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Segal JB, Strouse JJ, Beach MC, et al. Hydroxyurea for the Treatment of Sickle Cell Disease. Rockville (MD): Agency for Healthcare Research and Quality (US); 2008 Feb. (Evidence Reports/Technology Assessments, No. 165.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Hydroxyurea for the Treatment of Sickle Cell Disease

Hydroxyurea for the Treatment of Sickle Cell Disease.

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Since its approval for the treatment of sickle cell disease in 1998, hydroxyurea has been under intense study. The body of evidence supporting its use is large but is mainly based on observational data. There have been only two randomized controlled trials of the use of this drug in sickle cell disease, although an additional large trial is nearing completion. The other studies of this drug have included several controlled studies comparing patients receiving hydroxyurea to patients receiving another intervention or usual care, but the vast majority of the studies have been observational studies, including well-described prospective cohorts and many small studies reporting patient experiences pre- and post-treatment with hydroxyurea. In addition, the literature is replete with case reports describing toxicities ascribed to hydroxyurea, although the majority of these reports concern diseases other than sickle cell disease. Few studies have specifically identified barriers to the use of hydroxyurea in patients with sickle cell disease. No studies have tested an intervention to improve patient acceptance of this medication or patient adherence. For this report, we opted to review the literature related to barriers to the use of other medications and treatments in patients with sickle cell disease, since we believe that the barriers may often be similar.

In this section, we describe key findings from our literature review, describe the limitations of this body of literature, and discuss the limitations of our report. We also describe studies that are in progress and make suggestions, based on the gaps in the current evidence, with regard to studies that should be undertaken in the future.

Summary of the Key Findings

Key Questions 1 and 2

Efficacy and Effectiveness of Hydroxyurea in Children

A single, small RCT investigated the efficacy of hydroxyurea in children. In this Belgian study, the rate of hospitalization and number of days hospitalized per year were significantly lower in the hydroxyurea group than in the placebo group. 44 The small size of this study and the short duration of treatment with the drug (6 months) did not provide adequate data to permit assessment of the long-term responses to hydroxyurea. The results of this trial are supported by data from 20 observational studies in children. Interpretation of many of these observational studies is complicated by their incomplete description of losses to followup. The HUSOFT was the only study of very young children, with a mean age of 1.3 years; 60 this Phase I/II study also had a published followup study. 72 Hb F% was reported as an outcome in 16 of these observational studies. In the studies that reported Hb F% before and during treatment with hydroxyurea, the Hb F% increased substantially while patients were on treatment, with results comparable to those reported in the RCT. The mean pre-treatment Hb F% ranged from 5 to 10 percent, and the post-treatment values were in the range of 15 to 20 percent. In the study of infants, hydroxyurea therapy prevented the expected decline in Hb F% that is usually seen in this age group. Hemoglobin concentration increased only modestly (roughly 1 gm/dl) but significantly across studies.

The frequency of pain crises decreased in three of the five studies in which this variable was assessed; in one study without a comparison group, it was unclear how the rate differed from an untreated group. Hospitalization rates declined in all studies in which this was assessed. Two studies reported TCD velocities and demonstrated decreased velocity while the children were being treated. 62, 63 One study included a control group that showed an increase in velocity over the treatment period. 62 One other study demonstrated rates of recurrent stroke in patients receiving hydroxyurea to be comparable to the rate typically seen in children on chronic transfusion therapy. 67

Based on one RCT in children and on many observational studies, some of which were of high quality and most of which were consistent in their findings, we concluded that there was a high grade of evidence to support the claim that hydroxyurea raises Hb F in children. There was moderate evidence to support the contention that hydroxyurea reduces the frequency of pain crises, and a high grade of evidence that it reduces the frequency and/or duration of hospitalization in children. There was a low grade of evidence to support that claim that hydroxyurea reduces neurological events in children, and insufficient evidence to allow us to draw any conclusions regarding transfusion frequency.

