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NIH Consensus Development Conference:

Hydroxyurea Treatment
for Sickle Cell Disease


February 25-27, 2008
Bethesda, Maryland

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Final Panel Statement

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NIH consensus and state-of-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of (1) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality (AHRQ), (2) presentations by investigators working in areas relevant to the conference questions during a 2-day public session, (3) questions and statements from conference attendees during open discussion periods that are part of the public session, and (4) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the panel and is not a policy statement of the NIH or the Federal Government.

 

The statement reflects the panel’s assessment of medical knowledge available at the time the statement was written. Thus, it provides a “snapshot in time” of the state of knowledge on the conference topic. When reading the statement, keep in mind that new knowledge is inevitably accumulating through medical research.



 

Contents

 

Abstract

Introduction

  1. What is the efficacy (results from clinical studies) of hydroxyurea treatment for patients who have sickle cell disease in three groups: infants, preadolescents, and adolescents/adults?
  2. What is the effectiveness (in everyday practice) of hydroxyurea treatment for patients who have sickle cell disease?
  3. What are the short- and long-term harms of hydroxyurea treatment?
  4. What are the barriers to hydroxyurea treatment for patients who have sickle cell disease, and what are the potential solutions?
  5. What are the future research needs?

Conclusions

Panel

Speakers

Planning Committee

Sponsors

Additional Information

 


 

Abstract


Objective: To provide health care providers, patients, and the general public with a responsible assessment of currently available data on hydroxyurea treatment for sickle cell disease.


Participants: A non-DHHS, nonadvocate 14-member panel representing the fields of internal medicine, family practice, hematology, oncology, pediatrics, obstetrics, nursing, pediatric nursing, social work, pharmacology, pharmacokinetics, and pain research, mental health, epidemiology, biostatistics, public health, and health systems research, in addition to a public representative. In addition, 22 experts from pertinent fields presented data to the panel and conference audience.


Evidence: Presentations by experts and a systematic review of the literature prepared by The Johns Hopkins University Evidence-Based Practice Center, through the Agency for Healthcare Research and Quality. Scientific evidence was given precedence over anecdotal experience.


Conference Process: Answering pre-determined questions, the panel drafted its statement based on scientific evidence presented in open forum and on the published scientific literature. The draft statement was read in its entirety on the final day of the conference and circulated to the audience for comment. The panel then met in executive session to consider the comments received, and released a revised statement later that day at http://consensus.nih.gov. This statement is an independent report of the panel and is not a policy statement of the NIH or the Federal Government. A final copy of this statement is available, along with other recent conference statements, at the same web address of http://consensus.nih.gov.

 

Conclusions: The burden of suffering is tremendous among many patients who have sickle cell disease. These patients experience disease-related pain on many days of their lives and usually do not seek medical attention until their symptoms are overwhelming. They often attempt to treat themselves and thus do not always come to the attention of the healthcare system. Obtaining optimal care for patients who have sickle cell disease care is challenging. Many patients are not in a coordinated program aimed at prevention of long-term complications and acute pain crises. They rely heavily on emergency and acute care facilities for pain control.


Obtaining specialty care can be a significant challenge as the number of health professionals trained to treat the disease is limited and the number of professionals specializing in the treatment of this disease is decreasing. The likelihood that patients who have sickle cell disease have a principal physician is low. Transitioning from pediatric care to adult care poses particular challenges. Many children rely on public insurance for their care. Gaps in coverage occur, leading to gaps in care.


No population-based registries exist that provide good estimates of the number of people who have sickle cell disease. Surveys indicate that a large proportion of patients who have sickle cell disease are poor and from underserved communities. Most U.S. patients who have sickle cell disease are ethnic minorities. For many, the limited resources and lack of culturally competent care by experienced clinicians set the stage for suboptimal care.


Hydroxyurea is an important major advance in the treatment of sickle cell disease. Strong evidence supports the efficacy of hydroxyurea in adults to decrease severe painful episodes, hospitalizations, number of blood transfusions, and acute chest syndrome. Although the evidence for efficacy of hydroxyurea treatment for children is not as strong, the emerging data are encouraging. The current data on the risks of both short- and long-term harms of hydroxyurea therapy are reassuring, and the risks of hydroxyurea use in adults are acceptable compared with the risks of untreated sickle cell disease.


It is difficult to draw conclusions about the effectiveness of hydroxyurea in everyday practice because we lack precise estimates of the number of people with sickle cell disease in the United States and the number of people receiving hydroxyurea. Furthermore, although barriers to the use of hydroxyurea in persons with sickle cell disease seem to be extensive, little research exists on these patient-, parent/family/caregiver-, provider-, and system-level barriers. More studies are required to address these issues.


The best way to achieve optimal care for patients who have sickle cell disease, including preventive care, is for the patients to be treated in clinics specializing in the care of this disease. All sickle cell patients who have sickle cell disease should have a principal healthcare provider, and that provider, if not a hematologist, should be in frequent consultation with one. The National Institutes of Health funds sickle cell research centers, and several States currently support sickle cell specialty clinics. Increased funding for basic, clinical, and social research on this disease is critically needed. There is an urgent need for centers specializing in the treatment of sickle cell disease to organize and network.



 

Introduction

 

Sickle cell disease is an inherited blood disorder that affects between 50,000 and 100,000 people in the United States. It is estimated that 2,000 babies are born with sickle cell disease in the United States each year. Sickle cell disease was the first disease for which a specific molecular defect in a gene was identified, and it is the most common genetic disease identified as part of the Newborn Screening Program in the United States. The condition is chronic and lifelong, and it is associated with a decreased lifespan. Sickle cell disease is most common in people whose families come from Africa, South or Central America, Caribbean islands, Mediterranean countries (such as Turkey, Greece, and Italy), India, and Saudi Arabia.


