COSSACS: No Difference on Death and Disability After Stroke by Stopping vs Continuing Antihypertensive Therapy

Susan Jeffrey

June 04, 2010

June 4, 2010 (Barcelona, Spain) — A new study trying to tackle the question of whether to stop or continue preexisting antihypertensive therapy after a stroke finds no difference on death or disability at 2 weeks from either strategy but was unfortunately underpowered to actually answer the question.

The researchers found that continuing blood pressure–lowering treatment lead to a significantly lower blood pressure in that group compared with those who stopped therapy, and continuing treatment was not associated with any increased risk for neurologic deterioration, serious adverse event rates, or mortality, lead investigator Tom G. Robinson, MD, professor of stroke medicine at the University of Leicester, United Kingdom, told attendees here.

However, there was no significant reduction either in the primary outcome, the 2-week rate of death or dependency, or in secondary endpoints of 6-month mortality or cardiovascular outcomes.

"This clearly remains an important research question, and I would strongly encourage you to recruit to the ongoing trials," Dr. Robinson concluded.

The results, from the Continue or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS) were presented here at the XIX European Stroke Conference.

To Stop or Not Stop...

Poststroke hypertension is a common problem, and depending on the definition used, at least 60% of patients will have blood pressure levels considered to be hypertensive after an event, he said. "Increasingly an important problem, of course, is that patients are on preexisting blood pressure–lowering therapy when they present acutely with their stroke and the conservative estimate may be around 50%," Dr. Robinson noted.

It has been shown that mortality at 2 weeks increases with each 10-mm Hg increment in systolic pressure above 150 mm Hg, as well as trends to increase in 6-month death or disability.

"Equally, there are many arguments for not treating blood pressure," he noted. For example, the natural history is for blood pressure to be reduced, and in the setting of dysautoregulation, cerebral blood flow becomes pressure dependent. "Current guidelines acknowledge the lack of a clear evidence base to inform our management decisions," he said.

The COSSACS trial used a PROBE design and randomized patients within 48 hours of stroke onset and the last dose of antihypertensive either to continue or stop treatment for 2 weeks.

Patients were excluded if they had an urgent indication for treatment or a clear contraindication to stopping treatment, he noted. In addition, because of regulatory issues, they were obliged to give medications in their licensed form. That meant they were not able to crush tablets for patients with dysphagia, and these patients had to be excluded, limiting the population then to mild strokes only. The median National Institutes of Health Stroke Scale score was about 4 in both groups.

The primary outcome was death and dependency, defined as a modified Rankin Scale score of 3 or higher at 2 weeks. Secondary endpoints included mortality, functional outcomes, and blood pressure effects at 2 weeks and 6 months.

Their recruitment target was 2900 patients, which would have given them 90% power to detect a 10% reduction in the primary endpoint. "We did not meet that target," Dr. Robinson said. "Recruitment was slow, and we weren't able to persuade our funders to continue funding."

Instead, the randomized total was 763 patients, 379 to the continue treatment arm and 384 to the stop treatment arm. The population was about 90% white in both groups, with "modest" hypertension, he noted, at around 150/80 mm Hg. About a quarter of patients were taking 3 or more agents, with a broad spectrum of agents used.

"The primary outcome, death and dependency, occurred in 19% of the continue arm and 21% of the stop arm, which gives a relative risk reduction of 14%, which is not statistically significant," Dr. Robinson reported.

Table. COSSACS: Primary Outcome

Endpoint Continue Treatment Stop Treatment Relative Risk Reduction (95% CI) P Value
Death and dependency (mRS score >3) at 2 weeks, No. (%) 72 (19.0) 82 (21.4) 0.86 (0.65 – 1.14) .3

CI = confidence interval; COSSACS = Continue or Stop post-Stroke Antihypertensives Collaborative Study; mRS = modified Rankin Scale

There was, however, a significantly different blood pressure change between groups. Those continuing on treatment had an average 9/4-mm Hg reduction in BP from baseline to 2 weeks, whereas those who stopped treatment had an increase of 3/2 mm Hg.

None of the other secondary outcomes, including neurologic improvement, improvement on the Barthel Index, mortality, hospitalization, or serious adverse events in the first 2 weeks, were significantly different between groups.

A post hoc analysis of 444 patients who had neuroimaging evidence of an acute ischemic event showed a 19% reduction in the primary endpoint in the continue treatment arm and a 27% reduction in the stop treatment arm, a 30% risk reduction of borderline significance. Still, this was a post hoc analysis, he added, "so you can interpret this whichever way you wish."

In the end, he concluded, they had only a 9% power with the numbers they recruited to detect a 10% difference in the primary outcome. "I think perhaps as a warning to ongoing trials — for us to have achieved the primary outcome that we wished to, we would have had to recruit 15,000 patients to such a trial."

The study was funded by The Health Foundation and The Stroke Foundation of the United Kingdom.

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


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