8.1 Introduction

Endovascular treatment of complex and wide-neck aneurysms remains challenging, with the degree of complexity often related to size (very large or giant) and aneurysm morphology (dysplastic or fusiform). The recent introduction of flow-diverting devices represents a considerable advance in the treatment of these aneurysms. Multiple studies have supported the safety and efficacy of flow diversion. ¹ , ² One study showed complete aneurysm occlusion at 180 days in 93% of patients who were treated with Pipeline Embolization Device (PED). ³ The concept of flow diversion is based on reconstruction of the diseased parent artery rather than occlusion of the saccular portion of the aneurysm. Currently, the PED (Covidien/ev3) is the only flow diverter that has been cleared by the U.S. Food and Drug Administration. Other products such as the Silk (Balt Extrusion, Montmorency, France), the Surpass (Stryker), and the FRED (MicroVention) flow-diverting devices remain under investigation.

To prevent potential catastrophic consequences of neurosurgical thromboembolism after intracranial stenting procedures, the need for a safe and efficacious antiplatelet regimen is particularly important. The use of aspirin and clopidogrel has been shown to exhibit an optimal safety and efficacy profile. ⁴ , ⁵ , ⁶ However, about one-third of patients appear to be nonresponders to clopidogrel and alternative antiplatelets are now being used for this group of patients. ⁷ , ⁸ , ⁹ , ¹⁰

8.2 Antiplatelet Medications

Platelets provide the initial hemostatic plug at sites of vascular injury and also participate in pathological thrombosis leading to myocardial infarction, stroke, and peripheral vascular thrombosis. They are also believed to be the main cause of in-stent thrombosis. Antiplatelet agents act by inhibiting discrete mechanisms. Thus, in combination, their effects are additive or even synergistic. ¹¹

Aspirin inhibits thromboxane A2 (TxA2) synthesis by irreversibly acetylating cyclooxygenase-1 (COX-1). Ticlopidine, clopidogrel, and prasugrel irreversibly block P2Y12, a key ADP receptor on the platelet surface. Cangrelor and ticagrelor are reversible inhibitors of P2Y12. Abciximab, eptifibatide, and tirofiban inhibit the final common pathway of platelet aggregation by blocking fibrinogen and von Willebrand factor (vWF) from binding to activated glycoprotein (GP) IIb/IIIa. SCH530348 and E5555 inhibit thrombin-mediated platelet activation by targeting protease-activated receptor-1 (PAR-1), the major thrombin receptor on platelets. ¹¹

8.3 Dual-Antiplatelet Therapy

Typically, dual-antiplatelet therapy with aspirin and clopidogrel is instituted prior to placement of an intracranial stent due to concern for potential thrombus formation. ⁴ , ⁵ , ⁶ The risk of thrombosis is likely magnified by the high metal surface area of flow-diverting devices, which generally exhibit 30 to 35% of total metal surface area. The preventative strategy of dual-antiplatelet therapy with aspirin and an ADP receptor antagonist has been shown in multiple studies to reduce thromboembolic rates in neurointerventional patients and is commonly used in both coronary and carotid artery stenting. ¹² However, increasing reports of clopidogrel resistance along with stent thrombosis in certain cases has prompted many physicians to use alternative antiplatelet medications and to routinely use platelet function testing. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷

8.4 Aspirin (ASA)

Aspirin blocks production of TxA2 by inhibiting COX-1. Because platelets do not produce new proteins, the action of aspirin on platelet COX-1 is permanent, lasting for the life of the platelet (7–10 days). Complete inactivation of platelet COX-1 is achieved with a daily aspirin dose of 75 mg and numerous trials indicate that aspirin, when used as an antithrombotic drug, is maximally effective at doses of 50 to 320 mg/day. ¹⁸ Higher doses do not improve efficacy; moreover, they potentially are less efficacious because of inhibition of prostacyclin production, which can be largely spared by using lower doses of aspirin. ¹¹ Therefore, 325 mg/day is typically used for flow-diverting devices and other intracranial stents.

8.5 Clopidogrel (Plavix)

Clopidogrel is an irreversible inhibitor of platelet P2Y12 receptors. Clopidogrel is a prodrug with a relatively slow onset of action. The usual dose is 75 mg/day with or without an initial loading dose of 300 or 600 mg. The loading dose can be detected in blood within 2 hours with peak effect of 6 hours, whereas the maintenance dose typically is detected by the second day of treatment, with peak effect of 5 to 7 days. Platelet aggregation and bleeding time gradually return to baseline after about 5 days after discontinuation. ¹¹

8.6 Ticlopidine

Similar to clopidogrel, ticlopidine permanently inhibits the P2Y12 receptor by forming a disulfide bridge between the thiol on the drug and a free cysteine residue in the extracellular region of the receptor, and thus has a prolonged effect. Maximal inhibition of platelet aggregation is not seen until 8 to 11 days after starting therapy and the usual dose is 250 mg twice a day. Loading dose of 500 mg is sometimes given to achieve a more rapid onset of action. This drug, however, is associated with severe neutropenia which occurred in 2.4% of patients with stroke during premarketing clinical trials. Therefore, it is no longer available in the united States. ¹¹

8.7 Prasugrel (Effient)

Prasugrel is a third-generation thienopyridine. It has a faster onset of action and more completely converts to its active form, but has been associated with 30% increase in the relative risk of bleeding when compared with clopidogrel. ²⁸ In addition to the faster onset of action, it produces greater and more predictable inhibition of ADP-induced platelet aggregation. Virtually all of the absorbed prasugrel undergoes activation; on the contrary, only 15% of absorbed clopidogrel undergoes metabolic activation, with the remainder inactivated by esterases. Prasugrel binds irreversibly to the P2Y12 receptor and therefore also has a prolonged effect (typically 5 days) after discontinuation. ¹¹

Prasugrel has been compared with clopidogrel in patients with acute coronary syndromes undergoing a coronary intervention and has been shown to significantly decrease risk of cardiovascular death, myocardial infarction, and stroke in addition to lowering the incidence of stent thrombosis. However, it demonstrated higher rates of fatal and life-threatening bleeds. Because of this risk, the use of this drug for coronary interventions is contraindicated in patients with a history of cerebrovascular disease. In contrast to clopidogrel, CYP2C19 polymorphisms appear to be less important determinants of the activation of prasugrel; therefore, prasugrel may be a reasonable alternative to clopidogrel in patients with the loss-of-function CYP2C19 allele. ²⁸

Although there is limited published evidence to support its use in cerebrovascular procedures, there have been several reports of successful treatment with prasugrel. ²⁹ The typical loading dose is 60 mg with a 5- to 10-mg daily maintenance dose, depending on age or weight ( Table 8.1). Current medication labeling recommends a dose reduction from 10 to 5 mg daily in patients weighing less than 60 kg or who are older than 75 years.