In adults with sickle-cell disease who have ≥3 crises per year, does hydroxyurea decrease the frequency of sickle-cell crises as compared to placebo?
Raising the hemoglobin F concentration with hydroxyurea decreases the number of crises per year in patients with sickle-cell disease.
In patients with sickle-cell disease (SCD), a mutation in the beta chain of hemoglobin yields abnormal hemoglobin polymerization, red-cell sickling, and reduced capillary blood flow that leads to a variety of complications including painful crises. Fetal hemoglobin (Hgb F) is a form of hemoglobin that does not require the beta globin chain, and in patients with SCD, increasing its synthesis can decrease red-cell sickling. Hydroxyurea increases Hgb F synthesis, and this study tested its use in patients with SCD.
The Multicenter Study of Hydroxyurea in Sickle-Cell Anemia (MSH) was a randomized, double-blind, placebo-controlled trial enrolling 299 patients with a plan to follow them for 24 months. Patients with SCD and ≥3 sickle-cell crises in the prior year were randomized to hydroxyurea or placebo. Hydroxyurea was started at 15 mg/kg/d and adjusted according to marrow suppression to a maximum dose of 35 mg/kg/d. Blood work and clinic visits occurred every 2 weeks. The primary outcome was the number of SCD crises per year, including acute painful crises, acute chest syndrome, priapism, and acute hepatic sequestration.
The study was stopped early after a mean of 21 months of follow-up due to the efficacy of hydroxyurea. Patients in the hydroxyurea group experienced fewer pain crises per year (2.5 vs. 4.5) and a longer time to first pain crisis (3.0 vs 1.5 months). A post hoc analysis also revealed that hydroxyurea-treated patients developed fewer acute chest syndromes and required fewer transfusions than those receiving placebo. The dose limiting toxicity was myelosuppression which caused two patients to drop out of the study, but there were no deaths due to hydroxyurea observed. Hydroxyurea-associated secondary malignancies have been raised in other studies, but in long-term follow-up of this study's patients, only 3 developed cancer.
National Heart, Lung, and Blood Institute's Evidence Based Management of Sickle-Cell Disease: Expert Panel Report (2014, adapted)
- Educate all patients with SCD and their family members about hydroxyurea therapy. (Consensus–Panel Expertise)
- In adults with SCD who have ≥3 sickle-cell–associated moderate to severe pain crises in a 12-month period, treat with hydroxyurea. (Strong Recommendation, High-Quality Evidence)
- In adults with SCD who have sickle-cell–associated pain that interferes with daily activities and quality of life, treat with hydroxyurea. (Strong Recommendation, Moderate-Quality Evidence)
- In adults with SCD who have a history of severe and/or recurrent ACS, treat with hydroxyurea. (Strong Recommendation, Moderate-Quality Evidence)
- In adults with SCD who have severe symptomatic chronic anemia that interferes with daily activities or quality of life, treat with hydroxyurea. (Strong Recommendation, Moderate-Quality Evidence)
- In infants 9 months of age and older, children, and adolescents with SCD, offer treatment with hydroxyurea regardless of clinical severity to reduce SCD-related complications (eg, pain, dactylitis, ACS, anemia). (Strong Recommendation, High-Quality Evidence for ages 9–42 months; Moderate Recommendation, Moderate-Quality Evidence for children >42 months and adolescents).
