Abstract
The 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend offering hydroxyurea to all patients with sickle cell disease SS/ Sβ0 (SCD) aged ≥ 9 months. The relationship between early hydroxyurea initiation and the development of cerebrovascular disease (CVD) is unclear. This retrospective study describes trends in HU prescriptions and CVD outcomes in patients with SCD SS/ Sβ0 followed at a single center before and after guideline publication. CVD was defined as the first of abnormal transcranial Doppler ultrasound, silent cerebral infarct, steno-occlusive vasculopathy, or arterial ischemic stroke. Among 530 patients with SCD, hydroxyurea prescriptions rose post-guideline, with lower age at initiation. CVD was lower post-guideline (2.2/100py) versus pre-guideline (4.4/100py). However, MRI screening also decreased post-guideline, leading to lower CVD detection. Results suggest decreased CVD, including silent cerebral infarcts, in the era of early hydroxyurea use; further analyses addressing age at hydroxyurea initiation and relevant confounders are needed to confirm whether earlier hydroxyurea initiation improves protection against CVD.
Keywords: sickle cell disease (SCD), hydroxyurea, stroke, silent cerebral infarct (SCI), transcranial Doppler ultrasound (TCD)
Introduction
The 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend hydroxyurea (HU) for all patients over age 9 months with sickle cell disease (SCD) SS and S/β0 thalassemia.1 HU was previously reserved for patients with complications, with significant practice variation.2 HU improves survival and decreases acute chest syndrome (ACS) frequency in individuals with SCD 3–5 and has recently been found to play a role in preventing stroke and other neurologic abnormalities.6,7
SCD is the leading global cause of pediatric stroke.8 Screening for abnormal cerebral blood flow with transcranial Doppler ultrasound (TCD) identifies patients at high risk for arterial ischemic stroke (AIS).9 In certain patients, HU prevents stroke and reduces progression of TCD abnormalities.6,7 Silent cerebral infarcts (SCI), the most prevalent form of SCD-related cerebrovascular disease (CVD), triple the risk of overt stroke.10 SCI, steno-occlusive cerebral vasculopathy, and both abnormal and conditional TCD also lead to cognitive deficits.11 No strategies exist for primary SCI prophylaxis, and screening practices vary. The 2014 NHLBI guidelines recommended against routine brain imaging in asymptomatic patients.1
Whether increased and earlier use of HU has altered the natural history of SCD-CVD remains unclear. Claims-based studies show poor NHLBI guideline uptake. 12–14 However, there is center-driven variability in guideline adherence, with high rates of HU prescription in some practices.15,16 We describe changes in HU prescriptions and CVD occurrence before and after publication of the 2014 NHLBI guidelines in a single-center, retrospective cohort study.
Methods
Patients with SCD SS and S/β0 initiating care at any age at the Children’s Hospital of Philadelphia (CHOP) SCD Program January 1, 2006 - February 29, 2024, were included. Care initiation was defined as the first of at least 2 hematology visits within 12 months. Exclusion criteria included CVD or ongoing transfusions before cohort entry, neurologic imaging abnormalities unrelated to SCD, and the stroke risk factors of prior malignancy, severe congenital cardiac disease, and prematurity < 28 weeks gestational age.
Patients were included in either the pre- or post- guideline group based on the date of their first hematology visit at age ≥ 9 months (i.e. first visit January 1, 2006 – August 31, 2014, included in the pre-guideline group and on or after September 1, 2014, in the post-guideline group). Follow-up ended at initiation of transfusions, receipt of curative therapy, death, loss to follow-up (i.e. no encounter in 1 year), or end of the follow-up period (i.e. 08/31/2014 or 02/29/2024).
Electronic health record (EHR) data were extracted using automatic and manual methods (Supplemental Tables 1, 2). This study was deemed exempt by the CHOP Institutional Review Board.
We evaluated HU use (≥2 prescriptions), laboratory markers of adherence, and known HU effects, such as decreased ACS and pain, in the periods before and after publication of the NHLBI guidelines, i.e. September 1, 2014.
