NIH State-of-the-Science Conference Statement
Hydroxyurea Treatment for Sickle Cell Disease
February 2527, 2008
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. |
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.
It was the first disease for which a specific molecular defect in a gene was
identified. Sickle cell disease 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 life span. Sickle
cell disease is most common in people whose families come from Africa, South or
Central America (especially Panama), 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). There are several
additional sickle syndromes as a result of genotypes which include, but are not
limited to: SCD–Sß0, SCD–SC, SCD-SD,
SCD-Sß+, and SCD-SOarab.
The red blood cells in people who have sickle cell disease become
deoxygenated (or 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.
The chemical hydroxyurea was initially synthesized in Germany in
1869. Nearly 50 years ago, it was developed as an anticancer drug. It has been
used to treat myeloproliferative syndromes, some leukemias, melanoma, and
ovarian cancer. It also has been used to treat psoriasis. The drug hydroxyurea
was first tested on sickle cell disease in 1984. Initial studies show that it
acts to increase the production of fetal hemoglobin-containing red blood cells
and these dilute the number of sickled cells in circulation.
In the mid–1990s, a major study was conducted that
randomized nearly 300 adult sickle cell patients who had more than three
painful crises per year to hydroxyurea or placebo (an inactive pill). In the
past, the term "pain crises" has been used. Currently, the term "severe pain
episodes" is used. This study was stopped early, as it clearly showed that
hydroxyurea reduced the number and severity of pain crises in sickle cell
patients when compared to patients taking 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, a number of unresolved issues about the use of the drug
exist. These include a lack of providers devoted to treating sickle cell
disease, as well as patient and health practitioner concerns about the overall
safety and effectiveness of the drug.
To take a closer look at 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:
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- 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?
- What is the effectiveness (in everyday practice) of hydroxyurea
treatment for patients who have sickle cell disease?
- What are the short– and long–term harms of
hydroxyurea treatment?
- What are the barriers to hydroxyurea treatment for patients who
have sickle cell disease, and what are the potential solutions?
- What are the future research needs?
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 refers to the therapeutic effect of an intervention in a
controlled setting. This is in contrast to effectiveness, which is the
therapeutic effect of an intervention in real-world situations. This section
reviews the efficacy of hydroxyurea in the treatment of adults/adolescents,
preadolescents, and infants who have sickle cell disease.
In this document, sickle cell disease refers to people who have
the following genotypes: SCD-SS, SCD-Sß0, SCD-SC, SCD-SD,
SCD-Sß+, and SCD-SOarab. 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 haplotypes are Senegalese, Benin, and Bantu, and they are
phenotypically different. Other geographic areas of origin associated with
sickle cell disease include Saudi Arabia and the Indian subcontinent. Benin and
Bantu haplotypes are more common among people residing in the Western
Hemisphere and are associated with worse clinical outcomes. There may be
implications for variable response to hydroxyurea therapy based on haplotype
and/or genotype. Few attempts to assess efficacy have appropriately accounted
for the heterogeneity of study populations who differed by genotype and
phenotype. Also, few studies reported results for subgroups defined by
demographic factors (e.g., 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 Food and Drug
Administration–approved for use in adults and is the only treatment for
sickle cell disease that modifies the disease process. The strength of evidence
does vary greatly across the various age groups. Evidence is stronger in adults
but more limited for children because of a weaker study design, small numbers
of participants, and limited length of follow-up in the one available
randomized clinical trial. Nonetheless, the evidence in children does not
contradict the findings in adults that hydroxyurea improves hematological
parameters and decreases hospitalization rates. Published evidence using
weaker, observational study designs such as cohort studies, pre/poststudies,
case series, and case reports does suggest that, overall, 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 due
to the use of a variety of outcome measures such as hematological endpoints;
reduced incidence of pain crises, acute chest syndrome, hospitalizations,
strokes, and kidney and spleen damage; as well as the need for transfusion
therapy. The results of studies currently under way should provide more
information regarding the benefit of hydroxyurea in prevention of organ damage
and additional sickle cell disease outcomes. Also, learning more about how the
drug works is important in developing new drugs.
