In 1995, U.S. researchers published results of a major multi-center study showing that the compound hydroxyurea could cut in half the number of severe painful episodes patients with sickle cell anemia experience.
Now, an extension of that study shows that not only do patients on hydroxyurea have fewer crises, but they also have a significant survival advantage when compared to similarly affected patients who do not take the medication. Subjects treated with it overall showed 40 percent lower mortality than others.From the University of North Carolina at Chapel Hill:Major study: hydroxyurea reduces sickle cell mortality by 40 percent
By DAVID WILLIAMSON
UNC News Services
CHAPEL HILL — In 1995, U.S. researchers published results of a major multi-center study showing that the compound hydroxyurea could cut in half the number of severe painful episodes patients with sickle cell anemia experience.
Now, an extension of that study shows that not only do patients on hydroxyurea have fewer crises, but they also have a significant survival advantage when compared to similarly affected patients who do not take the medication. Subjects treated with it overall showed 40 percent lower mortality than others.
A report on the new cooperative study appears in the April 2 issue of the Journal of the American Medical Association. Among 27 authors are Drs. Martin H. Steinberg of Boston University, Eugene P. Orringer and Kenneth Ataga of the University of North Carolina at Chapel Hill and Laura DeCastro of Duke University. All are medical school faculty members.
“From the first study, it was clear to all of us that hydroxyurea could significantly reduce the frequency of these painful crises,” said Orringer, a sickle cell disease expert and executive associate dean of the UNC School of Medicine. “What we didn’t know was whether this would subsequently translate into any benefit to patients in terms of their long-term survival. This study clearly answers that question, and the results are very encouraging for patients with sickle cell disease.”
Soon after the initial part of the study was completed, the U.S. Food and Drug Administration approved hydroxyurea as the first specific treatment for sickle cell disease, he said. Today, the drug remains the only one specifically approved for that clinical indication.
“We think that hydroxyurea works, at least in part, by turning back on the production of fetal hemoglobin in adult sickle cell patients,” Orringer said. “Hemoglobin is the protein in red blood cells that enables them to carry oxygen throughout the body.
“Before we are born, all of our red blood cells are filled with fetal hemoglobin. After birth, this fetal hemoglobin is gradually replaced by adult hemoglobin, such that by age 1, our red cells contain almost exclusively adult hemoglobin. This is fine unless you have sickle cell disease, because it is the adult hemoglobin that carries the troublesome sickle mutation.”
In affected individuals, having more fetal hemoglobin is actually very beneficial since that version of the hemoglobin molecule is unaffected by the problem-causing genetic mutation, he said.
The original study of hydroxyurea was begun in 1991 and was completed in 1995. Twenty-one centers enrolled 299 patients with the most severe painful episodes in the follow-up, and of those, UNC enrolled 20. The recently completed follow-up study, in which the same patients were offered the choice to continue, to stop or to begin treatment with hydroxyurea, lasted from 1996 until 2001. On average, the researchers followed the patients for at least nine years.
The National Heart, Lung and Blood Institute, a division of the National Institutes of Health, sponsored all the research through grants.
“Individuals who had acute chest syndrome (fever, respiratory symptoms and abnormal chest X-rays) during the trial had 32 percent mortality compared with 18 percent of individuals without acute chest syndrome,” the authors wrote. “Patients with three or more painful episodes per year during the trial had 27 percent mortality compared with 17 percent of patients with less frequent episodes.
“We conclude that underlying disease severity remains critical to determining the prognosis of adults with sickle cell anemia, but hydroxyurea may mitigate disease severity.”
“Hydroxyurea provides hope and help for improving quality of life and lifespan for patients with this devastating disease,” said Drs. Debra L. Weiner and Carlo Brugnara of Harvard Medical School in an accompanying editorial. “Based on the work by Steinberg et al and of others, expanded use of hydroxyurea is clearly warranted.”
One issue relates to use of hydroxyurea in children with sickle cell disease, Orringer said.
“We do know that as they grow into adulthood, children with sickle cell disease typically develop sickle cell-related complications that affect many of their organs including kidneys, liver and lungs,” he said. “Therefore, the National Heart. Lung and Blood Institute is now supporting a study to determine whether treatment with hydroxyurea should be initiated in very young children with sickle cell disease.”
One problem with sickle cell crises is that they are so unpredictable, the physician said. In some patients, they can be rare, while in others they are frequent.
“An earlier NIH-funded ‘natural history’ study that followed 5,000 sickle cell patients reported that these individuals experience an average of one to 1.5 crises per year,” he said. “However, some patients can have one or more crises per week. Patients can be feeling fine and then an hour or two later experience pain so severe they have to go to an emergency room and require hospital admission.
“It is important to emphasize that sickle cell disease is not contagious,” Orringer said. “Rather, it is a genetic illness passed from parents to children. In the United States, sickle cell disease is found primarily in people whose ancestors came from Africa.”
A child born to parents who both carry the defective sickle cell gene has a 25 percent chance of being born with the disease. He or she has a 50-50 chance of being a carrier of the sickle cell gene (referred to as sickle cell trait) and a 25 percent chance of being entirely normal. Current estimates suggest that about 75,000 U.S. residents have sickle cell disease.
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