Addition Of Cilostazol Research Articles

Randomized Controlled Trial of Cilostazol Addition for In-Stent Restenosis After Carotid Artery Stenting.

Restenosis after carotid artery stenting (CAS) is associated with the risk of developing ischemic stroke. We aimed to evaluate the inhibitory effect of cilostazol addition on in-stent restenosis (ISR) in patients treated with CAS. In a randomized, open-label, blind-end point trial, patients with symptomatic and asymptomatic carotid artery stenosis and scheduled for CAS were randomly assigned to adding cilostazol (50 or 100 mg, twice per day) on other antiplatelets from 3 days before CAS or not adding cilostazol. Concomitant use of other antiplatelets was unrestricted. ISR was diagnosed by a peak systolic velocity of at least 1.75 m/s on duplex ultrasonography. The primary outcome was incidence of ISR within 2 years after CAS. Secondary outcomes included occurrences of cardiovascular events or any death and hemorrhagic events. Participants were recruited from December 2010 to September 2015. Although the sample size was initially set to be 900 (450 in each group), 631 patients (mean age 69.9 years, 558 men, 325 in the cilostazol, and 306 in the noncilostazol group) were included in the primary analysis. Within 2 years' follow-up, ISR occurred in 31 of 325 patients (cumulative incidence 10.8%) in the cilostazol group and 46 of 306 patients (19.6%) in the noncilostazol group (hazard ratio, 0.64 [95% CI, 0.41-1.0]; P=0.056). In the exploratory analysis, incidence of ISR beyond 30 days after CAS was lower in the cilostazol group than in the noncilostazol group (10.3% versus 19.3%; P=0.040). Incidences of cardiovascular events or any death and hemorrhagic events were similar between the groups (6.2% versus 6.7% and 2.3% versus 1.4%, respectively). The addition of cilostazol to other antiplatelet agents could contribute to the reduction of ISR in the chronic stage of patients who underwent CAS, the authenticity of which depends on further studies with sufficient statistical power. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01261234.

Blood pressure during long-term cilostazol-based dual antiplatelet therapy after stroke: a post hoc analysis of the CSPS.com trial

We determined the associations of follow-up blood pressure (BP) after stroke as a time-dependent covariate with the risk of subsequent ischemic stroke, as well as those of BP levels with the difference in the impact of long-term clopidogrel or aspirin monotherapy versus additional cilostazol medication on secondary stroke prevention. In a sub-analysis of a randomized controlled trial (CSPS.com), patients between 8 and 180 days after stroke onset were randomly assigned to receive aspirin or clopidogrel alone, or a combination of cilostazol with aspirin or clopidogrel. The percent changes, differences, and raw values of follow-up BP were examined. The primary efficacy outcome was the first recurrence of ischemic stroke. In a total of 1657 patients (69.5 ± 9.3 years, female 29.1%) with median 1.5-year follow-up, ischemic stroke recurred in 74 patients. The adjusted hazard ratio for ischemic stroke of a 10% systolic BP (SBP) increase from baseline was 1.19 (95% CI 1.03–1.36), that of a 10 mmHg SBP increase was 1.14 (1.03–1.28), and that of SBP as the raw value with the baseline SBP as a fixed (time-independent) covariate was 1.14 (1.00–1.31). Such significant associations were not observed in diastolic BP-derived variables. The estimated adjusted hazard ratio curves for the outcome showed the benefit of dual therapy over a wide SBP range between ≈120 and ≈165 mmHg uniformly. Lower long-term SBP levels after ischemic stroke were associated with a lower risk of subsequent ischemic events. The efficacy of dual antiplatelet therapy including cilostazol for secondary stroke prevention was evident over a wide SBP range.

Secondary Prevention of Multifocal Atherosclerosis Combined with Chronic Obstructive Pulmonary Disease

The problem of secondary prevention of multifocal atherosclerosis (MAS) combined with chronic obstructive pulmonary disease (COPD), is a leading cause of death in the world. Therefore, the search for drugs capable of affecting the destructive mechanisms underlying both MAS and COPD is an extremely urgent problem today. Objective — to reduce the risks of destabilization of atherosclerotic plaques by reducing the levels of metallomatrix metalloproteases (MMP)-2 and MMP-9 in patients on MAS combined with COPD. Materials and methods. The study included 62 men (68.1 ± 4.2) years old with MAS. All patients with MAS had clinical and functional signs of injury in coronary, cerebral and femoral vascular territories, 30 of these patients (group MAS-2) additionally had clinical and functional signs of COPD (GOLD-2). The control group (CG) consisted of 18 practically healthy men, aged (65.4 ± 3.7) years. Examination of the patients included echocardiography, dopplerography of the vessels of the neck and arteries of the lower extremities, determination of walking distance and ankle-brachial index, Holter ECG monitoring, spirography and determination of MMP-2 and MMP-9 levels in blood. Patients of both groups were prescribed cilostazol (50 mg twice a day) and GABA aminalon (250 mg twice a day) on the background of basic treatment. The course of treatment lasted 16 weeks. Results and discussion. During the initial examination of patients, MAS-2 group showed significantly (p < 0.001) lower volumetric blood flow in the studied arteries, and significantly (p < 0.01) higher levels of MMP-2 and MMP-9, as compared to CG, as well as with patients of the MAS-1 group. After 16 weeks of treatment, with the addition of cilostazol and aminalon, the level of MMP in the blood significantly (p < 0.05) decreased in both groups, in particular, in the MAS-2 group, in patients with the combined pathology of MAS and COPD, a significant decrease was found MMP-2 by 23.6 % (p < 0.01), and MMP-9 by 12.1 % (p < 0.05). Volumetric blood flow indicators increased significantly (p < 0.05) in all studied vascular territories, which led to improvement in clinical manifestations of the disease — a decrease in the number of painful and painless episodes of myocardial ischemia, and an increase in walking distance. Conclusions. The use of a complex therapy of statins, cilostazol and GABA in patients with MAS combined with COPD allows to reduce significantly the levels of MMP-2 and MMP-9, which ensures the stability of atheromatous plaques and significantly improves blood supply in vascular territories with atherosclerotic lesions.

