Embargoed for Release: December 5, 2004
Embargoed for Release: December 5, 2004
San Diego, CA, Dec. 5, 2004 -- The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) has stopped early a clinical trial studying whether children with sickle cell anemia at high risk for stroke could at some point after a minimum of 30 months (range 30-91 months) safely stop receiving the periodic blood transfusions that prevent strokes. The study found a return to high risk of stroke in children who stopped receiving the transfusions. The NHLBI is issuing a clinical alert on the study's results to inform physicians who treat children with sickle cell anemia.
The alert advises physicians that stopping transfusions cannot be recommended. The document urges them to carefully discuss with patients and their families the stroke prevention benefits of continuing periodic transfusions as well as the risks of these transfusions, which can include such long-term side effects as iron overload. Management of these side effects should also be discussed, according to the alert.
The results of the Stroke Prevention Trial II (STOP II) are being presented in San Diego today as a special "late-breaking" announcement at the annual meeting of the American Society of Hematology (ASH). To further inform physicians, the NHLBI is posting the alert on the National Library of Medicine's Clinical Alert and Advisories Web page. STOP II investigators are notifying patients enrolled in the study and their families.
STOP II, which began in 2000, expected to recruit 100 patients age 2 to 18 over 6 years. When the study was stopped 2 years early on November 10, 79 patients had been enrolled. At the time the study was halted, 14 of the 41 patients who had been randomly assigned to stop transfusions reverted to high risk of stroke as measured by a special ultrasound technique and 2 patients had suffered a stroke. There were no strokes or reversions to high stroke risk in the group that continued with transfusions.
"This important study shows the value of continuing periodic blood transfusions in preventing the serious and debilitating consequences of stroke," said NHLBI Acting Director Barbara Alving, M.D. "At the same time, there are risks of chronic transfusions and the decision to continue with this treatment must be made on a case-by-case basis," she added.
The risks of chronic blood transfusions include iron overload, which can be harmful to several vital organs and must be treated with chelation therapy. Other risks include alloimmunization, an immune system reaction which can interfere with the benefits of subsequent transfusions, and exposure to blood-borne infections.
The STOP II trial, conducted at 23 clinical centers in the U.S. and 2 in Canada, enrolled patients at increased risk of stroke. Stroke risk was determined with transcranial doppler (TCD) screening, an ultrasound technique that measures the velocity of blood flow in the brain. A high blood flow velocity in one or more major arteries of the brain is linked with narrowing in key blood vessels supplying the brain, which in turn increases the risk of a stroke.
STOP II participants had been transfused for at least 30 months before entering the trial. Eligibility criteria for entry into STOP II were a normal TCD velocity (indicating low risk of stroke) and a magnetic resonance imaging study of the patients' brain arteries showing no severe blockages. Upon entry, patients were randomly assigned to receive either standard care with periodic blood transfusions or to be taken off these transfusions.
Patients in the transfusion arm of the study received blood transfusions every 3 to 4 weeks to keep the amount of abnormal, or sickle, hemoglobin in their blood to no more than 30 percent of total hemoglobin. Transfused patients who received a cumulative dose of 250 ml/kg of blood began to develop iron overload and were given chelation therapy. Chelation involves subcutaneous infusions of deferoxamine, a drug that removes the iron.
After 79 patients had been enrolled in the study, the STOP II Data and Safety Monitoring Board (DSMB), an independent advisory committee charged with reviewing results and ensuring participant safety, conducted a regular review of the data. The analysis showed a highly significant difference in stroke risk and actual stroke between the transfusion and non-transfusion treatment arms. The DSMB recommended early closure of the clinical trial.
About 10 percent of sickle cell patients are at risk for stroke. Twenty percent of patients are at risk for "silent cerebral infarcts," small strokes that can interfere with cognitive functioning and school performance because brain tissue is damaged.
The importance of transfusion therapy in preventing strokes in patients with sickle cell anemia was established in 1997 when the results of the Stroke Prevention Trial in Sickle Cell Anemia (STOP I) were released in a clinical alert. STOP I found that administering blood transfusions every 3 to 4 weeks to children with sickle cell anemia who are at high risk for stroke reduces their rate of first-time stroke by 90 percent.
"STOP I showed that we could prevent stroke and its debilitating consequences, including brain damage. What we didn't know was whether the transfusions could be safely stopped at some point. This was an important question because there are some problems with blood transfusions, including increased risk of iron overload," said Robert Adams, M.D. principal investigator of both STOP I and STOP II and Regents Professor of Neurology and Professor of Pediatrics, Medical College of Georgia. Adams presented the STOP II findings at the ASH meeting.
"Now we know that for high-risk patients, it is not safe to stop transfusions even if the TCD has returned to normal range. We need to weigh carefully the risks of this preventive therapy and make sure we monitor patients closely with TCD. We also need to come up with a better way to maintain the stroke prevention benefit while lowering the side effects of transfusion treatment," added Adams.
The clinical alert calls for further research to identify and test therapies that will provide safe and effective protection from stroke with fewer side effects than transfusion.
Sickle cell anemia, the most common genetic blood disorder in the U.S., affects about 1 in 350 African-Americans and 1 in 1,000 Hispanic newborns every year. Patients with this disease have abnormal hemoglobin molecules in their red blood cells. The molecules damage the red cells, causing them to stick to blood vessel walls. This can lead to narrowed, or blocked, blood vessels in the brain, causing a stroke.
The participating centers in STOP II were:
Note: the New England Research Institute, Watertown, MA, was the Data Coordinating Center
To interview an NHLBI spokesperson about the STOP II study, please call the NHLBI Communications Office at 301-496-4236. To interview Dr. Adams, call Toni Baker at the Medical College of Georgia at 706-721-4421.