EXPRESS Long-Term Data Show Flagging Effect of Intensive Therapy for Stroke Prevention After TIA or Minor Stroke

Susan Jeffrey

June 03, 2010

June 3, 2010 (Barcelona, Spain) — A new analysis from the Early Use of Existing Preventive Strategies for Stroke (EXPRESS) study confirms that early aggressive treatment of patients with transient ischemic attacks (TIAs) or minor stroke can cut recurrent stroke risk at 90 days by about 80%, but suggests that during longer-term follow-up the early reduction in risk returns to high levels.

"There remains a need for better secondary prevention after TIA and stroke, and the current policy of prescribe and forget probably isn't enough," Peter Rothwell, MD, PhD, from the John Radcliffe Hospital, University of Oxford, United Kingdom, concluded.

Their findings also raise the possibility, even the likelihood, that the mechanism of early vs later recurrence is different, he speculated. The benefit in the early stage might well be mainly due to the antithrombotic therapy, he suggested, because thrombosis is the final common pathway leading to all of these strokes.

"You can perhaps reverse the acute thrombotic process but the underlying process progresses," leading to further strokes, he said. "So we've some work to do on long-term secondary prevention."

The results were presented here at the XIX European Stroke Conference.

EXPRESS Treatment

The EXPRESS trial was a prospective, population-based study looking at the effect of early assessment and treatment of TIA or minor stroke by comparing outcomes in two 30-month periods, before and after implementation of a "no-appointment-necessary" clinic, where patients could be seen within 24 hours of the event and preventive treatments, including antiplatelet therapy and statins, could begin immediately.

In the first period, phase 1, patients who presented with a TIA or minor stroke were referred to the same clinic but with the inherent delays in contacting patients and making appointments. Treatment recommendations were sent to the patient's primary care physician for implementation.

In the main EXPRESS analysis, the researchers showed that the 90-day risk for recurrent stroke decreased by 80%, from 10.6% in phase 1 to 2.1% in phase 2 (Rothwell PM, et al. Lancet. 2007;370:1432-1442).

"What we were surprised to find in the first phase when we looked back over the data is that time to going onto treatment had been very slow in the first phase; the family doctors were much slower than we expected," Dr. Rothwell noted. In the second phase, when they started treatment in the clinic, patients went onto medications immediately, including statins, blood pressure lowering, 2 blood pressure–lowering drugs, clopidogrel for 1 month, followed by dipyridamole.

"So we compared aggressive early treatment with essentially no treatment, somewhat by chance, not having realized how bad normal care was," he said.

An additional analysis, published separately, confirmed this approach was cost-effective, he noted.

They had also in the original analysis compared recurrent stroke risk in phase 1 to the equivalent population in the Oxford Community Stroke Project 20 years earlier. "In the exactly same population, the same general practices, nothing had changed for about 20 years, and then there was a sudden reduction in phase 2 of the EXPRESS study."

In new analyses presented here, the researchers looked at 2 additional questions: (1) could the results in phase 2 be replicated by continuation of the clinic service for an additional 30 months, now called phase 3, and (2) what was the-long term outcome among the patients originally seen in phase 2?

Dr. Rothwell reported that consistent with the phase 2 results, they found a very low risk for stroke with aggressive care in phase 3, "so this wasn't a chance effect," he said.

Table. EXPRESS: 90-Day Risk for Stroke by Phase

Endpoint OCSP Phase 1 Phase 2 Phase 3
Recurrent strokes, % 10.5 10.6 2.1 2.3

EXPRESS = Early Use of Existing Preventive Strategies for Stroke; OCSP = Oxford Community Stroke Project

The second question, "and perhaps the more important question, is long-term follow-up," he said. What happens to these patients when you send them back into the care of their family doctor?"

After the "impressive" 90-day result, the 4-year findings "don't look quite so impressive," he said. Results showed a high risk for late recurrent stroke in the subacute phase, particularly in the first year or 2, so that the initial 80% reduction at 90 days was down to about 20% lower risk compared with phase 1 results.

The problem did not appear to be with adherence to long-term secondary prevention, he noted. In the first month, nearly 96% of patients were receiving antithrombotic therapy, more than 80% were taking a statin, blood pressure–lowering therapy was fairly intensive, and there was rapid access to carotid endarterectomy, and these results were maintained at 1 and 2 years, he noted. "So we were using the best medical treatment that is currently available, and we weren't able to prevent the late recurrent strokes."

We've some work to do on long-term secondary prevention.

During the question period, Dr. Rothwell was asked about the etiology of the recurrent strokes that might provide clues to what is happening there. He said their numbers were too small to draw conclusions on this but said that Dr. Olivia Geraghty, MD, one of his colleagues, has found that irrespective of subtype, many of the patients who had a stroke in the acute phase had blood pressure levels that were not well controlled despite high rates of dual, even triple, therapy.

"I think the blood pressure effect applies to all subtypes of stroke, and that may well be an explanation," he said.

The study was funded by the UK Department of Health, UK Medical Research Council, Dunhill Medical Trust, Stroke Association, BUPA Foundation, National Institute for Health Research, Thames Valley Primary Care Research Partnership, and Oxford Partnership Comprehensive Biomedical Research Center. Dr. Rothwell reports he has received honoraria for talks and payment for occasional consultancy or research funding from Sanofi-Aventis, Bristol-Myers Squibb, Servier, Bayer, and Boehringer Ingelheim, which manufacture drugs used in the secondary prevention of stroke.

XIX European Stroke Conference (ESC): Large Clinical Trials B. Presented May 28, 2010.