Comparative effects of different antiplatelet strategies in carriers of CYP2C19 loss-of-function alleles: a network meta-analysis.

Carriers of cytochrome 2C19 (CYP2C19) loss-of-function (LoF) alleles treated with clopidogrel have impaired drug metabolism, resulting in reduced active metabolite levels, high platelet reactivity (HPR), and an increased risk of thrombotic events. Several alternative antiplatelet therapies have been proposed to overcome HPR in these patients, but their comparative effects remain poorly explored. Randomized controlled trials (RCTs) comparing different oral antiplatelet therapies in carriers of CYP2C19 LoF alleles undergoing percutaneous coronary interventions (PCI) were included. A frequentist network meta-analysis was conducted to estimate mean difference (MD) or odds ratios and 95% confidence intervals (CI). The primary outcome was platelet reactivity assessed by VerifyNow and reported as P2Y12 reaction unit (PRU). The secondary outcome was the rate of HPR. Standard dose of clopidogrel (75mg daily) was used as a reference treatment. A total of 12 RCTs testing 6 alternative strategies (i.e. clopidogrel 150mg, prasugrel 3.75mg, 5mg, and 10mg, ticagrelor 90mg bid, and adjunctive cilostazol 100mg bid) were included in the network. Compared with standard-dose clopidogrel, the greatest reduction in PRU was observed with prasugrel 10mg (MD -127.91; 95% CI -141.04; -114.78) and ticagrelor 90mg bid (MD -124.91; 95% CI -161.78; -88.04), followed by prasugrel 5mg (MD -76.33; 95% CI -98.01; -54.65) and prasugrel 3.75mg (MD -73.00; 95% CI -100.28; -45.72). Among other strategies, adjunctive cilostazol (MD -42.64; 95% CI -64.72; -20.57) and high-dose clopidogrel (MD -32.11; 95% CI -51.33; -12.90) were associated with a modest reduction in PRU compared with standard-dose clopidogrel. Among carriers of CYP2C19 LoF alleles undergoing PCI, standard-dose prasugrel or ticagrelor are most effective in reducing platelet reactivity, while double-dose clopidogrel and additional cilostazol showed modest effects. Reduced-dose of prasugrel may represent a balanced strategy to overcome HPR without a significant increase in bleeding. The clinical implications of these pharmacodynamic findings warrant further investigation.

A Systematic Review and Meta-Analysis of Efficacy and Safety of Cilostazol Prescription in Patients With Femoropopliteal Peripheral Artery Disease After Endovascular Therapy.

