Symptomatic Intracranial Atherosclerotic Disease

Further Evaluation

The patient was initiated on antithrombotic therapy on hospital day 2 (24 hours after IV tPA administration) with aspirin 325 mg daily and clopidogrel 300 mg oral load followed by 75 mg daily, ranitidine 150 mg twice a day to reduce gastroesophageal reflux and atorvastatin 80 mg daily. On hospital day 3, his neurological exam remained stable and he was initiated on losartan 25 mg daily with a plan to titrate the dose up as an outpatient to achieve target blood pressure. The patient and his wife were advised to maintain a blood pressure log and provide it to his physicians at follow-up and was provided smoking cessation counseling with a plan to remain off tobacco after discharge utilizing nicotine patches. The patient was discharged from the hospital 4 days after admission with a diagnosis of acute ischemic stroke secondary to symptomatic ICAD from regional thromboembolism. Early outpatient follow-up was scheduled with his primary physician within 1 week after discharge to evaluate BP and a vascular neurologist within 1 month after discharge.

• What factors predict recurrent stroke in patients with symptomatic ICAD?

As evidenced in the WASID post-hoc analysis, female sex, prior ischemic stroke (versus TIA), time from qualifying event to enrollment (≤ 17 days after ischemic event), severity of stenosis (≥ 70% stenosis) of the symptomatic vessel, and history of diabetes were identified as independent risk factors for recurrent stroke in this population [14].

• How do we manage patients who continue to have symptoms despite optimal medical therapy?

When evaluating symptomatic ICAD patients with recur-rent neurologic symptoms, several important factors should be considered:

• Do the recurrent neurologic symptoms localize to the original ICAD location?

Patients with symptomatic ICAD often have multiple risk factors that put them at risk for other subtypes of ischemic stroke including lacunar stroke. Repeat neuro-imaging with brain MRI is recommended to confirm the localization of a recurrent stroke is inside or outside of the territory of the ICAD.

• Were the recurrent neurologic symptoms provoked?

Patients with ICAD can be uniquely sensitive to fluctuations in cerebral blood flow and oxygenation. Diabetic patients with ICAD can develop autonomic neuropathy that results in orthostatic hypotension. If patients have recurrent transient ischemic events associated with postural changes, adequate treatment of orthostasis can reduce recurrent ischemic events. Other provoked circumstances include patients who develop anemia and patients with untreated severe obstructive sleep apnea who may awake with recurrent ischemic events due to hypoxemia.

•  Is the patient adhering to the medication regimen?

Patients with symptomatic ICAD frequently have multiple medications to take for treatment of their comorbidities. Discussion of the number of missed doses of medications over the prior month is important to ascertain adherence. Patients should also be counseled to avoid concomitant medications that may cause drug interactions; given the known drug interactions between nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin, specific counseling on the avoidance of NSAIDs should be encouraged.

• Are the patient’s risk factors optimally managed?

Risk factor control should be assessed on a routine (eg every 3-6 months) basis and again if an ICAD patient has recurrent ischemic symptoms. Regular review of blood pressure logs, interval assessment of lipids, optimization of glucose control with serial hemoglobin A1c, tobacco cessation, and attention to weight management are paramount.

• Does the patient have an appropriate metabolic response to antiplatelet therapy?

If risk factors are optimized and the patient reports adherence to their medication regimen, aspirin and clopidogrel response should be evaluated. Aspirin resistance can be assessed by measuring the urinary level of 11-dehydrothromboxane B2 [15]. A urine level >1500 pg/mg creatinine should be expected in healthy, aspirin-free individuals; however, if this level is identified in a patient who is prescribed aspirin, aspirin resistance can be diagnosed. Various causes of aspirin resistance have been reported including inadequate adherence to aspirin therapy, concomitant use of a NSAID, genetic mutations in the COX-1 gene, non-platelet sources of thromboxane A2, and high platelet turnover [15]. Aspirin dosage adjustments should be made in consultation with a hematologist.

Resistance to clopidogrel has been less widely evaluated, but one meta-analysis estimated a mean prevalence of clopidogrel non-responsiveness at 21% [16]. While there is limited data on the optimal assessment of clopidogrel responsiveness in stroke patients, on-treatment platelet reactivity has been measured in parallel by means of light transmittance aggregometry, Verifynow P2Y12 and Platelet works assays, and the IMPACT-R and PFA-100 system in one study of patients undergoing coronary stent implantation [17]; of the platelet function assays assessed, only light transmittance aggregometry, Verifynow, and Platelet works assays were significantly associated with clinical outcomes in patients undergoing coronary stent implantation. Various causes of clopidogrel resistance have been reported including inadequate adherence to clopidogrel therapy, concomitant use of medications that interfere with clopidogrel prodrug conversion in the liver to its active metabolite, and genetic mutations in the cytochrome p450 3A4 gene [18,19]. Clopidogrel dosage adjustments should be made in consultation with a hematologist.