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Protocol for Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com): a randomized, open-label, parallel-group trial.

ABSTRACT: Monotherapy with antiplatelet agents is only modestly effective in secondary prevention of ischemic stroke (IS), particularly in patients with multiple risk factors such as cervicocephalic arterial stenosis, diabetes, and hypertension. While dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduced IS recurrence, particularly in the early stages after IS, it increased the risk of bleeding. Compared with aspirin, cilostazol prevented IS recurrence without increasing the incidence of serious bleeds. In patients with intracranial arterial stenosis, no significant increase in bleeding events was observed for DAPT with cilostazol and aspirin, compared to that for aspirin monotherapy. DAPT involving cilostazol may therefore be safer than conventional DAPT. These findings prompted us to conduct the Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com; ClinicalTrials.gov identifier: NCT01995370) to evaluate the safety and efficacy of DAPT involving cilostazol for secondary IS prevention, in comparison with that of antiplatelet monotherapy.The CSPS.com is a multicenter, randomized, open-label, parallel-group trial. A total of 4000 high-risk patients with noncardioembolic IS will be randomized 8-180 days after onset to receive aspirin or clopidogrel monotherapy, or DAPT with cilostazol and aspirin or clopidogrel for at least one-year.The primary outcome is IS recurrence. Secondary outcomes are composite occurrences of any stroke, death from any cause, myocardial infarction, vascular death, and other vascular events.The CSPS.com is expected to provide evidence indicating whether secondary IS prevention in high-risk patients can be improved by using DAPT involving cilostazol.

SUBMITTER: Toyoda K

PROVIDER: S-EPMC4335602 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Protocol for Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com): a randomized, open-label, parallel-group trial.

Toyoda Kazunori K Uchiyama Shinichiro S Hoshino Haruhiko H Kimura Kazumi K Origasa Hideki H Naritomi Hiroaki H Minematsu Kazuo K Yamaguchi Takenori T

International journal of stroke : official journal of the International Stroke Society 20141208 2

<h4>Rationale and aims</h4>Monotherapy with antiplatelet agents is only modestly effective in secondary prevention of ischemic stroke (IS), particularly in patients with multiple risk factors such as cervicocephalic arterial stenosis, diabetes, and hypertension. While dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduced IS recurrence, particularly in the early stages after IS, it increased the risk of bleeding. Compared with aspirin, cilostazol prevented IS recurrence without in ...[more]

PMID: 25487817

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Project description:Background:A recent study shows that dual antiplatelet therapy with clopidogrel plus aspirin is superior to aspirin monotherapy for minor stroke, which is defined as a National Institutes of Health Stroke Scale (NIHSS)score of ?3. However, acute mild-moderate ischaemic stroke (4?NIHSS?10) still needs aggressive antiplatelet intervention to prevent deterioration and recurrence of stroke. The efficacy and safety of dual antiplatelet therapy versus aspirin monotherapy in the population are not clear. A multicentre clinical trial is designed to evaluate the efficacy and safety of clopidogrel plus aspirin therapy versus aspirin monotherapy within 48?hours of symptom onset of mild-moderate ischaemic stroke. Methods/Design:The study is a randomised, open-label, multicentre, prospective trial with a target enrolment of 2700 patients from 60 centres in Northeast China. A treatment allocation identification number to each enrolled patient will be provided by a random number generator. The follow-up time for the clopidogrel plus aspirin and aspirin monotherapy groups is 90 days. The primary efficacy endpoint is a stroke progression event, which is defined as ?4?point increase in the NIHSS score in 48?hours. The second efficacy endpoints include new ischaemic stroke within 90 days, change in the NIHSS score within 14?days, modified Rankin Scale score on day 90 and other vascular or death events within 90 days. The safety endpoints include mucocutaneous haemorrhage, organ haemorrhage and intracranial haemorrhage, adverse events and severe adverse events. ?2 test, t-test (or Mann-Whitney test), survival analysis and Cox proportional hazards models will be conducted. The findings of the study may provide an important evidence for clinical practice for these patients. Discussion:The trial will be conducted under a rational design and will provide valuable evidence on the appropriate treatment for this population. Ethics and dissemination:The study was reviewed and approved by the Ethics Committee of the General Hospital of Shen-Yang Military Region (no K(2016) 6). Trial registration number:NCT02869009; Pre-results.

