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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Painful crises in patients with sickle cell anemia are caused by vaso-occlusion and infarction. Occlusion of blood vessels depends on (at least) their diameter, the deformability of red cells, and the adhesion of blood cells to endothelium. Deoxygenated sickle cells are rigid because they contain linear polymers of hemoglobin S (Hb S); polymerization is highly concentration dependent, and dilution of Hb S by a nonsickling hemoglobin such as fetal hemoglobin (Hb F) would be expected to lead ultimately to a decrease in the frequency of painful crises. It might also be expected to decrease the severity of anemia, although the pathogenesis of anemia in sickle cell anemia (SS disease) is not clearly understood. Reversion to production of fetal rather than adult hemoglobin became practical with the discovery that HU was an orally effective and relatively safe "switching agent." Preliminary dose-ranging studies led to a double-blind randomized controlled clinical trial, the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), designed to test whether patients treated with HU would have fewer crises than patients treated with placebo. The MSH was not designed to assess the mechanism(s) by which a beneficial effect might be achieved, but it was hoped that observations made during the study might illuminate that question. The 2 MSH treatment groups were similar to each other and were representative of African-American patients with relatively severe disease. The trial was closed earlier than expected, after demonstration that median crisis rate was reduced by almost 50% (2.5 versus 4.5 crises per year) in patients assigned to HU therapy. Hospitalizations, episodes of chest syndrome, and numbers of transfusions were also lower in patients treated with HU. Eight patients died during the trial, and treatment was stopped in 53. There were no instances of alarming toxicity. Patients varied widely in their maximum tolerated doses, but it was not clear that all were taking their prescribed treatments. When crisis frequency was compared with various clinical and laboratory measurements, pretreatment crisis rate and treatment with HU were clearly related to crisis rate during treatment. Pretreatment laboratory measurements were not associated with crisis rates during the study in either treatment group. It was not clear that clinical improvement was associated with an increase in Hb F. Crisis rates of the 2 treatment groups became different within 3 months. Mean corpuscular volumes (MCVs) and the proportion of Hb F containing red cells (F cells) rose, and neutrophil and reticulocyte counts fell, within 7 weeks. When patients were compared on the basis of 2-year crisis rates, those with lower crisis rates had higher F-cell counts and MCVs and lower neutrophil counts. Neutrophil, monocyte, reticulocyte, and platelet counts were directly associated, and F cells and MCV were inversely associated, with crisis rates in 3-month periods. In multivariable analyses, there was strong evidence of independent association of lower neutrophil counts with lower crisis rates. F-cell counts were associated with crisis rate only in the first 3 months of treatment; MCV showed an association over longer periods of time. Overall, the evidence that decreased neutrophil counts played a role in reducing crisis rates was strong. Increased F cells or MCV and evidence of cytoreduction by HU were also associated with decreased crisis rates, but no definitive statement can be made regarding the mechanism of action of HU because the study was not designed to address that question. Future studies should be designed to explore the mechanism of action of HU, to identify the optimal dosage regimen, and to study the effect of HU when combined with other antisickling agents.
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PMID:Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. 898 48

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.
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PMID:An extension of stochastic curtailment for incompletely reported and classified recurrent events: the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH). 931 25

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) demonstrated the efficacy of hydroxyurea in reducing the rate of painful crises compared to placebo. We used resource utilization data collected in the MSH to determine the cost-effectiveness of hydroxyurea. The MSH was a randomized, placebo-controlled double-blind clinical trial involving 299 patients at 21 sites. The primary outcome, visit to a medical facility, was one of the criteria to define occurrence of painful crisis. Cost estimates were applied to all outpatient and emergency department visits and inpatient hospital stays that were classified as a crisis. Other resources for which cost estimates were applied included hospitalization for chest syndrome, analgesics received, hydroxyurea dosing, laboratory testing, and clinic visits for management of patient care. Annualized differential costs were calculated between hydroxyurea- and placebo-receiving patients. Hospitalization for painful crisis accounted for the majority of costs in both arms of the study, with an annual mean of $12,160 (95% CI: $9,440, $14,880) for hydroxyurea and $17,290 (95% CI: $13,010, $21,570) for placebo. The difference in means was $5,130 (95% CI: $60, $10,200; P = 0.048). Chest syndrome was the next largest cost with a mean difference of $830 (95% CI: $-340, $2,000; P = 0.16). The hydroxyurea arm was also associated with lower costs for emergency department visits, transfusion, and use of opiate analgesics. In total, the annual average cost per patient receiving hydroxyurea was $16,810 (95% CI: $13,350, $20,270) and the annual average costs per patient receiving placebo was $22,020 (95% CI: $17,340, $26,710). The difference in means was $5,210 (95% CI: $-610, $11,030; P = 0.21). The cost of hydroxyurea with the more intensive monitoring required when using this drug appears to be more than offset by decreased costs for medical care of painful crisis and analgesic use. Although the total cost difference was not significant statistically, these results suggest that hydroxyurea therapy is cost-effective compared to placebo in the management of adult patients with sickle cell anemia. If hydroxyurea can prevent development of chronic organ damage, long-term savings may be even greater.
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PMID:Cost-effectiveness of hydroxyurea in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. 1081 84

