Objectives

The STOP II trial evaluated whether prophylactic transfusion in patients with sickle cell disease and high risk of stroke can be safely halted after 30 months of treatment during which patients became low risk for stroke.

Background

Stroke causes substantial morbidity in children with sickle cell disease. To prevent first strokes, the Stroke Prevention Trial in Sickle Cell Anemia (STOP) used prophylactic transfusions in children who were identified by transcranial Doppler (TCD) ultrasonography as being at high risk for stroke. This strategy reduced the incidence of stroke among such children from 10% per year to less than 1% per year, leading to recommendations for TCD screening and prophylactic transfusion for children with abnormal velocities on ultrasonography.

Despite the reduced risk of stroke, long-term use of transfusions can cause adverse side effects, such as iron overload or alloimmunization. However, cessation of transfusions is associated with recurrence of stroke, and at the time of the STOP II trial, there were no clinical or laboratory indicators to guide the duration of prophylaxis. Therefore the STOP II trial was initiated to determine whether transfusions could be limited by monitoring patients with TCD examinations after transfusions were halted and resuming transfusions if the examination indicated a high risk of stroke.

Participants

The trial included children and young adults 2 to 20 years of age with sickle cell anemia and no history of stroke. To be eligible for randomization, participants must have been at high risk for stroke as determined by abnormal transcranial Doppler (TCD) screening results, and then received at least 30 months of transfusions for stroke prevention during which the TCD results normalized. Subjects were considered regardless of participation in the previous STOP study. All participants were required to have normal results on two consecutive TCDs performed at least two weeks apart while they were receiving prophylactic transfusions and within four months before randomization.

Design

Eligible subjects were randomized to either continue or halt transfusions. Blood for transfusions was matched for C, D, E and Kell antigens. Chelation therapy was recommended if serum ferritin levels exceeded 2500 ng/mL, but the type of transfusion and initiation of chelation treatment were at the discretion of the investigator. Patients who were assigned to the transfusion-halted group could receive transfusions that were indicated to treat complications of sickle cell disease. Initiation of hydroxyurea therapy or regular transfusion in a patient assigned to this group was designated as a crossover. Information on new neurologic symptoms was solicited quarterly, and changes in medication, interim illness, and episodic transfusion were recorded.

Transcranial Doppler (TCD) surveillance examinations were performed at least every 12 weeks. TCD results were recorded as velocity in the middle cerebral or internal carotid artery and were classified as normal (all mean velocities of <170 cm/second), conditional (at least one mean velocity of 170 to 199 cm/second but none ≥200 cm/second), abnormal (at least one mean velocity of at least 200 cm/second), or inadequate (no information available on one or both middle cerebral arteries). Magnetic resonance imaging of the brain was required before patients underwent randomization, at the end of the study, and at the time of suspected neurologic events. Images were reviewed by blinded experts for the presence, size, and location of ischemic lesions.

The primary composite end point was a stroke (cerebral infarction or intracranial hemorrhage) or reversion to abnormal velocity on TCD ultrasonography, defined as two consecutive studies with abnormal velocities, three consecutive studies with an average velocity of 200 cm/second or more, or three consecutive inadequate studies plus evidence of severe stenosis via imaging.

Conclusions

The trial was halted for safety concerns after 79 of a planned 100 children were randomized. Discontinuation of transfusion for the prevention of stroke in children with sickle cell disease resulted in a high rate of reversion to abnormal blood-flow velocities on Doppler studies and stroke incidence.

N Engl J Med. 2005 Dec 29;353(26):2769-78.

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