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The Annals of Pharmacotherapy Oct 2022A literature review of antiplatelet agents for primary and secondary stroke prevention, including mechanism of action, cost, and reasons for lack of benefit. (Review)
Review
OBJECTIVE
A literature review of antiplatelet agents for primary and secondary stroke prevention, including mechanism of action, cost, and reasons for lack of benefit.
DATA SOURCES
Articles were gathered from MEDLINE, Cochrane Reviews, and PubMed databases (1980-2021). Abstracts from scientific meetings were considered. Search terms included ischemic stroke, aspirin, clopidogrel, dipyridamole, ticagrelor, cilostazol, prasugrel, glycoprotein IIb/IIIa inhibitors.
STUDY SELECTION AND DATA EXTRACTION
English-language original and review articles were evaluated. Guidelines from multiple countries were reviewed. Articles were evaluated independently by 2 authors.
DATA SYNTHESIS
An abundance of evidence supports aspirin and clopidogrel use for secondary stroke prevention. In the acute phase (first 21 days postinitial stroke), these medications have higher efficacy for preventing further stroke when combined, but long-term combination therapy is associated with higher hemorrhage rates. Antiplatelet treatment failure is influenced by poor adherence and genetic polymorphisms. Antiplatelet agents such as cilostazol may provide extra benefit over clopidogrel and aspirin, in certain racial groups, but further research in more diverse ethnic populations is needed.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
This review presents the data available on the use of different antiplatelet agents poststroke. Dual therapy, recurrence after initiation of secondary preventative therapy, and areas for future research are discussed.
CONCLUSIONS
Although good evidence exists for the use of certain antiplatelet agents postischemic stroke, there are considerable opportunities for future research to investigate personalized therapies. These include screening patients for platelet polymorphisms that confer antiplatelet resistance and for randomized trials including more racially diverse populations.
Topics: Aspirin; Cilostazol; Clopidogrel; Drug Therapy, Combination; Humans; Ischemic Stroke; Platelet Aggregation Inhibitors; Stroke
PubMed: 35094598
DOI: 10.1177/10600280211073009 -
JAMA Neurology Jul 2023Cerebral small vessel disease (cSVD) is a common cause of stroke (lacunar stroke), is the most common cause of vascular cognitive impairment, and impairs mobility and... (Randomized Controlled Trial)
Randomized Controlled Trial
Isosorbide Mononitrate and Cilostazol Treatment in Patients With Symptomatic Cerebral Small Vessel Disease: The Lacunar Intervention Trial-2 (LACI-2) Randomized Clinical Trial.
IMPORTANCE
Cerebral small vessel disease (cSVD) is a common cause of stroke (lacunar stroke), is the most common cause of vascular cognitive impairment, and impairs mobility and mood but has no specific treatment.
OBJECTIVE
To test the feasibility, drug tolerability, safety, and effects of 1-year isosorbide mononitrate (ISMN) and cilostazol treatment on vascular, functional, and cognitive outcomes in patients with lacunar stroke.
DESIGN, SETTING, AND PARTICIPANTS
The Lacunar Intervention Trial-2 (LACI-2) was an investigator-initiated, open-label, blinded end-point, randomized clinical trial with a 2 × 2 factorial design. The trial aimed to recruit 400 participants from 26 UK hospital stroke centers between February 5, 2018, and May 31, 2021, with 12-month follow-up. Included participants had clinical lacunar ischemic stroke, were independent, were aged older than 30 years, had compatible brain imaging findings, had capacity to consent, and had no contraindications to (or indications for) the study drugs. Data analysis was performed on August 12, 2022.
INTERVENTIONS
All patients received guideline stroke prevention treatment and were randomized to ISMN (40-60 mg/d), cilostazol (200 mg/d), ISMN-cilostazol (40-60 and 200 mg/d, respectively), or no study drug.
MAIN OUTCOMES
The primary outcome was recruitment feasibility, including retention at 12 months. Secondary outcomes were safety (death), efficacy (composite of vascular events, dependence, cognition, and death), drug adherence, tolerability, recurrent stroke, dependence, cognitive impairment, quality of life (QOL), and hemorrhage.