A composite CVD outcome17,18 of first abnormal TCD, SCI, cerebral steno-occlusive vasculopathy, or AIS was evaluated before and after guideline publication (outcome details in Supplemental Table 3). Individual outcomes and conditional TCD results were additionally examined. All TCD studies were done with non-imaging methods. TCD reports were manually reviewed by one clinician (A.S.D.) and classified as normal, conditional, or abnormal based on established guidelines.19 All brain MRI and MRA images at our institution are read by board-certified pediatric neuroradiologists. MRI and MRA reports were manually reviewed for SCI and vasculopathy outcomes, respectively. MRI reports were initially scored as normal, indeterminate, or definitive SCI by one clinician (A.S.D). Indeterminate lesions present in at least two consecutive reports qualified as SCI, while those that were not present on repeat MRI, or for which no repeat MRI was available, did not qualify as SCI. MRI reports with abnormalities not related to our outcomes, such as hemorrhage from trauma, were noted separately for inclusion in censoring criteria. Qualifying vasculopathy outcomes required definitive MRA report of moderate or worse vessel stenosis.20 Indeterminate stenosis was classified similarly as with SCI. Arterial ischemic stroke (AIS) was identified by query of an institutional stroke registry. In all cases, diagnosis was initially made by vascular neurologists caring for the patient and was confirmed for this analysis by central review (RI), according to NIH-CDE criteria.21
All CVD outcomes except AIS are typically clinically silent and are diagnosed by imaging. We therefore calculated pre- and post-guideline brain magnetic resonance imaging/angiography (MRI/MRA) and TCD screening rates. TCD calculations included only patients ages 2–16 years, when routine screening is recommended.19
We described the prevalence and median age of HU initiation pre- and post- guideline, along with the distribution of MCV and HbF values to capture adherence. The proportion of patients diagnosed with ACS or hospitalized with pain was calculated pre- and post-guideline. The incident rates of composite and individual CVD outcomes were described in the 2 guideline eras. Analysis of individual outcomes included patients who had a different CVD event previously. For example, a patient with SCI followed by stroke contributed only SCI to the composite outcome, but each event was included in individual outcome calculations. To evaluate heterogeneity in trends by age at care initiation, a sensitivity analysis included only patients starting follow-up at our center by age 1 year, thus excluding patients transferring care from another institution after infancy.
All analyses were performed using STATA version 17.22
Results
Our study cohort included 530 patients with SCD (Supplemental Figure 2). Baseline patient characteristics are shown in Supplemental Table 4. The proportion of patients prescribed HU increased post-guideline (Fig 1) with initiation at a younger age post-guideline (median 3.0y, IQR 1.0–7.2) compared to pre-guideline (median 5.8y, IQR 3.8–8.5). Patients prescribed HU in 2011 or later, when electronic records were available, had a median of 4.1 (IQR 3.1–5.1) prescriptions annually. In children initiating care at our institution by age 1 year, 97/141 (68.8%) in the post-guideline group started HU at a median age of 1.0 year (IQR 0.9–1.3 yrs), and 68/185 patients (36.8%) in the pre-guideline group started HU at a median age of 4.4 years (IQR 3.0–6.0 yrs). Post-guideline, fetal hemoglobin percentage (HbF, analyzed only in patients ≥2 years) increased (Supplemental Figures 2 and 3), and more patients had at least one HbF level above 20% [163/214 (66.0%) vs. 84/210 (34.0%)]. Similarly, more patients in the post-guideline period had at least one MCV over 100fL [163/214 (66.0%) vs. 84/210 (34.0%)]. Fewer patients required hospitalization for ACS post-guideline (68/249, 27.3%) versus pre-guideline (119/281, 42.4%), and fewer patients required hospitalization for pain post-guideline (117/249, 47.0%) versus pre-guideline (198/281, 70.5%). Hospitalizations for splenic sequestration post-guideline (59/249, 23.7%) and pre-guideline (77/281, 27.4%) were similar.
FIGURE 1. Rates of HU Prescription and MRI screening in patients initiating care pre-guideline and post-guideline.
HU prescriptions increased after guideline publication given the recommendation to offer all children HU at 9 months, and MR screening rates declined as it was recommended not to obtain screening MRI in asymptomatic patients. (A) HU prescription rates, defined as the number of patients with ≥1 HU prescription in a calendar year divided by the number of patients followed that year. (B) MRI screening rates, defined as the number of patients with ≥1 MRI in a calendar year divided by the number of patients followed that year. Nearly all MRI included in our primary analysis were accompanied by MRA (345/375, 92%).
Number of patients followed per calendar year (N) shown under graph B.
Abbreviations: HU, hydroxyurea; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; NHLBI, National Heart, Lung, and Blood Institute.
* Brain MRI and MRA at our institution were done using 1.5 Tesla(T) scanners prior to 2005; after 2005, the majority of brain MRI were done using 3T scanners.
