Emerging therapies for cerebrovascular disorders.

New information about therapeutic interventions regarding several important aspects of cerebrovascular disease has appeared recently. This short review will focus on new therapeutic developments concerning the prevention of ischemic stroke, acute ischemic stroke therapy trials, and, lastly, the management of patients with intracranial aneurysms. Great strides have been made in the pharmacological management of patients to reduce the risk for developing ischemic stroke. Stroke prevention is now clearly a multimodal endeavor that encompasses not only the use of antithrombotic agents but also the identification and treatment of multiple, potential stroke risk factors.1 While the precise relationship of elevated total and LDL cholesterol to stroke risk remains to be determined, prior studies clearly demonstrated substantial primary stroke risk reduction with the use of various statins in patients with cardiovascular disease.2 A recent report by the Heart Protection Study Collaborative Group (HPS) suggests that the benefits of at least 1 statin, simvastatin, extend to stroke patients as well.3 In this study, 20 536 patients with 1 form of vascular disease or diabetes mellitus were randomized to 40 mg of simvastatin daily or placebo in addition to their baseline medications and followed on average for 5 years. Of patients randomized, 1820 had stroke alone and 1460 had stroke and coronary artery disease. Allocation to simvastatin was associated with an overall 25% reduction in first stroke. Patients with stroke in the study had a similar benefit for subsequent major vascular events, although precise characterization of risk reduction for secondary stroke was not provided. The results may in fact underestimate the benefits of simvastatin because on average 17% of placebo allocated patients took a nonstudy statin. The result of this study led to a change in the indications for simvastatin by the FDA, and the medication is now indicated in stroke patients, ie, secondary prevention. Another recent study, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), provided additional information about primary stroke risk reduction and potentially secondary risk reduction with atorvastatin.4 In this study, 10 305 hypertensive patients with moderate baseline cholesterol levels and vascular disease or other vascular risk factors received 10 mg of atorvastatin or placebo for a mean 3.3 years. Approximately 10% of the allocated patients had a history of stroke or TIA. The atorvastatin group had a 36% relative risk reduction for the primary end point of nonfatal or fatal coronary heart disease and a 27% relative risk reduction for nonfatal or fatal stroke. A separate analysis of the patients with prior stroke was not provided. This study does demonstrate that modest atorvastatin therapy reduces stroke risk in hypertensive patients with mild cholesterol elevations with a variety of vascular risk factors. The benefits of angiotensin converting enzyme (ACE) inhibitors on stroke prevention in normotensive and hypertensive patients with other vascular risk factors are established. Two new reports suggest better functional outcome in patients who suffer a primary or recurrent stroke treated with these drugs. A detailed analysis of the impact of ramipril on stroke and the related disability in the HOPE study appeared recently.5 This trial randomized 9541 patients with 1 form of vascular disease or diabetes mellitus plus 1 additional risk factor to ramipril, 10 mg daily or placebo, with an average follow-up of 4.5 years. The relative risk of fatal and nonfatal strokes was reduced by 32% (156 versus 226) in the group treated with ramipril compared with placebo, associated with a modest decrease of blood pressure (3/2 mm Hg). Significantly fewer patients on ramipril had cognitive or functional impairment at day 7 after stroke. New data demonstrated a better long-term functional outcome in patients treated with perindopril as well.6 In the PROGRESS study, 6105 patients with previous non–major disabling stroke or TIA were randomized to 4 mg daily of perindopril alone or in combination with indapamide (2.5 mg) or placebo during a median follow-up of 4 years. Active treatment reduced the odds of disability by 24%, and the odds of dependency by 16%, at the last available assessment due largely to a reduction in recurrent stroke. The effect was more consistent with the combination therapy and appeared to be similar in hypertensive and normotensive patients. The benefit of ACE inhibitors in reducing cardiovascular events in individuals with hypertension has been documented over the past decade; however, their relative value compared with older, less-expensive antihypertensive agents remains unclear. The ALLHAT study recently addressed this issue in patients with a history of hypertension and at least 1 additional cardiovascular risk factor.7 A total of 33 357 patients were randomly assigned to receive chlorthalidone 12.5 to 25 mg/d, amlodipine 2.5 to 10 mg/d, or lisinopril 10 to 40 mg/d to achieve a goal blood pressure 140/90 mm Hg. During a mean follow-up of 4.9 years, the target blood pressure was more frequently achieved in the chlorthalidone group. Allocation to chlorthalidone was associated with a 10% risk reduction of combined cardiovascular disease and with a 15% risk reduction of stroke in comparison with lisinopril, alThe opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association. Received November 12, 2003; accepted December 3, 2003. From the Departments of Neurology (M.F.), University of Massachusetts Medical School, Worcester, Mass; and Hospital Universitari Doctor Josep Trueta (A.D.), Girona, Spain. Correspondence to Dr Marc Fisher, UMASS/Memorial Healthcare, 119 Belmont St. Worcester, MA 01605. E-mail [email protected] (Stroke. 2004;35:367-369.) © 2004 American Heart Association, Inc.