A New Era in Secondary Stroke Prevention

It has been shown that three to four percent of all patients that experience a stroke will subsequently experience a second stroke. Assisting clinicians to prevent this occurrence of this event is the goal of this much-needed revised guideline. The new and revised recommendations are the result of strong research science, and will prove to be invaluable to clinicians to prevent stroke in a wide variety of co-morbid diseases and conditions. Although much has been accomplished to reduce the incidence of second stroke over the past 10 years, the incidence of a second stroke in some patients has not dropped significantly. This may be due to a plethora of differences in the cost, quality, and access to care, as well as differences in clinical presentation of stroke, especially among ethnic minorities and women.

The benefit of surgical intervention (carotid endarterectomy or carotid angioplasty and stenting) for prevention of stroke in patients with critical carotid stenosis is well documented. However, the optimal treatment for intracranial atherosclerotic disease is less clear. Large-vessel intracranial disease is one of the most common etiologies of stroke worldwide, especially in those of Asian and Hispanic descent.3 The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial demonstrated the superiority of antiplatelet medications, compared to anticoagulation, for stroke prophylaxis in this patient population. However, the risk of stroke was substantial in both medical groups.4 The higher risk of recurrent stroke reported in the WASID trial, compared to early intracranial angioplasty and stenting studies.5-7 suggested a potential benefit of endovascular treatment for stroke/TIA prevention in patients who suffered a cerebrovascular event. The Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) trial is the only randomized controlled trial examining stenting versus maximal medical management.8 The study was stopped early due to futility when an interim analysis revealed that the risk of future stroke or death in the stenting group was almost three times that of the medical management cohort. These results are likely influenced by the significant advances in medical stroke management since the time of completion of the WASID study.8 The results of the trial led to a change in the indications for the on-label use of the Wingspan stenting system. Current criteria for Wingspan treatment include two or more strokes from a 70-99% stenosis of an intracranial artery in the setting of maximal medical therapy.

While there may be a larger role for intracranial angioplasty and stenting in the future, these current guidelines are consistent with those of the Society of Neurointerventional Surgery. Each group recommends consideration of intracranial stenting after the failure of aggressive medical management. Current and future studies will attempt to determine the selection criteria and ideal patient populations that may benefit from intracranial angioplasty and stenting procedures.

In the Carotid Occlusion Surgery Study (COSS), Extracranial-Intracranial (EC-IC) bypass, when added to best medical therapy, failed to reduce subsequent ipsilateral stroke incidence in patients with complete internal carotid artery occlusion and an elevated oxygen extraction fraction.9,10 Nevertheless, it can be challenging for physicians to treat patients with severe, symptomatic stenoses with medications alone. We often feel that waiting for the patient to “fail” medical management to be eligible for an intervention is counterintuitive, as the next event may be a devastating stroke. While there may be a patient population that could benefit from EC-IC bypass, the ideal selection criteria are still being investigated.

The recent trial results suggest that the pathophysiologies underlying carotid and intracranial atherosclerotic disease are not straightforward. The belief that opening a stenotic artery or bypassing an occluded vessel will restore blood flow and universally improve clinical function appears to be overly simplistic. Functional outcomes are likely driven by a complex interplay between patient selection criteria, procedural expertise, and perioperative management algorithms. The current guidelines recommend these interventional/ surgical procedures only after a failure of medical therapy. This reflects the effectiveness of standard medical care with the use of antiplatelets, statins, and risk factor modification.

A new topic addressed in the current guidelines is long-term (30-day) monitoring for detection of atrial fibrillation (AF) in patients with newly diagnosed strokes. Monitoring reveals intermittent or paroxysmal AF in many patients, which is the likely etiology of their strokes. AF is a treatable condition. Direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban) are now considered acceptable anticoagulation alternatives to warfarin in patients with cardioembolic strokes secondary to underlying AF.11-13 It will be interesting to assess the implementation and utilization of these newer agents, as it is difficult to monitor their efficacy or reverse their anticoagulation effects in the setting of an intracerebral hemorrhage.

Another controversial topic addressed in the guidelines is patent foramen ovale (PFO) closure, and its role in stroke prevention. PFOs are common and estimated to be present in 15-25% of the population. Studies have demonstrated that patients with cryptogenic strokes in the setting of a PFO are at risk for future cerebrovascular events.14-16 There have been three randomized trials comparing PFO closure and medical management for the prevention of stroke. While all 3 studies demonstrated a trend toward benefit with closure, none were statistically significant.17-19 At the present time, there is no clear consensus on whether a PFO should be repaired. However, there are recommendations regarding anticoagulation, inferior vena cava filter placement, and PFO closure in the setting of a venous stroke source (e.g., DVT).

A final area of stroke prevention that has often been neglected and/ or misunderstood is nutritional balance. The importance of exercise, sound lifestyle choices, and a healthy diet is often lost on patients and physicians alike. These measures can impact a host of diseases, including stroke. Most medical schools offer little to no nutritional education, and students graduate with minimal knowledge regarding its impact on health and disease. The future of stroke prevention likely rests with early intervention via outpatient clinics in the community. To this end, The Secondary Stroke prevention by Uniting Community and Chronic care Model teams Early to End Disparities (SUCCEED) led by Towfighi et al. is an ongoing trial to improve control of stroke risk factors among stroke patients in Los Angeles County. The study employs “care managers” to help mobilize resources and support individuals with the use of workshops and home visits to reduce stroke risk factors. This strategy is compared to standard stroke care. The primary study outcome is systolic blood pressure, while other stroke risk factors are recorded as secondary outcomes. This promising study seeks to demonstrate that aggressive outpatient supportive care can have a significant impact on the prevention of future cerebrovascular events.

In conclusion, these new guidelines will help direct physicians and other healthcare providers in the secondary prevention of ischemic stroke and TIA. The clear emphasis on aggressive medical therapy, nutritional health, and risk factor modification stresses the importance of lifestyle choices in prevention of future cerebrovascular events.