Duane Bonds

Effect of hydroxyurea on the frequency of painful crises in Sickle cell anemia

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.

Prevention of a First Stroke by Transfusions in Children with Sickle Cell Anemia and Abnormal Results on Transcranial Doppler Ultrasonography

BACKGROUND Blood transfusions prevent recurrent stroke in children with sickle cell anemia, but the value of transfusions in preventing a first stroke is unknown. We used transcranial Doppler ultrasonography to identify children with sickle cell anemia who were at high risk for stroke and then randomly assigned them to receive standard care or transfusions to prevent a first stroke. METHODS To enter the study, children with sickle cell anemia and no history of stroke had to have undergone two transcranial Doppler studies that showed that the time-averaged mean blood-flow velocity in the internal carotid or middle cerebral artery was 200 cm per second or higher. The patients were randomly assigned to receive standard care or transfusions to reduce the hemoglobin S concentration to less than 30 percent of the total hemoglobin concentration. The incidence of stroke (cerebral infarction or intracranial hemorrhage) was compared between the two groups. RESULTS A total of 130 children (mean [+/-SD] age, 8.3+/-3.3 years) were enrolled; 63 were randomly assigned to receive transfusions and 67 to receive standard care. At base line, the transfusion group had a slightly lower mean hemoglobin concentration (7.2 vs. 7.6 g per deciliter, P=0.001) and hematocrit (20.4 vs. 21.7 percent, P=0.002). Ten patients dropped out of the transfusion group, and two patients crossed over from the standard-care group to the transfusion group. There were 10 cerebral infarctions and 1 intracerebral hematoma in the standard-care group, as compared with 1 infarction in the transfusion group -- a 92 percent difference in the risk of stroke (P<0.001). This result led to the early termination of the trial. CONCLUSIONS Transfusion greatly reduces the risk of a first stroke in children with sickle cell anemia who have abnormal results on transcranial Doppler ultrasonography.

Pregnancy in sickle cell disease: experience of the Cooperative Study of Sickle Cell Disease.

Objective To determine the maternal and fetal outcomes of pregnancy in women with sickle cell disease. Methods The subjects were part of a cohort recruited from 19 centers for a prospective study of the clinical course of sickle cell disease. Each participant was evaluated using a structured protocol in which steady-state data and information on both sickle- and non-sickle-related events were colleted. The rates of antepartum and intrapartum complications were tallied for pregnancies carried to delivery. Fetal outcome was assessed according to gestational age, birth weight, and Apgar score. Differences among genotypes in event rates were assessed using Fisher exact test. Differences in gestational age and birth weight, and predictors of these outcomes, were assessed using analyses of covariance. Results Two hundred eighty-six of the 445 reported pregnacies proceeded to delivery. Non-sickle-related antepartum and intrapartum complication rates were comparable with those of African-American women who did not have sickle cell disease. One of the two deaths observed during this study was directly related to the presence of sickle cell disease. Rates of maternal morbidity from sickle cell disease were the same during pregancy as during the nonpregnant state. Ninety-nine percent of those pregnancies carried to delivery resulted in a live birth. Twenty-one percent of the infants born to women of the SS genotype were small for gestational age (SGA). Preclampsia and acute anemic events were identified as risk factors for SGA infants. Conclusion Those caring for women with sickle cell disease should support them if they desire to have children.

Hydroxyurea and sickle cell anemia: Effect on quality of life

BackgroundThe Multicenter Study of Hydroxyurea (HU) in Sickle Cell Anemia (MSH) previously showed that daily oral HU reduces painful sickle cell (SS) crises by 50% in patients with moderate to severe disease. The morbidity associated with this disease is known to have serious negative impact on the overall quality of life(QOL) of affected individuals.MethodsThe data in this report were collected from the 299 patients enrolled in the MSH. Health quality of llife (HQOL) measures were assessed in the MSH as a secondary endpoint to determine if the clinical benefit of HU could translate into a measurable benefit perceptible to the patients. HQOL was assessed with the Profile of Mood States, the Health Status Short Form 36 (SF-36), including 4-week pain recall, and the Ladder of Life, self-administered twice 2-weeks apart pre-treatment and every 6 months during the two-year, randomized, double-blind, treatment phase. The effects of factors including randomized treatment, age, gender, pre-treatment crises frequency, Hb-F level mean, daily pain from 4-week pre-treatment diaries, and 2-year Hb-F response level (low or high) were investigated.ResultsOver two years of treatment, the benefit of HU treatment on QOL, other than pain scales, was limited to those patients taking HU who maintained a high HbF response, compared to those with low HbF response or on placebo. These restricted benefits occurred in social function, pain recall and general health perception. Stratification according to average daily pain prior to treatment showed that responders to HU whose average daily pain score was 5–9 (substantial pain) achieved significant reduction in the tension scale compared to the placebo group and to non-responders. HU had no apparent effect on other QOL measures.ConclusionTreatment of SS with HU improves some aspects of QOL in adult patients who already suffer from moderate-to-severe SS.

An extension of stochastic curtailment for incompletely reported and classified recurrent events: the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH).

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), a double-blind randomized clinical trial, compared the frequency of acute vaso-occlusive (painful) crises during 2 yr of follow-up in 299 patients randomly assigned to hydroxyurea or placebo. Most patients had more than one crisis; all crises reported were included in the primary outcome analysis. A total of 7,229 follow-up medical contact reports were classified as crises/not crises by a Crisis Review Committee. Because of the time required to report, document, and classify contacts, interim analyses were prepared with incomplete data. If a stopping boundary were crossed, early termination could be advised only after assessing the potential impact of the incomplete data. In an extension of stochastic curtailment methods, simulation procedures were used to estimate the probability of detecting differences when group crisis rates projected to the end of the study were compared using a rank test. To account for medical contacts not yet reported and the future occurrence of crises, Poisson process models assuming no treatment effect on crisis rates were used for these simulations. The number of unclassified contacts that would be classified as crises was simulated as a binomial random variable. These methods may be useful for interim monitoring in other studies of recurrent events with ongoing event reporting and classification.