Over 1,971 person-years of follow-up, first lifetime CVD occurred in 65 patients (3.3/100py, cumulative incidence 12.3%, Table 1). The composite outcome included 53 patients with SCI, 10 with abnormal TCD, 4 with vasculopathy, and 3 with overt stroke. Two patients had evidence of prior SCI and vasculopathy at the time of overt stroke and one patient was diagnosed with SCI and vasculopathy on the same date. Twenty-three CVD events (2.2/100py) occurred post-guideline compared with 42 (4.4/100py) that occurred pre-guideline.
TABLE 1.
Patient Follow-Up and Cerebrovascular Outcomes
| Total N=530 |
Pre-Guideline Group N=281 |
Post-Guideline Group N=249 |
|
|---|---|---|---|
|
| |||
| Patient follow-up | |||
| Median follow-up time, y (IQR) | 3.6 (1.6, 6.1) | 3.2 (1.1, 5.8) | 4.3 (1.9, 6.5) |
| Hematology visits per year, n (IQR) | 3.0 (2.3, 3.6) | 2.9 (2.3, 3.6) | 3.0 (2.4, 3.6) |
| Imaging | |||
| ≥1 MRI/MRA, n (%) | 236 (44.5) | 142 (50.5) | 94 (37.8) |
| ≥1 TCD*, n (%) | 385 (84.4) | 186 (78.2) | 199 (91.3) |
| CVD incidence rates per 100 person-years, n (IR) | |||
| Composite CVD outcome | 65 (3.3) | 42 (4.4) | 23 (2.2) |
| Age at CVD event, y (IQR) | 5.9 (3.3, 8.9) | 3.8 (2.8, 6.7) | 7.9 (6.11, 12.3) |
| Individual CVD outcomes* | |||
| Abnormal TCD** | 11 (0.7) | 7 (0.9) | 4 (0.5) |
| Conditional TCD**§ | 33 (3.4) | 18 (3.6) | 15 (3.2) |
| SCI | 55 (2.8) | 35 (3.7) | 20 (2.0) |
| Restrict to patients with >= 1 MRI | 55 (5.0) | 35 (5.6) | 20 (4.3) |
| Vasculopathy | 6 (0.3) | 2 (0.2) | 4 (0.4) |
| Restrict to patients with >= 1 MRI | 6 (0.5) | 2 (0.3) | 4 (0.8) |
| Stroke | 4 (0.2) | 3 (0.3) | 1 (0.1) |
Analysis of individual outcomes includes patients with a different CVD event previously. For example, a patient with SCI followed by stroke contributes only SCI to the composite outcome but both events are included in individual outcome calculations.
Includes only patients ages 2–17 years. Total N= 456, with n=238 pre-guideline and n=218 post-guideline.
Includes only patients initiating hematology care by 2 years of age, as chart review of prior care is insufficiently accurate to detect prior conditional TCD results. Total N = 278, with n=152 pre-guideline and n=126 post-guideline.
Abbreviations: CVD, cerebrovascular disease; IQR, inter-quartile range; IR, incidence rate; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; SCI, silent cerebral infarct; TCD, transcranial Doppler ultrasound; y, year.
When examining individual outcomes (Table 1), we identified four patients with abnormal TCD post-guideline (IR 0.5/100py) compared to seven pre-guideline (IR 0.9/100py). Conditional TCD rates were similar post- and pre-guideline (3.2/100py vs. 3.6/100py). SCI decreased post-guideline, including when considering only patients with at least 1 MRI during follow-up (4.3/100py vs. 5.6/100py). Six patients in our study developed moderate-severe cerebral vasculopathy, including 4 patients post-guideline (IR 0.4/100py) and 2 patients pre-guideline (IR 0.2/100py). One stroke occurred post-guideline and 3 occurred pre-guideline.
CVD trends were similar when examining only patients initiating care as infants, with larger relative decreases in the composite CVD outcome and abnormal TCD (Supplemental Table 5).
MRI screening rates decreased after guideline publication (Table 1, Fig 1), with 94 (37.8%) and 142 (50.5%) patients having at least one MRI in the post-guideline and pre-guideline groups, respectively. Median age at first MRI increased from 4.8y [IQR 2.7, 9.4] pre-guideline to 7.7y [IQR 6.0, 10.0] post-guideline, corresponding to fewer MRIs in young patients requiring sedation. Conversely, more patients underwent TCD screening post-guideline (Table 1).
Discussion:
This study shows increased HU utilization following publication of the 2014 NHLBI guidelines. In parallel, rates of acute pain and ACS declined. The incidence of CVD, including SCI, also decreased; however, MRI screening rates also declined.