Efficacy and Effectiveness of Hydroxyurea in Adults

Only one randomized trial tested efficacy in adults with sickle cell disease, the MSH Study. 39 Six additional analyses based on this trial or on followup studies have also been published. 21, 22, 4043 In the MSH, 18 percent of patients had permanent or complete cessation of the study medication during the trial. The significant hematological effects of hydroxyurea after 2 years (when compared to the placebo arm) included a small increase in total hemoglobin of 0.6 g/dl and a moderate absolute increase in fetal hemoglobin of 3.2 percent. 44 The results of the MSH study included significant differences in several critical clinical outcomes between the hydroxyurea arm and placebo. The median number of painful crises was 44 percent lower in the hydroxyurea arm, and the time to the first painful crisis was 3 months, as compared to 1.5 months for those in the placebo arm. There were fewer episodes of acute chest syndrome and transfusions, but no significant differences in deaths, strokes/chronic transfusion, or hepatic sequestration. The MSH study also included an evaluation of costs and quality of life, both of which favored the use of hydroxyurea.

The results of the 12 observational studies enrolling only adults supported the findings in the MSH study. In all six studies of adults that reported hematological outcomes, Hb F% was significantly higher for those receiving hydroxyurea. 45 46, 71, 74, 78, 80 The number of pain crises was given in three studies, all of which demonstrated a significant decline in frequency with drug treatment. 46, 61, 71 Similarly, hospitalization rates decreased for adults treated with the drug. In a group of patients treated for fewer than 24 months, however, the investigators did not find a significant difference in hospitalization rates from baseline, 52 although patients who discontinue before 24 months may represent a different population than those who are able to tolerate a longer duration of therapy.

There was only one study that assessed responses in patients with Hb SC, although many studies included at least some patients with Hb Sβ0/+ thalassemia. The results appeared to be comparable for patients with Hb SS and Hb Sβ0/+ thalassemia. Sex and age had little influence on outcomes.

Several interesting studies have described potential biomarkers of the response to hydroxyurea. One study identified significantly decreased rigidity and rates of elastic shear in patients with sickle cell disease treated with hydroxyurea, when compared to untreated sickle cell disease patients, but the values were still significantly higher than those for controls without sickle cell disease. 85 Another study described lower rates of arginase activity in those treated with hydroxyurea, but again the rates were lower in controls without sickle cell disease. Similarly, increased nitric oxide metabolites and cyclic GMP were reported in patients treated with hydroxyurea. 87 Levels of endothelin-1 were significantly lower in children with Hb SS on hydroxyurea at steady-state when compared to an untreated group, 88 but the levels of tumor necrosis factor-1 were similar for untreated patients with Hb SS and those receiving a single dose of hydroxyurea. 89 These studies suggest that other mechanisms may contribute to the benefit resulting from hydroxyurea in addition to the anti-sickling effect produced by an increase in Hb F concentration in red blood cells.

Based on one high-quality RCT in adults and many observational studies, we concluded that there was a high grade of evidence to support the claim that hydroxyurea raises fetal hemoglobin in adults with sickle cell disease and that future research is unlikely to substantially alter these conclusions. There was also high-grade evidence that hydroxyurea reduces the frequency of pain crises and that the drug reduces the frequency and/or duration of hospitalization in adults. There was also high-grade evidence that hydroxyurea reduces transfusions, but only a low grade of evidence that it reduces mortality. The evidence base was insufficient to allow us to comment on neurological events in adults.

Key Question 3

Toxicities of Hydroxyurea in Children and Adults

Our assessment of the strength of the evidence regarding the toxicity of hydroxyurea when used in children came largely from our review of the report by the panel of experts assembled by the CERHR. This panel reviewed articles, published through January, 2007, that were pertinent to the evaluation of adverse effects of hydroxyurea on development and reproduction in both humans and animals.26

