- 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.
While the majority of patients will have no recurrent ischemic symptoms on aggressive medical therapy, some patients may continue to experience recurrent ischemic stroke or TIA secondary to ICAD despite optimal medical management. Patients who have hypoperfusion resulting in borderzone infarctions may be at higher risk for recurrent ischemic symptoms despite optimal medical therapy [20]. The risks of intracranial stenting, including stroke and death, must be weighed against the potential benefits. In the angioplasty plus stenting arm of the SAMMPRIS trial, the risk of stroke or death at 30 days was 14.7% [7]. In the angioplasty plus stenting arm of the VISSIT clinical trial evaluating symptomatic ICAD patients, the 30-day risk of stroke or death was 24% [21]. While intracranial angioplasty without stenting has been proposed as an alternative, there have been no randomized clinical trials to evaluate its efficacy beyond medical therapy alone in symptomatic ICAD patients. If endovascular treatment is considered, neuro-interventionists with high volume experience appear to have lower peri-procedural complications than those with low volume experience [22].