Cited by 2,340Hemoglobinopathies and Related DisordersBlood groups and transfusionHemophilia Treatment and Research

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Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia

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Charache, Samuel, Terrin, Michael L., Moore, Richard D., Dover, George J., Barton, Franca B., Eckert, Susan V., McMahon, Robert P., Bonds, Duane R.·1995·New England Journal of Medicine

DOI 10.1056/nejm199505183322001

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Abstract

BACKGROUND: In a previous open-label study of hydroxyurea therapy, the synthesis of fetal hemoglobin increased in most patients with sickle cell anemia, with only mild myelotoxicity. By inhibiting sickling, increased levels of fetal hemoglobin might decrease the frequency of painful crises. METHODS: In a double-blind, randomized clinical trial, we tested the efficacy of hydroxyurea in reducing the frequency of painful crises in adults with a history of three or more such crises per year. The trial was stopped after a mean follow-up of 21 months. RESULTS: Among 148 men and 151 women studied at 21 clinics, the 152 patients assigned to hydroxyurea treatment had lower annual rates of crises than the 147 patients given placebo (median, 2.5 vs. 4.5 crises per year, P < 0.001). The median times to the first crisis (3.0 vs. 1.5 months, P = 0.01) and the second crisis (8.8 vs. 4.6 months, P < 0.001) were longer with hydroxyurea treatment. Fewer patients assigned to hydroxyurea had chest syndrome (25 vs. 51, P < 0.001), and fewer underwent transfusions (48 vs. 73, P = 0.001). At the end of the study, the doses of hydroxyurea ranged from 0 to 35 mg per kilogram of body weight per day. Treatment with hydroxyurea did not cause any important adverse effects. CONCLUSIONS: Hydroxyurea therapy can ameliorate the clinical course of sickle cell anemia in some adults with three or more painful crises per year. Maximal tolerated doses of hydroxyurea may not be necessary to achieve a therapeutic effect. The beneficial effects of hydroxyurea do not become manifest for several months, and its use must be carefully monitored. The long-term safety of hydroxyurea in patients with sickle cell anemia is uncertain.