Sickle cell disease occurs when an infant inherits the gene for sickle hemoglobin from both parents (Hb SS, or sickle cell anemia) or the gene for sickle hemoglobin from one parent and another abnormal hemoglobin gene from the other parent. In addition, approximately 2 million Americans have sickle cell trait (in which an infant inherits the gene for sickle hemoglobin from one parent and a normal hemoglobin gene from the other parent). Several additional sickle syndromes result from genotypes that include, but are not limited to: SCD–Sß0, SCD–SC, SCD-SD, SCD-Sß+, and SCD-SOarab.


Erythrocytes in people who have sickle cell disease become deoxygenated (depleted of oxygen), dehydrated, and crescent-shaped or “sickled.” The cells aggregate, or clump together, and stick to blood vessel walls. Aggregation blocks blood flow within limbs and organs. This can cause painful episodes and permanent damage to the eyes, brain, heart, lungs, kidneys, liver, bones, and spleen. Infections and lung disease are leading causes of death in people who have sickle cell disease.


Patients who have sickle cell disease are frequently seen in emergency departments and hospitalized for pain crises. Standard treatments for acute pain crises include painkilling medications, hydration, and oxygen.


Hydroxyurea was initially synthesized in Germany in 1869. Nearly 50 years ago, it was developed as an anticancer drug and has been used to treat myeloproliferative syndromes, some leukemias, melanoma, and ovarian cancer. It also has been used to treat psoriasis. Hydroxyurea was first tested in sickle cell disease in 1984. Initial studies show that it acts to increase the production of fetal hemoglobin-containing erythrocytes and dilute the number of sickled cells in circulation.


In the mid–1990s, a major study randomly assigned nearly 300 adults who have sickle cell disease who had more than three painful crises per year to hydroxyurea or placebo. In the past, the term “pain crises” has been used; currently, the term “severe pain episodes” is preferred. This study was stopped early because it clearly showed that hydroxyurea reduced the number and severity of pain episodes in patients with sickle cell disease compared with placebo. Follow-up with the trial participants, including patients who were originally given placebo and were later prescribed hydroxyurea after the drug was determined to be beneficial, has shown that hydroxyurea reduces the damaging effects of sickle cell disease and improves some aspects of quality of life. The drug also may extend survival. In 1998, the U.S. Food and Drug Administration approved hydroxyurea for prevention of pain crises in adults who have sickle cell anemia. Although the efficacy of hydroxyurea has been established in adults, the evidence of its efficacy in children is not as strong; however, the emerging data are supportive.


Although hydroxyurea is beneficial to some patients who have sickle cell disease, several issues about the use of the drug are unresolved. These include patient and health practitioner concerns about the overall safety and effectiveness of hydroxyurea, as well as a lack of providers devoted to treating sickle cell disease.


To more closely examine this important topic, the National Heart, Lung, and Blood Institute and the Office of Medical Applications of Research of the National Institutes of Health convened a Consensus Development Conference from February 25 to 27, 2008, to assess the available scientific evidence related to the following questions:

 


At the conference, invited speakers presented information pertinent to these questions, and a systematic literature review prepared under contract with the AHRQ (available at www.ahrq.gov/clinic/tp/hydscdtp.htm) was summarized. Conference attendees provided both oral and written statements in response to the key questions. The panel members weighed all of this evidence as they addressed the conference questions.


This consensus statement is intended to provide researchers, health care providers, patients, and other interested members of the general public with an objective assessment of what is known about hydroxyurea as a treatment for sickle cell disease, and what questions remain.

 



  1. What is the efficacy (results from clinical studies) of hydroxyurea treatment for patients who have sickle cell disease in three groups: infants, preadolescents, and adolescents/adults?

 

Efficacy is the therapeutic effect of an intervention in a controlled setting, in contrast to effectiveness, which is the therapeutic effect of an intervention in real-world situations. The spectrum of sickle cell disease includes the SCD-SS, SCD-Sß0, SCD-SC, SCD-SD, SCD-Sß+, and SCD-SOarab genotypes. Efficacy studies have varied in their inclusion of specific genotypes but almost exclusively include SCD-SS. In addition, the geographic origin of sickle cell disease is associated with different haplotypes and varying degrees of clinical severity. The three most common and phenotypically distinct haplotypes are Senegalese, Benin, and Bantu. Other geographic areas of origin associated with sickle cell disease include Saudi Arabia and the Indian subcontinent. The Benin and Bantu haplotypes are more common among people residing in the Western Hemisphere and are associated with worse clinical outcomes. Response to hydroxyurea therapy may vary by haplotype or genotype. However, few studies of efficacy have appropriately accounted for the heterogeneity of study populations that differed by genotype and phenotype as well as by demographic factors (such as sex and age group).


