Stroke Prevention: Title and subTitle BreakOptimizing the Response to a Common Threat

In this issue of JAMA, the articles by Tran and Anand¹ and Spagnoli and colleagues² contribute useful information about prevention of ischemic stroke. Tran and Anand rightly consider that atherosclerosis is a patchy disease for which platelet anti-aggregants, in addition to reduction of modifiable risk factors, are recommended and have chosen transient ischemic attack (TIA) and cerebral infarction as the indices for the successful intervention. The authors consider aspirin alone and in combination with clopidogrel, ticlopidine, and dipyridamole and conclude that clopidogrel alone or with aspirin is the most efficacious method for primary and secondary prevention of TIA and recurrent ischemic stroke. However, they concentrate only on antiplatelet therapy and do not specifically address the important effects of diet, lipids, exercise, smoking, and other modifiable risk factors.

As reviewed by Tran and Anand, aspirin and clopidogrel (or combined therapy) afford a 20% to 30% relative risk reduction for a variety of patients with vascular disease. Although these agents may represent the best available antiplatelet therapy for coronary artery disease, their prolonged use results in significant risk for neurovascular disease.³ For example, at least 5% and perhaps as many as 50% of patients do not have a complete antiplatelet response to aspirin⁴ and platelet inhibition by aspirin depends on the dose administered and the formulation (coated vs uncoated).⁵ Alberts et al⁶ found that 56% of patients with cerebrovascular disease treated with aspirin (≤162 mg/d) had an inadequate response, whereas half that many patients did not exhibit platelet inhibition at an aspirin dose of 325 mg/d. Furthermore, many patients will have further suppression of thromboxane A₂ production at doses of more than 325 mg/d. Clopidogrel resistance develops in as many as 15% of patients receiving chronic therapy⁷ and an inadequate response to clopidogrel may be associated with recurrent events.⁸ Consequently, a generally accepted definition of resistance to aspirin and to clopidogrel is needed, along with point-of-care instruments with which to monitor therapeutic response. Accurate identification of resistance should lead to changes in dose or to alternative regimens. In addition, possible deleterious effects of prolonged use of antiplatelet therapies must be considered, such as aspirin-induced gastrointestinal bleeding and brain hemorrhage or agranulocytosis with the use of ticlopidine.

The article by Spagnoli et al² provides innovative data on the role of carotid plaque inflammation and thrombotic activity as risk factors for major stroke, as does another article.⁹ The authors report that certain morphologic characteristics of carotid plaque were more common in patients with stroke or TIA than those with asymptomatic carotid lesions. Although the authors note that all patients were receiving aspirin therapy at the time of endarterectomy and that 43.8% were taking statins, the data would have been more informative if they had reported other therapies that undoubtedly were given to some patients before their initial events or after TIA or cerebral infarction and before the removal of plaque (in some cases, up to 21 months). Moreover, the authors could have considered the unique flow dynamics and physiology of the carotid bifurcation from which the pathologic specimens were removed. For instance, in low pressure and low flow systems, the coagulation cascade may be more important than platelet-initiated thrombogenesis and the reverse true in fast-flowing systems.¹⁰ Turbulence in the unique carotid sinus is thought to be a major factor for producing disruption of the endothelium.¹¹ The vasculature of the arterial wall is a putative cause for ulceration and increasing evidence suggests that plaque has a predilection for the arterial intima and media if its microcirculation has been disrupted.¹²

The dilemma is how best to identify patients at excess risk for stroke and other effects of atherothrombosis before events occur. Should populations, such as elderly persons, persons with diabetes mellitus and hypertension, and those with a strong family history, undergo screening using questionnaires and noninvasive studies such as carotid ultrasound? If ultrasound is to be performed, should the investigation include evaluation for high-intensity transient signals of bubbles, fragments of plaque, and aggregates of platelets and blood cells that may help to identify patients at increased risk for TIA or stroke? Likewise, platelet counts, adhesiveness, and aggregation before and after use of antiplatelet agents may offer possible ways by which to quantify stroke risk.

These and other innovative methods for stroke prevention will increasingly be used as less invasive interventions with carotid artery stents and balloon dilatation become more widely considered for treatment of asymptomatic carotid stenosis.¹³ Although technology is advancing at a stunning pace, information regarding long-term efficacy, safety, and validated indications for endovascular procedures for stroke prevention lag far behind. Evidence-based data addressing which patients should undergo carotid stenting or carotid angioplasty are currently lacking. Because endovascular manipulations can cause arterial injury and brain embolism of plaque material, catheter insertion site infection and hematoma, and carotid sinus trauma, there is urgent need to develop standards for angioplasty and stenting of carotid artery stenosis so that these procedures will be safe and efficacious for the vast majority of patients.¹⁴

Currently, there is no scientific evidence that stenting is preferable to carotid endarterectomy for symptomatic carotid artery disease or that stenting is indicated for asymptomatic carotid disease, for which carotid endarterectomy has been shown to significantly reduce the risk of disabling and fatal stroke.¹⁵ As a consequence, persons considered to be at excess risk for stroke should be screened appropriately with a baseline ultrasound examination of the carotid bifurcation. If a lesion is found, aggressive risk factor management is indicated followed by repeat duplex ultrasound studies to monitor progression or regression of plaque, change in vessel wall characteristics, and seeding of microemboli. Although screening is not generally available and large-scale screening studies are not yet planned, new approaches must be developed for reducing the ever-increasing incidence and prevalence of stroke.¹⁶

Because of increasing longevity with consequent aging of the population, an increasing number of persons are at excess risk for stroke. If the trend continues, the heart will no longer be the cause of most sudden deaths, leaving behind an ever-growing population of the elderly disabled by stroke, vascular dementia, and cancer. This prospect needs to be addressed nationally and internationally, with redoubled efforts for primary and secondary prevention of stroke.