The panel concluded that treatment of children aged 5 to15 years with hydroxyurea does not cause a growth delay. They felt that there were insufficient data to allow them to evaluate the effects of the drug on pubertal development. The expert panel also concluded that there were insufficient data regarding the effects on subsequent generations following exposure of germ cells to hydroxyurea, including exposure during fetal life, infancy, childhood, and adolescence. The CERHR report did not describe any studies on the long-term health effects, including carcinogenicity, of childhood exposure to hydroxyurea; we were also unable to find any such studies. The expert panel had concerns about the adverse effect of hydroxyurea on spermatogenesis in men receiving the drug at therapeutic doses, and we also identified relevant case reports in both patients with sickle cell disease and patients with other illnesses who had been treated with hydroxyurea. The CERHR report concluded that the use of the drug in pregnancy was not commonly associated with adverse perinatal outcomes and that there were no data on long-term outcomes in children who were exposed in utero.

Three cases of leukemia were described in the observational studies we reviewed that dealt with patients with sickle cell disease who had been treated with hydroxyurea; 53, 55, 82 we also identified another three case reports of hydroxyurea-treated patients with sickle cell disease who developed leukemia, and one report of a child developing Hodgkin's lymphoma. Without knowing how many patients had been treated with hydroxyurea, it was impossible to calculate whether this rate of leukemia was higher than the baseline rate for young adults with sickle cell disease. In one study, a higher rate of VDJ recombination events was reported in patients treated for 30 months than in those treated for 7 months; 57 another study found this not to be the case. 81 Two studies found no increase in chromosomal abnormalities in the treated patients. 46, 47 Other toxicities associated with hydroxyurea in patients with sickle cell disease that appeared likely to be causally related to its use were neutropenia, skin rashes, and nail changes. The other toxicities reported were rare.

We reviewed toxicity reports from patients with other diseases who were treated with hydroxyurea and found additional toxicities, including a high number of leg ulcers and skin cancers. Of the RCTs enrolling patients with polycythemia vera, MPD, HIV, and essential thrombocytosis, none demonstrated a greater number of cases of leukemia in the group treated with hydroxyurea as a single agent. This parameter could not be assessed in the trials enrolling patients with CML, since acute leukemia was evaluated as an outcome rather than as a medication-related toxicity. To further address this potential relationship between hydroxyurea and the risk of malignancy, we reviewed a case series consisting of 26 patients with AML who had a unique t(3;21) chromosomal translocation. 117 Among these 26 patients were 15 with CML who had been treated with hydroxyurea. We found no other reports describing an association between this translocation and the use of this drug.

In our analysis of patients with diseases other than sickle cell disease, we also found evidence from case reports that hydroxyurea could cause fever, hepatitis, and interstitial pneumonitis. The hematological toxicities (cytopenias) seen were often intensified when patients were receiving other myelotoxic drugs such as antiretroviral therapies.

We concluded, based on our review of toxicities in both patients with sickle cell disease and patients with other diseases, that there was low-grade evidence that hydroxyurea treatment in adults with sickle cell disease is not associated with leukemia. High-grade evidence supported the claim that hydroxyurea is not associated with leg ulcers in patients with sickle cell disease, although high-grade evidence also indicated that hydroxyurea is associated with leg ulcers in patients with other conditions. We hypothesized that the improvement in rheology offsets any increase in leg ulcer risk associated with the drug.

The evidence was insufficient with regard to sickle cell disease to allow us to determine whether hydroxyurea contributes to skin neoplasms, although high-grade evidence in other conditions suggested that it does. The other populations studied were largely light-skinned populations, so we were not surprised that the skin cancer risk was notably different across populations. Likewise, there was insufficient evidence to indicate whether hydroxyurea is associated with secondary malignancies in adults with sickle cell disease, and the evidence in other diseases was only low-grade.

Key Question 4

Barriers to the Use of Hydroxyurea and Other Treatments for Managing Sickle Cell Disease

We anticipated finding few data that specifically addressed barriers to the use of hydroxyurea. Indeed, only two studies explored barriers to use of this drug, 93, 138 and no study tested interventions to overcome such barriers. Given the scarcity of the data, we sought information on barriers to the use of other therapies for the treatment of sickle cell disease, including the receipt of routine, scheduled care; adherence to medications; and receipt of therapies, including pain control and prescriptions.