Although clinical experience on the use of hydroxyurea for treating sickle cell disease has been amassed over nearly 25 years, the strength of evidence supporting the efficacious use of hydroxyurea is not equivalent across age groups. Hydroxyurea is currently U.S. Food and Drug Administration-approved for use in adults and is the only treatment for sickle cell disease that modifies the disease process. Evidence is strong in adults but more limited in children because the sole randomized clinical trial in the latter population had a weak study design, small sample, and short follow-up. Nonetheless, the evidence in children does not contradict the findings in adults that hydroxyurea improves hematologic variables and decreases hospitalization rates. Published evidence based on weaker, observational study designs, such as cohort studies, pre/poststudies, case series, and case reports, suggests that hydroxyurea is efficacious. Adding to the difficulty in reaching a consensus on the use of hydroxyurea is that published efficacy studies are difficult to interpret because diverse outcome measures have been used including hematological end points; reduced incidence of pain episodes, acute chest syndrome, hospitalizations, strokes, and kidney and spleen damage; and need for transfusion therapy. Studies currently under way should provide more information regarding the benefit of hydroxyurea in prevention of organ damage and additional sickle cell disease outcomes. Elucidating the mechanism of action of hydroxyurea should prove useful in developing new agents.


Adolescents and Adults


Strong evidence supports the efficacy of hydroxyurea use in adults. The published clinical trials included adolescents; however, they were not analyzed or reported as a separate group. Outcomes were diverse and included blood markers as measures of treatment effect (e.g., hemoglobin level, hemoglobin F cells, percentage of hemoglobin F, mean corpuscular volume, leukocyte count, and platelet count). Studies used a variety of clinical outcome measures (severe pain episodes, hospitalizations, acute chest syndrome, blood transfusion therapy, mortality, priapism (unwanted, prolonged, painful erection), strokes, and leg ulcers) and examined the effects of hydroxyurea on the spleen, kidneys, and blood flow to the brain. A summary of the outcomes evaluated in the adult studies is shown in table 1.


Table 1. Study Outcomes for Adults Receiving Hydroxyurea for Sickle Cell Disease


Outcomes Effect
Blood Markers  
Hemoglobin level ↑↑↑
Percentage of fetal hemoglobin ↑↑↑
Mean corpuscular volume ↑↑↑
Leukocyte count ↑↑↑
Clinical Outcomes  
Pain crises ↓↓↓
Hospitalizations ↓↓↓
Blood transfusion therapy ↓↓↓
Acute chest syndrome ↓↓↓
Priapism (painful erection) ←→ (not evaluated)
Strokes ←→ (not evaluated)
Leg ulcer ←→ (not significantly different)
Sepsis ←→ (not evaluated)
Prevention of end-organ damage  
Spleen ←→ (not evaluated)
Kidney ←→ (not evaluated)
Brain (cerebral blood flow) ←→ (being evaluated)
Mortality


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

↓↓↓ = high-grade evidence for a decrease; ↓ = low-grade evidence for a decrease; ↑↑↑ = high-grade evidence for an increase; ←→ = not significantly different or not evaluated or insufficient data.


Although a reduction in mortality with hydroxyurea therapy has been reported, the published trial was not specifically designed to assess this end point. It is therefore difficult to draw definitive conclusions about the effect of hydroxyurea on mortality.


Preadolescents


The evidence varies on whether the use of hydroxyurea improves short-term end points, especially hematologic measures, in preadolescent populations beyond infancy. A summary of study outcomes for preadolescents is shown in table 2.


Table 2. Study Outcomes for Preadolescent Children Beyond Infancy Receiving Hydroxyurea for Sickle Cell Disease


Outcomes Impact
Blood Markers  
Hemoglobin level ←→ (not significantly different)
Percent of fetal hemoglobin ↑↑↑
Mean corpuscular volume ↑↑↑
Leukocyte count ↓↓↓
Clinical Outcomes  
Pain crises ↓↓
Hospitalizations ↓↓↓
Blood transfusion therapy ←→ (insufficient data)
Acute chest syndrome ←→ (insufficient data)
Priapism ←→ (not evaluated)
Stroke
Leg ulcer ←→ (not evaluated)
Sepsis ←→ (not evaluated)
Prevention of End Organ Damage  
Spleen ←→ (being evaluated)
Kidney ←→ (being evaluated)
Brain (cerebral blood flow) ←→ (being evaluated)
Mortality ←→ (insufficient data)


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

↓↓↓ = high-grade evidence for a decrease; ↓↓ = moderate-grade evidence for a decrease; ↓ = low–grade evidence for a decrease; ↑↑↑ = high-grade evidence for an increase; ←→ = not evaluated or not significantly different or insufficient data


Evidence is strong for an improvement in blood markers and reduced hospitalizations and moderate for a reduction in the incidence of pain crises. Ongoing investigations in this age group will determine the efficacy of hydroxyurea treatment for children who have SCD-SS, a history of stroke, and too much iron (iron overload).


Infants


No published, well-designed clinical trials have evaluated the efficacy of hydroxyurea treatment for infants. Ongoing prospective trials and observational studies are attempting to address this gap. The end points of these studies include prevention of damage to the kidney and spleen and improvements in blood markers that predict long-term clinical outcomes.


In summary, the efficacy of hydroxyurea treatment for adults who have SCD-SS is established. Although the evidence for efficacy of hydroxyurea treatment for children is not as strong, the emerging data are supportive. Future directions include evaluation of efficacy in preadolescent children and infants and further development of therapeutic techniques, including stem cell transplantation and gene therapy. Stem cell transplantation can cure sickle cell anemia.

