Patients who survive a first stroke are at increased risk for later strokes. That increased risk makes secondary prevention a priority. The question is, what treatment or treatments are most effective and when should they begin.

Speakers at the “Optimal Timing for In-Hospital Initiation of Secondary Prevention Therapies in Acute Ischemic Stroke (an AHA/ASA and Chinese Stroke Association Joint Symposium)” offered four recommendations:

• Begin oral statin therapy as soon as patients can safely swallow.
• For high-risk nondisabling ischemic cerebrovascular events, begin dual antiplatelet therapy with aspirin plus clopidogrel within 24 hours of the index event and continue no longer than 21 days.
• Endarterectomy, but no sooner than eight days following the index stroke.
• Active blood pressure management to reduce both baseline hypertension and blood pressure variability.

All of these recommendations are based on the best available evidence, the presenters noted, and all need to be explored with future randomized controlled trials.

Statin therapy

Statins have a recognized role in both primary and secondary stroke prevention, said Nerses Sanossian, MD, associate professor of neurology and director of the University of Southern California Stroke Center. “The initiation of timing for secondary prevention is less clear.

In the short term, statins alter changes mediated by nitric oxide to up regulate eNOS mRNA and protein and down regulation the inactivation of NO by reactive oxygen. Statins also attenuate changes in blood-brain barrier permeability, inhibit platelet aggregation, and have both antioxidant and anti-inflammatory effects.

In the long term, statins affect lipoprotein-mediated mechanisms as they enhance neo-vascularization, endothelial regeneration and collateral recruitment.

Animal models of statins and stroke show benefit both from pre-treating animals before inducing occlusion and treating with statins after an occlusion. Animals treated with statins have smaller brain infarctions and less severe neurological deficits. Animals treated with statins plus tPA have smaller strokes than animals treated with tPA alone.

“Human case control studies match the animal data,” Sanossian said. “If you are on a statin at the time of your stroke, you have a milder stroke and better outcomes. That is an important reason to put patients at risk of stroke on a statin, including treating after an initial stroke. Starting statins soon after stroke enhances angiogenesis, neurogenesis and synaptogenesis”

The most compelling data on statins and stroke comes from studies in acute coronary syndrome patients, he continued. The MIRACL trial showed a 59 percent reduction in the relative risk of strokes (p=0.024) for patients on statins compared to placebo. The data showed a reduction in all types of strokes when statin treatment was initiated in-hospital.

The direct evidence for statins in acute stroke is far smaller, at 300 to 400 patients, Sanossian said, and the results are inconclusive. What is clear is the in-hospital initiation of statins makes a difference.

A German study of nearly 13,000 patients hospitalized with acute ischemic stroke across 15 hospitals in Germany showed significantly lower in-hospital mortality, three-month mortality, disability discharge and three-month disability.

“Statins have mechanisms that could be beneficial in the acute setting of stroke,” Sanossian said. “You should start a statin as soon as it is safe to swallow during hospitalization for acute stroke. And never stop a statin in a stroke patient who is already taking a statin during  hospitalization.”

Dual antiplatelet therapy

Stroke is the leading cause of death and disability in China, said Yongjun Wang, MD, China National Clinical Research Center for Neurological Diseases and Beijing Tiantan Hospital at Capital Medical University in Beijing, China. The lifetime risk of stroke is 39.3 percent compared to 24.9 percent worldwide, according to the 2016 Global Burden of Disease study.

Between 10 and 20 percent of patients with non-disabling index event have recurrent disabling or fatal strokes within the next 12 months.

The China National Stroke Registry shows a strong association between antiplatelet therapy at hospitalization and lower levels of recurrent stroke, death or poor outcome three months later, Wang said. A meta-analysis of the FASTER, CHANCE and POINT trials found that dual antiplatelet therapy with aspirin and clopidogrel started with 24 hours of the index stroke reduces subsequent stroke by about 20 per 1,000. Continuing treatment for 10 to 21 days minimizes excess bleeding.

One problem is that some patients carry a CYP2C19 loss-of-function allele that reduces the effectiveness of clopidogrel. Ticagrelor is not affected by CYP2C19 status, Wang said.