Adolescents/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. There is a variety of outcomes,
including blood markers as measures of treatment effect (e.g., hemoglobin
level, hemoglobin F cells, percent hemoglobin F, mean corpuscular volume, white
blood cells, and platelets). Studies have used a variety of clinical outcome
measures (pain crises, hospitalizations, acute chest syndrome, blood
transfusion therapy, mortality, priapism (unwanted prolonged painful erection),
strokes, and leg ulcers). In addition, some studies have looked at effects of
hydroxyurea on the spleen, kidneys, and blood flow to the brain. A summary of
the outcomes evaluated in the adult studies is tabulated below.
Table 1. Summary of Study Outcomes for Adults
Receiving Hydroxyurea for Sickle Cell Disease
Outcomes
|
Impact
|
Blood
Markers |
|
Hemoglobin |
↑↑↑ |
Percent fetal hemoglobin
|
↑↑↑ |
Mean corpuscular volume |
↑↑↑ |
White blood cell count |
↓↓↓ |
Clinical
Outcomes |
|
Pain crises |
↓↓↓ |
Hospitalizations |
↓↓↓ |
Blood transfusion
therapy |
↓↓↓ |
Acute chest syndrome
|
↓↓↓ |
Priapism (painful
erection) |
←→ (not
evaluated) |
Strokes |
←→ (not
evaluated) |
Leg ulcers |
←→ (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 mortality reduction has been reported, the published
trial was not specifically designed to assess this endpoint. It is therefore
difficult to draw definitive conclusions about the impact of hydroxyurea on
mortality.
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Preadolescents
The evidence varies on whether the use of hydroxyurea improves
short-term endpoints, especially hematological measures, in the preadolescent
populations beyond infancy. A summary of study outcomes for preadolescents is
shown in table 2.
Table 2. Summary of Study Outcomes for
Preadolescent Children Beyond Infancy Receiving Hydroxyurea for Sickle Cell
Disease
Outcomes
|
Impact
|
Blood Markers |
|
Hemoglobin |
←→ (not significantly
different) |
Percent fetal hemoglobin |
↑↑↑ |
Mean corpuscular volume |
↑↑↑ |
White blood cell count |
↓↓↓ |
Clinical
Outcomes |
|
Pain crises |
↓↓ |
Hospitalizations |
↓↓↓ |
Blood transfusion therapy |
←→ (insufficient data) |
Acute chest syndrome |
←→ (insufficient data) |
Priapism (unwanted prolonged painful
erection) |
←→ (not evaluated) |
Strokes |
↓ |
Leg ulcers |
←→ (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
There is strong evidence for an improvement in blood markers and
reduced hospitalizations, and moderate evidence 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 strokes, and too much iron (iron overload).
Infants
At present, there are no published, well-designed clinical trials
evaluating hydroxyurea treatment for infants. There are ongoing trials and
observational studies assessing the efficacy of hydroxyurea in the treatment of
infants who have sickle cell disease. The endpoints 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 modalities of therapy, including stem cell
transplant and gene therapy. Stem cell transplant can be curative in this
disease.
2. What is the effectiveness (in everyday practice) of
hydroxyurea treatment for patients who have sickle cell disease?
Effectiveness is defined as the therapeutic effect of an
intervention as demonstrated or observed in patients in their usual care
setting. The efficacy of hydroxyurea in sickle cell disease has been
established. Although there are limited data regarding hydroxyurea's
effectiveness, the experience of multiple physicians and clinics strongly
suggests that the drug can be highly effective in widespread practice. One
problem in determining the effectiveness of hydroxyurea treatment is the lack
of a precise estimate of the number of people who have sickle cell disease in
the United States and the lack of a precise estimate of the number of people
actually receiving hydroxyurea treatment. Adherence is also affected by the
fact that it often takes 3 to 6 months of treatment for the patient to have a
clinical response. Another problem is that effectiveness is significantly
impacted by adherence. Reasons for nonadherence are not fully understood.