As expected, we found insufficient evidence to allow us to directly identify barriers to the use of hydroxyurea. Of the 18 cross-sectional studies we reviewed that tested whether hypothesized barriers affected the use of therapies, only one investigated barriers to hydroxyurea use. 138 This study found that the perceived efficacy and perceived safety of the drug had the largest influence on patients' (or parents') choice of hydroxyurea therapy over other therapies.

The one descriptive study that explored barriers to the use of hydroxyurea in patients with sickle cell disease found that providers reported such barriers to be patients' concerns about side effects, as well as the providers' own concerns about the use of the drug in older patients, about patient compliance, about a lack of contraception, about side effects and carcinogenic potential, doubts about effectiveness, and concern about the costs to patients. 93

Largely because of the relative paucity of relevant studies and their inconsistency, we concluded that there was only low-grade evidence that patient or family knowledge, the number of hospital visits, and patient age are barriers. We concluded that the evidence was of a moderate grade that sex is not a barrier to use of therapies. The evidence about the remaining barriers to the use of established therapies was insufficient to yield any firm conclusions.

Regarding barriers to adequate pain management that were identified in both cross-sectional studies and descriptive studies, we identified two barriers that were cited in more than two studies: negative provider attitudes and poor provider knowledge. Because of the quantity and consistency of these findings, we concluded that the evidence was high-grade that negative provider attitudes are barriers and moderate-grade that poor provider knowledge is a barrier to the use of pain medications for patients with sickle cell disease. The evidence for the remaining barriers to pain management was insufficient to allow us to draw any conclusions.

None of the three studies testing interventions to improve patient adherence to established therapies for chronic disease management showed any effect on patient adherence. 181183 However, because of the small sample sizes and diverse outcome measures in these studies, we concluded that there was only low-grade evidence that interventions cannot improve patient adherence. We concluded that there was moderate evidence that interventions can overcome barriers to the use of pain medications, and moderate evidence supported the possibility that interventions can overcome barriers to the receipt of routine, scheduled healthcare for patients with sickle cell disease.

We found it informative that when researchers chose barriers to investigate, they most often studied patient-related barriers. When patients were asked to identify barriers to use of therapies, they most often identified provider-related barriers. The barrier to pain management that was most often identified by patients and providers was negative provider attitudes. However, only one of the nine pain management intervention studies addressed this issue directly through provider sensitivity training. Although the barriers related to the use of pain medications during vaso-occlusive crisis may not seem immediately relevant to the use of hydroxyurea, we concluded that it is likely that patients who have bad experiences when seeking healthcare may lose trust in the healthcare system and be less willing to take recommended medications, including hydroxyurea.


This evidence base described here has significant limitations. Most notably, there were only two RCTs addressing hydroxyurea efficacy and safety in patients with sickle cell disease. 21, 44 While the trial enrolling adults was a high-quality trial, it was not long, with only 2 years elapsing since randomization. 21 Two years may be an adequate duration for an assessment of efficacy. However, we had no trial data available to allow us to comment on the effectiveness of this drug in a population that may be asked to take the medication for many years with less intense supervision and encouragement than is received in an RCT. The trial conducted in children was a moderate-quality trial, but it was even shorter than the trial in adults, involving only 6 months of treatment. 44 Thus, the evidence base here was limited by a lack of effectiveness trials and a paucity of trials of efficacy, even though the MSH trial may be considered a definitive efficacy trial of this drug in adults. 21 Also, these trial results cannot be generalized to all patients with sickle cell disease because they included only patients with Hb SS, and clinical response and toxicities appear to differ to some extent by genotype.

The most frequently reported outcomes in the observational studies were hematological outcomes. The data convincingly demonstrated an increase in Hb F% with use of this drug; however, there was far less evidence regarding the clinically relevant outcomes of hospitalization, stroke, pain crises, acute chest syndrome, and mortality. Furthermore, we are concerned that the observational data may have been plagued with issues of regression to the mean; if patients are started on hydroxyurea after a period of worsening of symptoms, it is expected that they would, in time, return to their usual disease severity, even without a change in therapy. This is a major concern in interpreting the pre/post data from many of these observational studies reporting clinical outcomes.