 


 

  1. What is the effectiveness (in everyday practice) of hydroxyurea treatment for patients who have sickle cell disease?


Effectiveness is the therapeutic effect of an intervention as demonstrated or observed in patients in their usual care setting. The efficacy of hydroxyurea in treating adults who have sickle cell disease is established. Data on the effectiveness of hydroxyurea are limited, but the experience of multiple physicians and clinics strongly suggests that the drug is highly effective in widespread practice. One problem in determining the effectiveness of hydroxyurea treatment is that precise estimates of the number of people who have sickle cell disease in the United States and the number of people receiving hydroxyurea treatment are lacking. Another problem is that adherence to hydroxyurea therapy substantially affects its effectiveness. The fact that it often takes 3 to 6 months of treatment for the patient to have a clinical response decreases adherence. Additional reasons for nonadherence are not fully understood.


Most people who have received hydroxyurea seem to be treated in specialty clinics. Only a fraction of patients who might benefit from hydroxyurea have received treatment. Potentially, many more patients could benefit from treatment, including patients who have been excluded from past research studies. Reasons for exclusion have been pregnancy, substance abuse problems, previous hydroxyurea therapy, HIV infection, stroke in the past 6 years, and long-term use of opioids. Therefore, some of the sickest patients with sickle cell anemia have been excluded from studies.


Observational studies in both adults and children support the use of hydroxyurea in reducing the complications of sickle cell disease (including pain, hospitalizations, blood transfusions, and acute chest syndrome) and decreasing mortality. Although data are limited regarding effectiveness of hydroxyurea treatment for sickle cell disease, it does appear to be effective but is currently underutilized.



 

  1. What are the short- and long-term harms of hydroxyurea treatment?

 

Hydroxyurea treatment has potential short-term and long-term negative effects. The known and potential side effects of this agent seem to be related to its interference with rapidly dividing cells, particularly newly formed blood cells. We have defined short-term effects as conditions that generally occur within 6 months of initiation on hydroxyurea therapy and long-term effects as conditions that are chronic or occur more than 6 months after initiation of hydroxyurea.


Short–Term Effects


The blood–related, short-term effects of hydroxyurea are dose-related and can be predicted based on its mechanism. These are intrinsic to the therapeutic effect of hydroxyurea. They include:

 


A decrease in leukocyte count may predispose the patient to infection, and a decrease in platelet count may predispose the patient to bleeding; these blood cells are therefore monitored regularly during therapy. The effect of hydroxyurea on blood is temporary and reversible. If leukocyte or platelet counts are too low, the dose of hydroxyurea is reduced or the hydroxyurea is discontinued. Careful monitoring of blood-related laboratory tests and dose adherence will usually prevent these side effects.


Another possible short-term effect among men taking hydroxyurea is decreased sperm production, which may be temporary and reversible. Data are limited. No large studies are available of sperm production among men receiving hydroxyurea for sickle cell disease. We are not aware of any reports of an increase in birth defects among the offspring of men who take hydroxyurea.


Hydroxyurea appears to cause dryness of the skin and darkening of the skin and nails (hyperpigmentation); this also may be a long-term side effect.


Leg ulcers are common in adults who have sickle cell disease. In a randomized clinical trial comparing hydroxyurea and placebo, hydroxyurea did not appear to affect the development of leg ulcers in people who have sickle cell disease. Gastrointestinal tract symptoms were no more common among people who were receiving hydroxyurea for sickle cell disease than among those not receiving hydroxyurea.


Long–Term Effects


The potential long–term effects of hydroxyurea are birth defects in the offspring of people receiving the drug, growth delays in children receiving the drug, and cancer in both children and adults who have received the drug. These long–term harms may be permanent and irreversible, but they are not yet proven.


There have been concerns the potential for hydroxyurea to cause birth defects in humans, because it has caused birth defects in experimental animals. Pregnant rats and mice given hydroxyurea in very high doses have an increased number of offspring with birth defects. However, the number of birth defects among the offspring of women who received hydroxyurea during pregnancy does not seem to be increased. The long–term effects of hydroxyurea on children exposed to the drug in utero are unknown. Nonetheless, because of concerns about the potential of hydroxyurea to cause birth defects, the drug is generally not prescribed to pregnant women. Men and women who are receiving hydroxyurea are advised to use contraception. Women who are trying to become pregnant or who do become pregnant while taking hydroxyurea should stop taking the drug.


Children aged 5 to 15 who have sickle cell disease and receive hydroxyurea show a growth rate similar to that of peers who have sickle cell disease who are not receiving hydroxyurea.


Hydroxyurea has an excellent and longstanding safety profile in the treatment of myeloproliferative disorders, although cases of leukemia and other cancers have been reported in patients who have received hydroxyurea for other blood conditions. Most of these conditions are blood disorders, such as polycythemia vera or essential thrombocytosis, and these conditions can progress spontaneously to leukemia. This makes it difficult to determine whether hydroxyurea itself causes leukemia. Cases of leukemia and other types of cancer also have been reported among both children and adults who have taken hydroxyurea to treat sickle cell disease. These cases are rare and seem to be no more common than among the general population. The risk of cancer does not appear to differ for people who have sickle cell disease who have received hydroxyurea and those who have not.


Because both patients and providers have identified side effects as a concern that limits the use of hydroxyurea, more information on the incidence and severity of these side effects is essential for both patients and providers to make informed choices. These data could come from a registry of patients who have sickle cell disease. Nevertheless, the currently available data are reassuring with respect to the risks of both the short- and long-term harms of hydroxyurea.


The natural history of sickle cell disease results in frequent, severe pain episodes and permanent damage to the eyes, brain, heart, lungs, kidneys, liver, bones, and spleen. Hydroxyurea reduces the frequency and severity of pain episodes. The risks of hydroxyurea are acceptable compared to the risks of untreated sickle cell disease.