It appears that most people who have received hydroxyurea have
been 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 research studies in the past. Studies have excluded patients
who:
- Are pregnant
- Have substance abuse problems
- Have prior hydroxyurea therapy
- Have HIV infection
- Have had strokes within the past 6 years
- Have chronic opioid use
Some of the sickest sickle cell anemia patients have been excluded
from studies. A much broader range of patients might benefit. For example,
patients who have persistent sickle cell disease-induced pain require chronic
opioid use.
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.
3. What are the short– and long–term harms of
hydroxyurea treatment?
There are potential short-term and long-term effects of
hydroxyurea treatment. The precise mechanisms by which hydroxyurea produces its
varied effects are not known. However, a major mechanism is believed to be
interference with an enzyme, ribonucleotide reductase, that is essential for
DNA synthesis. Hydroxyurea's known and potential side effects appear to be
related to its interference with rapidly dividing cells, particularly newly
formed blood cells. We have defined short–term, or acute, effects as
those conditions generally occurring within 6 months of hydroxyurea initiation;
long–term effects are defined as conditions that are chronic and/or have
an onset of greater 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 white blood cell count
(leukopenia)
- A decrease in platelet count (thrombocytopenia)
- Decreased red blood cell count (anemia)
- Decreased reticulocytes (newly formed red blood cells)
A decrease in white blood cell count may predispose the patient to
infection, and a decrease in platelets may predispose the patient to bleeding,
so these blood cells are monitored regularly during therapy. Hydroxyurea's
effect on blood is temporary and reversible. If white blood cell 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 short–term effect among men taking hydroxyurea may
be decreased sperm production, which may be temporary and reversible. Data are
limited. There are no large studies of sperm production among men taking
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, or hyperpigmentation (which also may be a long-term side effect).
Long–Term Effects
The potential long–term effects of hydroxyurea are birth
defects in the offspring of people taking the drug, growth delays in children
taking the drug, and malignancies in both children and adults who have taken
the drug. These long–term harms may be permanent and irreversible, but
they are not yet proven.
There have been concerns about hydroxyurea's potential to cause
birth defects in humans, because it can cause birth defects in experimental
animals. Pregnant rats and mice given hydroxyurea in very high doses have an
increased number of offspring with birth defects. There does not, however,
appear to be an increase in the number of birth defects among the offspring of
women who have taken hydroxyurea during pregnancy. The long–term effects
of hydroxyurea on children exposed to the drug in utero are unknown.
Nonetheless, because of concerns about hydroxyurea's potential to cause birth
defects, the drug is generally not prescribed to pregnant women. Men and women
who are taking hydroxyurea are advised to use contraception. Women who are
trying to become pregnant or become pregnant while taking hydroxyurea should
stop taking the drug.
Children aged 5 to 15 who have sickle cell disease and are treated
with hydroxyurea show growth rates similar to peers with sickle cell disease
who are not on hydroxyurea.
Hydroxyurea has an excellent and longstanding safety profile in
the treatment of myeloproliferative disorders, although cases of leukemia and
other malignancies also have been reported in patients who have taken
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 malignancies also have been reported among both children and adults who
have taken hydroxyurea for the treatment of sickle cell disease. These cases
are rare and appear to be no more common than among the general population. The
risk of cancer appears to be no different for people who have sickle cell
disease who have taken hydroxyurea than for 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
sickle cell disease patients. Nevertheless, the data currently available 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,
painful crises and permanent damage to the eyes, brain, heart, lungs, kidneys,
liver, bones, and spleen. Hydroxyurea reduces the frequency and severity of
painful crises. The risks of hydroxyurea are acceptable compared to the risks
of untreated sickle cell disease.
Table 3. Short– and Long–Term Side
Effects of Hydroxyurea Treatment in People Who Have Sickle Cell Disease
Short-Term Side Effects
|
Decreased
white blood cell count (leukopenia) Decreased platelet count
(thrombocytopenia) Decreased red blood cell count (anemia)
(These
side effects typically can be anticipated and prevented by temporary
discontinuation of hydroxyurea or decrease in hydroxyurea dose. These side
effects usually resolve within 1 to 2 weeks.) |
Frequent, expected,
and dose–related |
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 theoretically 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 grade is either insufficient or low that this is actually associated
with the use of hydroxyurea.
