Meta-Analysis of Cilostazol Versus Aspirin for the Secondary Prevention of Stroke

doi:10.1016/j.amjcard.2013.05.067

The American Journal of Cardiology

Volume 112, Issue 8, 15 October 2013, Pages 1230-1234

https://doi.org/10.1016/j.amjcard.2013.05.067 Get rights and content

Aspirin is the most widely prescribed antiplatelet agent for the secondary prevention of stroke. Cilostazol, an antiplatelet and vasodilating agent, has shown promise for the secondary prevention of stroke. A systematic review and meta-analysis of randomized controlled trials using Ovid MEDLINE, PubMed, and Excerpta Medica (EMBASE) was searched up to October 2012. Four trials, in 3,917 patients, comparing cilostazol with aspirin were identified. Compared with aspirin, cilostazol was associated with a 73% reduction in hemorrhagic stroke (relative risk [RR] 0.27, 95% confidence interval [CI] 0.13 to 0.54, p = 0.0002), 28% reduction in the composite end point of stroke, myocardial infarction, or vascular death (RR 0.72, 95% CI 0.57 to 0.89, p = 0.003), and 48% reduction in total hemorrhagic events (RR 0.52, 95% CI 0.34 to 0.79, p = 0.002), with trend for lesser gastrointestinal bleeds (RR 0.60, 95% CI 0.34 to 1.06, p = 0.08). In conclusion, compared with aspirin, cilostazol is associated with significantly less hemorrhagic stroke, the combined end point of stroke, myocardial infarction, and vascular death, and total hemorrhagic events, with numerically fewer gastrointestinal bleeds when used for the secondary prevention of stroke.

Section snippets

Methods

A systematic review of the available published studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for the conduct of systematic reviews of intervention studies was performed.¹³

Studies were identified through searches in the following sources: Ovid MEDLINE (2001 to 2012), PubMed (1982 to 2012), and EMBASE (2001 to 2012). To identify further potentially relevant studies missed by the electronic database search, reference lists from identified

Results

The search in published studies yielded 367 titles, of which 5 were reviewed in full text on the basis of the inclusion criteria (Figure 1). Of these, 4 studies were deemed eligible for inclusion (Figure 1).17, 18, 19, 20 Tables containing the characteristics of the included studies are available by request.

All trials were comparison randomized controlled trials of cilostazol compared with aspirin for the secondary prevention of stroke (none were comparing dual antiplatelet therapy). All

Discussion

This systematic review of 4 randomized controlled trials in 3,917 patients determined that the use of cilostazol (100 mg twice daily) compared with aspirin (81 to 300 mg once daily) was associated with a significant reduction in hemorrhagic stroke, the combined end point of stroke, MI, and vascular death, and the complication of total hemorrhagic events, with trends in the reduction of GI bleeds for the secondary prevention of stroke. The potential mechanisms responsible for the observed

Disclosures

The authors have no conflicts of interest to disclose.

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Cited by (41)

Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischaemic stroke in Japan: a multicentre, open-label, randomised controlled trial
2019, The Lancet Neurology
Although dual antiplatelet therapy with aspirin and clopidogrel reduces early recurrence of ischaemic stroke, with long-term use this type of therapy is no longer effective and the risk of bleeding increases. Given that cilostazol prevents stroke recurrence without increasing the incidence of serious bleeding compared with aspirin, we aimed to establish whether dual antiplatelet therapy involving cilostazol is safe and appropriate for long-term use.
In a multicentre, open-label, randomised controlled trial across 292 hospitals in Japan, patients with high-risk non-cardioembolic ischaemic stroke identified on MRI were randomly assigned to two groups in a 1:1 ratio to receive monotherapy with either oral aspirin (81 or 100 mg, once per day) or clopidogrel (50 or 75 mg, once per day) alone, or a combination of cilostazol (100 mg, twice per day) with aspirin or clopidogrel. Randomisation was done centrally (using block randomisation with a block size of six per each participating hospital) through a web-based registration system and was done by EPS Corporation. The patients were required to have at least 50% stenosis of a major intracranial or extracranial artery or two or more of the vascular risk factors. Trial medication was continued for half a year or longer, for a maximum of 3·5 years. The primary efficacy outcome was the rate of first recurrence of symptomatic ischaemic stroke. Safety outcomes were severe or life-threatening bleeding; any adverse events; serious adverse events; and any bleeding events. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in the as-treated population. This trial was registered with ClinicalTrials.gov (number NCT01995370) and UMIN Clinical Trials Registry (number 000012180).
Participants were recruited from Dec 13, 2013, to March 31, 2017. 932 patients assigned to the dual therapy group and 947 patients assigned to the monotherapy group were included in the intention-to-treat analysis. The trial was stopped after the enrolment of 1884 patients of an anticipated 4000 patients because of the delay in recruitment. Ischaemic stroke recurred in 29 (3%) of 932 patients (annualised rate 2·2%) on dual therapy including cilostazol and 64 (7%) of 947 patients (annualised rate 4·5%) on monotherapy during a median 1·4 years follow-up (hazard ratio [HR] 0·49, 95% CI 0·31–0·76, p=0·0010). Severe or life-threatening bleeding occurred in eight patients (annualised rate 0·6%) on dual therapy and 13 patients (annualised rate 0·9%) on monotherapy (HR 0·66, 95% CI 0·27–1·60, p=0·35). Occurrence of any type of adverse event was similar between the groups (255 [28%] of 910 patients in the dual therapy group vs 219 [24%] of 921 patients in the monotherapy group); as was occurrence of serious adverse events (87 [10%] vs 142 [15%]) and bleeding events (38 [4%] vs 33 [4%]). Gastrointestinal bleeding, which affected nine (<1%) of 910 patients in the monotherapy group and nine (<1%) of 921 patients in the dual therapy group, was the most common type of bleeding.
The combination of cilostazol with aspirin or clopidogrel had a reduced incidence of ischaemic stroke recurrence and a similar risk of severe or life-threatening bleeding compared with treatment with aspirin or clopidogrel alone in patients at high risk for recurrent ischaemic stroke.
Otsuka Pharmaceutical.
Antiplatelet drugs in the management of cerebral ischemia
2019, Platelets
In this chapter we present the evidence that platelets play significant roles in the development of ischemic stroke, and that their activation can also contribute to the evolution of brain injury. Those observations support the clinical observations that antiplatelet approaches can reduce the incidence of second stroke in the setting of transient ischemic attacks or minor stroke, and second stroke after a completed stroke. However, antiplatelet therapy increases the risk of intracerebral hemorrhage. Aspirin and other antiplatelet agents have been used as adjunctive treatment for carotid artery atherosclerotic disease and cardiac source emboli. Considerations of newer settings for the use of antiplatelet agents are discussed.
Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial
2018, The Lancet Neurology
Citation Excerpt :