The PRINCE trial, comparing ticagrelor-aspirin to clopidogrel-aspirin, did not find a statistically significant difference in stroke recurrence. But a strong numeric trend for better efficacy with ticagrelor plans prompted a second trial of ticagrelor-aspirin versus clopidogrel-aspirin in patients with CYP2C19 loss-of -unction allele.

“We have a rapid genotyping machine that can give the genotype results in 20 minutes,” he said. “The new technology makes this trial practical.”

For now, the recommendation remains dual antiplatelet therapy with aspirin plus clopidogrel, starting within 24 hours of the index event and continuing no longer than 21 days, Wang concluded.

Endarterectomy

The data favoring endarterectomy over stenting and later intervention over earlier surgery are compelling, said Thomas G. Brott, MD, Eugene and Marcia Applebaum Professor of Neurosciences and James C. and Sarah K. Kennedy Deal for Research at Mayo Clinic Florida. He cited three European randomized trials comparing carotid endarterectomy versus coronary stenting.  A meta-analysis of SPACE, EVA-35 and ICS found a 53 percent increase in the risk of stroke or death with stenting during the perioperative follow-up period.

“We thought in 2000 that older patients would do better with carotid stenting, and how wrong we were,” he said. “This is why practice should be evidence-based and not eminence-based.”

The evidence for later endarterectomy versus early surgery is strong, Brott added, but not definitive because there have been no randomized trials comparing timing. The strongest case for delaying intervention is based on Vascular Quality Initiative data on all carotid interventions performed on stroke patients between 2012 and 2017.

More than 8,400 patients were stratified based on the timing of surgery, less than 48 hours after their stroke, three to seven days post stroke, eight to 14 days and more than 15 days.

Patients treated less than 48 hours after their index stroke had the greatest risk of postoperative stroke or death. Delaying surgery for three to seven days post-stroke was protective for postop stroke or death (p=0.003) and any postop complication (p=0.003). Delaying endarterectomy for more than eight days post stroke was even more protective for postop stroke or death and complications (p<0.001 for both).

“If you have a patient with a sizable stroke, rushing into endarterectomy is not a good idea,” Brott said. “But we can’t know for sure until we have a randomized trial.”

Antihypertensive therapy

Blood pressure management is crucial for both stroke prevention and stroke management. Current AHA/ASA guidelines set > 140/90 as the target for patients with stroke or TIA.” Patients already on hypertension treatment should be restarted in the first several days of admission. But how long is “several days?”

A pooled analysis of multiple trials of blood pressure lowering in early ischemic stroke published in 2016 found no significant effect from starting treatment within three days of stroke onset, said Bin Peng, MD, Department of Neurology, Peking Union Medical College Hospital in Beijing, China.

A post-hoc analysis of the Third International Stroke Trial of Thrombolytic Treatment of Acute Ischemic Stroke found an advantage for hypertension treatment within the first 24 hours.  An early decline in blood pressure and blood pressure lowing treatment given during the first 24 hours were both associated with a favorable prognosis.

“These findings lend weight to the importance of blood pressure after ischemic stroke,” Peng said. “Early changes in blood pressure may be of greater importance than previously considered. Agents that lower blood pressure or reduce blood pressure variability should be tested further in the hyperacute phase of ischemic stroke to determine whether current guidelines for management of blood pressure in this situation are too conservative.”

The importance of variations in blood pressure after acute stroke was underlined by findings in large vessel occlusion published in 2017. High maximum systolic blood pressure were independently associated with three-month mortality and functional dependence in large vessel occlusion patients. Moderate blood pressure control, less than 160/90, was associated with lower odds of three-month mortality.

Peng suggested integrating strategies for early blood pressure management with current guidelines. The 2018 guidelines for early management of acute ischemic stroke call for early treatment of hypertension as required by comorbid conditions such as a concomitant acute coronary event, acute heart failure and other conditions.

“More active blood pressure management might be considered while carefully lowering the baseline and reducing blood pressure variability may be appropriate,” Peng said. “Future trials are needed.”