A summary of side effects of hydroxyurea treatment is shown in table 3.


Table 3. Short– and Long–Term Side Effects of Hydroxyurea Treatment in People Who Have Sickle Cell Disease


Short-Term Side Effects Comment
Decreased leukocyte count (leukopenia)
Decreased platelet count (thrombocytopenia)
Decreased erythrocyte count (anemia)
Frequent, expected, and dose related; typically can be anticipated and prevented by temporary discontinuation of hydroxyurea or decrease in hydroxyurea dose; usually resolve within 1 to 2 weeks.
Nausea (usually mild) *
Skin rash
Pneumonitis (lung inflammation)
Infrequent
Temporarily decreased sperm counts or sperm abnormalities* Not adequately evaluated
Long-Term Side Effects  
Increased risk of superficial skin cancers*
Skin and nail darkening (hyperpigmentation)
Infrequent
Permanently decreased sperm counts* Not adequately evaluated
Reproductive Side Effects* When taken during pregnancy, hydroxyurea can in theory increase the risk of miscarriage, birth defects, restricted fetal growth, or postnatal development. Sexually active couples should avoid pregnancy if either is on hydroxyurea.


* Evidence is insufficient or low that this side effect is associated with the use of hydroxyurea.

 


 

  1. What are the barriers to hydroxyurea treatment for patients who have sickle cell disease, and what are the potential solutions?

 

Barriers to hydroxyurea treatment for patients who have sickle cell disease can arise at four levels—patient, parent/family/caregiver, provider, and system. A systematic evidence review of the barriers to hydroxyurea treatment found only three studies that specifically addressed this issue and none that tested interventions to overcome barriers to hydroxyurea. Barriers to hydroxyurea treatment are shown in table 4.


Table 4. Barriers to Hydroxyurea Treatment in Persons Who Have Sickle Cell Disease


Barrier Level
Patient Patient/
Family/
Caregiver
Provider
Fears or concerns about cancer, birth defects, infertility, and the uncertainty of long-term risks checkmark graphic checkmark graphic checkmark graphic
Lack of knowledge about hydroxyurea as a therapeutic option checkmark graphic checkmark graphic checkmark graphic
Lack of perception that hydroxyurea is currently the only therapy that directly modifies the disease process checkmark graphic checkmark graphic checkmark graphic
Concern that the nonapproved status of hydroxyurea for children means that hydroxyurea is an experimental drug checkmark graphic checkmark graphic  
Difficulty in communication between patients and their caregivers regarding the use of hydroxyurea and other therapeutic options   checkmark graphic  
Need for frequent monitoring of response to hydroxyurea checkmark graphic    
Lack of adherence to treatment regimen checkmark graphic    
Provider bias and negative attitudes toward patients who have sickle cell disease and their treatment     checkmark graphic
Lack of clarity in hydroxyurea treatment regimens and undertreatment in adults     checkmark graphic
Limited number of physicians who have expertise in the use of hydroxyurea for sickle cell disease     checkmark graphic
Failure to engage patients/caregivers in treatment decisionmaking in a developmentally appropriate manner     checkmark graphic


Some social, economic, and cultural characteristics of patients who have sickle cell disease are important in reviewing both barriers and solutions to access to hydroxyurea. Patients who have sickle cell disease are often poorer than the national average and are often covered by Medicaid. They also may be immigrants who cannot obtain insurance. The care of children and adults who have sickle cell disease and the barriers to their care must be viewed in the context of their families, communities, and the U.S. healthcare system. The care of patients who have sickle cell disease needs to be longitudinal across the lifespan, and the difficulties in transitioning their care from pediatric to adult settings remain a challenge.


System-level barriers to hydroxyurea treatment for sickle cell disease include:

 


Solutions


We propose the following solutions to these barriers:

 



 

  1. What are the future research needs?

 

We support the use of hydroxyurea for the treatment of sickle cell disease but recognize that additional research is required to provide information that will ensure the most appropriate application of this therapy.


A surveillance system is needed for patients who have sickle cell disease who will be followed prospectively. This system should contain demographic, laboratory, clinical, treatment, and outcome information.


Additional efficacy studies are also required. These studies should evaluate the efficacy of hydroxyurea as measured in terms of clinical and laboratory outcomes and define the mechanisms of action of hydroxyurea in a clinical setting; use pharmacokinetic and clinical measures to determine optimal dosing, dose titration, and clinical efficacy; identify the factors that predict clinical response and nonresponse to hydroxyurea; and confirm the validity of hemoglobin F as a surrogate measure of benefit.


Additional effectiveness studies are also required. These studies should determine the number of patients with sickle cell disease and those who will benefit from hydroxyurea. They should also determine when to begin the use of hydroxyurea to treat or prevent complications of sickle cell disease and how long to continue its use. These studies should complement those currently in progress.


Although we believe hydroxyurea to be safe and effective, additional studies of the safety, clinical effectiveness, and cost-effectiveness are required. Appropriate studies are needed to provide more information about:

 

 


 

Conclusions

 

The burden of suffering is tremendous among many patients who have sickle cell disease. These patients experience disease-related pain on many days of their lives and usually do not seek medical attention until their symptoms are overwhelming. They often attempt to treat themselves and thus do not always come to the attention of the healthcare system. Obtaining optimal care for patients who have sickle cell disease care is challenging. Many patients are not in a coordinated program aimed at prevention of long-term complications and acute pain crises. They rely heavily on emergency and acute care facilities for pain control.


