CLINICAL ALERT - DRUG TREATMENT FOR SICKLE CELL ANEMIA 
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 CLINICAL ALERT - DRUG TREATMENT FOR SICKLE CELL ANEMIA

      CLINICAL ALERT - DRUG TREATMENT FOR SICKLE CELL ANEMIA
                        JANUARY 30, 1995

SOURCE: NATIONAL HEART, LUNG, AND {*filter*} INSTITUTE (NHLBI)

ASTRACT  -     The National Heart, Lung, and {*filter*} Institute (NHLBI) today
      announced a drug treatment for sickle cell anemia.  Findings from
      a multicenter clinical trial show that daily administration of
      the drug hydroxyurea reduced by about 50% the frequency of
      painful episodes and hospital visits for those episodes.  The
      treatment also reduced the frequency of acute chest syndrome and
      the number of {*filter*} transfusions for patients in the study.

           Hydroxyurea has been used primarily to treat
      myeloproliferative disorders such as polycythemia vera.  Although
      the exact mechanism of action in sickle cell anemia is not
      completely understood, it is believed that hydroxyurea works by
      increasing the production of fetal hemoglobin in red {*filter*} cells.
      This may prevent the cells from becoming rigid and clogging the
      {*filter*} vessels.  Hydroxyurea is not currently approved by the U.S.
      cooking.net">food and Drug Administration to treat sickle cell anemia although
      physicians can prescribe it for that purpose.

          Hydroxyurea may not be appropriate for all patients with
      sickle cell anemia, and this study only enrolled {*filter*}s with
      severe recurrent painful episodes.  It is a cytotoxic agent, and
      has the potential to cause life-threatening cytopenia.  In
      addition, this drug should not be used in patients likely to
      become pregnant or those unwilling or unable to follow
      instructions regarding treatment.  Hydroxyurea is a treatment,
      not a cure, and any beneficial effects experienced will last only
      as long the patient continues to take the prescribed dose.

          These findings are the results of data analyzed from the
      Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH),
      which was a double-blind, placebo-controlled trial.  The data
      were so compelling that the trial's Data and Safety Monitoring
      Board recommended that the trial be terminated before the
      scheduled date of May 1995.  NHLBI contact:  Dr. Duane Bonds,
      (301) 496-6931.

          The full text of this alert has been mailed to all libraries
      that are members of the National Network of Libraries of
      Medicine.

FULL TEXT  -     The National Heart, Lung, and {*filter*} Institute (NHLBI)
      announced today a treatment which reduces the frequency of
      painful episodes or crises in patients with sickle cell anemia.
      Recurrent painful episodes are the most disabling feature of
      sickle cell anemia, interfering with education, vocational
      training, job retention and psychosocial development. The
      treatment, daily administration of the drug hydroxyurea, reduced
      the frequency of painful episodes and hospital admissions for
      painful episodes by approximately 50 percent. In addition,
      hydroxyurea therapy significantly reduced the frequency of acute
      chest syndrome, a life-threatening complication of sickle cell
      anemia characterized by chest pain, fever, prostration, and an
      abnormal chest x ray. The patients treated with hydroxyurea
      required fewer {*filter*} transfusions during the study, an outcome
      which has important public health implications.

          Hydroxyurea is a drug which up until this trial had primarily
      been used to treat myeloproliferative disorders such as
      polycythemia vera. Although the exact mechanism of action in
      sickle cell anemia is not completely understood, it is believed
      that hydroxyurea works by increasing the production of fetal
      hemoglobin in red {*filter*} cells. Sickle hemoglobin forms long
      strands or polymers inside of red {*filter*} cells that have released
      their oxygen into the circulation, causing the red {*filter*} cells to
      become rigid. Rigid sickle red {*filter*} cells clog the {*filter*}
      vessels, causing vaso-occlusion and painful episodes, which are
      the hallmarks of sickle cell anemia. Increased levels of fetal
      hemoglobin inside sickle red {*filter*} cells may prevent the cells
      from becoming rigid, thereby preventing vaso-occlusion.

