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Abstract & Commentary
Source: Bravata DM, et al. Thrombolysis for acute stroke in routine clinical practice. Arch Intern Med 2002;162: 1994-2001.
The national institute of neurological disorders and Stroke rt-PA (NINDS) study demonstrated that tissue plasminogen activator (tPA) therapy for acute ischemic stroke can be given safely and effectively.1 Over the last several years, only a small percentage of patients with acute strokes were treated with tPA, and many stroke experts are pushing for increased tPA use in the United States. However, only a small number of studies using tPA for stroke have been completed since the NINDS trial, with mixed results.
Studies performed in stroke centers and by NINDS investigators have shown favorable outcomes and low rates of major complications. Studies performed in other settings have shown much higher rates of intracranial hemorrhage (ICH) and other complications, possibly related to large numbers of protocol violations. The purpose of this retrospective cohort study was to compare adverse outcomes among patients given intravenous tPA in routine clinical practice to those given tPA in the NINDS cohort, and to examine the relationship of protocol deviations to adverse outcomes.
Sixty-three patients in 16 Connecticut hospitals were identified for study inclusion. The authors collected rates of in-hospital mortality, symptomatic and asymptomatic ICH, and major or minor extracranial hemorrhage (ECH). A protocol deviation was defined as deviation from the American Heart Association (AHA) Guidelines for Thrombolytic Therapy for Acute Stroke, and was classified as either major (presence of a contraindication to use indicated on the tPA package insert) or minor (deviation from AHA guidelines which was not classified as major).
In-hospital mortality was higher in the Connecticut cohort than in the NINDS cohort (25% vs 13%), as was the rate of ICH (17% vs 11%). The rate of symptomatic ICH was similar in the two cohorts (6% vs 6%), but the rate of asymptomatic ICH was higher in the Connecticut cohort (11% vs 4%, p = not significant). The rate of major ECH was higher in the Connecticut group (13% vs 2%), but the rate of minor ECH was similar.
In the Connecticut group, 67% of patients treated with tPA had at least one major protocol deviation, and 90% had at least one minor protocol deviation. Over-all, 97% had at least one protocol deviation. The most common major protocol deviations were dosing errors, initiation of therapy after the three-hour window, known bleeding diathesis, and evidence of active internal bleeding.
Not surprisingly, in-hospital mortality increased as the number of major protocol deviations increased. The in-hospital mortality rate of patients with one major protocol deviation was 29%, and was 36% for patients with two or more major protocol deviations. The in-hospital mortality rate was 23% for patients with one minor protocol deviation, and 32% for those with at least two minor protocol deviations. Among patients without any major protocol deviations, the mortality rate of the Connecticut cohort was similar to that of the NINDS cohort (14% vs 13%).
In 30% of the 63 cases, the clinicians documented that they were aware of the protocol deviations. Most of these included physician documentation by the clinician that tPA was being given outside of recommended guidelines.
Commentary by Jacob W Ufberg, MD
This study looked at only a small cohort of patients receiving tPA, but the results mimic those of the Cleveland study.2 When the physicians do not adhere tightly to the NINDS/AHA protocol, the number of complications greatly increases, probably enough to wipe out the advantages demonstrated by the NINDS investigators.
No matter where you stand on the tPA for ischemic stroke controversy, one fact is perfectly clear: If you are using tPA, do it properly! Have a protocol in place that easily can be followed, and make sure it adheres strictly to the guidelines proposed by the NINDS investigators and the AHA. If a patient does not meet the strict criteria for receiving tPA, or if you are not sure whether the patient meets criteria, go with conservative therapy.
Dr. Ufberg, Assistant Professor of Emergency Medicine, Assistant Residency Director, Department of Emergency Medicine, Temple University School of Medicine, Philadelphia, PA, is on the Editorial Board of Emergency Medicine Alert.
1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581-1587.
2. Katzan IL, et al. Use of tissue-type plasminogen activator for acute ischemic stroke: The Cleveland-area experience. JAMA 2000;283:1151-1158.