largely light-skinned, and we were not surprised that the skin cancer risk differed across populations.
This evidence base has important limitations. Most notably, only 1 randomized trial studied efficacy (18
). Although the MSH was a high-quality study, concerns have been raised (88
) about its overreliance on secondary analyses. The MSH investigators used a more stringent threshold for statistical significance in the secondary analysis of the results of the randomized trial, and these analyses were planned before study initiation. Similar adjustments, however, were not made in the secondary analysis of overall mortality published in the long-term observational follow-up study of MSH.
We are also concerned that the observational data may be confounded by regression to the mean. For example, if physicians started hydroxyurea therapy in patients after a period of increased disease activity, it is likely that in time, the patient may have returned to his or her usual level of disease activity even without a change in therapy. This effect would overstate the benefits of the therapy (89
). No trial data are available with which to comment on effectiveness of this drug in a population that may take the medication for many years with less intense supervision and encouragement than is received in a typical efficacy trial. Thus, the evidence base is limited by the lack of effectiveness trials and the paucity of trials of efficacy, even though the MSH may be considered a definitive efficacy trial of this drug in adults (18
). These results cannot be generalized to all patients with sickle cell disease because the MSH included almost entirely patients with hemoglobin SS; clinical response and toxicities seem to differ to some extent by genotype.
These relatively short studies cannot provide strong evidence for toxicities that may require many years of exposure. The follow-up studies from these trials are important contributors to the literature, but they become observational studies after the randomization period ends and thus are subject to the limitations of any observational study. The losses to follow-up were substantial in most of the observational studies. The studies of toxicity were also weakened by the absence of control groups.
Many subgroups require further study. Patients with hemoglobin SC, the second most common genotype of sickle cell disease, were particularly understudied. Additional studies of hydroxyurea at doses other than the maximum tolerated dose are appropriate, particularly as the use of a maximum tolerated dose in resource-poor populations may be less practical or safe. Other subgroups of interest are patients with comorbid illnesses, specifically HIV, AIDS, or hepatitis C. The interactions between hydroxyurea and these underlying diseases, and between hydroxyurea and therapies for these diseases, need to be clarified. Additional longer-term studies are needed to further assess toxicities of hydroxyurea.
Further research on the role of hydroxyurea in the lifelong treatment of sickle cell disease is indicated; current studies do not tell us the optimal timing of initiation of hydroxyurea therapy and the indicators of failed hydroxyurea therapy. Several other questions also remain: Is there a role for rechallenge with the drug if there was no previous efficacy? Is there a role for hydroxyurea as an adjunctive therapy with other drugs? What are the best intermediate outcomes that will predict clinical response to the drug? Additional trials with other clinical outcomes are appropriate, including randomized trials to prevent other complications of sickle cell disease, such as kidney disease, pulmonary hypertension, and neurologic events in adults. Effectiveness trials are needed to test hydroxyurea in a regular care setting. These could be clustered randomized trials in which some providers are randomly assigned to prescribe hydroxyurea in all patients and others are randomly assigned to provide usual care, including the use of hydroxyurea when clinically indicated, or effectiveness studies in which a group of providers is actively encouraged to consider hydroxyurea when appropriate and another group is not targeted for education.
Hydroxyurea is the only U.S. Food and Drug Administration–approved medication for the treatment of sickle cell disease. It is the only available drug that alters the disease process, and its toxicities or potential toxicities should be interpreted in this light, particularly when it is used to treat a disease that causes great morbidity and predictably shortens the life span.