Patients with mild stroke or high-risk transient ischemic attack (TIA) had a greater benefit from dual antiplatelet therapy if their blood pressure was lower at presentation, a new analysis of the POINT trial shows.
The findings give rise to the idea that a strategy of mild blood pressure reduction combined with dual antiplatelet therapy started within 12 hours of stroke onset may further lower early risk for stroke recurrence, the authors suggest.
The POINT trial showed that early initiation of dual antiplatelet therapy with aspirin and clopidogrel (Plavix) significantly reduced the rate of recurrent stroke events during follow-up compared with aspirin monotherapy in patients with mild acute ischemic stroke or high-risk TIA.
The current post-hoc analysis of the trial, published online in JAMA Network Open June 4, investigated whether the benefit of dual antiplatelet therapy varied with blood pressure at baseline.
“The POINT trial showed that adding clopidogrel to aspirin was very effective at preventing early recurrent stroke. This trial was resoundingly positive and changed the standard of care for patients with mild ischemic stroke and TIA,” lead author Adam de Havenon, MD, assistant professor of neurology at the University of Utah School of Medicine, Salt Lake City, told Medscape Medical News. “The current analysis is addressing whether this benefit may have been even greater if dual antiplatelet therapy is combined with blood pressure lowering.
“Because we didn’t intervene on blood pressure in the POINT trial, we cannot answer that question directly, but for a preliminary look at this issue we examined the effect of dual antiplatelet therapy on patients with higher and lower blood pressures at baseline,” he added.
Results of this analysis showed a greater effect of dual antiplatelet therapy vs aspirin alone in patients with lower blood pressures compared with those with higher blood pressures.
Among the 4781 patients in the trial, there were 946 patients (19.8%) with baseline systolic blood pressure <140 mm Hg and 3835 (80.2%) with systolic blood pressure ≥140 mm Hg.
In the subgroup of patients with systolic blood pressure <140 mm Hg, dual antiplatelet therapy reduced recurrent stroke by 64% vs aspirin alone (hazard ratio, 0.36; P = .004). In contrast, in the group with systolic pressures ≥140 mm Hg, the risk for recurrent stroke was reduced by 21% (HR, 0.79; P = .08).
When just considering recurrent stroke in the first 7 days, dual antiplatelet therapy had an even greater effect in the lower blood pressure group with a hazard ratio of 0.19 (P = .002).
De Havenon explained that it is well established that patients with ischemic stroke or TIA who present with high blood pressure are at risk for worse outcomes after stroke.
“This has led to a number of trials to reduce blood pressure in acute stroke, but these have consistently been neutral or negative, and have not shown better outcomes from lowering blood pressure in the acute phase of ischemic stroke. This has been very frustrating for us as clinicians,” he commented.
He noted that there are two main contributing factors to recurrent strokes — new clots forming and traveling to the brain, and the effect of high blood pressure on artery walls. De Havenon suggested that both these mechanisms may need to be targeted to show optimum benefits.
“A possible reason for the results from this new analysis could be that in patients with higher blood pressure, the risks associated with these raised levels of blood pressure could have eclipsed the benefit of the dual antiplatelet therapy. The high blood pressure could be seen as a competing risk which didn’t allow the dual antiplatelet therapy to be as beneficial as it could have been,” he suggested.
“Potentially, the lower stimulus on the arteries with lower blood pressure and the reduced thrombogenic effect brought about by dual antiplatelet therapy could produce a synergistic relationship to reduce stroke risk.”
Although this is currently just a hypothesis-generating observation, De Havenon believes it may be part of the explanation as to why previous trials of blood pressure lowering in acute stroke have not been successful. “We may need to combine this with dual antiplatelet therapy,” he said.
“I never fully believed that lowering blood pressure in the acute period after ischemic stroke wouldn’t be beneficial. I always felt there was probably something else confounding the picture,” he added. “This analysis suggests that ongoing clot formation might be counterbalancing the blood pressure-lowering benefit.”
The authors note that additional research is needed to replicate these findings and potentially test whether mild systolic blood pressure reduction and dual antiplatelet therapy within 12 hours of stroke onset lowers early risk for stroke recurrence.
Another trial, CHANCE, which also showed a reduction in recurrent stroke after dual antiplatelet therapy, has shown different results in its post-hoc analysis of baseline blood pressures, with dual antiplatelet therapy appearing to show greater benefit in those with higher blood pressures.
De Havenon says he cannot explain this difference between POINT and CHANCE, but he pointed out that CHANCE was conducted in an Asian population who have different comorbidities and mechanisms of stroke.
“POINT had a predominately White North American population who have a relatively low rate of intracranial atherosclerosis as a cause of stroke, whereas in Asian populations this is a much more common cause of strokes. It may be that if the arteries are very narrow, increased blood pressure is beneficial,” he suggested.
“The CHANCE blood pressure findings surprised me,” De Havenon acknowledged. “We wanted to see if we had the same observations in the POINT trial and it turned out to show the opposite.”
The POINT trial was funded by the US National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS). De Havenon reported receiving grants from AMAG Pharmaceuticals and Regeneron outside the submitted work.
JAMA Netw Open. Published online June 4, 2021. Full text