RESULTS
Of the 400 participants planned for this trial, 363 (90.8%) were recruited. Their median age was 64 (IQR, 56.0-72.0) years; 251 (69.1%) were men. The median time between stroke and randomization was 79 (IQR, 27.0-244.0) days. A total of 358 patients (98.6%) were retained in the study at 12 months, with 257 of 272 (94.5%) taking 50% or more of the allocated drug. Compared with those participants not receiving that particular drug, neither ISMN (adjusted hazard ratio [aHR], 0.80 [95% CI, 0.59 to 1.09]; P = .16) nor cilostazol (aHR, 0.77 [95% CI, 0.57 to 1.05]; P = .10) alone reduced the composite outcome in 297 patients. Isosorbide mononitrate reduced recurrent stroke in 353 patients (adjusted odds ratio [aOR], 0.23 [95% CI, 0.07 to 0.74]; P = .01) and cognitive impairment in 308 patients (aOR, 0.55 [95% CI, 0.36 to 0.86]; P = .008). Cilostazol reduced dependence in 320 patients (aHR, 0.31 [95% CI, 0.14 to 0.72]; P = .006). Combination ISMN-cilostazol reduced the composite (aHR, 0.58 [95% CI, 0.36 to 0.92]; P = .02), dependence (aOR, 0.14 [95% CI, 0.03 to 0.59]; P = .008), and any cognitive impairment (aOR, 0.44 [95% CI, 0.23 to 0.85]; P = .02) and improved QOL (adjusted mean difference, 0.10 [95% CI, 0.03 to 0.17]; P = .005) in 153 patients. There were no safety concerns.
CONCLUSIONS AND RELEVANCE
These results show that the LACI-2 trial was feasible and ISMN and cilostazol were well tolerated and safe. These agents may reduce recurrent stroke, dependence, and cognitive impairment after lacunar stroke, and they could prevent other adverse outcomes in cSVD. Therefore, both agents should be tested in large phase 3 trials.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03451591.
Topics: Male; Humans; Aged; Middle Aged; Female; Cilostazol; Quality of Life; Stroke, Lacunar; Stroke; Cerebral Small Vessel Diseases; Treatment Outcome
PubMed: 37222252
DOI: 10.1001/jamaneurol.2023.1526 -
Arteriosclerosis, Thrombosis, and... Mar 2019Aortic aneurysms in both abdominal and thoracic aortic regions have complex pathophysiological features. In recent years, a considerable increase in research on aneurysm... (Review)
Review
Aortic aneurysms in both abdominal and thoracic aortic regions have complex pathophysiological features. In recent years, a considerable increase in research on aneurysm pathogenesis has resulted in the discovery of novel mechanisms and implementation of clinical trials that seek to assess strategies for preventing aneurysm expansion. Despite progress on our understanding of aortic aneurysms, there are still many unanswered questions and conflicting findings requiring clarification. This uncertainty highlights the importance of continual cooperation between preclinical and clinical researchers in validating findings from preclinical studies to the human disease, in order to discover medical treatments that prevent or halt the progression of aortic aneurysmal disease. We hope that this brief review prompts interest in reading these highlighted articles and spurs further investigation into this complex and devastating disease.
Topics: Adaptor Proteins, Signal Transducing; Aged; Aged, 80 and over; Animals; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Aortitis; Cilostazol; Disease Models, Animal; Female; Genetic Predisposition to Disease; Humans; Macrophage Activation; Male; Mice; Risk Factors; Sex Factors; Transforming Growth Factor beta
PubMed: 30811252
DOI: 10.1161/ATVBAHA.119.312000 -
Stroke and Vascular Neurology Oct 2022Antiplatelet therapy is one of the mainstays for secondary stroke prevention. This narrative review aimed to highlight the current evidence and recommendations of... (Meta-Analysis)
Meta-Analysis
Antiplatelet therapy is one of the mainstays for secondary stroke prevention. This narrative review aimed to highlight the current evidence and recommendations of antiplatelet therapy for stroke prevention.We conducted advanced literature search for antiplatelet therapy. Landmark studies and randomised controlled trials evaluating antiplatelet therapy for secondary stroke prevention are reviewed. Results from Cochrane systematic review, pooled data analysis and meta-analysis are discussed.Single-antiplatelet therapy (SAPT) with aspirin, aspirin/extended-release dipyridamole or clopidogrel reduces the risk of recurrent ischaemic stroke in patients with non-cardioembolic ischaemic stroke or transient ischaemic attack (TIA). Dual-antiplatelet therapy (DAPT) with aspirin and clopidogrel or ticagrelor for 21-30 days is more effective than SAPT in patients with minor acute noncardioembolic ischaemic stroke or high-risk TIA. Prolonged use of DAPT is associated with higher risk of haemorrhage without reduction in stroke recurrence than SAPT. Compared with placebo, aspirin reduces the relative risk of recurrent stroke by approximately 22%. Aspirin/dipyridamole and cilostazol are superior to aspirin but associated with significant side effects. Cilostazol or ticagrelor might be more effective than aspirin or clopidogrel in patients with intracranial stenosis.SAPT is indicated for secondary stroke prevention in patients with non-cardioembolic ischaemic stroke or TIA. DAPT with aspirin and clopidogrel or ticagrelor for 21-30 days followed by SAPT is recommended for patients with minor acute noncardioembolic stroke or high-risk TIA. Selection of appropriate antiplatelet therapy should also be based on compliance, drug tolerance or resistance.