We note also that the evidence was scanty regarding benefits for patients with genotypes other than Hb SS. Many of the studies included mixed genotypes, although predominantly Hb SS, without separately reporting outcomes by genotype. There were notable exceptions, 45, 59, 74, 75, 81 with several of these being high-quality studies. 75, 81 Similarly, there was only limited evidence about the use of doses other than the MTD. Most of the observational studies described titration of the dose either on a schedule or according to patients' hematological parameters, although the HUSOFT investigators used a fixed dose in their infants, 60 and one study specifically assessed the response to a fixed dose. 50 Thus, there was little evidence to guide the choice of dose based on clinical outcomes.

The evidence regarding toxicities had limitations as well. Again, the relatively short clinical trials we found could not provide strong evidence for toxicities that may require many years of exposure. The followup studies from these trials are important contributors to the literature, but they became observational studies after the period of randomization ended and were subject to the limitations of any observational study. The losses to followup were substantial in the majority of the observational studies. Approximately half of the observational studies carefully described the reasons for these losses, while the others did not. We cannot draw conclusions about the magnitude of risks and benefits of this drug without knowing whether patients left a study because of inadequate response to the drug or because of the development of adverse events or complications. As noted above, many of the observational studies were too short to adequately address the most critical toxicities, such as leukemia and other secondary malignancies. Very few studies required active surveillance for toxicities, such as periodic skin examination or cytogenetic studies, again with notable exceptions. 46, 57 The studies of toxicities suffered from a lack of control groups; for example, studies that describe impaired spermatogenesis would require a control of group of comparably ill men with sickle cell disease in order to make it possible to determine whether this is symptom is disease- or treatment-related.

In reviewing the evidence, we opted to include toxicity data from patients treated with hydroxyurea for conditions other than sickle cell disease. We appreciate that this approach provides only indirect evidence of toxicity, in that the patient populations were markedly different than patients with sickle cell disease. The populations were substantially older and predominantly comprised of light-skinned individuals, and many of the patients had an underlying disease of the bone marrow. We still believe that these studies were useful in providing some evidence regarding potential toxicities of hydroxyurea, although the indirect nature of this evidence was an acknowledged limitation of this body of data.

Our investigation of barriers to the use of hydroxyurea was limited by the paucity of data regarding this question. Since there were only two studies specifically addressing barriers to the use of this drug, we again needed to bring in supporting evidence related to interventions that might have been associated with barriers comparable to those related to hydroxyurea treatment. The majority of the potential barriers considered in the cross-sectional studies (i.e., those chosen by the researcher) were patient-related factors, which suggested a lack of attention to provider and societal-level contributions. Very few of these studies included adult patients. Only half of the cross-sectional studies used multivariate techniques to attempt to control for the effects of potential confounders, an omission that notably reduced the quality of the evidence provided by these studies. Another concern was that many of the intervention studies used indirect outcomes, such as length of stay or total hospital costs, to assess improvement in pain management. We are not certain that these are the best outcome measures for this question.

We acknowledge that there are also limitations to our report. In particular, we restricted our literature review to studies published in English because of the limited resources available. Also, although we used a previously validated scale for assessing the quality of the randomized trials, we created our own quality assessment tools for the other study designs, based on recommendations in the literature. While these tools have not been formally validated (e.g., shown to correlate with outcomes), we used items in our scales that have been used previously and are widely thought to be indicators of high-quality reporting. We chose to consider publications that were letters to the editor and therefore not peer-reviewed, although they were reviewed by the editorial staff. We made this decision because of our familiarity with several unique studies that provided information that was not available elsewhere in the published literature and because we wanted to be very inclusive in our search for reports of malignancies. We opted not to exclude studies based on their quality scores, although this may have been a valid choice. Given our interest in identifying toxicities, we chose to include even the lowest-quality studies. We had some difficulty in clearly notating the duration of followup of patients in these studies, as the data were often reported within a single study in many different forms, with results reported separately for patients with different lengths of followup. We chose not to quantitatively pool these data because there was marked qualitative heterogeneity between studies, and pooling data from observational studies is even more problematic than combining results from trials. We do not consider this a limitation of our approach, but it did make the results more challenging to report in a succinct fashion.