4. 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.
The first study found that providers of adult sickle cell patients were
reluctant to prescribe hydroxyurea because of patient concerns about side
effects and their own concerns about patient adherence, patient age, side
effects and carcinogenic risk, lack of patient contraception, and the costs to
patients. Two additional studies examined barriers in pediatric patients who
have sickle cell disease. The first study found that patients and
parents/families/caregivers chose hydroxyurea therapy over chronic transfusion
and stem cell transplantation after hearing nonbiased information about all
three potential treatments. Perceived efficacy and safety of potential
treatments were used most commonly by patients and parents/families/caregivers
to decide treatment. In the second study, the researchers concluded that some
parents were unwilling to accept the use of hydroxyurea in their children
because of concerns about cancer and birth defects. The Panel agreed to the
inclusion of evidence obtained from expert testimony and studies analyzing
barriers to the delivery of quality health care to sickle cell disease. These
studies examined potential barriers to hydroxyurea treatment, including the
receipt of routine, scheduled care; the adherence to medications; and receipt
of therapies including pain control and prescriptions.
Some of the 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 poorer than the national average but are more often covered by Medicaid.
They also may be immigrants who are unable to obtain insurance. The care of
children and adults who have sickle cell disease and the barriers to their care
must be viewed within the context of their families, communities, and the
American 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.
Patient Level
- Fears about cancer, birth defects, infertility, and the
uncertainty of other potential long–term risks
- Concern that the non-Food and Drug Administration-approved
status of hydroxyurea for children means that hydroxyurea is an experimental
drug
- Lack of knowledge about hydroxyurea as a therapeutic option
- Lack of perception that hydroxyurea is currently the only
therapy that directly modifies the disease process
- Lack of adherence to treatment regimen
- Need for frequent monitoring of hydroxyurea response
Parent/Family/Caregiver Level
- Fears about cancer, birth defects, infertility, and the
uncertainty of long-term risks
- Concern that the non-Food and Drug Administration-approved
status of hydroxyurea for children means that hydroxyurea is an experimental
drug
- Lack of knowledge about hydroxyurea as a therapeutic option
- Lack of perception that hydroxyurea is currently the only
therapy that directly modifies the disease process
- Difficulty in communication between patients and their
caregivers regarding the use of hydroxyurea and other therapeutic options
Provider Level
- Lack of knowledge about hydroxyurea as a therapeutic option
- Concerns about cancer, infertility, birth defects, and the
uncertainty of long-term risks
- Provider bias and negative attitudes toward patients who have
sickle cell disease and their treatment
- Lack of clarity in hydroxyurea treatment regimens and
undertreatment in adults
- Limited number of physicians who have expertise in the use of
hydroxyurea for sickle cell disease
- Failure to engage patients/caregivers in treatment
decisionmaking in a developmentally appropriate manner
- Lack of perception that hydroxyurea is currently the only
therapy that directly modifies the disease process
System Level
- Financing (lack of insurance, type of insurance,
underinsurance, scope of coverage, copays, reimbursement, payment structures)
- Geographic isolation
- Lack of coordination between academic centers and
community-based clinicians
- Limited access to comprehensive care centers and comprehensive
care models
- Problems in transitioning from pediatric to adult care
- Limited access (e.g., geographic distribution, recruitment, and
retention of clinicians competent in the provision of comprehensive care to
patients who have sickle cell disease)
- Inadequate Government, industry, and philanthropic support for
the care of patients who have sickle cell disease
- Development and promotion of hydroxyurea are hindered by lack
of commercial interest in the development and promotion of hydroxyurea
- Lack of visibility and empowerment of sickle cell disease
advocacy groups
- Cultural and language barriers to the provision of appropriate
care
- Inadequate information technology systems to support the
long-term care of patients who have sickle cell disease
Solutions
- Promote models of care (e.g., comprehensive care, medical home,
family–centered) across the lifespan that support quality of care and
improved access to evidence-based treatment, including
hydroxyurea.