Obtaining specialty care can be a significant challenge as the number of health professionals trained to treat the disease is limited and the number of professionals specializing in the treatment of this disease is decreasing. The likelihood that patients who have sickle cell disease have a principal physician is low. Transitioning from pediatric care to adult care poses particular challenges. Many children rely on public insurance for their care. Gaps in coverage occur, leading to gaps in care.


No population-based registries exist that provide good estimates of the number of people who have sickle cell disease. Surveys indicate that a large proportion of patients who have sickle cell disease are poor and from underserved communities. Most U.S. patients who have sickle cell disease are ethnic minorities. For many, the limited resources and lack of culturally competent care by experienced clinicians set the stage for suboptimal care.


Hydroxyurea is an important major advance in the treatment of sickle cell disease. Strong evidence supports the efficacy of hydroxyurea in adults to decrease severe painful episodes, hospitalizations, number of blood transfusions, and acute chest syndrome. Although the evidence for efficacy of hydroxyurea treatment for children is not as strong, the emerging data are encouraging. The current data on the risks of both short- and long-term harms of hydroxyurea therapy are reassuring, and the risks of hydroxyurea use in adults are acceptable compared with the risks of untreated sickle cell disease.


It is difficult to draw conclusions about the effectiveness of hydroxyurea in everyday practice because we lack precise estimates of the number of people with sickle cell disease in the United States and the number of people receiving hydroxyurea. Furthermore, although barriers to the use of hydroxyurea in persons with sickle cell disease seem to be extensive, little research exists on these patient-, parent/family/caregiver-, provider-, and system-level barriers. More studies are required to address these issues.


The best way to achieve optimal care for patients who have sickle cell disease, including preventive care, is for the patients to be treated in clinics specializing in the care of this disease. All sickle cell patients who have sickle cell disease should have a principal healthcare provider, and that provider, if not a hematologist, should be in frequent consultation with one. The National Institutes of Health funds sickle cell research centers, and several States currently support sickle cell specialty clinics. Increased funding for basic, clinical, and social research on this disease is critically needed. There is an urgent need for centers specializing in the treatment of sickle cell disease to organize and network.

 


 

State-of-the-Science Panel

 

Otis W. Brawley, M.D.
Panel and Conference Chairperson

Professor of Hematology, Oncology,
Medicine, and Epidemiology
Emory University
Chief Medical Officer
American Cancer Society
Atlanta, Georgia

 

Llewellyn J. Cornelius, Ph.D., L.C.S.W.
Professor
University of Maryland School of Social Work
Baltimore, Maryland

 

Linda R. Edwards, M.D.
Division Chief and Associate Professor
Division of General Internal Medicine
College of Medicine
University of Florida, Jacksonville
Jacksonville, Florida

 

Vanessa Northington Gamble, M.D., Ph.D.
University Professor of Medical Humanities
The George Washington University
Washington, DC

 

Bettye L. Green, R.N.
Saint Joseph Regional Medical Center,
Community Outreach/IRB
President Emeritus
African-American Women in Touch
South Bend, Indiana

 

Charles Inturrisi, Ph.D.
Professor of Pharmacology
Weill Medical College of Cornell University
New York, New York

 

Andra H. James, M.D., M.P.H.
Director
Women's Hemostasis and Thrombosis Clinic
Assistant Professor of Obstetrics and Gynecology
Duke University Medical Center
Durham, North Carolina

 

 

Danielle Laraque, M.D.
Debra and Leon Black Professor of Pediatrics
Chief, Division of General Pediatrics
Mount Sinai School of Medicine
New York, New York

 

Magda Mendez, M.D.
Assistant Professor of Clinical Pediatrics
Weill Medical College of Cornell University
Associate Program Director
Lincoln Medical and Mental Health Center
Bronx, New York

 

Carolyn J. Montoya, R.N., M.S.N., C.P.N.P.
President
National Association of Pediatric Nurse Practitioners
Coordinator, Family Nurse Practitioner Concentration
Pediatric Nurse Practitioner Concentration
College of Nursing
University of New Mexico
Albuquerque, New Mexico

 

Brad H. Pollock, M.P.H., Ph.D.
Professor and Chairman
Department of Epidemiology and Biostatistics
School of Medicine
University of Texas Health Science Center at San Antonio
San Antonio, Texas

 

Lawrence Robinson, M.D., M.P.H.
Deputy Health Commissioner
Philadelphia Department of Public Health
Philadelphia, Pennsylvania

 

Aaron P. Scholnik, M.D., F.A.C.P.
Director, Cancer Research Office
Upper Peninsula Hematology/Oncology Associates
Marquette General Health System
Marquette, Michigan

 

Melissa Schori, M.D., M.B.A., F.A.C.P.
Senior Vice President
Chief Medical Officer
Princeton Healthcare System
Princeton, New Jersey

 


 

Speakers

 

Kenneth I. Ataga, M.D.
Assistant Professor of Medicine
Division of Hematology/Oncology
Department of Medicine
School of Medicine
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

 

Mary Catherine Beach, M.D., M.P.H.
Assistant Professor of Medicine and Health Policy and Management
Division of General Internal Medicine
School of Medicine
The Johns Hopkins University
Baltimore, Maryland

 

Melissa S. Creary, M.P.H.
Associate Service Fellow
Division of Blood Disorders
National Center on Birth Defects and Developmental Disabilities
Centers for Disease Control and Prevention
Atlanta, Georgia

 

