Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin

Background and Purpose-Prior use of antiplatelet agents improves stroke outcome in patients undergoing thrombolytic therapy as shown by reduced arterial reocclusion, although the risk of cerebral hemorrhage can be increased. Methods-The effect of cilostazol, an antiplatelet drug that improves endothelial function through upregulation of intracellular cAMP, on cerebral hemorrhage after thrombolytic therapy was investigated using a highly reproducible transient ischemia model. Results-Treatment with cilostazol for 7 days before ischemia significantly suppressed the risk and severity of cerebral hemorrhage after injection of tissue-type plasminogen activator, although treatment with aspirin had no such protective effect compared with nontreated mice. Immunohistological analysis revealed that treatment with cilostazol suppressed disruption of the microvasculature in the ischemic area associated with reduced matrix metalloproteinase-9 activity. Conclusions-Our results suggest that patients treated with cilostazol before onset of stroke could have a lower risk of cerebral hemorrhage after thrombolytic therapy and might also have a longer therapeutic time window for thrombolysis. Furthermore, the risk of cerebral hemorrhage can be significantly altered by prestroke therapies, and analysis of the effects of multiple drugs on tissue-type plasminogen activator-induced cerebral hemorrhage in animal models is essential for the extending safe and effective thrombolytic therapy to a wider group of patients.

Section: Kasahara Et Al Cilostazol and Tpa-induced Hemorrhage 503supporting

confidence: 90%

mentioning

confidence: 99%

Cilostazol Reduces the Risk of Hemorrhagic Infarction After Administration of Tissue-Type Plasminogen Activator in a Murine Stroke Model

Kasahara

Nakagomi

Matsuyama

et al. 2012

“…The theoretical benefits of improved NO bioavailibility in SVD are supported by the efficacy of NO modulators in secondary stroke prevention trials. 51,52 Tolerability of agents with vasodilating properties in SVD patients is suggested by findings of the SPS3 trial, 53 where achievement of lower target BP was associated with significant reductions in intracerebral hemorrhage, stroke, and few serious side effects. Sapropterin, a NO modulator, was well tolerated at low doses in our CADASIL population with normal-low BP values.…”

Section: Discussionmentioning

confidence: 99%

Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL

Maria

Campolo

Frontali

et al. 2014

Background and Purpose-Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare autosomal dominant disorder caused by NOTCH3 mutations, is characterized by vascular smooth muscle and endothelial cells abnormalities, altered vasoreactivity, and recurrent lacunar infarcts. Vasomotor function may represent a key factor for disease progression. Tetrahydrobiopterin, essential cofactor for nitric oxide synthesis in endothelial cells, ameliorates endothelial function. We assessed whether supplementation with sapropterin, a synthetic tetrahydrobiopterin analog, improves endothelium-dependent vasodilation in CADASIL patients. Methods-In a 24-month, multicenter randomized, double-blind, placebo-controlled trial, CADASIL patients aged 30 to 65 years were randomly assigned to receive placebo or sapropterin 200 to 400 mg BID. The primary end point was change in the reactive hyperemia index by peripheral arterial tonometry at 24 months. We also assessed the safety and tolerability of sapropterin. Analysis was done by intention-to-treat. Results-The intention-to-treat population included 61 patients. We found no significant difference between sapropterin (n=32) and placebo (n=29) in the primary end point (mean difference in reactive hyperemia index by peripheral arterial tonometry changes 0.19 [95% confidence interval, −0.18, 0.56]). Reactive hyperemia index by peripheral arterial tonometry increased after 24 months in 37% of patients on sapropterin and in 28% on placebo; however, after adjustment for age, sex, and clinical characteristics, improvement was not associated with treatment arm. The proportion of patients with adverse events was similar on sapropterin and on placebo (50% versus 48.3%); serious adverse events occurred in 6.3% versus 13.8%, respectively. Conclusions-Sapropterin

“…In a meta-analysis comprising these 2 trials with 3477 patients, cilostazol was not associated with a lower relative risk of ischemic stroke (RR, 0.80; 95% CI, 0.61-1.07) but lowered the risk of hemorrhagic stroke by 74% as compared with aspirin. 53 We also included the Secondary Prevention of Small Subcortical Strokes (SP3) study into the meta-analysis. 21 The SP3 trial was prematurely withdrawn because of an increased risk of overall bleeding and mortality with combination therapy of clopidogrel and aspirin in patients with subcortical (lacunar) stroke.…”

Section: Strokementioning

confidence: 99%

Antiplatelet Treatment for Prevention of Cerebrovascular Events in Patients With Vascular Diseases

Gouya

Arrich

Wolzt

et al. 2014

492S troke is a major healthcare problem attributable to ≈10% of deaths worldwide. 1 In industrialized countries, stroke is the third most common cause of death, and the leading cause of disability, with 20% of survivors requiring institutional care after 3 months and 15% to 30% being permanently disabled. 2Because of the aging population, the risk of stroke is predicted to rise even further.3 As most strokes and transient ischemic attacks (TIAs) are caused by a thromboembolic occlusion of cerebral arteries, antithrombotic agents are the cornerstone of stroke prevention.The benefit of antiplatelet agents is uncertain in primary prevention. 4 In contrast, antiplatelet agents such as aspirin, clopidogrel, or the combination of aspirin and extended-release dipyridamole are recommended for secondary prevention in patients who have experienced a noncardioembolic stroke or transient ischemic attack (TIA).5-7 The probability of a recurrent stroke after the first stroke is >3% to 10% in the first month and ≈5% to 14% in the first year. 8,9 A recurrent stroke event can be devastating, with twice the probability of death and increased cardiovascular complications as compared with the first stroke.10 A necessary balance between risks (bleeding complications) and benefits (reduction in ischemic events) makes the search for ADP receptor inhibitors challenging.Aspirin, the most widely used antiplatelet agent, reduces the relative risk of recurrent vascular events by 13% to 22% and the risk of recurrent stroke by 15% as compared with placebo. 4,6 Clopidogrel monotherapy has been shown to be superior to aspirin when measured by a composite end point of stroke, myocardial infarction, or vascular death in the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Background and Purpose-The efficacy and safety of different antiplatelet regimes for prevention of stroke in patients at high risk were investigated in a systematic review and meta-analysis. Methods-We