Project description:BackgroundAlthough statin therapy is beneficial for the prevention of initial stroke, the benefit for recurrent stroke and its subtypes remains to be determined in Asian, in whom stroke profiles are different from Caucasian. This study examined whether treatment with low-dose pravastatin prevents stroke recurrence in ischemic stroke patients.MethodsThis is a multicenter, randomized, open-label, blinded-endpoint, parallel-group study of patients who experienced non-cardioembolic ischemic stroke. All patients had a total cholesterol level between 4.65 and 6.21 mmol/L at enrollment, without the use of statins. The pravastatin group patients received 10 mg of pravastatin/day; the control group patients received no statins. The primary endpoint was the occurrence of stroke and transient ischemic attack (TIA), with the onset of each stroke subtype set to be one of the secondary endpoints.FindingAlthough 3000 patients were targeted, 1578 patients (491 female, age 66.2 years) were recruited and randomly assigned to pravastatin group or control group. During the follow-up of 4.9 ± 1.4 years, although total stroke and TIA similarly occurred in both groups (2.56 vs. 2.65%/year), onset of atherothrombotic infarction was less frequent in pravastatin group (0.21 vs. 0.64%/year, p = 0.0047, adjusted hazard ratio 0.33 [95%CI 0.15 to 0.74]). No significant intergroup difference was found for the onset of other stroke subtypes, and for the occurrence of adverse events.InterpretationAlthough whether low-dose pravastatin prevents recurrence of total stroke or TIA still needs to be examined in Asian, this study has generated a hypothesis that it may reduce occurrence of stroke due to larger artery atherosclerosis.FundingThis study was initially supported by a grant from the Ministry of Health, Labour and Welfare, Japan. After the governmental support expired, it was conducted in collaboration between Hiroshima University and the Foundation for Biomedical Research and Innovation.

Project description:Both hyperglycaemia and hypoglycaemia in acute ischaemic stroke (AIS) are associated with increased infarct size and worse functional outcomes. Thus, therapies that can maintain normoglycaemia during stroke are clinically important. Glucagon-like peptide 1 (GLP-1) analogues, including exenatide, are routinely used in the treatment of hyperglycaemia in type 2 diabetes, but data on the usefulness of this class of agents in the management of elevated glucose levels in AIS are limited. Owing to their glucose-dependent mechanism of action, GLP-1 analogues are associated with a low risk of hypoglycaemia, which may give them an advantage over intensive insulin therapy in the acute management of hyperglycaemia in this setting.The Short-Term EXenatide therapy in Acute ischaemic Stroke study is a randomised, open-label, parallel-group pilot study designed to investigate the efficacy of exenatide at lowering blood glucose levels in patients with hyperglycaemia with AIS. A total of 30 patients presenting with AIS and blood glucose levels >10 mmol/L will be randomised to receive the standard therapy (intravenous insulin) or intravenous exenatide for up to 72 h. Outcomes including blood glucose levels within the target range (5-10 mmol/L), the incidence of hypoglycaemia and the feasibility of administering intravenous exenatide in this patient population will be assessed. A follow-up visit at 3 months will facilitate evaluation of neurological outcomes post-stroke.This study has been approved by the local Institutional Review Board (Northern Sydney Local Health District Human Research Ethics Committee). The study results will be communicated via presentations at scientific conferences and through publication in peer-reviewed journals.As GLP-1 analogues require elevated glucose levels to exert their insulin potentiating activity, the use of exenatide in the management of hyperglycaemia in AIS may reduce the incidence of hypoglycaemia, thereby conferring a benefit in morbidity and mortality for patients in the long term.ACTRN12614001189617.

Project description:BackgroundAntiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.MethodsThe REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).FindingsBetween May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92).InterpretationThese results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention.FundingBritish Heart Foundation.

Dataset Information

Protocol for Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com): a randomized, open-label, parallel-group trial.

Publications

Protocol for Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com): a randomized, open-label, parallel-group trial.

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