Michael R. DeBaun, M.D., M.P.H.
Professor of Pediatrics, Biostatistics, and Neurology
Director, Sickle Cell Medical Treatment and Education Center
Washington University School of Medicine
St. Louis Children’s Hospital
St. Louis, Missouri

 

James R. Eckman, M.D.
Director Georgia Sickle Cell Comprehensive Care Center
Winship Cancer Institute
Emory University
Atlanta, Georgia

 

Bruce L. Evatt, M.D.
Clinical Professor of Medicine Emory University School of Medicine
Retired Former Director
Division of Hereditary Blood Disorders
National Center on Birth Defects and Developmental Disabilities
Centers for Disease Control and Prevention
Atlanta, Georgia

 

Regina Hutchins-Pullins
Cincinnati, Ohio

 

Cage S. Johnson, M.D.
Director
University of Southern California Comprehensive Sickle Cell Center
Professor of Medicine
Keck School of Medicine
University of Southern California
Los Angeles, California

 

Sophie Lanzkron, M.D.
Assistant Professor of Medicine and Oncology
Director, Sickle Cell Center for Adults at Johns Hopkins
School of Medicine
The Johns Hopkins University
Baltimore, Maryland

 

Erica L. Liebelt, M.D., FACMT, F.A.A.P.
Professor of Pediatrics and Emergency Medicine
Director, Medical Toxicology Services
University of Alabama School of Medicine
Children's Hospital and University Hospital
Co-Medical Director
Regional Poison Control Center
Birmingham, Alabama

 

Richard Lottenberg, M.D.
Director University of Florida Adult Sickle Cell Disease Program
Professor
Division of Hematology/Oncology
Department of Medicine
University of Florida
Gainesville, Florida

Kwaku Ohene-Frempong, M.D.
Professor of Pediatrics University of Pennsylvania School of Medicine
Director, Comprehensive Sickle Cell Center
The Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania

 

Eugene P. Orringer, M.D.
Professor of Medicine Executive Associate Dean, Faculty Affairs and Faculty Development
Dean's Office, School of Medicine
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

 

Griffin P. Rodgers, M.D., M.A.C.P.
Director
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Bethesda, Maryland

 

Wally R. Smith, M.D.
Professor of Medicine
Chairman, Division of Quality Health Care
Department of Internal Medicine
Virginia Commonwealth University
Richmond, Virginia

 

Martin H. Steinberg, M.D.
Director
Center of Excellence in Sickle Cell Disease
Professor of Medicine and Pediatrics
Boston University School of Medicine
Boston, Massachusetts

 

John J. Strouse, M.D.
Assistant Professor of Pediatrics
Division of Pediatric Hematology
School of Medicine
The Johns Hopkins University
Baltimore, Maryland

 

Trevor K. Thompson, M.A.
Chairman, Patient Advisory Board
Diggs-Kraus Sickle Cell Center
Memphis, Tennessee

 

Marsha J. Treadwell, Ph.D.
Director, Patient Services Core
Northern California Comprehensive Sickle Cell Center
Children's Hospital and Research Center at Oakland
Oakland, California

 

Russell E. Ware, M.D., Ph.D.
Chair
Department of Hematology
St. Jude Children’s Research Hospital
Memphis, Tennessee

 

Richard Watkins
Director of Technical Specialists
Oracle Corporation
Potomac, Maryland

 

Thomas S. Webb, M.D., M.Sc.
Assistant Professor of Clinical Internal Medicine and Pediatrics
Principal Investigator, Cincinnati Sickle Cell Network, HRSA SCD Treatment Demonstration Program
Division of General Internal Medicine
University of Cincinnati
Cincinnati Children’s Hospital
Institute for the Study of Health
Cincinnati, Ohio

 


 

Planning Committee

 

Ellen M. Werner, Ph.D.
Planning Committee Chairperson

Health Science Administrator
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
National Institutes of Health
Bethesda, Maryland

 

Lisa Ahramjian, M.S.
Communication Specialist
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland

 

David Atkins, M.D., M.P.H.
Chief Medical Officer
Center for Outcomes and Evidence
Agency for Healthcare Research and Quality
Rockville, Maryland

 

Lennette J. Benjamin, M.D.
Professor of Medicine
Albert Einstein College of Medicine
Clinical Director
Comprehensive Sickle Cell Center
Montefiore Medical Center
Bronx, New York

 

Otis W. Brawley, M.D.*
Panel and Conference Chairperson

Medical Director
Grady Cancer Center of Excellence
Winship Cancer Institute
Emory University
Atlanta, Georgia

 

Virginia Cain, Ph.D.
Health Scientist
National Center for Health Statistics
Centers for Disease Control and Prevention
Hyattsville, Maryland

 

Beth A. Collins Sharp, Ph.D., R.N.
Director
Evidence-Based Practice Centers Program
Center for Outcomes and Evidence
Agency for Healthcare Research and Quality
Rockville, Maryland

 

Jennifer Miller Croswell, M.D.
Senior Advisor for the Consensus Development Program
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland

 

George Dover, M.D.
Director
Department of Pediatrics
Johns Hopkins Medical Center
Baltimore, Maryland

 

Kathryn Hassell, M.D.
IPA Assignment, NHLBI
Department of Medicine
Division of Hematology
University of Colorado Health Sciences Center
Denver, Colorado

 

Cage S. Johnson, M.D.
Director
University of Southern California Comprehensive Sickle Cell Center
University of Southern California
Los Angeles, California

 

Susan K. Jones, R.N.
Clinical Research Supervisor
University of North Carolina Comprehensive Sickle Cell Program
University of North Carolina at Chapel Hill
General Clinical Research Center
Chapel Hill, North Carolina