Research in Progress

We identified eight studies that are in progress by searching, which is a service of the National Institutes of Health. These studies are detailed in Appendix C *, Evidence Table 29. Six of these studies are interventional, and two are observational. The BABY-HUG study is a Phase III randomized trial treating children from 9 months to 18 months old with hydroxyurea or placebo in order to look for a reduction in rates of damage to the major organs during followup. Study recruitment began in October, 2003 and ended in June, 2007. The study was designed to enroll 200 randomized participants. As of October 4, 2007, 233 patients had entered the screening process, 191 were eligible to begin study treatment, 191 had started study treatment, and 59 had completed 2 years of study treatment.

The SWiTCH study is enrolling children with severe disease into a randomized trial of transfusions and chelation versus hydroxyurea and phlebotomy. The primary outcomes are secondary stroke and iron overload. Study recruitment began in October, 2006 at 21 sites across the United States. As of October 4, 2007, a total of 114 patients had been screened, 80 had consented to enrollment, and 52 had been randomized to treatment. The study target is 130 randomized patients.

A small observational study in Israel will assess long-term outcomes in patients with Hb SS or SB thalassemia who have been treated with hydroxyurea for 5 to 12 years. The other observational study is expecting to enroll 285 patients and follow them prospectively for long-term outcomes. Details of this study from St. Jude Children's Research Hospital are sparse, but the long-term outcomes will include cellular and molecular outcomes. Of the interventional studies, three are funded by the National Heart, Lung, and Blood Institute, and two are funded by the FDA. One of the studies is a phase I study designed to look at the effect of hydroxyurea on morbidity and aerobic capacity in patients with chronic kidney disease and pulmonary hypertension. In this trial, erythropoetin will be administered as well. Another phase I/II study will use tricuspid regurgitant jet velocity as an endpoint to assess improvement in patients with pulmonary hypertension. Two trials were described as evaluating the use of clotrimazole with hydroxyurea, but these trials were listed as starting in 1997 and 1999, so we are uncertain if these trials are in progress or were never initiated.

In addition, analyses based on the MSH trial and the subsequent followup studies are continuing. From an e-mail communication with Bruce Barton, PhD, of the Maryland Medical Research Institute, we are aware of 17 analyses at various stages of development that will be extremely useful contributions to this body of knowledge. These are listed in Appendix C, Evidence Table 30, and include analyses of reproductive outcomes associated with the use of hydroxyurea, analgesia usage, pulmonary hypertension progression in patients on hydroxyurea, and others.

Future Research Needs

The studies described above should answer some of the important questions that remain, particularly regarding the use of hydroxyurea in infants and the role of this drug in reducing the risk of secondary stroke. However, there are still substantial research needs that relate to the use of hydroxyurea in patients with sickle cell disease.

The paucity of randomized trials suggests that additional RCTs with other clinical outcomes may be appropriate, including randomized trials that are aimed at preventing other complications of sickle cell disease, such as kidney disease, pulmonary hypertension, neurological events in adults, and psychiatric complications. Also, effectiveness trials are needed to assess the use of hydroxyurea in a regular care setting. These could be clustered randomized trials in which some providers are randomized to use hydroxyurea in all patients and other are randomized to usual care, including the use of hydroxyurea when clinically indicated, or effectiveness studies in which one group of providers is actively encouraged to consider hydroxyurea when appropriate and another clinic is not targeted for education.

