Current guidelines on the use of thrombolytic therapy for acute ischemic stroke are “hopelessly outdated,” Louis R. Caplan, M.D., said in an editorial that accompanied several reports of patient outcomes studies published in the Journal of the American Medical Association.

The guidelines, which are nearly a decade old, exclude from thrombolytic therapy patients who may indeed benefit from it and do not consider the major advances in diagnostic technology that have occurred during the past two decades, said Dr. Caplan, chief of the division of cerebrovascular diseases at Beth Israel Deaconess Medical Center in Boston.

The results of two recent studies on outcomes after thrombolysis are “an important reminder” that few patients with ischemic stroke receive thrombolytic therapy, he said (JAMA 2004;292:1883-5).

On the other hand, this treatment “is not a panacea and may actually cause intracerebral hemorrhage or death” in some patients, said Dr. Caplan, who is also professor of neurology at Harvard Medical School, Boston.

In a study by the German Stroke Registers Study Group on predictors of in-hospital mortality after thrombolysis, only 3% of almost 60,000 patients presenting with acute stroke received intravenous tissue plasminogen activator (tPA). Of the treated patients, 10% died during hospitalization.

In the second study, more than half (51%) of 216 patients treated with alteplase in London, Ont., failed to improve significantly after treatment when the published guidelines were followed.

Neither study reported on causative vascular lesions, or on the extent of infarction before or after treatment—information that can be identified with modern imaging techniques, Dr. Caplan noted.

“If the present guidelines continue to be followed, as in the [two studies], physicians will never know which patients with what degree of infarction and with what vascular lesions and at-risk tissue will benefit from thrombolysis,” he said.

Nor will physicians know “whether intravenous, intraarterial, or combined intravenous and intraarterial [therapies] are best and in what circumstances,” he said. “Clinicians also will not know how alteplase compares with other promising newer thrombolytic agents and, possibly, with other therapies.”

In the German study—a prospective, observational cohort study at 225 community and academic hospitals throughout Germany—researchers reported that the factors predicting in-hospital death after thrombolytic therapy were decreased level of consciousness (an odds ratio of 3.5) and older age (an adjusted odds ratio of 1.6 for each 10-year increment of age).

Each factor independently increased the risk of death, reported Peter U. Heuschmann, M.D., of the University of Münster (Germany), and his associates (JAMA 2004;292:1831-38).

The overall rate of symptomatic intracranial hemorrhage was 7%, and the rate increased with age. One or more serious complications occurred in 27% of all patients in the study, and in 84% of those who died after treatment.

Hospital expertise with use of tPA also was independently associated with the probability of early death after tPA treatment. The risk of in-hospital death decreased by 3% for each additional patient treated with tPA per year, Dr. Heuschmann and his associates reported.

In the Ontario study—a prospective study of acute stroke patients who received alteplase at a university hospital over a 4-year period—investigators reported that a lack of improvement at 24 hours was associated with poor patient outcomes and death at 3 months. At the 3-month follow-up, 20% of the patients had died.

They identified three factors—elevated baseline glucose level (144 mg/dL), cortical involvement, and time to thrombolytic therapy—that predicted a lack of improvement at 24 hours.

For each 5-minute increase in the time that elapsed from symptom onset to treatment, the chance of no improvement increased by 5%, said Gustavo Saposnik, M.D., of the London Health Sciences Centre, and his associates (JAMA 2004;292:1839-44).

Lack of improvement was defined as a difference of 3 points or less between the NIH Stroke Scale score at baseline and at 24 hours.

In his editorial, Dr. Caplan said that although earlier treatment is better, studies have shown that the mandated 3-hour time window for thrombolytic therapy may not be appropriate. “Patients with stroke do not become poor candidates for alteplase when the clock strikes 4 hours,” he said.

In a third study that was reported in the Journal of the American Medical Association, for instance, some patients with basilar artery occlusion improved when alteplase was given intravenously more than 12 hours after symptom onset, Dr. Caplan noted.

On the other hand, some patients have large infarcts in less than 2 hours, “so the risk of thrombolytic treatment may outweigh the benefit,” he said.

Dr. Caplan cautioned against “cookbook guidelines” and said that treatment decisions must utilize modern diagnostic technology and be individually focused on “each given patient with a given lesion and a known extent of infarction.”

There is also an urgent need for more qualified stroke centers, more experienced stroke clinicians, and new ways to get patients to the centers quickly, he said.

Guidelines for Thrombolytics Need Updating