Probucol added to cilostazol or aspirin might be a good option for the prevention of cardiovascular events in patients with ischaemic stroke with a high risk of cerebral haemorrhage. Cilostazol, a phosphodiesterase-3 inhibitor, was shown to significantly reduce recurrent ischaemic stroke and haemorrhagic events compared with aspirin in patients with non-cardioembolic ischaemic stroke.14,15 Probucol, an activator of cholesteryl ester transfer protein, is a cholesterol-lowering drug with pleiotropic effects on endothelial function.
The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients.
In this randomised, controlled, 2 × 2 factorial trial, we enrolled patients with ischaemic stroke with a history of or imaging findings of intracerebral haemorrhage or two or more microbleeds from 67 centres in three Asian countries. Patients were randomly assigned (1:1:1:1) to receive oral cilostazol (100 mg twice a day), aspirin (100 mg once a day), cilostazol plus probucol (250 mg twice a day), or aspirin plus probucol with centralised blocks stratified by centre. Cilostazol versus aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to assignment. The co-primary outcomes were incidence of the composite of stroke, myocardial infarction, or vascular death (efficacy) and incidence of haemorrhagic stroke (safety), which were assessed in intention-to-treat and modified intention-to-treat populations. Efficacy was analysed with a non-inferiority test and a superiority test if non-inferiority was satisfied. Safety was assessed with a superiority test only. This trial is registered with ClinicalTrials.gov, NCT01013532.
Between Aug 1, 2009, and Aug 31, 2015, we randomly assigned 1534 patients to one of the four study groups, of whom 1512 were assessed for the co-primary endpoints. During a median follow-up of 1·9 years (IQR 1·0–3·0), the incidence of composite vascular events was 4·27 per 100 person-years in patients who received cilostazol and 5·33 per 100 person-years in patients who received aspirin (HR 0·80, 95% CI 0·57–1·11; non-inferiority p=0·0077; superiority p=0·18). Incidence of cerebral haemorrhage was 0·61 per 100 person-years in patients who received cilostazol and 1·20 per 100 person-years in those who received aspirin (HR 0·51, 97·5% CI 0·20–1·27; superiority p=0·18). The incidence of vascular events was 3·91 per 100 person-years in the probucol group compared with 5·75 per 100 person-years in the non-probucol group (HR 0·69, 95% CI 0·50–0·97; superiority p=0·0316). The incidence of cerebral haemorrhage was 0·72 per 100 person-years in the probucol group and 1·11 per 100 person-years in the non-probucol group (HR 0·65, 97·5% CI 0·27–1·57; p=0·55). Adverse events were similar across the four study groups; the most common events were dizziness, headache, diarrhoea, and constipation.
In patients with ischaemic stroke at high risk of cerebral haemorrhage, cilostazol was non-inferior to aspirin for the prevention of cardiovascular events, but did not reduce the risk of haemorrhagic stroke. Addition of probucol to aspirin or cilostazol could be beneficial for reducing the incidence of cardiovascular events.
Korea Otsuka Pharmaceutical.
Post-stroke Dementia: Epidemiology, Mechanisms and Management
2017, International Journal of Gerontology
Citation Excerpt :
These drugs inhibit the action of phosphodiesterase and reduce breakdown of cyclic adenosine monophosphate (cAMP). A meta-analysis showed that cilostazol, a PDE-3 inhibitor with several pleiotropic activities can improve mild cognitive impairment.51 Other PDE inhibitors, such as pentoxifylline and related agents pentifyline, propentofylline, and triflusal were being studied as possible treatment for dementia.52
Post-stroke dementia (PSD) is a clinical entity that encompasses all types of dementia following an index stroke, which may affect up to one third of stroke survivors. Unlike physical disability after stroke, cognitive function usually worsens over time and are often overlooked with detrimental impacts on the quality of life of survivors. The risk factors for post-stroke dementia are multifactorial and includes genetic predisposition, demographic factors (like older age and lower education status), pre-stroke cognitive and functional status, prior transient ischemic attack or stroke, vascular risk factors, characteristics and medical diseases associated with complications of stroke. Neuroimaging determinants are global cerebral atrophy or regional atrophy like hippocampal atrophy or medial temporal lobe atrophy, white matter lesions and changes, silent infarcts, lacunar infarcts and microbleeds. The mechanism of post-stroke dementia remains unknown and its neuropathology is poorly defined. Post-stroke dementia patients may benefit from target treatment of dementia with anti-dementia drugs as well as prevention and treatment of strokes. This review focus on the epidemiology, presumed mechanisms, recent studies on biomarkers, diagnostic workup and promising management strategies with functional outcome for post-stroke dementia.