The purpose of this study is to assess the efficacy and safety of cilostazol prescription in patients with femoropopliteal peripheral artery disease (PAD) after endovascular therapy (EVT). We conducted a systematic review and meta-analysis of all studies reporting the outcomes of cilostazol after femoropopliteal EVT of PAD up to September 2022. Clinical outcomes of interest included primary patency, in-stent restenosis (ISR), vessel re-occlusion, freedom from target lesion revascularization (TLR), repeat revascularization, all-cause mortality, amputation, major adverse cardiovascular events (MACEs) and major adverse limb events (MALEs), and bleeding complication. A total of 4 randomized controlled trials (RCTs) and 8 observational studies containing a total of 4898 patients met the inclusion criteria and were included in this systematic review and meta-analysis. We found that the use of cilostazol was associated with higher primary patency after femoropopliteal artery EVT (odds ratio [OR]=1.67, 95% confidence interval [CI]=1.50-1.87, p<0.001, I2=33.2%), a lower risk of ISR (OR=0.43, 95% CI=0.29-0.63, p<0.001, I2=37.6%), repeat revascularization (OR=0.43, 95% CI=0.24-0.76, p<0.005, I2=27.4%), and vessel re-occlusion (OR=0.59, 95% CI=0.38-0.93, p<0.05, I2=0%). There was an increase in freedom from TLR rate (OR=2.19, 95% CI=1.58-3.05, p<0.001, I2=0%), as well as a reduction in the occurrence of MALEs (OR=0.50, 95% CI=0.29-0.85, p<0.05, I2=0%). However, there was no significant difference in amputation, MACEs, all-cause mortality, and major bleeding complications. Subgroup analysis showed that cilostazol treatment in patients with femoropopliteal drug-eluting stents (DES) implantation remained associated with higher primary patency and a lower risk of ISR. After EVT of femoropopliteal artery lesions, additional oral cilostazol enhances primary patency, reduces the occurrences of ISR and vessel re-occlusion, diminishes the risks associated with MALEs, lowers the need for repeat revascularization, and increases freedom from TLR rates. However, it does not impact amputation, MACEs, all-cause mortality, or major bleeding complications. These findings suggest cilostazol as a potentially safe and effective adjunct therapy in patients with femoropopliteal PAD after EVT. After undergoing endovascular therapy (EVT) for femoropopliteal artery lesions, the addition of cilostazol to antiplatelet therapy can significantly improve primary patency, reducing the incidence of in-stent restenosis, repeat revascularization, vessel re-occlusion, and major adverse limb events while increasing freedom from target lesion revascularization rate. The simultaneous use of drug-eluting stents in the femoropopliteal artery lesions, combined with cilostazol, potentially results in a synergistic anti-stenotic effect. This therapeutic approach does not appear to be associated with an increased risk of major bleeding events or all-cause mortality. These findings provide additional evidence supporting the treatment of anti-stenosis in patients with femoropopliteal artery lesions after EVT.

Cilostazol addition to aspirin may worsen the short-term outcome in patients with large artery disease: ADS subanalysis

Our previous acute dual study (ADS) reported that dual antiplatelet therapy (DAPT) using cilostazol and aspirin did not reduce the rate of neurological deterioration in non-cardioembolic stroke patients. In this post-hoc analysis, we investigated whether the impact of dual antiplatelet therapy (DAPT) may depend on neurological severity, as represented by large artery disease. Neurological deterioration was defined as neurological progression with an increment of the National Institutes of Health Stroke Scale (NIHSS) score of ≥2. NIHSS score subgroups were divided into that of 0-1, 2-4, 5-10, and >10. Among 1014 patients, 203 (20%) had the large artery disease, and 811 (80%) did not. In the total cohort, the rate of neurological deterioration was 10.8% in the DAPT group and 8.3% in the aspirin group (P=0.197). When we focused on the large artery disease group, DAPT group had a higher rate of neurological deterioration as 18.3% compared to 8.2% in the aspirin group (P=0.036). Among patients with NIHSS score of 0-1 and 2-4, the rates of neurological deterioration were not different between the two group (both, P=1.000). However, when NIHSS score elevated to 5-10, 45% in the DAPT group and 9.1% in the aspirin group deteriorated (P=0.013). Among the patients with NIHSS score of >10, 60% in the DAPT group and none (0%) in the aspirin group had the neurological deterioration (P=0.045). DAPT with aspirin and cilostazol was associated with higher rate of neurological deterioration when patients have large artery disease and not mild neurological deficits.

Adjunctive cilostazol in patients with acute ST-elevation myocardial infarction: a multicenter, randomized, open-label, phase 4 trial

Abstract Background/Aims Previous studies showed that triple antiplatelet therapy (TAT), involving the addition of cilostazol to conventional dual antiplatelet therapy (DAT; aspirin + clopidogrel), has better clinical outcomes in patients with ST-elevation myocardial infarction (STEMI) than that with DAT; however, the optimal duration of TAT has not yet been determined. Methods Altogether, 985 patients who underwent primary percutaneous coronary intervention (PCI) with drug-eluting stents (DES) were prospectively enrolled in 14 medical centers in Korea. We randomly assigned patients into three groups: DAT (aspirin and clopidogrel for 12 months), TAT 1M (aspirin, clopidogrel, and cilostazol for 1 month), and TAT 6M (aspirin, clopidogrel, and cilostazol for six months). The primary endpoint was 1-year major adverse cardiovascular events (MACEs), defined as the composite of all-cause death, recurrent myocardial infarction (MI), stroke, or repeat revascularization. Results The primary endpoint was not different among the three groups (8.8% in the DAT, 11.0% in the TAT 1M, and 11.6% in the TAT 6M; hazard ratio for TAT 1M vs. DAT, 1.302; 95% confidence interval [CI], 0.792–2.141; p=0.297; hazard ratio for TAT 6M vs. DAT, 1.358; 95% CI, 0.829–2.225; p=0.225). With in-hospital outcomes, more bleeding events occurred in the TAT group than in the DAT group (1.3% vs. 4.7% vs. 2.6%, p=0.029) without significant differences in major bleeding. Besides, the TAT groups had higher incidence of headache (0% vs. 1.6% vs. 2.6%, p=0.020). Conclusions The addition of cilostazol to the DAT did not reduce the incidence of 1-year MACE compared to that with DAT alone. Instead, it may be associated with an increased risk of cumbersome side effects such as in-hospital bleeding and headaches.

