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San Antonio, TX — How soon should recombinant tissue plasminogen activator (rtPA) be given? Is combined intravenous (IV) and intra-arterial (IA) tPA safe as standard thrombolytic therapy? Can early ischemic changes on computed tomography (CT) scans predict adverse outcomes after stroke? Can ramipril, an angiotensin converting enzyme (ACE) inhibitor, significantly reduce the risk of second stroke in patients with normal blood pressure?

These were among the questions addressed by four new trials presented in February here on the final day of the American Stroke Association's International Stroke Conference.


The presenter of a pooled analysis of randomized rtPA trials told the audience he would present his data as quickly as possible, “because that's the message from this trial.”

“The quicker rtPA is given to stroke patients, the greater the benefit,” said Thomas B. Brott, MD, Professor of Neurology at the Mayo Clinic in Jacksonville, FL. Pooled data from the National Institute of Neurological Disorders and Stroke (NINDS), ECASS I and ECASS II, and Atlantis data sets included 2,776 patients with a median age of 68 years and a median National Institutes of Health (NIH) Stroke Scale score of 12. Very importantly, median time from onset to treatment was four hours, Dr. Brott said, and one-third of the patients (929) were treated within three hours.

“We were fortunate to have original patient data for all of these trials, unlike a meta-analysis where individual patient data are not generally available,” he said.

“Unnecessary delays resulting in IV rtPA initiation beyond 90 minutes are not acceptable,” he concluded. “Door-to-needle times of less than one hour, as recommended by the NINDS consensus panel, should be the treatment goal.” But that is nowhere near a reality in the US, Dr. Brott said. “The zero-to-three hour window has resulted, practically speaking, in a 2.5-to-three hour window,” Dr. Brott said. “We are not treating patients in less than 90 minutes.”

He noted that this pooled analysis suggests a potential for a small treatment benefit beyond three hours. Although other studies assessing treatment with IV rtPA initiated after three hours have been negative, those studies may have been underpowered, he said.


Dr. Joseph Broderick said patients treated in two hours or more with rtPA had an absolute benefit of 10 percent at three months, while treatment within two hours increased the benefit to 18 percent.


Preliminary results of the Interventional Management of Stroke (IMS) study show combined IV and IA tPA was safe as standard thrombolytic therapy, as measured by life threatening bleeding complications during the first 36 hours after rtPA infusion.

The study also found the combined IV and IA tPA approach was more effective than the placebo-treated patients in another trial, the NINDS Stroke Trial.

Joseph Broderick, MD, Professor of Neurology at the University of Cincinnati in Ohio, presented three-month outcomes for 80 trial patients, all of whom had a baseline NIH Stroke Scale score of 10 or greater.

In the IMS trial, 80 subjects were started on IV rtPA within three hours of stroke symptom onset. If no clot was seen on angiography, no further treatment was given. But if a clot or thrombus was seen, the patient could receive intra-arterial rtPA by microcatheter. This was done for 62 patients.

When a favorable outcome was defined as a Modified Rankin Scale score of 0 to 1, 30 percent of the IMS study patients had favorable outcomes compared with 18 percent of the 211 patients in the NINDS placebo group. For Rankin 0 to 2, the rates were 43 percent for the IMS study group and 28 percent for the NINDS placebo group.

Dr. Broderick said the outcomes of IMS patients were compared with those in the NINDS tPA trial who had similar stroke scores and age. In the NINDS trial only 29 percent of patients with scores of 10 or greater had minimal or no disability at three months, and that dropped to three percent for patients with scores greater than 20. Dr. Broderick said the decline is due to substantial injury that occurs when IV rtPA is not sufficient to open clots in patients who have large clots.

Dr. Broderick emphasized the importance of time to treatment in this cohort. Patients treated in two hours or more with rtPA had an absolute benefit of 10 percent at three months (as compared with the NINDS placebo group), while treatment within two hours increased the benefit to 18 percent.


Subtle early ischemic changes are quite prevalent in stroke, but the detection and quantification of these changes by computed tomography (CT) scans are not reliable for assessing adverse outcomes after tPA treatment, according to researchers at Henry Ford Hospital in Detroit, MI.

The research team used data from the NINDS rtPA Stroke Trial to study the clinical significance of baseline CT scans within three hours of acute ischemic stroke onset.

In the randomized controlled NINDS Stroke Trial, CT images were obtained within three hours of symptom onset and prior to the initiation of rtPA or placebo. For the current analysis, researchers reevaluated baseline head CT scans with pretreatment clinical data for 616 patients. They found subtle and clearly visible early ischemic changes that could be correlated with baseline NIH stroke scale severity and with increased time from stroke onset to CT scan.

But presence of early ischemic changes was not independently associated with increased risk of adverse outcome within three months after rtPA treatment.

Suresh C. Patel, MD, of the Division of Radiology at Henry Ford Hospital, said that in his substudy, early ischemic changes were seen in 31 percent of patients: 28 percent in the tPA group, and 35 percent in the placebo group, not a statistically significant difference (Journal of the American Medical Association 2001; 286 (22):2830–2838).


A substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial found that ramipril, an ACE-inhibitor, reduced the risk of stoke by 32 percent and the risk of fatal stroke by 61 percent in high-risk patients. The investigators also found that there was less cognitive and functional impairment among patients treated with ramipril.


Dr. Jeffrey Probstfield reported that ramipril, an ACE-inhibitor, reduced the risk of stroke by 32 percent in a substudy of the Heart Outcomes Prevention Evaluation trial.

Because of the magnitude of this benefit the researchers believe there are mechanisms beyond blood-pressure reduction involved in the protection from stroke.

Jeffrey Probstfield, MD, Professor of Medicine and Epidemiology at the University of Washington in Seattle, said the HOPE trial, first reported at the Congress of the European Society of Cardiology in 1999, found that long-term treatment with ramipril led to significant reduction in cardiovascular events in patients with atherosclerotic disease, including those with prior myocardial infarction and symptomatic heart failure (Curr Control Trials Cardiovasc Med 2001; 2(4):151–155).

Dr. Probstfield reported specifically on stroke outcomes, however. Approximately half the patients had normal blood pressure at the beginning of HOPE, three quarters were taking aspirin or some other antiplatelet therapy, 11 percent had stroke prior to study admission, and 52 percent had previous myocardial infarction.

Dr. Probstfield reported 156 strokes in the ramipril group versus 276 in the placebo group. Fewer patients taking ramipril had cognitive and functional impairment after stroke, he said, even when there was only a modest reduction in blood pressure.

He added that the 61 percent reduction in fatal stroke should be regarded with some caution, however, because the actual numbers were small (17 with ramipril and 44 on placebo), and a change in a few outcomes in either group could greatly change the numbers.