- Provide multidisciplinary care (e.g., health educators, social
workers, case managers, physicians, and nurses) to improve the physical and
mental health of patients who have sickle cell disease and the financing
structures to support such care.
- Provide support for community health worker models (e.g.,
patient navigators, patient advocates, and peer advocates).
- Provide support for coordination and comanagement of patients
with the use of telemedicine.
- Ensure better translation of findings to the patient and
caregiver populations using culturally or language-appropriate written and
visual materials.
- Implement health promotion models in educational interventions
for adherence to therapies.
- Engage and support community-based efforts to improve knowledge
of the benefits and risks of hydroxyurea.
- Improve Federal, State, and local coordination of activities
regarding sickle cell disease.
- Provide support for cultural competency training across the
interdisciplinary team regarding care for sickle cell disease.
- Improve insurance coverage of sickle cell disease (e.g., extend
Medicare coverage to adult sickle cell disease patients, or extend the age
qualifications of Medicaid).
- Eliminate barriers that restrict access to public insurance.
- Support ongoing training of health professionals to achieve and
maintain competence in the care of patients who have sickle cell disease,
including hydroxyurea treatment.
- Increase funding by Government, industry, and philanthropic
organizations for patients who have sickle cell disease.
- Encourage partnership and support of advocacy groups for sickle
cell disease.
- Develop enhanced information systems to better coordinate
delivery of care in the healthcare system.
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6. What are the future research needs ?
There is a need for a surveillance system of patients who have
sickle cell disease that will be followed prospectively. This system should
contain demographic, laboratory, clinical, treatment, and outcome
information.
Based on the information presented in answers to questions 1
through 4, we support the utilization 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
modality.
Additional efficacy studies of hydroxyurea are required. These
studies will evaluate the efficacy of hydroxyurea as measured in terms of
clinical and laboratory outcomes:
- To define the mechanisms of action of hydroxyurea in a clinical
setting
- To use pharmacokinetic and clinical measures to determine
optimal dosing, dose titration, and clinical efficacy
- To identify the factors that predict clinical response and
nonresponse to hydroxyurea
- To confirm the validity of hemoglobin as a surrogate for
benefit
Additional effectiveness studies are required. These studies will
examine the effectiveness of hydroxyurea as measured in terms of clinical and
laboratory outcomes. These effectiveness studies should determine the
population of patients who have sickle cell disease and who will benefit from
hydroxyurea. This would include considerations of 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 that are
currently in progress.
Although we believe hydroxyurea to be safe and effective,
additional studies of the safety, clinical effectiveness, and
cost-effectiveness of hydroxyurea are required. Appropriate studies need to be
conducted to provide more information about:
- Developmental and reproductive adverse effects
- Carcinogenic risk
- Long-term clinical outcomes, including quality of life
- Evaluation of the utility and cost-effectiveness of the
comprehensive care and medical home models for the delivery of hydroxyurea
treatment
- Evaluation of the role of the case manager in delivery of
hydroxyurea treatment
- Evaluation of interventions aimed at reducing parent/caregiver,
provider, and healthcare system barriers to hydroxyurea treatment
Conclusions
The burden of suffering is tremendous among many patients who have
sickle cell disease. These patients experience disease–related pain 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 is challenging for the patient who has sickle cell disease. 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
declining. The likelihood of patients who have sickle cell disease having a
principal physician is low. There is a special challenge in transitioning from
pediatric care to adult care. 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 this disease. Surveys do indicate
that a large proportion of patients who have sickle cell disease are poor and
from underserved communities. The overwhelming majority of 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.
- 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?
- Strong evidence is found in support of the efficacy of
hydroxyurea use in adults (decrease in pain crises, hospitalizations, blood
transfusions, and acute chest syndrome).
- Variable evidence is available in the preadolescent
population (decrease in hospitalizations and pain crises).
- No well-designed clinical trial evidence in infants is
available.
- Although the evidence for efficacy of hydroxyurea treatment
for children is not as strong, the emerging data are supportive.
- What is the effectiveness (in everyday practice) of
hydroxyurea treatment for patients who have sickle cell disease?