                 These findings are the results of data analyzed from the
      Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH),
      which was a double-blind, placebo-controlled trial in which half
      of the patients received hydroxyurea and half received a placebo
      capsule. The primary analysis compared annual crisis rates of
      patients assigned to receive hydroxyurea to rates of patients
      assigned to receive placebo. A painful or vaso-occlusive crisis
      was defined as a visit to a health care facility lasting more
      than 4 hours for treatment of an acute painful event which
      required treatment with either (1) parenteral narcotics; or, (2)
      an equianalgesic dose of {*filter*}narcotics, (if the episode was
      treated at a facility in which parenteral narcotics were not
      routinely used to treat crises); or, (3) parenteral non-steroidal
      anti-inflammatory {*filter*} (NSAID's). Episodes of acute chest
      syndrome, hepatic sequestration, and priapism were also
      considered to be crises, but surgical procedures and pain due to
      acute exacerbations of chronic conditions (e.g. ankle ulcer, hip
      necrosis, or osteomyelitis) were not considered to be crises.
      Between January 1992 and April 1993, the NHLBI-sponsored trial
      headquartered at Johns Hopkins University (Dr. Samuel Charache)
      and the Maryland Medical Research Institute (Dr. Michael Terrin)
      enrolled 299 {*filter*} sickle cell anemia (Hb SS) patients who had
      experienced at least 3 painful crises in the previous year. The
      patients were drawn from 21 clinical centers around the United
      States (list attached). Only patients with moderate-to-severe
      disease who were age 18 and older were allowed to participate.
      The drug was supplied by Bristol-Meyers Squibb.

          The dosing of hydroxyurea was achieved as follows: patients
      were begun on 15 mg/kg, and the dose was increased by 5 mg/kg
      every 12 weeks unless toxicity was observed or the maximum dose
      of 35 mg/kg/day was reached. If toxicity occurred, treatment was
      stopped until the bone marrow recovered, and then was restarted
      at a lower dose (2.5 mg/kg less than the previous dose). If no
      toxicity occurred after 12 weeks on the lower dose, the
      subsequent dose was increased by 2.5 mg/kg/day. The maximum
      tolerated dose was a dose just less than that which produced
      toxicity. Patients were carefully monitored every 2 weeks. Toxic
      bone marrow depression was defined as absolute neutrophil counts
      less than 2,000/cubic millimeters, absolute reticulocytes less
      than 80,000/cubic millimeters (if the hemoglobin concentration is
      below 9 gm/dL), platelet counts less than 80,000/cubic
      millimeters, or a fall in hemoglobin concentration from > or =
      7.0 gm/dL (pre-enrollment) to 4.5 - 5.0 if reticulocytes <
      320,000, or hemoglobin concentration < 4.5 gm/dL.  The only
      evidence of toxicity noted was reversible bone marrow
      suppression.

          Hydroxyurea may not be appropriate for all patients with
      sickle cell anemia, and this study only enrolled {*filter*}s with
      severe recurrent painful episodes. It is a cytotoxic agent, and
      has the potential to cause life-threatening cytopenia. In
      addition, this drug should not be used in patients likely to
      become pregnant or in those unwilling or unable to follow
      instructions regarding treatment. Therefore, each sickle cell
      anemia patient must be evaluated carefully before hydroxyurea
      therapy is begun, and careful monitoring must continue while the
      patient is on this agent. Patients must also understand that
      hydroxyurea treatment is not a cure. If hydroxyurea therapy has
      any beneficial effects, they last only as long as the patient
      continues to take the prescribed dose.

