Sickle cell disease (SCD) is the most common inherited blood condition in the United States. The molecular basis of SCD has been known for more than 50 years, and while the genetics are straightforward, the pathophysiology is surprisingly complex, and management poses many challenges for patients and providers. SCD is uncommon (but not rare), and consequently individual physicians may have limited experience both in developing a comprehensive, longitudinal care plan and in managing complications of the disease. To aid non-expert practitioners, clinical practice guidelines (CPGs) have been developed by several groups including the National Heart, Lung, and Blood Institute (NHLBI). First published in 1984, NHLBI’s “The Management of Sickle Cell Disease” (the Red Book) underwent three subsequent revisions with the fourth edition being published in 2002. Now, after more than five years in development, the Red Book has been supplanted by NHLBI’s Expert Panel Report titled “ Evidence-Based Management of Sickle Cell Disease,”1 and key aspects of the report have been summarized recently in the Journal of the American Medical Association.2,3 The guidelines are intended to assist health professionals with management of both common issues and adverse events associated with SCD, including health maintenance, acute pain, chronic complications, blood transfusions, and indications for using and monitoring of hydroxyurea (Table). The target audience for these new NHLBI guidelines is primary and secondary care providers who manage patients (children and adults) with SCD.
More on ASH's Endorsement of the NHLBI Report
ASH's support of the report from NHLBI is based on its overall merits as well as its potential to improve care. And while ASH recognizes the limitations of the recommendations that are based on low-quality or insufficient evidence, the Society is taking the following steps in ensuring that clinicians understand how to best implement them:
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ASH's support of the report from NHLBI is based on its overall merits as well as its potential to improve care. And while ASH recognizes the limitations of the recommendations that are based on low-quality or insufficient evidence, the Society is taking the following steps in ensuring that clinicians understand how to best implement them:
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Clinical practice guidelines (CPGs) have been promulgated for numerous conditions with variable quality and therefore variable utility. In general, guidelines are prepared by expert panels that use the scientific literature to collect, organize, interpret and assess evidence as part of a formal systematic review process. Results of the review are evaluated along with other evidence that incorporates expert opinion and patient preferences to produce CPGs and recommendations with a goal of optimizing patient care. CPGs can also assist health-care providers in weighing treatment options when there is limited evidence, absence of a consensus, or both. And deficiencies in published literature identified during the review and CPG development can be used to highlight priorities for research.
In March 2011, the Institute of Medicine (IOM) published the report “Clinical Practice Guidelines We Can Trust,”4 which summarized the work of an expert committee tasked with examining best methods for developing high-quality CPGs. In this document, the IOM proposed a set of standards for the development of robust and reliable guidelines that included establishment of representative multidisciplinary committees to complete a rigorous, systematic review of existing evidence. The report emphasized that CPG development process should be transparent and should minimize bias, distortion, and conflicts of interest. Further, the quantity or quality of evidence should be weighed, and this information should be incorporated into a measure of the strength of the recommendations. The process should consider patient preferences and provide both clear explanations and alternative care options as appropriate. Finally, trustworthy CPGs require revision and reconsideration as new evidence arises.
Highlights of the Sickle Cell Disease Expert Panel Report
| Health Maintenance . |
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| Management of Acute Complications . |
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| Management of Chronic Complications . |
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| Hydroxyurea and Transfusion Therapies . |
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| Health Maintenance . |
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| Management of Acute Complications . |
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| Management of Chronic Complications . |
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| Hydroxyurea and Transfusion Therapies . |
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The CPG development process has limitations and many of them are reflected in the NHLBI SCD Expert Panel Report. The NHLBI Expert Panel was convened prior to publication of the IOM report. Nonetheless their process and methodology encompassed many of the IOM standards, but regrettably excluded others. The Expert Panel included professionals in hematology, primary care, psychiatry, and emergency medicine who were very knowledgeable about SCD, but there was no patient or public involvement in the development of the NHLBI-sponsored guidelines. Representatives from community-based patient advocacy organizations were, however, among the stakeholders providing external review of the final report. Results of a systematic literature review identified randomized control clinical trials, other nonrandomized intervention studies, and observational studies that were supplemented with additional information from case series or case reports only when considering outcomes that might involve harm. One inherent challenge in developing CPGs for SCD is that there are limited numbers of large-scale, randomized controlled clinical trials, and the relatively small numbers of subjects in many nonrandomized studies weakens the strength of evidence. In areas where a comprehensive review was not feasible due to limited or absence of high-quality evidence, the Expert Panel provided consensus recommendations or made recommendations based on existing guidelines developed by specialty societies. Some areas of emerging importance in SCD were not addressed at all.