- In adults and children with SCD who have chronic kidney disease and are taking erythropoietin, hydroxyurea therapy can be added to improve anemia. (Weak Recommendation, Low-Quality Evidence)
- In females who are pregnant or breastfeeding, discontinue hydroxyurea therapy. (Moderate Recommendation, Very Low-Quality Evidence)
- To ensure proper use of hydroxyurea and maximize benefits and safety, use an established prescribing and monitoring protocol. (Strong Recommendation, High-Quality Evidence)
- In people with HbS β+-thalassemia or HbSC who have recurrent sickle-cell–associated pain that interferes with daily activities or quality of life, consult a sickle-cell expert for consideration of hydroxyurea therapy. (Moderate Recommendation, Low-Quality Evidence)
- In people not demonstrating a clinical response to appropriate doses and duration of hydroxyurea therapy, consult a sickle-cell expert. (Moderate Recommendation, Very Low-Quality Evidence)
- Multicenter, randomized, double-blind, placebo-controlled trial
- N=299 patients with SCD and ≥3 crises in the prior year
- Hydroxyurea (n=152)
- Placebo (n=147)
- Setting: 21 US and Canadian centers
- Enrollment: 1992-1994
- Mean follow-up: 21 months (originally planned 24 months, but terminated early due to efficacy)
- Analysis: Intention-to-treat
- Primary outcome: Number of SCD crises per year
- Age ≥18 years
- SCD or sickle-cell–α-thalassemia
- ≥3 SCD crises in the prior year, defined as:
- A visit to a medical facility lasting >4 hours for acute sickling-related pain treated with narcotics
- Acute chest pain (fever and chest wall pain plus new pulmonary infiltrate)
- Hepatic sequestration (acute painful hepatomegaly, ↑LFTs, ↓hemoglobin by 2 g/dL)
- Hematuria and chronic pain exacerbations were not considered crises
- If patients had received transfusions, hemolysates of their red cells must contain ≤15% of hemoglobin A
- Sickle-cell–β+-thalassemia or sickle-cell–β0-thalassemia
- Narcotic addiction or regular consumption of more than 30 oxycodone capsules every 2 weeks
- Participation in a long-term transfusion program
- Treatment with another potential anti-sickling agent or prior hydroxyurea therapy
- History of stroke in prior 6 years
- Known HIV
From the hydroxyurea group.
- Number of crises in the year prior to enrollment (%):
- 3-5: 44%
- 6-9: 26%
- ≥10: 30%
- Complications of SCD:
- Chest syndrome: 66%
- Ankle ulcer: 31%
- Aseptic necrosis of bone: 20%
- Hemoglobin: 8.4 g/dL
- MCV: 94
- WBC: 12.6K
- Platelets: 468K
- Reticulocytes: 327
- Hgb F: 5%
- Randomized to hydroxyurea therapy or placebo
- Starting dose was 15 mg/kg/d
- Dose increased by 5 mg/kg/d every 12 weeks unless marrow suppression occurred
- Marrow suppression was defined as ANC <2K, reticulocyte count <80K, hemoglobin <4.5 g/dL, or platelets <80K
- If marrow suppression occurred, treatment was held until counts recovered, then treatment resumed at a dose 2.5 mg/kg/d lower than the prior dose
- All patients received folate 1 mg/d
- Clinic visits with laboratory assessments every 2 weeks
Comparisons are hydroxyurea vs. placebo.
- SCD crises
- 2.5 vs. 4.5 per year (RR 0.56; P<0.001)
- SCD crises requiring hospitalization
- 1.0 vs. 2.4 per year (P<0.001)
- Acute chest syndrome
- 25 vs. 51 (P<0.001)
- Transfusion received
- 48 vs. 73 (P=0.001)
- Units of blood transfused
- 336 vs. 586 (P=0.004)
- Time to first cries (median)
- 3.0 vs. 1.5 months (P=0.01)
- Time to second crisis (median)
- 8.8 vs. 4.6 months (P<0.001)
- Achievement of maximum hydroxyurea dose
- At 6 months: 33%
- At 21 months (end of study): 51%
- Hydroxyurea compliance (>80% of prescribed capsules)
- 75% based on capsule counts
- 2 vs. 5 (none were attributed to medication)
- Permanent cessation of therapy
- 14 vs. 6
- No patient developed cancer while on study
- Short duration of follow-up yields insufficient estimates for risk of malignancy due to hydroxyurea
- The high medication compliance in this study may be difficult to achieve in real-world practice, thus limiting the generalizability of these findings.
- Bristol-Myers Squibb provided study drug
- Liu DP et al. Treatment of severe beta-thalassemia (patients) with myleran. Am. J. Hematol. 1990. 33:50-5.
- Steinberg MH et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA 2003. 289:1645-51.
- Yawn BP et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014. 312:1033-48.