Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS・com)

To examine the efficacy and safety of dual antiplatelet therapy (DAPT) including cilostazol (Pletaal OD Tablet ®) in comparison with antiplatelet monotherapy (excluding cilostazol) for secondary prevention of ischemic stroke in high-risk patients for stroke

Study Overview

• Status: Completed
• Conditions: Noncardioembolic Cerebral Infarction
• Intervention / Treatment: Drug: aspirin; Drug: clopidogrel; Drug: cilostazol

• Study Type: Interventional
• Enrollment (Actual): 1884
• Phase: Phase 4

Contacts and Locations

Study Locations

• Japan
  • Osaka, Japan, 565-8565
    • Japan Cardiovascular Research Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with a diagnosis of noncardioembolic IS that developed between 8 and 180 days before the start of the protocol treatment
• Patients with a responsible lesion identified by MRI
• Patients aged 20 to 85 years old when providing informed consent
• Patients taking clopidogrel or aspirin alone as antiplatelet therapy when providing informed consent

• Patients meeting at least one of the following criteria a-c:

  1. at least 50% stenosis of a major intracranial artery (to the level of A2, M2, or P2)
  2. at least 50% stenosis of an extracranial artery (the common carotid artery，internal carotid artery，vertebral artery，brachiocephalic artery，or subclavian artery)

  3. Two or more of the following risk factors

     • Aged 65 years or more
     • Diabetes mellitus
     • Hypertension
     • Peripheral arterial disease
     • Chronic kidney disease
     • History of IS (excluding the index IS for this study)
     • History of ischemic heart disease
     • Smoking (only current smokers)
• Patients considered to be able to visit the study site for ambulatory care throughout the observation period
• Patients who provided written informed consent

Exclusion Criteria:

• Patients with emboligenic heart disease
• Patients taking any anticoagulant agents
• Patients who cannot undergo MRI examination for reasons such as claustrophobia and implanted pacemaker
• Patients scheduled to undergo any surgery, such as percutaneous angioplasty, stent placement, and bypass grafting, during the study period
• Patients with a drug-eluting coronary stent implanted within one year
• Patients with a history of symptomatic non-traumatic intracranial hemorrhage, any other hemorrhagic disease (eg, active peptic ulcer), bleeding predisposition, or blood clotting disorders
• Patients with a history of hypersensitivity to cilostazol
• Patients with congestive heart failure or uncontrolled angina pectoris
• Patients with thrombocytopenia (platelet count ≦ 100,000/mm3)
• Patients with severe liver or renal dysfunction
• Women who are pregnant, breast-feeding, or of child-bearing potential
• Patients with a malignant tumor requiring treatment

• Patients who are taking aspirin, and meet any of the following criteria:

  • History of hypersensitivity to aspirin or salicylic acid analogues
  • Current peptic ulcer
  • Aspirin-induced asthma or its history

• Patients who are taking clopidogrel, and meet the following criterion:

  ・History of hypersensitivity to clopidogrel

• Patients who are participating in any other clinical studies
• Patients considered by the investigator/subinvestigator to be unsuitable for participating in this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Monotherapy group; Aspirin (81mg or 100mg) or clopidogrel (50mg or 75mg) will be orally administered once daily. The treatment period will begin with the first visit of the first subject and end one year after the first visit of the last subject.	Drug: aspirin; Aspirin (81mg or 100mg) will be orally administered once daily.The treatment period will begin with the first visit of the first subject and end one year after the first visit of the last subject.; Other Names: Bayaspirin; Drug: clopidogrel; Clopidogrel (50mg or 75mg) will be orally administered once daily.The treatment period will begin with the first visit of the first subject and end one year after the first visit of the last subject.; Other Names: Plavix
Experimental: DAPT group; Cilostazol (100mg twice daily) will be orally administered in combination with aspirin (81 or 100mg once daily) or clopidogrel (50 or 75mg once daily). The treatment period will begin with the first visit of the first subject and end one year after the first visit of the last subject.	Drug: aspirin; Aspirin (81mg or 100mg) will be orally administered once daily.The treatment period will begin with the first visit of the first subject and end one year after the first visit of the last subject.; Other Names: Bayaspirin; Drug: clopidogrel; Clopidogrel (50mg or 75mg) will be orally administered once daily.The treatment period will begin with the first visit of the first subject and end one year after the first visit of the last subject.; Other Names: Plavix; Drug: cilostazol; Cilostazol (100mg twice daily) will be orally administered. The treatment period will begin with the first visit of the first subject and end one year after the first visit of the last subject.; Other Names: Pletaal OD Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence of symptomatic ischemic stroke, with the symptoms lasting for at least 24 hours	An "ischemic stroke" hereafter indicates a symptomatic ischemic stroke.	every 6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Any stroke [ischemic stroke (IS), intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH)]	every 6 months
SAH or ICH	every 6 months
IS or transient ischemic attack (TIA)	every 6 months
Death from any cause	every 6 months
Stroke (IS，ICH，SAH), myocardial infarction (MI), or vascular death	every 6 months
All vascular events: stroke, MI, and other vascular events	every 6 months
Adverse events and adverse drug reactions	every 6 months
Severe or life-threatening hemorrhage (GUSTO Criteria)	every 6 months