- One problem in determining effectiveness is the lack of a
precise estimate of the number of people who have sickle cell disease in the
United States and the number of people actually receiving
hydroxyurea.
- Most published studies have strict entry criteria, meaning
some patients with comorbidities who might benefit have not been assessed.
- Overall, data regarding effectiveness are very
limited.
- What are the short– and long–term harms of
hydroxyurea treatment?
- Short–term, dose–related, usually temporary,
and reversible effects may be:
- Decrease in white blood cell count (increased risk for
infections).
- Decrease in platelet count (increased risk for
bleeding).
- Decreased sperm counts or increased sperm abnormalities
in men.
- Dryness and darkening of the skin and nails.
- No high–quality evidence supports:
- Increased incidence of cancer.
- Increased incidence of birth defects (although
contraception is advised for men and women taking hydroxyurea, and
discontinuation of hydroxyurea with pregnancy is recommended).
- Moderate evidence shows that hydroxyurea does not affect
growth rate in patients who have sickle cell disease.
- The data currently available are reassuring with respect to
the risks of both short– and long–term harms of hydroxyurea
treatment.
- The risks of hydroxyurea in adults are acceptable compared
to the risks of untreated sickle cell disease.
- What are the barriers to hydroxyurea treatment for
patients who have sickle cell disease, and what are the potential solutions?
- Four levels of barriers exist: patient,
parent/family/caregiver, provider, and system.
- Only three studies specifically address barriers, and none
addresses hydroxyurea interventions.
- Patient and parent/family/caregiver barriers include:
- Fears about cancer, birth defects, infertility, and
uncertainty of other potential long–term risks.
- Lack of knowledge of hydroxyurea as a therapeutic
option for sickle cell disease.
- Provider barriers include:
- Limited number of physicians who have expertise in the
use of hydroxyurea for sickle cell disease.
- Provider bias and negative attitudes toward patients
who have sickle cell disease and their treatment.
- Lack of clarity in hydroxyurea treatment regimens and
undertreatment.
- System barriers include:
- Financing: lack of insurance and coverage.
- Geographic isolation, limited access to comprehensive
care models.
- Problems in transitioning from pediatric to adult
care.
- What are the future research needs?
- A comprehensive registry of all patients who have sickle
cell disease that will be followed prospectively
- Studies to better define the mechanism of action of
hydroxyurea, as well as optimal dosing, titration, and monitoring
- Studies that identify factors that predict clinical
hydroxyurea response/nonresponse
- Effectiveness studies considering when to begin use of
hydroxyurea to prevent or treat complications of sickle cell disease and how
long to continue the therapy
- Evaluation of the utility and cost–effectiveness of
the comprehensive care and medical home models for the delivery of hydroxyurea
treatment
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
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. There is a critical need for
increased funding for basic, clinical, and social research on this disease.
There is an urgent need to organize and network centers specializing in the
treatment of this disease.
Back to Top
Consensus Development 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 Childrens 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 Childrens 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 Childrens 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 Childrens Hospital Institute for the Study
of Health Cincinnati, Ohio
Back to Top
Planning Committee
Ellen M. Werner, Ph.D. 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.
Conference Sponsors
National Heart, Lung, and Blood
Institute Elizabeth G. Nabel, M.D. Director
Office of Medical Applications of
Research Barnett S. Kramer, M.D., M.P.H. Director
Conference Co-sponsors
National Human Genome Research
Institute Francis S. Collins, M.D., Ph.D. Director
National Institute of Child Health and Human
Development Duane Alexander, M.D. Director
National Institute of Diabetes and Digestive and
Kidney Diseases Griffin P. Rodgers, M.D.,
M.A.C.P.
Director
National Institute of Neurological Disorders and
Stroke Story C. Landis, Ph.D. Director
Office of Rare Diseases Stephen C.
Groft, Pharm.D. Director
Conference Partners
Centers for Disease Control and
Prevention Julie Louise Gerberding, M.D., M.P.H. Director
Health Resources and Services
Administration Elizabeth M. Duke, Ph.D. Administrator
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