Published in UAB Insight, Spring 2007
Improving options for stroke prevention, iron chelation
Stroke is the most devastating complication of sickle cell anemia (SCA). About 11% of SCA patients have a first stroke by age 20 years, leaving those who survive with cognitive, motor, and neuropsychological deficits. Fifty percent to 80% of those who have a first stroke suffer a second if left untreated, says UAB hematologist Lee M. Hilliard, MD.
Physicians have used red cell transfusions to prevent secondary stroke in SCA patients since the 1970s. Primary stroke prevention began after the 1998 Stroke Prevention Trial in Sickle Cell Anemia (STOP) showed that transcranial Doppler (TCD) ultrasonography accurately identifies patients at high risk for stroke and that prophylactic transfusion significantly reduces patients¡¯ chances of primary stroke.
STOP investigators randomized SCA patients with two abnormal TCDs (blood flow velocities ¡Ý200 cm per second) to transfusion or standard care. Investigators stopped the trial 16 months early when interim analysis revealed transfusion reduced stroke risk by up to 90% (N Engl J Med. 1998;339:5-11). STOP led to recommendations for routine TCD screening and chronic prophylactic transfusion in children with abnormal velocities.
High Velocity Damage
Stroke in pediatric SCA is associated with abnormal blood flow velocities in large intracranial vessels. Higher velocities indicate arterial stenosis, which in SCA patients is caused by lesions that form as sickled cells adhere to and injure endothelial cells, activating inflammatory processes and leading to arterial narrowing, Hilliard says.
STOP showed transfusions prevent this process by replacing up to 70% of patients¡¯ sickled cells with normal cells. STOP 2 found that patients must continue transfusions indefinitely to prevent stroke (N Engl J Med. 2005;353:2769-2778). ¡°Investigators called an early halt to STOP 2 when patients who discontinued transfusions quickly reverted to abnormal blood velocities,¡± she says. ¡°Although transfusion effectively prevents stroke, it confers risks, including infection, alloimmunization, and most significantly, iron overload.¡±
Standard of care for SCA patients who have had a stroke or are at high risk for stroke now involves monthly blood transfusion and iron chelation to prevent hemochromatosis. Until 2006, the only option for iron chelation was nightly subcutaneous infusions of desferrioxamine. Desferrioxamine infusions are painful and prolonged, taking up to 12 hours, and SCA patients are often noncompliant. ¡°As a consequence, many of these individuals will eventually die from hemochromatosis-related organ damage,¡± she says. ¡°Fortunately, deferasirox, a new oral iron chelator, is now available, but the drug requires long-term evaluation of safety and efficacy.¡±
UAB is 1 of 21 sites across the nation enrolling SCA patients aged 5 to 19 years for a 5-year, $18 million trial investigating whether alternative treatment can prevent secondary stroke with equivalent efficacy and fewer complications compared with monthly blood transfusion and iron chelation infusion.
Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) is randomizing 130 patients to two treatment regimens: transfusion and deferasirox or monthly phlebotomy to remove excess iron combined with hydroxyurea therapy, which smaller studies have shown reduces stroke risk in SCA patients.
For more information:
Dr. Lee Hilliard
1.800.UAB.MIST
mist@uabmc.edu