Longer studies are needed to assess the toxicities of this drug. Studies are needed in which patients are treated for a longer time, as are studies in which patients are followed for a longer time, even if the treatment is discontinued. This design is most relevant to assessing outcomes with a long latency period, such as leukemia and secondary malignancies, including skin cancers. Certainly, it may not be feasible to run randomized trials for many years, so a well-designed prospective study may be the optimal design. A registry of users of hydroxyurea could also be considered if the data collection and followup can be sufficiently rigorous. Other toxicities requiring further study are the developmental toxicities and risk to subsequent generations that are described in detail in the CERHR report.

Many subgroups require further study, particularly patients with genotypes other than Hb SS. While there have been observational studies of patients with other genotypes, the randomized trials enrolled only patients with Hb SS. Patients with Hb SC were particularly understudied. Additional studies of hydroxyurea at doses other than the MTD are appropriate, particularly since the use of the MTD in resource-poor populations may be less practical. Effectiveness studies of the drug in resource-poor populations would be particularly beneficial. Other subgroups of interest are patients with comorbid illnesses, specifically HIV/AIDS and/or hepatitis C. The interactions between hydroxyurea and these underlying diseases, and between hydroxyurea and therapies for these diseases, need to be understood. Further research on the place of hydroxyurea in therapy is indicated, since the existing studies have not defined the optimal time for initiation of the drug or identified the indicators that a patient has “failed” therapy with hydroxyurea. Other questions remain to be answered: 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?

Given that we have concluded that there is evidence to support the efficacy of hydroxyurea, there is clearly a need for further research on the barriers to the use of this drug. We identified no studies that specifically addressed this question. These studies should specifically aim to identify barriers at the level of the patient, at the level of the provider, and at a societal level, perhaps with special attention to adult patients. After these barriers are better characterized, interventions to overcome these barriers should be tested, including replication of the one promising study that demonstrated improved receipt of routine care in patients with sickle cell disease. The barriers and intervention that we identified as influencing the use of other treatments in sickle cell disease may provide an appropriate starting point for further study, and comparative effectiveness studies may be appropriate as well, in particular for testing established interventions for improving pain control.


This systematic review has important implications for clinicians, policymakers, and researchers. Clinicians should be encouraged by the established efficacy of hydroxyurea in sickle cell anemia. This drug has been demonstrated to have favorable hematological effects that, importantly, have been shown to clearly translate into clinical benefits. These findings affect the care of both children and adults with sickle cell disease. However, clinicians must also be aware of the paucity of long-term safety data, although the scanty evidence that exists is somewhat reassuring. In addition, clinicians must appreciate that there is very little information available regarding many important clinical issues, including the optimal dose for producing the best clinical outcomes, as well as clear indicators for initiating therapy or for discontinuing therapy because of a poor response. The major gaps in our knowledge about hydroxyurea, described in this report, should motivate researchers to search for answers. Also, if this drug is shown to have long-term safety, research needs to be directed at testing interventions to overcome barriers to the use of this drug so that patients have the opportunity to enjoy its benefits.

One should consider in interpreting this report that this is the only FDA-approved medication for the treatment of sickle cell disease. This medication is not being evaluated for comparative effectiveness or comparative safety with reference to established therapies. It is the only available drug that alters the disease process, and therefore its toxicities or potential toxicities should be interpreted in this light, particularly since it is being used to treat a disease that has tremendous morbidity and predictably shortens patients' lifespan.

Although it was beyond the scope of this report to describe the funding challenges in sickle cell disease research, we note a recent article that describes the state of funding for such research.186 In their paper, Smith et al. describe both federal and foundation funding for both sickle cell disease and cystic fibrosis. The report noted that even though cystic fibrosis affects fewer than half the number of Americans affected by sickle cell disease, there is a dramatic discrepancy in their funding. The total amount of funding from both private philanthropic support and NIH research support per person affected with sickle cell disease was found to be $1,130, as compared to $9,340 for each person affected by cystic fibrosis. The implication is that patients from racial minorities, and often a low-socioeconomic stratum, may not have the organizational strength and resources to command research dollars.



Appendixes cited in this report are provided electronically at: http://www​​.htm


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