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Hydroxycarbamide Decreases Sickle Reticulocyte Adhesion to Resting Endothelium by Inhibiting Endothelial Lutheran/Basal Cell Adhesion Molecule (Lu/BCAM) through Phosphodiesterase 4A Activation
Chaar, V., Laurance, S., Lapouméroulie, C., Cochet, S., Grandis, M. D., Colin, Y., Élion, J., Kim, C. L. V., & Nemer, W. E. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.506121 · Cited by 50
“Hydroxycarbamide (HC, the recommended international nonproprietary name of hydroxyurea) is the only drug that has demonstrated clinical benefits for SCD patients by reducing VOC and hospitalization frequencies (17).”
Background
Improved survival among sickle cell kidney transplant recipients in the recent era
Huang, E., Parke, C. Y., Mehrnia, A., Kamgar, M., Pham, P. T., Danovitch, G. M., & Bunnapradist, S. (2013) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfs585 · Cited by 50
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“Hydroxyurea was the first FDA approved drug for use in sickle cell disease.(51,52) It is well established that hydroxyurea reduces mortality and morbidity in sickle cell anemia.”
Background
Sickle cell nephropathy: an update on pathophysiology, diagnosis, and treatment
Hariri, E. H., Mansour, A. G., Alam, A. E., Daaboul, Y., Korjian, S., & Bahous, S. A. (2018) · International Urology and Nephrology · doi:10.1007/s11255-018-1803-3 · Cited by 50
“It is the only FDA-approved drug effective for the management of SCD in adults [78].”
Background
MIR-144-mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell disease
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Pain and other non‐neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: Results from the SWiTCH clinical trial
Alvarez, O. A., Yovetich, N. A., Scott, J. P., Owen, W. C., Miller, S. T., Schultz, W. H., Lockhart, A., Aygün, B., Flanagan, J. M., Bonner, M. J., et al. (2013) · American Journal of Hematology · doi:10.1002/ajh.23547 · Cited by 50
Adhesion molecules and hydroxyurea in the pathophysiology of sickle cell disease
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Mastocytosis and adverse reactions to biogenic amines and histamine-releasing foods: what is the evidence?
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Amrolia, P. J., Almeida, A. M., Halsey, C., Roberts, I. A. G., & Davies, S. C. (2003) · British Journal of Haematology · doi:10.1046/j.1365-2141.2003.04143.x · Cited by 50
Barriers to hydroxyurea use from the perspectives of providers, individuals with sickle cell disease, and families: Report from a U.S. regional collaborative
Treadwell, M. J., Du, L., Bhasin, N., Marsh, A., Wun, T., Bender, M. A., Wong, T. E., Crook, N., Chung, J. H., Norman, S., et al. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.921432 · Cited by 54
“In the present study, healthcare utilization was not associated with hydroxyurea use, unlike prior studies (Charache et al., 1995; Thornburg et al., 2012) that demonstrated that hydroxyurea use was associated with decreased frequency of pain and ED and inpatient admissions.”
Result
Clinical Pharmacology of Deferasirox
Tanaka, C. (2014) · Clinical Pharmacokinetics · doi:10.1007/s40262-014-0151-4 · Cited by 49
Sickle Cell Disease: An Opportunity for Palliative Care Across the Life Span
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The rationale for using hydroxycarbamide in the treatment of sickle cell disease
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Use of Hydroxyurea in Children Ages 2 to 5 Years With Sickle Cell Disease
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“SCD treatment also requires interrupting the interaction of sickle cells with the endothelium (Brugnara et al., 1993; Charache et al., 1995; Kinney et al., 1999; Claster and Vichinsky, 2003; Vadolas et al., 2004).”
Background
Optimal response to thalidomide in a patient with thalassaemia major resistant to conventional therapy.
Masera, N., Tavecchia, L., Capra, M., Cazzaniga, G., Vimercati, C., Pozzi, L., Biondi, A., & Masera, G. (2010) · PubMed Central · doi:10.2450/2009.0102-09 · Cited by 47
Sickle Cell Disease and the “Difficult Patient” Conundrum
Bergman, E. J., & Diamond, N. J. (2013) · The American Journal of Bioethics · doi:10.1080/15265161.2013.767954 · Cited by 48
Key endothelial cell angiogenic mechanisms are stimulated by the circulating milieu in sickle cell disease and attenuated by hydroxyurea
Lopes, F. C. M., Traina, F., Almeida, C. B., Leonardo, F. C., Franco‐Penteado, C. F., Garrido, V. T., Colella, M. P., Soares, R. A., Saad, S. T. O., Costa, F. F., et al. (2015) · Haematologica · doi:10.3324/haematol.2014.119727 · Cited by 48
“as a therapy in SCD.(25) Hydroxyurea is a cytostatic drug that inhibits ribonucleotide reductase, arresting cell division in the S-phase; additionally, data suggest that hydroxyurea can generate nitric oxide following administration.”
Background
Pain Management in Sickle Cell Disease: Palliative Care Begins at Birth?
Benjamin, L. J. (2008) · Hematology · doi:10.1182/asheducation-2008.1.466 · Cited by 48
Genetic disruption of the KLF1 gene to overexpress the γ‐globin gene using the CRISPR/Cas9 system
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Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease
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Medical Resource Use and Costs of Treating Sickle Cell-related Vaso-occlusive Crisis Episodes: A Retrospective Claims Study
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Hydroxyurea in the Treatment of HIV Infection
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Iron Nitrosyl Hemoglobin Formation from the Reactions of Hemoglobin and Hydroxyurea
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“The clinical trial which resulted in the approval of hydroxyurea for adults with SCD remains so far the only prototype for current trials aiming at pharmacologic reductions of clinical complications of SCD [27].”
Background
Established and experimental treatments for sickle cell disease.
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Authors: Charache, S., Terrin, M. L., Moore, R. D., Dover, G. J., Barton, F. B., Eckert, S. V., McMahon, R. P., & Bonds, D. R.
Affiliations: Johns Hopkins University (US)
Maryland Medical Research Institute (US)
National Heart, Lung, and Blood Institute (US)
ORCID: Terrin, Michael L.
Moore, Richard D.
Barton, Franca B.
McMahon, Robert P.
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 1995-05-18
Volume: 332
Issue: 20
Pages: 1317-1322
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejm199505183322001
OpenAlex: W2313541759
Semantic Scholar: 2c0939e2f6480b519903bb15870e5b894887e70d
Cited by: 2,340
References: 26
Citations by year: 2026: 67 · 2025: 97 · 2024: 77 · 2023: 88 · 2022: 95 · 2021: 92 · 2020: 80 · 2019: 78 · 2018: 85 · 2017: 104 · 2016: 114 · 2015: 101 · 2014: 82 · 2013: 79 · 2012: 73
FWCI: 34.43
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: Bristol-Myers Squibb
National Institutes of Health (5u01hl045696-05)
National Heart, Lung, and Blood Institute (UO1-HL 45696, UO1 HL 45692, U01HL045692)
National Center for Research Resources (RR00046, M01RR000046)
Topics: Health Sciences › Medicine › Genetics (clinical) › Hemoglobinopathies and Related Disorders
Health Sciences › Medicine › Hematology › Blood groups and transfusion
Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
Keywords: hydroxyurea, sickle cell disease, vaso-occlusive crisis, fetal hemoglobin, blood transfusion, myelosuppression, treatment efficacy, adverse effects
MeSH terms: Adult, Anemia, Sickle Cell, Double-Blind Method, Female, Follow-Up Studies, Humans, Hydroxyurea, Male, Pain

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Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia

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