On September 9, 2014, the National Heart, Lung, and Blood Institute (NHLBI) released an evidence-based expert panel report on the management of sickle cell disease (SCD) – the first-ever comprehensive guidelines providing guidance for all clinicians who care for patients with SCD, from primary-care physicians to specialists.
To get the behind-the-scenes look at how the guidelines went from plan to conception to reality, ASH Clinical News spoke with George R. Buchanan, MD, a co-chair of the Expert Panel.
Let’s first talk about the need for this type of guideline – was there anything like this before now?
NHLBI had previously published some recommendations over the years, often referred to as “The Black Book” or “The Red Book,” which contained expert-written chapters regarding various aspects of SCD and disease management, but these were not evidence-based. There had also been comprehensive systematic literature reviews of hydroxyurea – one of the two disease-modifying treatments for SCD – published in 2008, but, to my knowledge, no systematic, comprehensive, evidence-based reviews regarding other treatments and management issues regarding SCD have existed prior to the document we developed.
Who is the target audience for this report?
These new guidelines are mainly designed for the frontline primary-care physicians, general practitioners, family physicians, pediatricians, general internists, and other specialists or subspecialists who deal with sickle cell patients – rather than hematologists who have historically been more involved with managing SCD.
Hematologists who frequently encounter SCD may not really “need” these guidelines, at least not as much as the other physicians who are less involved with the disease. However, hematologists and oncologists who may be less directly involved with SCD may also be called upon to help with managing SCD, so, hopefully, all ASH members will derive some benefit from the publication of these guidelines. And, there is no question that hematologists are very keen on having these comprehensive evidence-based recommendations compiled in one document.
How long did it take to develop the report?
This process began in 2009, when Dr. Susan Shurin, then the deputy director of NHLBI, asked me to co-chair this report. Our first face-to-face meeting occurred in early 2009, with the initial thinking that the report would be complete in a couple of years.
There were a couple of major reasons behind the delay. First, there was initially some turnover in the membership of the committee and then a change in the methodology group who assisted the writing panel with literature review and grading of the evidence. Second, this set of guidelines was fundamentally different from any others that NHLBI has developed. Typically, NHLBI guidelines deal with the management of one aspect of a disease, but our task here was to develop the recommendations for an entire disease – meaning every organ, every part of the patient’s body, and managing all of the unique complications from SCD.
During the process, we also stopped temporarily to allow for public comments and input from ASH and other professional societies, which offered many helpful recommendations. We did make a fair number of modifications as a result of those comments.
How did the expert panel begin the process of making recommendations and grading supporting evidence?
In the early meetings, we developed our major strategy and the overarching questions we needed to answer in five major topic areas:
- Ongoing health maintenance (i.e., necessary monitoring and laboratory testing)
- Managing acute complications
- Managing chronic complications
- Hydroxyurea therapy
- Blood transfusion
After identifying those areas and specific questions we wished to answer, we got involved with the methodologists who actually performed the systematic review of the literature. Around 12,000 publications were reviewed, dating back from 1970 to April 2014, to make sure we didn’t miss any pertinent information. Then, the promising data from each paper or manuscript were assessed according to the GRADE system and entered into “evidence tables.” The GRADE system had to be modified because it only allowed for two levels of evidence – high- or low-quality. Obviously, the strongest evidence came from randomized controlled clinical trials (RCTs), while the lowest grade of evidence resulted generally from observational studies or studies that had flaws of one kind or another.
However, given the paucity of high-quality research in SCD, if we relied solely on high-grade evidence from RCTs, the report would have been very short. So, we incorporated a third level of “moderate” evidence to be able to make recommendations in most areas. With the graded evidence in hand, we began the actual process of developing recommendations in those five areas, and this process took a couple of years.
The guidelines really stress the underuse of the two approved treatments for SCD. Why do you think this is a problem, and how do the guidelines tackle those issues?
After about two years of planning, we made the decision to initially release recommendations for hydroxyurea use. Since 1998, hydroxyurea has been the only FDA-approved treatment for SCD; its approval was based on very carefully conducted, definitive RCTs by NIH. Patients receiving hydroxyurea had fewer crises, fewer episodes of chest syndrome, fewer hospitalizations, and longer lifespans than those who took placebo.
