Physical activity and decreased recurrent strokes

The SAMMPRIS trial (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) compared aggressive medical management of patients with intracranial stenosis and a non-disabling stroke/TIA, versus stenting plus aggressive medical management, finding that aggressive medical management was superior (see stroke prevention exercise neurology2016 in dropbox, or doi 10.1212/WNL.0000000000003534​).​ In a prespecified analysis, they looked at the relationship between risk factor control during follow-up and outcomes in the aggressive medical arm.

Details:

-- 227 patients were analyzed, with risk factors recorded at baseline, 30 days, 4 months, and then every 4 months for up to 32 months.

-- aggressive medical therapy included aspirin 325 mg per day along with clopidogrel 75 mg daily for the first 90 days, as well as treating the systolic blood pressure and LDL cholesterol to target (see below). Secondary risk factors included the non-HDL cholesterol, hemoglobin A1c in diabetics, smoking, weight management, and physical activity. Coaching on healthy lifestyle behaviors was done at regularly scheduled times throughout the follow-up

-- Target for risk factors:

   -- cholesterol: LDL <70 mg/dl (47% in target over the course of the study)

   -- blood pressure: systolic blood pressure < 140, or <130 if diabetic (53% in target)

   -- hemoglobin A1c < 7% if diabetic (42% in target)

   -- smoking cessation (65% target)

   -- weight management (if initial BMI 25-27, target <25;  initial BMI >27, target 10% weight loss; 19% in target)

   -- physical activity, assessed using the 8 point Physician-based Assessment and Counseling for Exercise (PACE) questionnaire (target score 4-8; 44% in target), where:

        -- PACE 3= trying to do vigorous or moderate exercise but not exercising regularly

        -- PACE 4= moderate exercise (brisk walking or slow cycling for at least 10 minutes at a time) <5 times per week or vigorous exercise (jogging or fast cycling for at least 20 minutes at a time) <3 times a week

        -- PACE 6= at least 30 minutes of moderate exercise a day for at least 5 days a week for the past 6 months or more

Results:

-- at 3 years, the likelihood of the endpoint of a recurrent stroke, MI, or vascular disease in multivariate analysis, controlling for the above risk factors:

   -- higher PACE score decreased the likelihood by 40% [OR 0.6 (0.4 0.8)], with a dose effect for exercise (ie, more exercise, more benefit)

   -- blood pressure, cholesterol, as target variables (ie, dichotomized to above and below target) were nonsignificant. smoking, BMI, and hemoglobin A1c were also not significant

   -- for recurrent ischemic stroke as the only endpoint at 3 years:

         -- PACE had a highly significant odds ratio of 6.7 (2.5- 18.1)

         -- LDL overall was not statistically significant as a dichotomized variable, though there was a significant odds ratio of 1.1 (1.0- 1.3) looking at it as a continuous variable, for each increase of 10 mg/dL)

         -- systolic blood pressure was similarly nonsignificant though had a significant odds ratio 1.2 (1.0- 1.6) as a continuous variable, for each increase of 10 mmHg

         -- hemoglobin A1c for diabetic patients had an odds ratio of 2.3 (1.0-5.0)

         -- smoking, BMI remained nonsignificant

Commentary:

-- patients with intracranial atherosclerotic stenosis are at particularly high risk of recurrent stroke. Other trials had found that poorly controlled blood pressure and elevated cholesterol are important risk factors for this. The above SAMMPRIS trial was an NIH-funded trial for intensive risk factor management, evaluating patients within 30 days of a TIA or non-disabling stroke caused by a 70-99% stenosis of a major intracranial artery. And the primary outcomes were stroke, MI or vascular death within 30 days after enrollment, as well as ischemic stroke in the territory of the qualifying artery beyond 30 days

-- although the study did show that controlling blood pressure and cholesterol were important for reducing vascular events, the independent effect of physical activity was considerably stronger for the prevention of recurrent vascular events, and especially for recurrent ischemic stroke. Other studies had shown that exercise decreased mortality among stroke patients and decreased the incidence of incident stroke among healthy people.

-- Although the above trial was an observational trial, and there is certainly a potential bias from post-stroke depression, they did note that the percentage of patients involved in physical activity increased from 32% at 30 days to 56% at the 4-month follow-up visit, perhaps reflecting the focus on lifestyle modification by the researchers. This increase in exercise would make less likely but not eliminate the potential depression bias.

-- One side concern in post-stroke patients is how rapidly to lower blood pressure. This study did suggest that in those enrolled within 30 days of a TIA or nondisabling stroke, they did better with more intensive blood pressure control (33.8% had blood pressure at the target at baseline, increasing to 47.6% at 30 days). As in another study, they did not find that diabetes, weight, or smoking cessation were significantly related to recurrent vascular events, though part of this may be due to lack of power to detect a significant effect.

--the likely mechanisms for the positive effect of exercise include augmented arterial blood to the brain (including collaterals), improvement in other risk factors (HDL, insulin resistance, blood pressure), and decreased arterial stiffness.

So, this post hoc analysis (but of a prespecified endpoint) demonstrated the remarkable predictive power of exercise for fewer recurrent vascular events; and this relationship was increasingly evident as the amount of exercise increased. Unfortunately, they did not look at dietary interventions as part of their lifestyle modification. But, to me, bottom line is that we should be aggressively encouraging patients to increase their exercise as much as possible if they have intracranial-arterial stenosis causing a TIA or nondisabling stroke, as well as prescribing the usual culprits to control blood pressure, lipids, and give an antiplatelet drug.