Clinical Impact of Additional Cilostazol Treatment on Restenosis Risk following Heparin-Bonded Stent Graft Implantation: Sub-Analysis from the Viabahn Stent-Graft Placement for Femoropopliteal Diseases Requiring Endovascular Therapy (VANQUISH) Study.

The present study investigated the effects of additional cilostazol administration on the 12-month risk of restenosis after femoropopliteal heparin-bonded stent graft implantation. This study was a sub-analysis of the Viabahn stent graft placement for femoropopliteal disease reQUIring endovaScular tHerapy (VANQUISH) study, which was a prospective multicenter study investigating patients who received Viabahn stent graft (W.L. Gore & Associates, Flagstaff, AZ, USA) and dual-antiplatelet therapy with aspirin and a thienopyridine. The comparison of clinical outcomes between subgroups with and without cilostazol treatment were performed using the propensity score-matching method to minimize the intergroup differences in baseline characteristics. Cilostazol-treated patients had a lower 12-month proportion of restenosis than cilostazol-free patients (8.2% vs 27.3%). The odds ratio of cilostazol for the 12-month restenosis was 0.27 [95% CI, 0.08 to 0.97] (p=0.045). Furthermore, the cumulative incidence rates of surgical reconstruction, target lesion revascularization and acute thrombotic occlusion (p values by the log-rank test) were 2.6% versus 1.8% (P=0.43), 5.3% versus 20.5% (P=0.067), and 0.0% versus 11.8% (P=0.0499), respectively. The rates of surgical reconstruction and target lesion revascularization (TLR) were not significantly different between both groups. Our study revealed the clinical impact of additional cilostazol treatment on the risk of restenosis and acute thrombotic occlusion following heparin-bonded stent graft implantation, while TLR and surgical reconstruction were not significantly different.

Efficacy and safety of cilostazol-based triple antiplatelet therapy compared with clopidogrel-based dual antiplatelet therapy in patients with acute ST-elevation myocardial infarction undergoing percutaneous coronary intervention: A multicenter, randomized, open-label, phase 4 trial

Previous studies reported that compared to conventional dual antiplatelet therapy (DAT; aspirin+clopidogrel), triple antiplatelet therapy (TAT), involving the addition of cilostazol to DAT, had better clinical outcomes in patients with ST-elevation myocardial infarction (STEMI). However, the optimal duration of TAT is yet to be determined. In total, 985 patients with STEMI who underwent primary percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) were prospectively enrolled in 15 PCI centers in South Korea and China. We randomly assigned patients into 3 groups: DAT (aspirin and clopidogrel for 12 months), TAT 1M (aspirin, clopidogrel, and cilostazol for 1 month), and TAT 6M (aspirin, clopidogrel, and cilostazol for 6 months). The primary endpoint was 1-year major adverse cardiovascular events (MACEs), defined as a composite of all-cause death, recurrent myocardial infarction, stroke, or repeat revascularization. The primary endpoint did not differ among the 3 groups (8.8% in DAT, 11.0% in TAT 1M, and 11.6% in TAT 6M; hazard ratio for TAT 1M vs DAT, 1.302; 95% confidence interval [CI], 0.792-2.141; P=.297; hazard ratio for TAT 6M vs DAT, 1.358; 95% CI, 0.829-2.225; P=.225). With respect to in-hospital outcomes, more bleeding events occurred in the TAT group than in the DAT group (1.3% vs 4.7% vs 2.6%, P=.029), with no significant differences in major bleeding events. Additionally, the TAT group had a higher incidence of headaches (0% vs 1.6% vs 2.6%, P=.020). The addition of cilostazol to DAT did not reduce the incidence of 1-year MACEs compared with DAT alone. Instead, it may be associated with an increased risk of drug intolerance and side effects, including in-hospital bleeding and headaches.

Reno-protective effects of GLP-1 receptor agonist and anti-platelets in experimentally induced diabetic kidney disease in male albino rats.

The prevalence of chronic kidney disease in diabetics is progressively increasing with an increased risk of fatal complications. Sixty male albino rats were used in the study, and type 2 diabetes mellitus were induced. Diabetic rats were divided randomly into 5 groups, the control diabetic group and 4 treated groups were treated with metformin (group3), dulaglutide (group 4), metformin & cilostazol (group 5), and the last group was treated with dulaglutide & cilostazol (group 6). At the end of the experiment, the weight of rats and systolic blood pressure were estimated. After overnight fasting, the serum levels of blood glucose, lipid profile, and kidney function were measured. After scarification, gene expression of eNOS and NFKB in kidney tissue were estimated and kidney tissues were examined for histopathology. Diabetic rats showed a significant increase in body weight, blood pressure, serum blood glucose, lipid profile, and impaired kidney function. Metformin and dulaglutide are associated with a significant decrease in blood pressure, blood glucose level, serum lipid profile, and improved kidney function. These changes are associated with a significant increase in anti-oxidative markers, and decreased inflammatory and fibrotic markers, especially with the addition of cilostazol. Metformin and dulaglutide have been shown to ameliorate kidney damage in diabetics by stimulating the anti-oxidant defense system, normalizing kidney functional parameters, and improving histopathological changes. The addition of cilostazol to metformin or dulaglutide increased some of their anti-oxidants and anti-inflammatory properties.