Multicenter Retrospective Study of the Risk Factors of Hemorrhage After Tooth Extraction in Patients Receiving Antiplatelet Therapy
2017, Journal of Oral and Maxillofacial Surgery
To identify the risk factors affecting hemorrhage after tooth extraction in patients receiving antiplatelet therapy, this study investigated the relation between various factors and hemorrhage events after tooth extraction.
The records of 264 patients receiving antiplatelet therapy who underwent tooth extraction were retrospectively reviewed from 6 institutions belonging to the Japanese Study Group of Cooperative Dentistry with Medicine. Demographic information, hemorrhage events after tooth extraction, the presence or absence of comorbidities, antiplatelet agent, the use of preoperative antibiotics or nonsteroidal anti-inflammatory drugs, number of teeth extracted, serum creatinine level, estimated glomerular filtration rate, and alanine transaminase level were assessed. Risk factors for hemorrhage after tooth extraction were evaluated by univariate and multivariate analyses.
The study population of 264 patients consisted of 153 men and 111 women with a mean age of 73.6 years (range, 24 to 96 yr). Six hundred ninety-four teeth were extracted (mean, 2.6 ± 2.3 teeth per patient). In patients receiving antiplatelet therapy, the frequency of hemorrhage after tooth extraction, including mild and self-controlled hemorrhages, was 17.4%. Univariate analysis showed that serum creatinine level and dual antiplatelet therapy were correlated with hemorrhage after tooth extraction (P = .001 and P = .049, respectively). Only serum creatinine was identified as an independent risk factor for hemorrhage after tooth extraction in patients receiving antiplatelet therapy (P = .037).
The risk of hemorrhage after tooth extraction is increased in patients receiving dual antiplatelet therapy with or without chronic kidney disease. Local hemostatic treatments, such as at least suturing, are recommended.
Design and Rationale for a Cognitive Outcome Substudy in Ischemic Stroke Patients with High Risk of Cerebral Hemorrhage
2016, Journal of Stroke and Cerebrovascular Diseases
Cognitive impairment and dementia are common disabilities after stroke and are associated with increased risks of mortality and recurrent stroke. The prevention of dementia and preserving cognitive function are also important in stroke patients, but its strategy is not established yet. This PICASSO-COG (PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage for reducing COGnitive decline) substudy aims to assess the effects of cilostazol and/or probucol on cognitive function.
The substudy aims to assess the reduction in cognitive decline of patients treated with cilostazol and/or probucol in the PICASSO trial. Patients will be assessed using the Korean version of mini-mental state examination and Montreal Cognitive Assessment at 4, 7, 10, 13, 25, 37, and 49 months after randomization. The primary outcome is the change in mini-mental status examination score, compared between treatment groups, with a modified intention-to-treat population using a restricted maximum likelihood-based mixed effects model repeat measurement. This will allow a within-subject correlation due to repeated cognitive tests as well as a different number of measurements among subjects at baseline and each follow-up period.
PICASSO-COG is a novel study for assessing the effect on cognitive function of different antiplatelet regimens and the addition of a nonstatin lipid-lowering agent to the current standard statin therapy in patients who have a recent ischemic lesion and prior intracerebral macro- or microbleeds.

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MiscellaneousMeta-Analysis of Cilostazol Versus Aspirin for the Secondary Prevention of Stroke

Section snippets

Methods

Results

Discussion

Disclosures

Lancet

Lancet Neurol

Brain Res

J Stroke Cerebrovasc Dis

Ann Vasc Surg

Control Clin Trials

Lancet Neurol

Lancet Neurol

Lancet

Timing of TIAs preceding stroke: time window for prevention is very short

Neurology

Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia

J Neurol Neurosurg Psychiatry

Cumulative meta-analysis of aspirin efficacy after cerebral ischaemia of arterial origin

J Neurol Neurosurg Psychiatry

Miscellaneous
Meta-Analysis of Cilostazol Versus Aspirin for the Secondary Prevention of Stroke