Little is known about changes in SCD-CVD epidemiology since publication of the 2014 guidelines. While the NHLBI recommends HU initiation at age 9 months, guidance around HU varies globally, and it is unclear to what extent HU’s benefits depend on age of initiation.23,24 CVD, once present, does not spontaneously resolve and likely progresses.25,26 Given that CVD often develops in the first decade of life,8 effective prevention must start early. Our sensitivity analysis excluded patients starting follow-up after age 1, ensuring that all patients in the post-guideline group were eligible to receive HU at our institution as infants. In this analysis, the rate of abnormal TCD decreased by 80% after guideline publication, suggesting that patients initiating HU earlier in life may receive the most benefit.
Whether HU protects against SCI, the most common form of SCD-CVD, is unclear. Fewer SCI occurred in patients initiating HU by age 2 years in a pilot trial.18 Further study of the impact of early HU on SCI will likely need observational data given the ethical issues presented by withholding a guideline-recommended therapy. Variability in MRI screening presents a significant challenge in the management and study of SCI. SCI diagnosis qualifies patients for appropriate services and identifies candidates for transfusions, which are effective in secondary SCI prophylaxis.27 The American Society of Hematology recommended in 2020 that individuals with SCD SS/Sβ0 undergo at least one brain MRI once sedation is not needed.19 Whether this guidance will have widespread uptake remains to be seen. Prospective, large studies with systematic MRI screening would build on our preliminary results.
Abnormal TCD and ischemic stroke, outcomes not requiring MRI, decreased after guideline publication. HU protects against CVD progression in those who have TCD abnormalities.6,7,28 It is reasonable that this protection would extend to those with normal TCD.
We present single-center descriptive results, without accounting for confounders, and SCI and vasculopathy can be misclassified when ascertained from radiology reports rather than images. Nevertheless, these data are an important step in understanding SCD-CVD epidemiology. Standardized MRI screening is needed to understand the modern epidemiology of SCI in patients with SCD, identify candidates for increased CVD screening, and develop alternative CVD prevention strategies.
Supplementary Material
Acknowledgements:
This work was supported by grants from the National Institutes of Health, National Heart, Lung and Blood Institute (T32 HL0007150–45 (A.S.D.) and 5K01HL143153-05 (K.G.))
The authors would like to thank David F. Friedman, MD for assisting with the collection of red blood cell transfusion data.
Abbreviations:
- ACS
Acute Chest Syndrome
- AIS
Arterial Ischemic Stroke
- CHOP
Children’s Hospital of Philadelphia
- CVD
Cerebrovascular Disease
- EHR
Electronic Health Record
- HU
Hydroxyurea
- HbF
Fetal Hemoglobin
- IR
Incidence Rate
- MCV
Mean Corpuscular Volume
- MRA
Magnetic Resonance Angiography
- MRI
Magnetic Resonance Imaging
- NHLBI
National Heart, Lung, and Blood Institute
- SCD
Sickle Cell Disease
- SCI
Silent Cerebral Infarcts
- TCD
Transcranial Doppler Ultrasound
- PY
Person-Years
Footnotes
Presented in abstract form at the 66th annual meeting of the American Society of Hematology, San Diego, CA, December 9–12, 2023 (https://ashpublications.org/blood/article/142/Supplement%201/1129/505810/Impact-of-the-2014-NHLBI-Hydroxyurea-Guidelines-on) and the 19th Annual Sickle Cell & Thalassaemia Conference, London, UK, October 2–5, 2024 (https://onlinelibrary.wiley.com/doi/full/10.1002/hem3.70009).
Disclosure Statement: A.V. serves in an advisory role for DeepSight Technology and as a consultant for Syneos Health. J.L.K. has a consultancy role with the following companies: Agios, Forma Therapeutics, Vertex Pharmaceuticals, BioMarin, Chiesi, Bristol Myers Squibb, bluebird bio, Inc, Imara, Silence Therapeutics, and Novo-Nordisk. J.L.K. receives research funding from: Forma Therapeutics, Agios, bluebird bio, Inc., Editas Medicine, Pfizer, Vertex Pharmaceuticals, and Apopharma. For the remaining authors, no relevant conflicts of interest were declared.
Data Availability:
The data that support the findings of this study are available on request from the corresponding author, [ASD]. The data are not publicly available due to their containing information that could compromise the privacy of research participants.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author, [ASD]. The data are not publicly available due to their containing information that could compromise the privacy of research participants.