Abstract 10920: Efficacy of Cilostazol After Endovascular Therapy for Peripheral Artery Disease: A Meta-Analysis

Introduction. Endovascular therapies (EVT) for peripheral arterial disease (PAD) have been useful in improving quality of life outcomes; however, rates of restenosis after EVT remain high and lead to worse clinical outcomes. Use of cilostazol with antiplatelet therapy following EVT has been shown to improve clinical outcomes, although its role remains debatable. This meta-analysis aims to examine the clinical outcome of cilostazol use post-EVT in randomized controlled trials, and provide some basis for recommending this as a useful adjunct post-EVT in PAD patients. Objectives. This study aims to assess the efficacy of cilostazol as added therapy with antiplatelets after EVT in terms of decreasing restenosis, revascularization incidence, and incidence of bleeding and adverse effects. Methods. An electronic literature search for randomized controlled trials published up to June 2021 was conducted. Four randomized control trials which compared the efficacy of adding cilostazol to antiplatelet therapy in decreasing the risk of restenosis in patients with PAD who underwent EVT were selected. Data from all included studies were entered, compiled and analyzed using the Review Manager version 5.3 software. Results. A total of 589 patients from the four randomized controlled trials were analyzed in this meta-analysis. The efficacy of addition cilostazol post-EVT showed benefit of cilostazol in lowering restenosis (SMD 0.39 [95% CI 0.26, 0.57] P &lt; 0.00001), revascularization (SMD 0.44 [95% CI 0.30, 0.64] P &lt; 0.0001), and no significant differences between groups in preventing major cardiac cardiac events (SMD 0.80 [95% CI 0.51, 1.24] P=0.32) for post-EVT patients occurrence for post-EVT patients. Conclusion. The addition of Cilostazol to antiplatelet therapy post-EVT in patients with PAD may decrease rates of restenosis and revascularization. Keywords: cilostazol, EVT, restenosis, revascularization, major adverse cardiac events

Cost-Effectiveness of Cilostazol Added to Aspirin or Clopidogrel for Secondary Prevention After Noncardioembolic Stroke.

BackgroundThe objective of the study was to assess the cost‐effectiveness of cilostazol (a selective phosphodiesterase 3 inhibitor) added to aspirin or clopidogrel for secondary stroke prevention in patients with noncardioembolic stroke.Methods and ResultsA Markov model decision tree was used to examine lifetime costs and quality‐adjusted life years (QALYs) of patients with noncardioembolic stroke treated with either aspirin or clopidogrel or with additional cilostazol 100 mg twice daily. Cohorts were followed until all patients died from competing risks or ischemic or hemorrhagic stroke. Probabilistic sensitivity analysis using Monte Carlo simulation was used to model 10 000 cohorts of 10 000 patients. The addition of cilostazol to aspirin or clopidogrel is strongly cost saving. In all 10 000 simulations, the cilostazol strategy resulted in lower health care costs compared with aspirin or clopidogrel alone (mean $13 488 cost savings per patient; SD, $8087) and resulted in higher QALYs (mean, 0.585 more QALYs per patient lifetime; SD, 0.290). This result remained robust across a variety of sensitivity analyses, varying cost inputs, and treatment effects. At a willingness‐to‐pay threshold of $50 000/QALY, average net monetary benefit from the addition of cilostazol was $42 743 per patient over their lifetime.ConclusionsBased on the best available data, the addition of cilostazol to aspirin or clopidogrel for secondary prevention following noncardioembolic stroke results in significantly reduced health care costs and a gain in lifetime QALYs.

Abstract TP81: Cost Effectiveness Of Cilostazol Added To Aspirin Or Plavix For Secondary Stroke Prevention Following Non-cardioembolic Stroke

Background: The objective of the study is to compare the cost-effectiveness of cilostazol (a selective phosphodiesterase 3 inhibitor) added to aspirin (ASA) or Plavix in patients with non-cardioembolic stroke for secondary stroke prevention. Methods: A Markov model decision tree was used to examine lifetime costs and Quality Adjusted Life Years (QALYs) of patients with non-cardioembolic stroke treated with either single antiplatelet (ASA or Plavix) or with additional cilostazol 100 mg twice daily. Cohorts were followed until all patients died from competing risks, ischemic or hemorrhagic stroke. Input parameters are shown in Table 1. Probabilistic sensitivity analysis using Monte-Carlo simulation was used to model 10 000 cohorts of 10 000 patients. Results: The addition of cilostazol to ASA or Plavix is strongly cost saving (Figure 1). In all 10 000 simulations, the cilostazol strategy resulted in lower health care costs compared to ASA or Plavix alone (mean $14 450 lower per patient, SD $8 466 USD). In 9 998/10 000 simulations, the cilostazol strategy resulted in higher QALYs (mean 0.6016 QALY per patient, SD 0.0704). This result remained robust across a variety of sensitivity analyses varying cost inputs and treatment effects. Conclusion: Based on best available data, the addition of cilostazol to ASA or Plavix for secondary prevention results in significantly reduced healthcare costs and higher lifetime QALYs for patients with non-cardioembolic stroke. Confirmation with high quality data from a randomized trial including a high proportion of non-Asian patients is needed to increase generalizability.