There are several areas of the Expert Panel Report where strong recommendations are based on moderate- to high-quality evidence, and many deal with issues where there is broad acceptance of scientific evidence, but perhaps less than universal practice, including the following:
Penicillin prophylaxis in young children with SCD
Annual Transcranial Doppler (TCD) screening with transfusions for primary stroke prevention in children with abnormal TCD velocities
Use of parenteral opioids for children and adults with severe SCD-related pain
Hydroxyurea therapy for recurrent severe pain or acute chest syndrome
Watchful waiting for asymptomatic children and adults with gallstones
Guidelines from the American Pain Society in collaboration with the American Association of Pain Medicine on management of acute and chronic pain in SCD were largely the basis for “adapted consensus” and “panel expertise” recommendations. Similarly, recommendations by the Expert Panel on Routine Vaccinations follow existing guidelines from the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. The Panel also made strong to moderate recommendations in several areas where evidence is fairly weak. These include screening for pulmonary hypertension, use of exchange transfusions for acute chest syndrome, and use of hydroxyurea to prevent stroke recurrence. Such disparity between strength of evidence and strength of recommendation has prompted at least one alternative set of guidelines (focused on pulmonary hypertension) to be developed (in this case by the American Thoracic Society).5 Conflicting guideline recommendations erode the confidence of relatively inexperienced providers who are charged with managing patients with complex problems.
The Expert Panel Report is extensive but not comprehensive. Guidance on assessments and interventions for neurocognitive deficits, which impacts both children and adults with SCD, was not included in the NHLBI-sponsored document. Based on low to very low evidence, the Expert Panel strongly recommended against neuroimaging with MRI or CT. This recommendation is unfortunate as it may limit insurance coverage for clinically driven neuroimaging and may discourage scientific exploration into an area where knowledge is evolving. The recent publication from the Silent Infarct Transfusion Trial suggests that benefit may accrue from chronic transfusions in SCD-related silent cerebral infarcts, which might only be detected in asymptomatic children by using MRI.6 The Report recommendations for consultation with an expert hematologist when patients have serious complications such as multisystem organ failure, acute intrahepatic cholestasis, or splenic sequestration, or require perioperative transfusion management, seems to be prudent (if not evidence-based). Hematopoietic stem-cell transplantation, a curative therapy for SCD, is not addressed in the Expert Panel Report.
NHLBI sponsored the development of the guidelines but at present has no provisions for revising or updating them — a notable departure from the CPG standards set by the IOM. Regular monitoring of the scientific literature may reveal new data that contradict existing evidence or that suggest an alternative therapy not included in current CPGs. The investment needed to create the Expert Panel Report was substantial, but the report’s impact on optimizing patient care will likely diminish without regular surveillance and maintenance. The establishment of the Expert Panel Report as an authoritative CPG for SCD could generate opportunities for comparative effectiveness research. It could also inform further studies in the emerging area of implementation science, which seeks to investigate and address major impediments (social, behavioral, political, and economic) to adoption of evidence-based interventions. This report and similar CPGs can facilitate integration of research findings into clinical practice and health-care policy for SCD; however, doing so will require continued evaluation of their validity.
How has ASH contributed to the SCD guidelines? Several participants on the Expert Panel as well as external reviewers of final drafts are active ASH members. During the public comment period, ASH solicited additional input from members of the ASH SCD Taskforce, compiling an extensive list of suggestions for revision. ASH has formally endorsed the SCD guidelines and is examining ways to disseminate them. Transformation of key elements into more targeted and concise guides (in the form of an ASH pocket guide) will increase the accessibility, and likely the implementation, of the Expert Panel Report’s recommendations that are interspersed throughout the document (the full report comes in at about 100 pages while the Quick-Reference Guide is 41 pages long).
The “Evidence-Based Management of Sickle Cell Disease” is an ambitious endeavor by NHLBI to provide a rational framework that can assist providers in medical decision-making for a vulnerable and often underserved population. The methodology used for the systematic review and the inclusion of more information from the scientific literature has resulted in a document that is very different from the treasured Red Book. Still, where the quality or quantity of published data was insufficient to support a conclusion, recommendations were based on expert consensus that was generally grounded in what might be considered common practice standards. As such, the Expert Panel Report identifies knowledge gaps that can and should be used to drive a research agenda. The recently released ASH Research Priorities for Sickle Cell Disease and Sickle Cell Trait further highlights areas where discovery and innovation, accompanied by research funding and training, are needed. Acknowledging that there are parts of the document that could be improved upon, and imploring support for a living document, the NHLBI-sponsored SCD guidelines are a valuable resource whose wide-scale adoption and implementation by hematologists will empower more informed health-care choices and thereby improve outcomes and quality of life for patients.
