Phase 4 of Atorvastatin for Preventing Occlusion and Restenosis After Intracranial Artery Stenting

Severe intracranial atherosclerosis with concomitant stenosis is responsible for approximately 10% of all strokes. In Asian populations intracranial stenoses are even the most commonly found vascular lesions. Retrospective studies indicated that up to 50% patients with recently symptomatic intracranial stenosis experienced recurrent ischemic events. The risk of recurrent stroke increases with the aggravation of intracranial artery stenosis. In Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial, 14% and 23% of the patients with TIA or stroke attributable to high-grade intracranial stenosis had further ipsilateral ischemic stroke over the next year despite best medical treatments. If percentage of intracranial stenosis exceeded 70%, the stroke risk went up to 20% in the first year. These results spurred the enthusiasm for endovascular approaches, including percutaneous transluminal balloon angioplasty (PTA) and stenting to treat this potentially harmful disease. Due to the high stroke risk, patients with high-grade ≥70% symptomatic intracranial stenosis represent the main target group for endovascular treatment.

Endovascular management of intracranial arthrosclerosis is, however, associated with an appreciable number of potential complications, including local thrombosis, thromboembolism and, especially, restenosis and in-stent occlusion. To date, the reported 1-year restenosis rates after intracranial stenting in case series and small trials have varied widely, ranging from less than 10% in some to more than 50% in others. According to a recent review, the overall 1-year restenosis rate of intracranial stenting was 25%, and the in-stent occlusion rate was nearly 10%. These relatively high rates of restenosis and re-occlusion after procedure have raised the question about whether stenting improves the natural course of intracranial atherosclerosis.

Compared with the relatively good durability of angioplasty and stenting procedures within the extracranial carotid artery, the high incidence of restenoses appears to be a major drawback of intracranial stenting. Recent studies suggested that especially younger patients treated with self-expandable stents within the anterior circulation have a higher risk for this complication. Considering about 33% of restenoses were symptomatic (TIA or stroke), decreasing restenosis rates after intracranial stenting became the key issue for improving the clinical feasibility of this treatment strategy.

Animal studies have indicated that statins can inhibit platelet aggregation and release of platelet-derived mediators, reduce inflammatory responses of vascular wall, improve artery endothelial function, all of which may contribute to decrease proliferative responses after stent implantation. These profiles make statin optimal for preventing restenosis or occlusion after intracranial stenting, but this strategy has not been tested by clinical trials to date, although statin has been proved by several recent clinical trials to be efficacious in preventing restenosis after stent implantation in coronary arteries.

The initial attempts to lower restenosis rates after coronary balloon angioplasty have failed to demonstrate beneficial effects of statin therapy, although the FLuvastatin Angioplasty REstenosis (FLARE) trial reported a reduction in mortality and myocardial infarction in the fluvastatin treatment patients. Subsequent studies, however, did confirm that statin therapy can decrease restenosis rates and the related ischemic events after stent implantation in patients with coronary artery diseases. Unlike chronic vessel shrinkage may account for ≥70% of recurrence rates after balloon angioplasty, restenosis after coronary stent implantation is entirely due to neointimal proliferation. Experimental studies have shown that statins are capable of inhibiting intimal proliferation after arterial injury. Results from other studies suggested that statins interfere with proliferative responses after coronary stent implantation in humans. Statin therapy was associated not only with a significant reduction in late lumen loss, but also with a greater net gain after coronary stent implantation. Thus, the discrepancy of the effects of statin therapy on restenosis development after balloon angioplasty compared with coronary stent implantation may be easily reconciled by the different mechanisms underlying the recurrence of luminal narrowing.