This report coincided with a symposium held by NHLBI, called the Herrick Symposium, which is dedicated to the physician who first described SCD in 1910. This very well-attended symposium focused on the value of hydroxyurea. The release of that recommendation three years ago really paved the way for the refinement and completion of the longer report.
In my opinion, almost every person with sickle cell anemia should be taking hydroxyurea – it’s as simple as that. The major problem with that, however, is suboptimal compliance and adherence. Hydroxyurea has to be taken once a day and it requires periodic monitoring, so there is some inconvenience for patients. In the guidelines, we tried to provide very clear, straightforward prescribing and monitoring recommendations for primary-care physicians.
Blood transfusion therapy is widely employed as the other “specific” disease-modifying treatment for SCD, but its use requires caution because of its potential risks and complications; we really have to better characterize the balance between potential benefits and potential risks.
Given the studies supporting hydroxyurea, it was an easy recommendation to make, but how did the expert panel make recommendations where there wasn’t that level of evidence?
Well, there have been only about 10 high-quality trials involving SCD, so the expert panel struggled when trying to make their recommendations given the substantial number of gaps in research. I would say this is one of the weaknesses of the document, but it did serve to uncover for everyone involved with SCD the need for far more research.
Because of the huge number of gaps and uncertainties in many important areas we relied on consensus opinion, such as recommendations from other organizations. For instance, for recommendations on the management of acute and chronic pain, we adapted the American Pain Society’s recommendations. We also relied greatly on the U.S. Preventive Services Task Force because we didn’t want to overlook other important aspects of care, regardless of a patient’s sickle cell status.
In some cases, the 12 members of the expert panel developed consensus recommendations when virtually no high-quality evidence was available in the literature, and some of these recommendations are going to be debatable. Although all the panel members are very experienced, these recommendations generally are rated as “weak” or “moderate” in the report because they relied on consensus opinion when there was scant published literature to back these up.
Once we had a working draft of the recommendations, that’s when the “fine-tuning” process started. I’m proud of the final document that we produced, but it does have imperfections, so critique and opinions from ASH and other societies will again be very important.
Looking forward, what areas will need more attention?
It is clear that we need much more research in SCD. We found knowledge gaps in almost every area, and a serious deficiency of RCTs. But I think there is some light at the end of the tunnel already; NHLBI and other institutes within NIH realize the need to provide additional funding for high-quality research in these areas where we lack knowledge. I’m also hoping that the pharmaceutical industry will sponsor more research because we can’t rely solely on the federal government for funding.
There are also great opportunities for individual pediatric and adult hematologists to initiate research in various aspects of clinical SCD. Well thought-out and carefully conducted longitudinal observational studies or pilot interventional studies in their own patient populations could provide very useful information.
The overarching subject that we hope to have covered in the guideline document is the importance of continuous, collaborative care. SCD patients need continuity of care and doctors who know them well which, unfortunately, is now lacking for many patients. The care many SCD patients receive is episodic, fragmented, and often – frankly – not very good. There just aren’t enough hematologists who specialize in SCD to go around. This is further complicated by the fact that SCD patients are usually from ethnic minorities and may have limited income and lack the necessary access to care that patients with other chronic illnesses have.
So, many patients with SCD in the United States do not derive the benefits from comprehensive collaborative care that includes sickle cell experts, as well as the primary physician who provides ongoing care and knows the patient’s history, family, psychosocial situation, and ongoing clinical status. Having collaborative care, including that delivered by individuals other than hematologists, is critically important for all SCD patients.
There are, of course, many cases where a primary-care physician should consult a hematologist. In the guidelines, we outline those situations quite clearly, with statements like, “If XYZ occurs, consult a sickle cell disease expert.” This is important because the average primary-care doctor might not know where the nearest sickle cell expert is – that is where the ASH membership comes in. I’m very hopeful that all ASH members – whether or not their primary interest is in SCD – will step up to the plate when patients are in need and be responsive and available for consultation and assistance with ongoing care.