 

Barnett S. Kramer, M.D., M.P.H.
Director
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland

 

Roshni Kulkarni, M.D.
Director
Division of Hereditary Blood Disorders
National Center for Birth Defects and Developmental Disabilities
Centers for Disease Control and Prevention
Atlanta, Georgia

Richard Lottenberg, M.D.
Director
University of Florida Adult Sickle Cell Disease Program
Professor
Division of Hematology/Oncology
Department of Medicine
University of Florida
Gainesville, Florida

 

Harvey Luksenburg, M.D.
Medical Officer/Project Officer
Division of Blood Diseases and Resources
Blood Diseases Branch
National Heart, Lung, and Blood Institute
Bethesda, Maryland

 

Marie Y. Mann, M.D., M.P.H.
Medical Officer
Genetic Services Branch
Maternal and Child Health Bureau
U.S. Department of Health and Human Services
Health Resources and Services Administration
Rockville, Maryland

 

Kelli K. Marciel, M.A.
Communications Director
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland

 

Ernestine (Tina) Murray, R.N., M.A.S.
Captain
U.S. Public Health Service
Evidence-Based Practice Centers Program
Center for Outcomes and Evidence
Agency for Healthcare Research and Quality
Rockville, Maryland

 

Kwaku Ohene-Frempong, M.D.
Professor of Pediatrics
University of Pennsylvania School of Medicine
Director, Comprehensive Sickle Cell Center
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania

 

Betty S. Pace, M.D.
Professor
Department of Molecular and Cell Biology
Director
Sickle Cell Disease Research Center
University of Texas at Dallas
Richardson, Texas

 

Kenneth Rivlin, M.D., Ph.D.
Lincoln Medical and Mental Health Center
Bronx, New York

 

Kathy Robie Suh, M.D., Ph.D.
Medical Team Leader for Hematology
Division of Medical Imaging and
Hematology Products
Office of Oncology Drug Products
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
Silver Spring, Maryland

 

Susan C. Rossi, Ph.D., M.P.H.
Deputy Director
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland

 

Susan Shurin, M.D.
Deputy Director
National Heart, Lung, and Blood Institute
National Institutes of Health
Bethesda, Maryland

 

Claudia Steiner, M.D., M.P.H.
Senior Research Physician
Healthcare Cost and Utilization Project
Center for Delivery, Organization, and Markets
Agency for Healthcare Research and Quality
Rockville, Maryland

 

Russell E. Ware, M.D., Ph.D.
Chair
Department of Hematology
St. Jude Children's Research Hospital
Memphis, Tennessee

 

*Otis W. Brawley, M.D., accepted a position at American Cancer Society in November 2007.


 

Sponsors


National Heart, Lung, and Blood Institute
Office of Medical Applications of Research
of the National Institutes of Health

 

Cosponsors

 

National Human Genome Research Institute
National Institute of Child Health and Human Development
National Institute of Diabetes Digestive and Kidney Diseases
National Institute of Neurological Disorders and Stroke

Office of Rare Diseases Research


Partners


Centers for Disease Control and Prevention
Health Resources and Services Administration


The Agency for Healthcare Research and Quality provided additional conference development support.

 


 

Additional Information

 

About the NIH Consensus Development Program


National Institutes of Health (NIH) consensus and state-of-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of 1) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality (AHRQ), 2) presentations by investigators working in areas relevant to the conference questions during a 2-day public session, 3) questions and statements from conference attendees during open discussion periods that are part of the public session, and 4) closed deliberations by the panel during the remainder of the second day and the morning of the third. This statement is an independent report of the panel and is not a policy statement of the NIH or the federal government.

 

The statement reflects the panel's assessment of medical knowledge available at the time the statement was written. Thus, it provides a "snapshot in time" of the state of knowledge on the conference topic. When reading the statement, keep in mind that new knowledge is inevitably accumulating through medical research, and that the information provided is not a substitute for professional medical care or advice.

 

Publications Ordering Information


NIH Consensus Statements, State-of-the-Science Statements, and related materials are available by visiting http://consensus.nih.gov; by calling toll free 1-888-644-2667; or by e-mailing consensus@mail.nih.gov. Or, written requests can be mailed to the NIH Consensus Development Program Information Center, P.O. Box 2577, Kensington, MD 20891. When ordering copies of this statement, please reference item number 2008-00119-STMT.

The Evidence Report prepared for this conference by the Agency for Healthcare Research and Quality is available on the Web via http://www.ahrq.gov/clinic/tp/hydscdtp.htm. Printed copies may be ordered from the AHRQ Publications Clearinghouse by calling 1-800-358-9295. Requestors should ask for AHRQ Publication No. No. 08-E007.

Disclosure Statement


All of the panelists who participated in this conference and contributed to the writing of this statement were identified as having no financial or scientific conflict of interest, and all signed forms attesting to this fact. Unlike the expert speakers who present scientific data at the conference, the individuals invited to participate on NIH Consensus and State-of-the-Science panels are reviewed prior to selection to assure that they are not proponents of an advocacy position with regard to the topic and are not identified with research that could be used to answer the conference questions. For more information about conference procedures, please see http://consensus.nih.gov/aboutcdp.htm.

 

Archived Conference Webcast


The NIH Consensus Development Conference on Hydroxyurea for Sickle Cell Disease was webcast live February 25-27, 2008. The webcast is archived and available for viewing free of charge at
http:// consensus.nih.gov
.

 


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