We genotyped single nucleotide polymorphisms (SNPs) in: (1) the beta-globin gene-like cluster, (2) quantitative trait loci (QTL) previously associated with fetal hemoglobin (HbF) concentration on chromosomes 6q, 8q, and Xp, and (3) candidate genes that could effect HbF levels, in sickle cell anemia subjects. HbF concentration was modeled as a continuous variable with values in a finite interval using a novel Bayesian approach. We first tested the associations of SNPs with HbF in a group of 1,518 adults and children (CSSCD study), and validated the results in a second independent group of 211 adults (MSH study). In subjects aged >or=24 years, 5 SNPs in TOX (8q12.1), 2 SNPs in the beta-globin gene-like cluster, 2 SNPs in the Xp QTL, and 1 SNP in chromosome 15q22 were associated with HbF in the CSSCD and also validated in the MSH. Four other SNPs in 15q22 were associated with HbF only in the larger CSSCD data. When patients aged <24 years in the CSSCD were examined, additional genes, including 4 with roles in nitric oxide metabolism, were associated with HbF level. These studies confirm prior analyses using traditional analytical approaches showing associations of SNPs in TOX, GPM6B, and the beta-globin gene-like cluster with HbF levels. We also identified an additional candidate regulatory region in chromosome 15q22 that is associated with HbF level. By stratifying patients by age, our results also suggest that different genes might modulate the rate of decline of HbF and the final level of HbF levels in sickle cell anemia.
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PMID:Fetal hemoglobin in sickle cell anemia: Bayesian modeling of genetic associations. 1791 49

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) was a randomized double-blind placebo-controlled trial to test whether hydroxyurea could reduce the rate of painful crises in adults who had at least 3 painful crises per year. Because hydroxyurea is known to be carcinogenic, mutagenic, and teratogenic in animals, a major inclusion criterion in MSH was the use of contraceptives both by females and males in order to avoid exposure of the fetus to hydroxyurea. Despite this precautionary measure, some women became pregnant while taking hydroxyurea or their male partners were on hydroxyurea. We followed surviving patients who were enrolled in the original MSH trial for up to 17 years postrandomization. Our findings suggest that exposure of the fetus to hydroxyurea does not cause teratogenic changes in those pregnancies that terminate in live birth whether full-term or premature. This seems to be true whether the parent taking hydroxyurea was the mother or the father. The same argument seems to apply for exposure to opioids. However, it will take a much longer follow-up of many more hydroxyurea-exposed sickle cell disease subjects to establish the results conclusively.
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PMID:Exposure to hydroxyurea and pregnancy outcomes in patients with sickle cell anemia. 1986 Mar 5

The purpose of this study was to determine the association between hydroxyurea treatment and changes in employment status, if any, among patients with sickle cell anemia enrolled in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH). To that end, we compared the employment status among treatment responders, treatment nonresponders, and placebo groups of patients enrolled in MSH during the clinical trial and follow-up periods. Treatment with hydroxyurea did not significantly (p > .05) affect employment status, but there was a trend for more consistent employment in the hydroxyurea group. Given the fact that patients enrolled in MSH had moderate to severe disease with irreversible complications such as avascular necrosis, if would be attractive to hypothesize that future treatment of young patients with hydroxyurea could prevent or mitigate the incidence of complications of sickle cell anemia and, hence, improve the employment status of treated patients.
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PMID:The impact of hydroxyurea on career and employment of patients with sickle cell anemia. 2114 Dec 86