Association of Timing for Starting Dual Antiplatelet Treatment With Cilostazol and Recurrent Stroke

Background and ObjectivesLong-term treatment with the combination of cilostazol with aspirin or clopidogrel showed a lower risk of stroke recurrence compared to aspirin or clopidogrel alone after high-risk noncardioembolic ischemic stroke in a randomized trial. We aimed to determine whether the effect of the dual medication compared to monotherapy on risk of recurrent ischemic stroke differs according to timing of starting medication after stroke onset.MethodsIn a subanalysis of the randomized controlled trial, patients between 8 and 180 days after stroke onset were randomly assigned to receive aspirin or clopidogrel alone or a combination of cilostazol with aspirin or clopidogrel. They were divided into 3 groups according to the timing of starting trial treatment: between 8 and 14 days after stroke onset (8–14 days group), between 15 and 28 days after stroke onset (15–28 days group), and between 29 and 180 days after stroke onset (29–180 days group). The primary efficacy outcome was the first recurrence of ischemic stroke. Safety outcomes included severe or life-threatening bleeding.ResultsOf 1,879 patients, 498 belonged to the 8–14 days group, 467 to the 15–28 days group, and 914 to the 29–180 days group. There was a significant treatment-by-subgroup interaction for the recurrence of ischemic stroke between trial treatment and trichotomized groups. The recurrence of ischemic stroke was less common with dual therapy than with monotherapy in the 15–28 days group (annualized rate 1.5% vs 4.9%, respectively; adjusted hazard ratio 0.34 [95% CI 0.12–0.95]) and the 29–180 days group (1.9% vs 4.4%, respectively; 0.27 [0.12–0.63]) and similarly common in the 8–14 days group (4.5% for both; 1.02 [0.51–2.04]). Severe or life-threatening bleeding occurred similarly between patients on dual therapy and those on monotherapy in any of the trichotomized groups (crude hazard ratio 0.22 [95% CI 0.03–1.88] in the 8–14 days group, 1.07 [0.15–7.60] in the 15–28 days group, and 0.76 [0.24–2.39] in the 29–180 days group).DiscussionLong-term dual antiplatelet therapy using cilostazol starting 15–180 days after stroke onset, compared to therapy started 8–14 days after onset, was more effective for secondary stroke prevention than monotherapy without increasing hemorrhage risk.Trial Registration InformationClinicalTrials.gov NCT01995370; UMIN Clinical Trials Registry 000012180.Classification of EvidenceThis study provides Class II evidence that for patients with acute noncardioembolic stroke taking either aspirin or clopidogrel, the addition of cilostazol 15–180 days after stroke onset decreases the risk of recurrent ischemic stroke.

Thromboembolic events during endovascular coiling for unruptured intracranial aneurysms: Clinical significance of platelet reactivity unit and adjunctive cilostazol

ObjectiveThis study aimed to reveal the clinical significance of the platelet reactivity unit (PRU) and the efficacy of adjunctive cilostazol and its association with thromboembolic and microembolic events after coil embolization for unruptured intracranial aneurysms (UIAs). MethodsWe retrospectively analyzed the data of 427 patients with UIAs who underwent endovascular treatment between July 2011 and June 2014. When clopidogrel resistance was confirmed via PRU assay after dual antiplatelet medication (aspirin plus clopidogrel) administration for 5 days, triple antiplatelet therapy with cilostazol was administered (Group I, 274 patients). The other group was placed on standard dual antiplatelet therapy (Group II, 153 patients). All patients underwent magnetic resonance diffusion-weighted imaging within 2 days after endovascular coiling. ResultsNo significant associations with the occurrence of thromboembolic and microembolic events were found between the groups. The occurrence of thromboembolic and microembolic events showed no statistical difference between groups I and II (p = 0.725 for thromboembolic events and p = 0.109 for microembolic events). Also, the PRU value and the occurrence of microembolic events, using a PRU cutoff value of 240, showed no statistical difference (p = 0.114 in group I and 0.064 in group II). There was significant increase in microembolic events after the use of a stent-assisted endovascular procedure. As the PRU value increased, there was a trend toward an increase in the mean number of microembolic lesions without statistical significance. ConclusionEven though there is a presumed anti-thromboembolic effect for clopidogrel resistance in other literature, the clinical efficacy of adjustment of additional cilostazol for endovascular coiling of unruptured aneurysms may be limited due to the unspecified cutoff value of the PRU assay for evaluating the resistance.