Topics: Humans; Aspirin; Brain Ischemia; Cilostazol; Clopidogrel; Dipyridamole; Ischemic Attack, Transient; Ischemic Stroke; Platelet Aggregation Inhibitors; Stroke; Ticagrelor
PubMed: 35393359
DOI: 10.1136/svn-2021-001166 -
PloS One 2022To evaluate the efficacy and safety of cilostazol, pentoxifylline, beraprost for intermittent claudication due to lower extremity arterial occlusive disease. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the efficacy and safety of cilostazol, pentoxifylline, beraprost for intermittent claudication due to lower extremity arterial occlusive disease.
METHODS
Randomized controlled clinical trials were identified from PubMed, Scopus, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, SinoMed, Wanfang and Chongqing VIP databases, from the database inception to 31/12/2021. The outcome measures were walking distance measured by treadmill (maximum and pain-free walking distance), ankle-brachial index and adverse events. The quality of included studies was assessed by the Cochrane bias risk assessment tool. A network meta-analysis was carried out with Stata 16.0 software.
RESULTS
There were 29 RCTs included in the study, covering total 5352 patients. Cilostazol was ranked first for both maximum and pain-free walking distance, followed by beraprost and pentoxifylline. For cilostazol, pentoxifylline and beraprost, maximum walking distance increased by 62.93 95%CI(44.06, 81.79), 32.72 95%CI(13.51, 55.79) and 43.90 95%CI(2.10, 85.71) meters, respectively relative to placebo, and pain-free walking distance increased by 23.92 95%CI(11.24, 36.61), 15.16 95%CI(2.33, 27.99) and 19.78 95%CI(-3.07, 42.62) meters. For cilostazol, pentoxifylline, beraprost and cilostazol combined with beraprost, ankle-brachial index increased by 0.06 95%CI(0.04, 0.07), -0.01 95%CI(-0.08, 0.05), 0.18 95%CI(0.12, 0.23) and 0.23 95%CI(0.18, 0.27), respectively relative to placebo. The pentoxifylline and cilostazol was associated with a lower ratio of adverse events than beraprost and cilostazol combined with beraprost.
CONCLUSION
Cilostazol, pentoxifylline and beraprost were all effective treatments for intermittent claudication; cilostazol with good tolerance was likely to be the most effective in walking distance, while beraprost and cilostazol combined with beraprost were more prominent in the ankle-brachial index.
Topics: Humans; Cilostazol; Intermittent Claudication; Network Meta-Analysis; Pentoxifylline; Vasodilator Agents; Randomized Controlled Trials as Topic
PubMed: 36318524
DOI: 10.1371/journal.pone.0275392 -
JAMA Network Open Dec 2023Recent evidence indicates the efficacy of β-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote β-amyloid removal from the... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Recent evidence indicates the efficacy of β-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote β-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage.
OBJECTIVE
To determine the safety and efficacy of cilostazol in mild cognitive impairment.
DESIGN, SETTING, AND PARTICIPANTS
The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020.
INTERVENTIONS
The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks.
MAIN OUTCOMES AND MEASURES
The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events.
RESULTS
The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02491268.
Topics: Adult; Humans; Male; Aged; Female; Cilostazol; Cognitive Dysfunction; Dementia; Alzheimer Disease; Amyloid beta-Peptides
PubMed: 38048134
DOI: 10.1001/jamanetworkopen.2023.44938 -
British Journal of Clinical Pharmacology Oct 2011Inhibition of platelet aggregation can be achieved either by the blockade of membrane receptors or by interaction with intracellular signalling pathways. Cyclic... (Review)
Review
Inhibition of platelet aggregation can be achieved either by the blockade of membrane receptors or by interaction with intracellular signalling pathways. Cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) are two critical intracellular second messengers provided with strong inhibitory activity on fundamental platelet functions. Phosphodiesterases (PDEs), by catalysing the hydrolysis of cAMP and cGMP, limit the intracellular levels of cyclic nucleotides, thus regulating platelet function. The inhibition of PDEs may therefore exert a strong platelet inhibitory effect. Platelets possess three PDE isoforms (PDE2, PDE3 and PDE5), with different selectivity for cAMP and cGMP. Several nonselective or isoenzyme-selective PDE inhibitors have been developed, and some of them have entered clinical use as antiplatelet agents. This review focuses on the effect of PDE2, PDE3 and PDE5 inhibitors on platelet function and on the evidence for an antithrombotic action of some of them, and in particular of dipyridamole and cilostazol.