Collaborators and Investigators

• Sponsor: Japan Cardiovascular Research Foundation
• Collaborators: Otsuka Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Takenori Yamaguchi, President emeritus, National Cerebral and Cardiovascular Center

Publications and helpful links

General Publications

• Toyoda K, Omae K, Hoshino H, Uchiyama S, Kimura K, Miwa K, Minematsu K, Yamaguchi K, Suda Y, Toru S, Kitagawa K, Ihara M, Koga M, Yamaguchi T; CSPS.com Trial Investigators. Association of Timing for Starting Dual Antiplatelet Treatment With Cilostazol and Recurrent Stroke: A CSPS.com Trial Post Hoc Analysis. Neurology. 2022 Mar 8;98(10):e983-e992. doi: 10.1212/WNL.0000000000200064. Epub 2022 Jan 24.
• Uchiyama S, Toyoda K, Omae K, Saita R, Kimura K, Hoshino H, Sakai N, Okada Y, Tanaka K, Origasa H, Naritomi H, Houkin K, Yamaguchi K, Isobe M, Minematsu K, Matsumoto M, Tominaga T, Tomimoto H, Terayama Y, Yasuda S, Yamaguchi T. Dual Antiplatelet Therapy Using Cilostazol in Patients With Stroke and Intracranial Arterial Stenosis. J Am Heart Assoc. 2021 Oct 19;10(20):e022575. doi: 10.1161/JAHA.121.022575. Epub 2021 Oct 8.
• Hoshino H, Toyoda K, Omae K, Ishida N, Uchiyama S, Kimura K, Sakai N, Okada Y, Tanaka K, Origasa H, Naritomi H, Houkin K, Yamaguchi K, Isobe M, Minematsu K, Matsumoto M, Tominaga T, Tomimoto H, Terayama Y, Yasuda S, Yamaguchi T; CSPS.com Trial Investigators. Dual Antiplatelet Therapy Using Cilostazol With Aspirin or Clopidogrel: Subanalysis of the CSPS.com Trial. Stroke. 2021 Nov;52(11):3430-3439. doi: 10.1161/STROKEAHA.121.034378. Epub 2021 Aug 18.
• Toyoda K, Uchiyama S, Yamaguchi T, Easton JD, Kimura K, Hoshino H, Sakai N, Okada Y, Tanaka K, Origasa H, Naritomi H, Houkin K, Yamaguchi K, Isobe M, Minematsu K; CSPS.com Trial Investigators. Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischaemic stroke in Japan: a multicentre, open-label, randomised controlled trial. Lancet Neurol. 2019 Jun;18(6):539-548. doi: 10.1016/S1474-4422(19)30148-6.
• Toyoda K, Uchiyama S, Hoshino H, Kimura K, Origasa H, Naritomi H, Minematsu K, Yamaguchi T; CSPS.com Study Investigators. Protocol for Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com): a randomized, open-label, parallel-group trial. Int J Stroke. 2015 Feb;10(2):253-8. doi: 10.1111/ijs.12420. Epub 2014 Dec 8.

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2013
• Primary Completion (Actual): December 7, 2018
• Study Completion (Actual): December 7, 2018

Study Registration Dates

• First Submitted: November 15, 2013
• First Submitted That Met QC Criteria: November 21, 2013
• First Posted (Estimate): November 26, 2013

Study Record Updates

• Last Update Posted (Actual): March 28, 2019
• Last Update Submitted That Met QC Criteria: March 26, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Aspirin; Clopidogrel; Cilostazol; Noncardioembolic cerebral infarction; Dual antiplatelet therapy (DAPT)
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Stroke; Brain Infarction; Infarction; Cerebral Infarction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Neuroprotective Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Aspirin; Clopidogrel; Cilostazol
• Other Study ID Numbers: 021-TADD-1300-1; 000012180 (Other Identifier: UMIN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No