Abstract 12823: Efficacy, Optimal Duration and Safety of Adjunctive Cilostazol in Acute ST-elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention With Drug-Eluting Stents; a Multicenter, Randomized, Open Label, Phase 4 Trial

Background: Previous studies showed that the triple antiplatelet therapy (TAT) which is an addition of cilostazol on the top of conventional dual antiplatelet therapy (DAT, aspirin + clopidogrel) was associated with better clinical outcomes in ST-elevation MI (STEMI) patients as compared with DAPT but the optimal duration of TAT was not determined yet. Method: A total 985 patients underwent primary percutaneous coronary intervention (PCI) with drug-eluting stents (DES) were prospectively enrolled in 14 medical centers in Korea. We randomly assigned patients into 3 groups of DAT (aspiring and clopidogrel) for 12 months, TAT (aspirin, clopidogrel and cilostazol) for 1month or 6months. The primary end point was 1-year major adverse cardiovascular events (MACE), defined as the composite of all-cause death, non-fatal myocardial infarction (MI), stroke or repeat revascularization. The secondary endpoints were the incidence of cardiac death, stent thrombosis, bleeding events and each component of primary end point. Results: The primary end point was not different among the 3 groups (8.4% in the DAT, 11.0% in the TAT for 1month, 11.3% in the TAT for 6 months, p=0.427). However, incidence of cardiac death was significantly higher in TAT groups (0.3% vs 2.5% vs 1.3%, respectively, p=0.047). Regarding in-hospital outcomes, higher bleeding events occurred in TAT groups than DAT group (0.3% vs 3.2% vs 1.9%, p=0.027) without significant difference in major bleeding. Conclusion: TAT strategy with cilostazol on the top of DAT did not associated with reduced incidence of 1-year MACE as compared with DAT but may be associated with increased cardiovascular death and bleeding risk. Whether routine additional use of cilostazol for STEMI patients would be beneficial need further studies with larger study population.

Cilostazol Addition to Aspirin could not Reduce the Neurological Deterioration in TOAST Subtypes: ADS Post-Hoc Analysis

BackgroundOur previous trial acute dual study (ADS) reported that dual antiplatelet therapy (DAPT) using cilostazol and aspirin did not reduce the rate of short-term neurological worsening in non-cardioembolic stroke patients. Present post-hoc analysis investigated whether the impact of combined cilostazol and aspirin differed among stroke subtypes and factors associated with neurological deterioration and/or stroke recurrence. MethodsUsing the ADS registry, the rate of neurological deterioration, defined as clinical worsening and/or recurrent stroke, including transient ischemic attack was calculated. Stroke subtypes included large-artery atherosclerosis (LAA), small vessel occlusion (SVO), other determined etiology (Others), and undetermined etiology of stroke (Undetermined). ResultsData of 1022 patients were analyzed. Deterioration was seen in 104 (10%) patients, and the rates were not markedly different between patients treated with DAPT vs. aspirin in any stroke subtypes: LAA, 19% vs. 11%, (p=0.192); SVO, 10% vs. 10% (p=1.000); Others, 6% vs. 6% (p=1.000); Undetermined, 11% vs. 8% (p=0.590). Diabetes mellitus was the independent factor associated with deterioration (odds ratio 4.360, 95% confidence interval 1.139–16.691, p=0.032) in the LAA group. Age (1.030 [1.004–1.057], p=0.026), systolic blood pressure (1.012 [1.003–1.022], p=0.010), and infarct size (2.550 [1.488–4.371], p=0.001) were associated with deterioration in SVO group, and intracranial stenosis/occlusion was associated with it in the Undetermined group (3.744 [1.138–12.318], p=0.030). ConclusionsCombined cilostazol and aspirin did not reduce the rate of short-term neurological deterioration in any clinical stroke subtype. The characteristics of patients whose condition deteriorates in the acute period may differ based on the stroke subtypes.

