Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial

Shinohara, Yukito; Katayama, Yasuo; Uchiyama, Shinichiro; Yamaguchi, Takenori; Handa, Shunnosuke; Matsuoka, Kempei; Ohashi, Yasuo; Tanahashi, Norio; Yamamoto, Hiroko; Genka, Chokoh; Kitagawa, Yasuhisa; Kusuoka, Hideo; Nishimaru, Katsuya; Tsushima, Motoo; Koretsune, Yukihiro; Sawada, Tohru; Hamada, Chikuma

doi:10.1016/s1474-4422(10)70198-8

Cited by 437 publications

(339 citation statements)

References 32 publications

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“…The rate of stroke recurrence was reported to the study investigators by observers who were blinded to the study protocol. Secondary outcome end points included improvement of the NIHSS score (≥8 points or≤1 point from the baseline) or a mRS of 0-2 [28][29][30].…”

Section: Clinical Outcome Evaluation End Pointsmentioning

confidence: 99%

Ischemic Conditioning Is Safe and Effective for Octo- and Nonagenarians in Stroke Prevention and Treatment

et al. 2015

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Symptomatic intracranial arterial stenosis (SIAS) is very common in octo-and nonagenarians, especially in the Chinese population, and is likely the most common cause of stroke recurrence worldwide. Clinical trials demonstrate that endovascular treatment, such as stenting, may not be suitable for octogenarians with systemic diseases. Hence, less invasive methods for the octogenarian patients are urgently needed. Our previous study (unique identifier: NCT01321749) showed that repetitive bilateral arm ischemic preconditioning (BAIPC) reduced the incidence of stroke recurrence by improving cerebral perfusion (confirmed by single photon emission computed tomography and transcranial Doppler sonography) in patients younger than 80 years of age; however, the safety and effectiveness of BAIPC on stroke prevention in octo-and nonagenarians with SIAS are still unclear. The objective of this study was to evaluate the safety and effectiveness of BAIPC in reducing stroke recurrence in octo-and nonagenarian patients with SIAS. Fifty-eight patients with SIAS were enrolled in this randomized controlled prospective study for 180 consecutive days. All patients enrolled in the study received standard medical management. Patients in the BAIPC group (n=30) underwent 5 cycles consisting of bilateral arm ischemia followed by reperfusion for 5 min each twice daily. Those in the control group (n=28) underwent sham-BAIPC twice daily. Blood pressure, heart rate, local skin status, plasma myoglobin, and plasma levels of thrombotic and inflammatory markers were documented in both groups before beginning the study and for the first 30 days. Finally, the incidences of stroke recurrence and magnetic resonance imaging during the 180 days of treatment were compared. Compared with the control, BAIPC had no adverse effects on blood pressure, heart rate, local skin integrity, or plasma myoglobin, and did not induce cerebral hemorrhage in the studied cohort. BAIPC reduced plasma high sensitive C-reactive protein, interleukin-6, plasminogen activator inhibitor-1, leukocyte count, and platelet aggregation rate and elevated plasma tissue plasminogen activator (all p<0.01). In 180 days, 2 infarctions and 7 transient ischemic attacks were observed in the BAIPC group compared with 8 infarctions and 11 transient ischemic attacks in the sham BAIPC group (p<0.05). BAIPC may safely inhibit stroke recurrence, protect against brain ischemia, and ameliorate plasma biomarkers of inflammation and coagulation in octo-and nonagenarians with SIAS. A multicenter trial is ongoing.Clinical Trial Registration: www.clinicaltrials.gov, unique identifier: NCT01570231.

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Section: Clinical Outcome Evaluation End Pointsmentioning

confidence: 99%

Ischemic Conditioning Is Safe and Effective for Octo- and Nonagenarians in Stroke Prevention and Treatment

et al. 2015

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“…The clinical relevance of crosstalk between activating and cyclic nucleotide‐dependent inhibitory pathways is further highlighted by the success of drugs targeting either the Gi‐coupled P2Y12 receptor or PDEs 3A and 5A,12, 104, 105 which prevent the blockade of cyclic nucleotide production or degradation, respectively 106. Stimulators of the cGMP pathway are commonly used to treat vascular disease due to their ability to lower vascular tone by acting on smooth muscle cells, however, simultaneous platelet inhibition might contribute to their beneficial effects.…”

Section: Discussionmentioning

confidence: 99%

“…Combining stimulators of endothelium‐dependent cAMP pathways such as the PDE3A inhibitor cilostazol with P2Y12 inhibitors might improve anti‐thrombotic protection 17. Interestingly, cilostazol treatment has been associated with fewer hemorrhagic events compared to aspirin 104, 111. Although P2Y12 and PDE inhibitors are widely used in anti‐platelet therapy, their downstream effects on the platelet signaling network are unappreciated, and likely involve systems‐level changes, including altered phosphorylation of many PKA substrate proteins and their functional implications.…”

Section: Discussionmentioning

confidence: 99%

Cyclic nucleotide‐dependent inhibitory signaling interweaves with activating pathways to determine platelet responses

Nagy

Smolenski

2018

Research and Practice in Thrombosis and Haemostasis

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Platelets are regulated by extracellular cues that impact on intracellular signaling. The endothelium releases prostacyclin and nitric oxide which stimulate the synthesis of cyclic nucleotides cAMP and cGMP leading to platelet inhibition. Other inhibitory mechanisms involve immunoreceptor tyrosine‐based inhibition motif‐containing receptors, intracellular receptors and receptor desensitization. Inhibitory cyclic nucleotide pathways are traditionally thought to represent a passive background system keeping platelets in a quiescent state. In contrast, cyclic nucleotides are increasingly seen to be dynamically involved in most aspects of platelet regulation. This review focuses on crosstalk between activating and cyclic nucleotide‐mediated inhibitory pathways highlighting emerging new hub structures and signaling mechanisms. In particular, interactions of plasma membrane receptors like P2Y12 and GPIb/IX/V with the cyclic nucleotide system are described. Furthermore, differential regulation of the RGS18 complex, second messengers, protein kinases, and phosphatases are presented, and control over small G‐proteins by guanine‐nucleotide exchange factors and GTPase‐activating proteins are outlined. Possible clinical implications of signaling crosstalk are discussed.

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“…Так, в сравнительном рандомизированном двойном слепом пилотном исследовании ци-лостазол выступил в качестве альтернативы АСК. Частота повторных инсультов в обеих группах была сопоставима, однако при лече-нии АСК чаще развивались церебральные кро-воизлияния [35]. Необходимо отметить, что цилостазол не изучался на неазиатской попу-ляции, в которой эффекты от лечения могут быть другими.…”

Section: новые антитромбо-цитарные препаратыunclassified

Current Views on Antithrombotic Therapy in Non-Cardioembolic Stroke

Фонякин¹,

Гераскина²

2017

Aterotromboz

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Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial

Cited by 437 publications

References 32 publications

Ischemic Conditioning Is Safe and Effective for Octo- and Nonagenarians in Stroke Prevention and Treatment

Ischemic Conditioning Is Safe and Effective for Octo- and Nonagenarians in Stroke Prevention and Treatment

Cyclic nucleotide‐dependent inhibitory signaling interweaves with activating pathways to determine platelet responses

Current Views on Antithrombotic Therapy in Non-Cardioembolic Stroke

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