Topics: Blood Platelets; Cilostazol; Clinical Trials as Topic; Dipyridamole; Humans; Phosphodiesterase Inhibitors; Platelet Aggregation; Platelet Aggregation Inhibitors; Tetrazoles; Thrombosis
PubMed: 21649691
DOI: 10.1111/j.1365-2125.2011.04034.x -
Journal of Pharmacological Sciences Jul 2016Cilostazol is a phosphodiesterase-3 inhibitor and is known to have pleiotropic effects including antiplatelet and vasodilatation effects and protective effects on... (Review)
Review
Cilostazol is a phosphodiesterase-3 inhibitor and is known to have pleiotropic effects including antiplatelet and vasodilatation effects and protective effects on endothelial cells. Cilostazol also reportedly reduced stroke recurrence, poststroke intracranial hemorrhage, and extracranial bleeding in a meta-analysis. Although it is known that cilostazol has the potential to suppress hemorrhagic stroke, the precise mechanisms remained unclear. Therefore, we evaluated the protective effects and mechanisms of cilostazol against hemorrhagic stroke. We found that cilostazol prevented the hemorrhagic transformation induced by focal cerebral ischemia in mice treated with intravenous tissue plasminogen activator or warfarin via protecting endothelial cells and tight junction proteins. We also demonstrated that cilostazol attenuated collagenase-induced intracranial hemorrhage in mice. In vitro studies showed that endothelial cells, pericytes, tight junction proteins, adherence junction proteins, and the basement membrane, which are all components of the blood-brain barrier, were protected by the administration of cilostazol following collagenase injury. These results suggested that cilostazol reduces hemorrhagic stroke by protecting the entire blood-brain barrier. Here, we review the protective effects of cilostazol on the blood-brain barrier that result in the prevention of hemorrhagic stroke, discuss the results we obtained using multiple hemorrhagic stroke models, and introduce potential future applications of cilostazol.
Topics: Animals; Blood-Brain Barrier; Cilostazol; Humans; Mice; Phosphodiesterase 3 Inhibitors; Rats; Stroke; Tetrazoles
PubMed: 27381422
DOI: 10.1016/j.jphs.2016.04.023 -
Stroke Jan 2022Cerebral small vessel disease-a major cause of stroke and dementia-is associated with cerebrovascular dysfunction. We investigated whether short-term isosorbide... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND PURPOSE
Cerebral small vessel disease-a major cause of stroke and dementia-is associated with cerebrovascular dysfunction. We investigated whether short-term isosorbide mononitrate (ISMN) and cilostazol, alone or in combination, improved magnetic resonance imaging-measured cerebrovascular function in patients with lacunar ischemic stroke.
METHODS
Participants were randomized to ISMN alone, cilostazol alone, both ISMN and cilostazol, or no medication. Participants underwent structural, cerebrovascular reactivity (to 6% carbon dioxide) and phase-contrast pulsatility magnetic resonance imaging at baseline and after 8 weeks of medication.
RESULTS
Of 27 participants (mean age, 68±7.7; 44% female), 22 completed cerebrovascular reactivity and pulsatility imaging with complete datasets. White matter cerebrovascular reactivity increased in the ISMN (β=0.021%/mm Hg [95% CI, 0.003-0.040]) and cilostazol (β=0.035%/mm Hg [95% CI, 0.014-0.056]) monotherapy groups and in those taking any versus no medication (β=0.021%/mm Hg [95% CI, 0.005-0.037]).
CONCLUSIONS
While limited by small sample size, we demonstrate that measuring cerebrovascular function with magnetic resonance imaging is feasible in clinical trials and that ISMN and cilostazol may improve cerebrovascular function. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02481323. URL: www.isrctn.com; Unique identifier: ISRCTN12580546. URL: www.clinicaltrialsregister.eu; Unique identifier: EudraCT 2015-001953-33.
Topics: Aged; Cerebral Small Vessel Diseases; Cilostazol; Female; Hemodynamics; Humans; Isosorbide Dinitrate; Lipoproteins; Magnetic Resonance Imaging; Male; Middle Aged; Treatment Outcome; Vasodilator Agents
PubMed: 34847709
DOI: 10.1161/STROKEAHA.121.034866