РІВЕНЬ СЕРОТОНІНУ У ХВОРИХ НА ГЕНЕРАЛІЗОВАНИЙ АТЕРОСКЛЕРОЗ ТА ЙОГО ДИНАМІКА ПІД ВПЛИВОМ ЦИЛОСТАЗОЛУ

Метою даної роботи є вивчення впливу цилостазолу на регіональну гемодинамі- ку, рівень серотоніну та функціональну активність мозку, серця, нижніх кінцівок у хворих на генералізований атеросклероз. У 12-тижневе відкрите рандомізоване плацебо-контрольоване дослідження було включено 52 осіб чоловічої статі з генералізованим атеросклерозом та 26 осіб чоловічої статі з хронічним коронарним синдромом (група порівняння). Пацієнти основної групи, які мали генералізований атеросклероз були рандомізовані на дві підгрупи: 26 чоловіків додатково до базисної терапії отримували цилостазол в дозі 100 мг двічі на добу та 26 паці- єнтів, які додатково отримували плацебо. Пацієнти з генералізованим атеросклерозом мали ураження чотирьох судинних басейнів: церебрального, коронарного, мезентеріального та ниж- ніх кінцівок. Виявлено, що у хворих на генералізований атеросклероз рівень серотоніну в плазмі крові перевищував показник групи порівняння в 7,8 рази, а ряд інших показників, таких як: показники об’ємного кровотоку (р&lt;0,001), когнітивної функції, дистанції безбольової ходьби, були нижче групи порівняння. Під впливом лікування, з додаванням цилостазолу протягом 12 тижнів до базисної терапії, стан показників покращився: рівень серотоніну в плазмі зменшив- ся в 2,9 рази (р&lt;0,001), достовірно (р&lt;0,001) збільшився об’ємний кровотік в усіх досліджуваних судинних басейнах, що сприяло зменшенню кількості як больових, так і безбольових епізодів ішемії міокарда (за даними добового електрокардіографічного моніторування), збільшенню безбольової та максимальної дистанції ходьби та поліпшенню когнітивної функції головного мозку. У групі пацієнтів з генералізованим атеросклерозом, які приймали плацебо, під впли- вом лікування зміни були не достовірні. Отримані нами дані вказують на позитивний вплив цилостазолу як доповнення до базисної терапії у хворих на генералізований атеросклероз та важливість проведення подальших досліджень у даному напрямку.

Cilostazol restores autophagy flux in bafilomycin A1-treated, cultured cortical astrocytes through lysosomal reacidification: roles of PKA, zinc and metallothionein 3

Cilostazol, a phosphodiesterase 3 inhibitor, reduces the amyloid-beta (Aβ) burden in mouse models of Alzheimer disease by as yet unidentified mechanisms. In the present study, we examined the possibility that cilostazol ameliorates lysosomal dysfunction. Astrocytes treated with bafilomycin A1 (BafA1) exhibited markedly reduced DND-189 and acridine orange (AO) fluorescence, indicating reduced lysosomal acidity. In both cases, BafA1-induced alkalization was reversed by addition of cilostazol, dibutyryl cAMP or forskolin. All three agents significantly increased free zinc levels in lysosomes, and addition of the zinc chelator TPEN abrogated lysosomal reacidification. These treatments did not raise free zinc levels or reverse BafA1-mediated lysosomal alkalization in metallothionein 3 (Mt3)-null astrocytes, indicating that the increases in zinc in astrocytes were derived mainly from Mt3. Lastly, in FITC-Aβ-treated astrocytes, cilostazol reversed lysosomal alkalization, increased cathepsin D activity, and reduced Aβ accumulation in astrocytes. Cilostazol also reduced mHtt aggregate formation in GFP-mHttQ74–expressing astrocytes. Collectively, our results present the novel finding that cAMP/PKA can overcome the v-ATPase blocking effect of BafA1 in a zinc- and Mt3-dependent manner.

Abstract WP115: Cilostazol Addition to Aspirin Does Not Alter the Short-Term Neurological Outcome in Each Clinical Subtype of Acute Stroke

Hypothesis: Our previous study, ADS reported that dual antiplatelet therapy (DAPT) using cilostazol and aspirin did not reduce the rate of short-term neurological worsening in non-cardioembolic stroke patients. The aim of the present study is to investigate 1) whether the impact of cilostazol addition to aspirin differ among each stroke subtype, and 2) factors associated with neurological deterioration and/or stroke recurrence in order to find therapeutic target. Methods: This is a retrospective analysis using the ADS databank. Neurological worsening and the rates of stroke recurrence within 14 day of onset were evaluated. Stroke subtype included large-artery atherosclerosis (LAA), lacunae infarct (LI), branch atheromatous disease (BAD), other, and undetermined. Results: Data on 1,160 patients (773 [67%] men; median age, 69 [61-77] years, NIHSS score was 2 [1-4]) were analyzed. At discharge, 167 (14%) were diagnoses as having LAA; LI, 532 (46%); BAD, 173 (15%); other, 132 (11%); and undetermined, 156 (14%). Neurological deterioration and/or recurrence were seen in 130 (11%) patients, and the rates were not different between patients treated with DAPT and aspirin in any stroke subtypes: LAA, 19% (DAPT) vs. 11% (aspirin alone), (p=0.185); LI, 4% vs. 3% (p=0.645); BAD, 33% vs.34%, (p=0.872), other, 8% vs.14% (p=0.272); undetermined, 13% vs. 8% (p=0.301). When we evaluated factors related to the deterioration/recurrence, age (p&lt;0.001), NIHSS score (p&lt;0.001), systolic and diastolic blood pressures (p&lt;0.001, and 0.025), whiter matter change (p=0.002), large infarcts &gt;1.5cm (p&lt;0.001), and intracranial stenosis/occlusion (p&lt;0.001) were found. Multivariate regression analysis revealed older age (p=0.003), systolic blood pressure (p=0.013), larger infarct (p=0.001), intracranial stenosis/occlusion (p&lt;0.035) were the independent factors associated with neurological deterioration/stroke recurrence. Conclusions: Dual antiplatelet therapy using cilostazol and aspirin does not reduce the rate of short-term neurological worsening in each clinical stroke subtype. Improvement of hyperacute therapy targeting the elder patients with elevated blood pressure, large infarct and intracranial stenosis/occlusion should be required.