Stop ii trial

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Publications automatically indexed to this study by ClinicalTrials. C-reactive protein CRP as a biomarker of pulmonary exacerbation presentation and treatment response. J Cyst Fibros. However, chronic intermittent blood transfusions are cumbersome, expensive and associated with morbidity from iron overload.

Thus, this study to determine if transfusion can be safely halted after 30 months of treatment is critically important to the continued clinical care of patients with sickle cell disease at risk for stroke. In this multicenter, randomized clinical trial, children will be randomized to continue to receive periodic transfusion therapy and 50 to discontinue receiving periodic transfusion therapy. Recruitment will be in two phases. Phase I will include those patients who began transfusions before April 1, These will come mainly from the STOP 1 cohort.

Those who begin transfusions after April 1, but before April 1, will be eligible for Phase II of recruitment. All patients will receive quarterly TCD examinations. Patients who revert to high risk will be offered return to transfusion. The overall design includes a three month start-up, the two phases of recruitment established STOP patients and new patients for a total of 36 months, 18 months of observations after recruitment ends and then 3 months of wrap-up.

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Although the survival analyses could be underestimated because of exclusion of 4 stroke events, the difference in stroke risk between those who were and were not transfused was still highly significant, with markedly lower risk in the transfused group similar to the findings in the randomized trial. An interesting observation is the flattening of the stroke-free survival curve in the SC group after 30 months, suggesting that in a subgroup of patients the risk of stroke diminishes after some time even without transfusion.

The 25 patients remaining in the SC group who did not develop stroke had lower baseline and follow-up TCD velocities compared with the group who developed stroke. Most patients had converted to normal or conditional TCD results at last examination during follow-up, perhaps explaining the decline in stroke risk. Those at higher risk could have stroke if not transfused, while certain patients at lower risk may remain stroke-free without transfusion, even in a few with prolonged abnormal TCD findings.

Nine patients resumed transfusion, leaving 16 patients remaining with normal TCD results and without stroke off transfusion. The data confirm that stroke risk increases with TCD velocity. This follow-up study allowed an opportunity to observe longitudinal changes in TCD velocities. In the posttrial follow-up, patients were followed over an extended period of about 55 months and a similar proportion Whether this reflects the poorly understood gradual decrease in stroke risk as age progresses into young adulthood is unclear.

Our data may have overestimated the likelihood of TCD conversion to normal results without transfusion due to selection after those who had stroke were removed and those at highest risk were continued on transfusion.

Some patients may have also been started on hydroxyurea, perhaps accounting for some decline in TCD velocities. Elevated cerebral blood-flow velocities in SCD are related to severe anemia, vessel stenosis, and cerebral vasodilatation caused by tissue hypoxia. Transfusion reduces cerebral blood flow velocities by correcting these abnormalities to some degree, and may explain the reduction in stroke risk.

Studies have reported using TCD monitoring during chronic transfusion for both primary and secondary stroke prevention and found that TCD results correlated well with MRA findings. STOP II was based on the hypothesis that the former patients were potential candidates for stopping transfusion; unfortunately, this did not prove to be the case. Discontinuation of transfusion after at least 30 months in patients who have converted to normal velocities was associated with high risk of reversion to abnormal and chance of stroke.

The single institution experience of secondary stroke prevention using hydroxyurea and phlebotomy, 17 if confirmed to be effective, may be an attractive alternative to chronic transfusion in the primary prevention of stroke; this approach has been explored in France. Our report demonstrated in 2 patients that persistently abnormal TCD results while on transfusion is ominous and may predict the uncommon stroke that occurs on transfusion therapy.

Although the efficacy of the STOP strategy for primary stroke prevention has been proven in a randomized clinical trial, 4 and its effectiveness in reducing stroke incidence suggested in a statewide stroke incidence survey, 21 the potential morbidity from long-term transfusion, particularly iron overload, has deterred its universal acceptance among clinicians and patients.

This issue remains controversial and is a matter of clinical judgment and patient preference. The extended data of the STOP study we present, coupled with the results of STOP II, provide additional valuable information for medical decision making and in counseling patients and families regarding treatment choices for primary stroke prevention.

Given the difficulties and risks of prolonged transfusion, alternative therapies of primary stroke prevention in SCD are desirable. The recent availability of an oral iron chelator may render prolonged transfusion more acceptable. The publication costs of this article were defrayed in part by page charge payment. National Center for Biotechnology Information , U.

Prepublished online Apr 6. Margaret T. Miller , Shannon Harkness , Donald J. Brambilla , Robert J. Author information Article notes Copyright and License information Disclaimer. Reprints: Margaret T. Received Oct 20; Accepted Mar This article has been cited by other articles in PMC. Patients, materials, and methods STOP trial The design of the randomized trial is described in detail elsewhere.

Posttrial follow-up phase After termination of the randomized trial, patients who had not developed stroke were notified of the results of the study and given the option to start, resume, or continue transfusion. Statistical analysis The probability of remaining stroke-free was analyzed by the Kaplan-Meier method based on the original treatment assignment and measured from the time of randomization to the earliest of stroke, change in treatment, or end of the follow-up study.

Open in a separate window. Figure 1. Stroke outcome In addition to the 12 stroke events in the STOP trial, 6 patients developed stroke during the posttrial follow-up 5 from the SC group and 1 from the TX group. Table 1. Pt no. BS indicates before stroke. Figure 2. TCD velocity changes All 6 patients who developed stroke during the posttrial follow-up had a last interpretable TCD that was abnormal prior to stroke regardless of transfusion status.

Table 2. Transfusion data A number of patients 79 received transfusion, entirely or partially, for primary prevention of stroke during the posttrial follow-up. Table 3. Discussion This extended analysis of the STOP trial further confirmed the reliability of TCD in identifying children with SCD at high risk for stroke and the efficacy of transfusion in reducing this risk. References 1. Cerebrovascular accidents in sickle cell disease: rates and risk factors.

The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med. Long-term stroke risk in children with sickle cell disease screened with transcranial Doppler. Ann Neurol. Prevention of a first stroke by transfusion in children with abnormal results of transcranial Doppler ultrasonography. Accessed August 6, Adams RJ, Brambilla D.

STOP 2 Trial investigators: discontinuing prophylactic transfusions to prevent stroke in sickle cell disease. Silent infarcts in children with sickle cell anemia and abnormal cerebral artery velocity. Arch Neurol. Magnetic resonance angiography in children with sickle cell disease and abnormal transcranial Doppler ultrasonography findings enrolled in the STOP study.