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

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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  • Inhibition of HbS polymerization with hydroxyurea reduces the incidence of acute chest syndrome.

    “inhibition of HbS polymerization with hydroxyurea reduces the incidence of ACS (205).”

    From Pathophysiology of Sickle Cell Disease (2019) · cites this paper as [205]

    The Results in the Abstract report fewer cases of chest syndrome with hydroxyurea than with placebo (25 vs. 51). The Abstract explains that fetal hemoglobin interferes with HbS polymerization, but the Discussion says hydroxyurea’s clinical mechanism is unclear; the paper does not establish polymerization inhibition as the cause of the reduction in chest syndrome. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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  • By inducing increased levels of HbF through mechanisms that include suppressing erythropoiesis, hydroxyurea was first associated with reduction of morbidity and mortality in adults.

    “By inducing increased levels of HbF through mechanisms that include suppressing erythropoiesis, hydroxyurea was first associated with reduction of morbidity and mortality in adults.81,82”

    From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [81]

    The Abstract reports fewer painful crises, cases of chest syndrome, and transfusions among adults receiving hydroxyurea, supporting reduced morbidity. Results According to Treatment Assignment states that deaths did not differ significantly between groups, so reduced mortality is not established. The Discussion notes hematopoietic depression but says the mechanism of benefit is unclear; it does not establish suppression of erythropoiesis as the route to increased HbF. Page numbers were not available in our copy. (LLM, conf=0.92)

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  • Administration of hydroxyurea induces expression of HbF, which interferes with polymerization of HbS.

    “Administration of hydroxyurea has been shown to induce expression of HbF, which interferes with the polymerization of HbS (33).”

    From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [33]

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Research works printed but not linked: 9

  1. [7]7. Charache S, Dover GJ, Moore RD, et al. Hydroxyurea: effects on hemoglo- bin F production in patients with sickle cell anemia. Blood 1992;79:2555- 65.
  2. [10]10. Charache S, Terrin ML, Moore RD, et al. Design of the Multicenter Study of Hydroxyurea. Control Clin Trials (in press).
  3. [15]15. Fienberg SE. The analysis of cross-classified categorical data. 2nd ed. Cam- bridge, Mass.: MIT Press, 1980:8-26.
  4. [17]17. Kalbfleisch JD, Prentice RL. The stastistical analysis of failure time data. New York: John Wiley, 1980:1-20, 70-142.
  5. [26]26. Ferm VH. Severe developmental malformations: malformations induced by urethane and hydroxyurea in the hamster. Arch Pathol 1966;81:174-7.
  6. [31]31. Weichselbaum RR, Hallahan DE, Chen GTY. Biological and physical basis to radiation oncology. In: Holland JF, Frei E III, Bast RC Jr, Kufe DW, Mor- ton DL, Weichselbaum RR, eds. Cancer medicine. 3rd ed. Vol. 1. Philadel- phia: Lea & Febiger, 1993:539-66.
  7. [32]32. Chemotherapeutic agents. In: Holland JF, Frei E III, Bast RC Jr, Kufe DW, Morton DL, Weichselbaum RR, eds. Cancer medicine. 3rd ed. Vol. 1. Phil- adelphia: Lea & Febiger, 1993:698-814.
  8. [33]33. Berk PD, Wasserman LR, Fruchtman SM, Goldberg JD. Treatment of poly- cythemia vera: a summary of clinical trials conducted by the Polycythemia Vera Study Group. In: Wasserman LR, Berk PD, Berlin NI, eds. Poly- cythemia vera and the myeloproliferative disorders. Philadelphia: W.B. Saunders, 1995:166-94.
  9. [37]37. Triadou P, Maier-Redelsperger M, Krishnamoorty R, et al. Fetal haemoglo- bin variations following hydroxyurea treatment in patients with cyanotic congenital heart disease. Nouv Rev Fr Hematol 1994;36:367-72.

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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
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
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 › 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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