Incomplete implementation of guideline‐based stroke prevention therapy in sickle cell disease
Authors: Alyssa M. Schlenz, Joannie Hayes, Martina Mueller, Shannon Phillips, Robert J. Adams, Julie Kanter
Journal: American Journal of Hematology (2018)

Stroke is a devastating, but often preventable complication associated with sickle cell disease (SCD). The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) established that routine transcranial doppler ultrasound (TCD) screening with indefinite chronic red cell transfusions (CRCT) for children with abnormal TCD can significantly reduce stroke risk in SCD.1, 2 These data led to the "STOP protocol," which is strongly recommended in the 2014 National Institute of Heart, Lung, and Blood (NHLBI) guidelines and endorsed by the American Stroke Association. This protocol includes: (a) annual TCD screening and (b) indefinite CRCT for patients with abnormal TCD or previous cerebral infarct.3 Subsequently, the TCD With Transfusions Changing to Hydroxyurea (TWiTCH) study demonstrated that children with SCD with abnormal TCD treated with CRCT could be safely transitioned to Hydroxyurea if there were no significant cerebrovascular abnormalities on neuroimaging.4 However, individuals with prior stroke or cerebral vasculopathy must remain on indefinite CRCT for optimal stroke prevention.5 Despite these guidelines, CRCT is likely underutilized.3 Barriers to CRCT implementation are likely multi-factorial, involving multiple patient and health care factors (eg, transition to adult care, socioeconomic/geographic variables).6 No prior studies have examined barriers to lifelong CRCT implementation in individuals with SCD at high stroke risk. This study's goals were to: (i) describe the CRCT status of patients with SCD at high stroke risk in a large, Southeastern urban clinic and (ii) examine differences in patient-level characteristics related to CRCT implementation. We hypothesized that age, provider type, and proximity to comprehensive care would be associated with CRCT utilization. Treatment indication for CRCT and insurance status were exploratory variables. This retrospective chart review study was approved by the Medical University of South Carolina's (MUSC) Institutional Review Board. Individuals with SCD at high stroke risk were identified using clinic rosters and previous stroke prevention trial registries from January 1, 2000 to December 31, 2014. CRCT Status was treatment status as of December 31, 2014: (i) patients currently receiving CRCT (transfusions >8×/year); (ii) patients not currently receiving CRCT; and (iii) patients lost to follow-up (LTFU) (absence of care at MUSC for 12 months) and no identification of "deceased" in the medical record. Age was determined as of December 31, 2014. Provider Type was separated into SCD specialist versus non-SCD provider (ie, primary care, no provider) according to last encounter. Region was based on last known zip code of residence. The Tri-County (counties closest to MUSC) was compared with all other regions of South Carolina. Treatment Indication (neurological indication) for CRCT was classified as prior stroke, abnormal TCD, and/or other indication. Insurance Status was classified as Medicare, Medicaid, Other Insurance, or None based on last encounter. Patient characteristics were compared based on CRCT status using one-way anova and Chi-square tests or Fisher's Exact tests (Table 1). Age was examined as a confounding variable using Chi-square tests or Fisher's Exact tests, and logistic regression was used to examine specific characteristics and CRCT status adjusting for variables confounded by age. Analyses were conducted in SAS version 9.4; significance level α was maintained at 0.05. We identified 143 patients with SCD at high stroke risk, 9% (13 patients) of whom were confirmed deceased. Of these patients, 52% (68/130) were being treated with CRCT, 24% (31/130) were off CRCT therapy, and 24% (31/130) were LTFU. Initial treatment indication included: prior stroke (n = 81), abnormal TCD (n = 39), subarachnoid hemorrhage (n = 2), abnormal brain imaging (n = 3), seizure (n = 1), and multiple neurological indications (n = 1). The majority of patients not on CRCT (74%; 23/31) had CRCT stopped by provider choice, of whom 57% (13/23) were started on Hydroxyurea. These individuals had been receiving CRCT for greater than 5 years (exact duration is unknown) prior to termination. Historical encounters indicate some concern for iron overload in many patients, but not as the reason for stopping transfusion. No concerns for alloimmunization were noted. Further, many of these individuals had not undergone updated neuroimaging to assess for cerebrovascular changes. Patients currently on CRCT were significantly younger than patients off therapy or those LTFU. Over 91% of patients on CRCT had a SCD specialist versus 45% not on CRCT (P < .0001). Region did not differentiate those on CRCT versus off therapy; however, the majority of patients LTFU lived outside the Tri-County (P = .005). Results for CRCT indication showed 62% of patients on CRCT had prior stroke compared with 48% not on CRCT and 77% LTFU (P = .020). There were no significant differences for insurance status (P = .072). Age confounded provider type and treatment indication. Children were more likely to have a SCD specialist compared with adults (90% vs. 44%, respectively, P < .0001). Abnormal TCD was the primary indication for children receiving CRCT versus prior stroke for adults on CRCT (P = .041). Logistic regression suggested that adult and pediatric patients who were seen by a SCD specialist had 7.8 times the odds of continuing CRCT versus those not treated by a specialist, adjusting for age (P < .0001). For treatment indication, patients with prior stroke had 4.1 times the odds of receiving CRCT versus those with abnormal TCD, adjusting for age (P = .012). Limitations include the following. Results were limited to MUSC's records and it is possible (though unlikely) that providers outside of MUSC were implementing CRCT. Generalizability is also limited by South Carolina characteristics, including the large patient population, rurality of the state, and presence of only one adult SCD center. This preliminary study suggests that CRCT may be poorly implemented for stroke prevention in high risk patients with SCD, particularly adults and those without SCD specialty providers. Treatment indication (abnormal TCD vs. prior stroke) was an additional risk. Results also suggest the possibility of a vulnerable group of adults with SCD who are LTFU due to geographical or other vulnerabilities. Future directions include multisite evaluation of CRCT implementation, care environment characteristics, and novel methods to improve CRCT implementation. Nothing to report. A.M.S.'s work on this paper was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number U54 GM104941 (PI: Binder-Macleod). S.P.'s work on this paper was supported in part by the South Carolina Clinical & Translational Research (SCTR) Institute, with an academic home at the Medical University of South Carolina, National Institute of Health grant numbers KL2 TR001452 & UL1 TR001450. This research was presented as an oral presentation at the 57th Annual Meeting and Exposition for the American Society of Hematology, Orlando, FL (December, 2015).