          Hydroxyurea is used for treatment of polycythemia vera, a
      disease in which too many red {*filter*} cells are produced. In an
      open label study of polycythemia vera now entering its 15th year,
      patients treated with hydroxyurea have a higher rate of leukemia
      that is not statistically significant when compared to those
      treated with phlebotomy alone.  Because the long term side
      effects of hydroxyurea are unknown, the patients participating in
      the MSH clinical trial will be followed and examined annually to
      ascertain rates of malignancies and other health problems. Safety
      of this agent for children with sickle cell anemia must be
      determined.

          Physicians can prescribe hydroxyurea for the treatment of
      sickle cell anemia in their patients, although the drug is not
      approved for this use by the U.S. cooking.net">food and Drug Administration
      (FDA).  The FDA will consider approval of this use of the drug
      following the submission of the data by the manufacturer.

          The MSH clinical trial was scheduled to continue until May
      1995. The results found during interim analyses were so
      compelling that the study's Data and Safety Monitoring Board,
      composed of independent, outside experts in the fields of
      hematology, biostatistics, and ethics, recommended that the study
      be terminated early. The Data and Safety Monitoring Board felt
      that the patients who had been receiving the placebo should
      immediately be offered an effective treatment. On January 14,
      1995, the study was stopped, and the clinical investigators in
      the 21 participating centers were notified of the study's results
      and the efficacy and safety of hydroxyurea therapy.  During the
      last two weeks, the results were discussed with patients in both
      treatment arms.

          NHLBI contact:  Dr. Duane Bonds, (301) 496-6931.

          --------------------------------------------------------

          MSH Principal Investigators:

          Samuel Charache, M.D., The Johns Hopkins Hospital, (410) 955-
      6315;

          Michael L. Terrin, M.D., C.M., M.P.H., Maryland Medical
      Research Institute, (410) 435-4200.

          --------------------------------------------------------

          MSH Clinic Directors:

          Eugene Orringer, M.D., University of North Carolina School of
      Medicine, (919)966-2467.

          Wendell Rosse, M.D., Duke University Medical Center (919)
      684-6464.

          Paul Milner, M.D., Medical College of Georgia, (706) 721-
      2171.

          Samir K. Ballas, M.D., Thomas Jefferson University, (215)
      955-8485.

          Martin Steinberg, M.D., Veterans Administration Medical
      Center, (601) 364-1315.

          Charles H. Pegelow, M.D., University of Miami School of
      Medicine, (305) 585-7752.

          Stephen H. Embury, M.D., San Francisco General Hospital,
      (415) 206-8573.

          Mabel Koshy, M.D., University of Illinois Hospital, (312)
      996-5680.

          Oswaldo Castro, M.D., Howard University, (202) 806-7930.

          Pedro Gascon, M.D., University of Medicine and Dentistry of
      New Jersey, (201) 456-5256.

          James R. Eckman, M.D., Emory University School of Medicine,
      (404) 616-3572.

          Gloria Ramirez, M.D., St. Luke's/Roosevelt Hospital Center,
      (212) 523-3116.

          Elliott Vichinsky, M.D., Children's Hospital of Oakland,
      (510) 428-3651.

          Paul Swerdlow, M.D., Medical College of {*filter*}ia, (804) 230-
      1364.

          Susan B. Shurin, M.D., Rainbow Babies & Children's Hospital,
      (216) 844-3345.
          Nancy Olivieri, M.D., The Hospital for Sick Children,
      Toronto, (416) 813-6823.

          Kenneth Bridges, M.D., Brigham and Women's Hospital, (617)
      732-7288.

          Rita Bellevue, M.D., Interfaith Medical Center, (718) 935-
      7888.

          Josef Prchal, M.D., University of Alabama at Birmingham,
      (205) 934-2721.

          Timothy Carlos, M.D., University of Pittsburgh, (412) 648-
      6776.

          Margaret Telfer, M.D., Michael Reese Hospital Medical Center,
      (312) 791-3123.

          The full text of this alert has been mailed to all libraries
      that are members of the National Network of Libraries of
      Medicine.



Tue, 29 Jul 1997 01:20:50 GMT
 
 [ 1 post ] 

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