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.

Association Between Adherence to a 3-Month Cardiac Rehabilitation Program and Long-Term Clinical Outcomes in Japanese Patients With Cardiac Implantable Electronic Devices.

PURPOSE: The objective of this study was to evaluate the association between comprehensive cardiac rehabilitation (CCR) completion and long-term clinical outcomes in patients with cardiac implantable electronic devices (CIED). METHODS: This retrospective cohort study included 834 patients with CIED who participated in CCR, which included a cardiopulmonary exercise test or 6-min walk test. Patients with a left ventricular ejection fraction ≤40%, predicted peak oxygen uptake ≤80%, or B-type natriuretic peptide level ≥80 pg/mL were eligible. The primary outcome was all-cause mortality. RESULTS: After excluding 241 patients with duplicate records and 69 who underwent CCR in the outpatient department, the data of 524 patients were analyzed. Mean age was 64 ± 15 yr, 389 (74%) patients were men, left ventricular ejection fraction was 31 ± 15%, and 282 (54%) patients had a history of hospitalization for worsening heart failure. Of the patients referred for CCR, 294 (56%) completed the program, and an additional 230 patients started but did not complete CCR. Over a 3.7-yr median follow-up period, all-cause mortality occurred in 156 (30%) patients. Completers had lower all-cause mortality rates than non-completers (log-rank 15.77, P < .001). After adjusting for prognostic baseline characteristics, completers had 58% lower all-cause mortality risks than non-completers (HR = 0.42; 95% CI, 0.27-0.64, P < .001). CONCLUSIONS: Three-mo CCR program completion was associated with lower mortality risks in patients with CIED. New programs or management methods are needed to decrease mortality risks, especially for those who cannot complete CCR programs.

Efficacy and Safety of Edoxaban in Anticoagulant Therapy Early After Surgical Bioprosthetic Valve Replacement: Rationale and Design of the ENBALV Trial.

BACKGROUND AND PURPOSE: Anticoagulant therapy with vitamin K antagonists is recommended within 3 to 6 months after bioprosthetic valve replacement to prevent thromboembolic events. However, data regarding whether direct oral anticoagulants can be an alternative to warfarin in such patients are limited. The purpose of this study is to compare the efficacy and safety of edoxaban versus warfarin within 3 months after bioprosthetic valve replacement. METHODS: The ENBALV trial is an investigator-initiated, phase 3, randomized, open-label, multicenter study. It involves patients aged 18 to 85 years undergoing bioprosthetic valve replacement at the aortic and/or mitral position. They are randomized 1:1 to receive either edoxaban or warfarin. Administration of edoxaban or warfarin is to be continued for 12 weeks after surgery. The primary outcome is the occurrence rate of stroke or systemic embolism at 12 weeks after surgery. The net clinical outcome is a composite of stroke, systemic embolism, or major bleeding, which is included in the secondary outcomes. CONCLUSION: The ENBALV trial demonstrates the efficacy and safety of edoxaban compared with warfarin in patients early after bioprosthetic valve replacement, including patients with sinus rhythm, which will bring a significant benefit to patients in clinical practice. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) 2051210209. 30 Mar 2022 https://jrct.niph.go.jp/latest-detail/jRCT2051210209 .

REsveratrol for VAscular cognitive impairment investigating cerebral Metabolism and Perfusion (REVAMP trial): a study protocol for a randomized, double-blind, placebo-controlled trial.

Background: Carotid artery stenosis or occlusion (CASO) is a major cause of vascular cognitive impairment (VCI). There is currently no effective treatment for VCI induced by CASO. Resveratrol, a type of polyphenol, improves cognitive performance in rat CASO models via pleiotropic effects. Furthermore, we previously reported the longevity gene, SIRT1, which can be activated by resveratrol, improves cognitive and cerebral blood flow impairment in mouse CASO models by activating endothelial nitric oxide synthase. However, clinical evidence remains limited. Methods: The REsveratrol for VAscular cognitive impairment investigating cerebral Metabolism and Perfusion (REVAMP) trial is a randomized, double-blind, placebo-controlled trial involving patients with asymptomatic CASO. Each participant will receive either 150 mg/day of resveratrol or a placebo for 35 weeks. The primary objective is to determine whether resveratrol improves cognitive impairment, as assessed using the Alzheimer's disease Assessment Scale-cognitive subscale 13. One of our secondary objectives is to determine whether resveratrol improves cerebral hemodynamic impairment as assessed via 15O-gas positron emission tomography. We will recruit 100 patients (50 per group). Discussion: The REVAMP trial may provide valuable insights into new therapeutic options, as multitarget neuroprotection could potentially improve cognitive function along with enhancements in cerebral hemodynamic status in patients with asymptomatic CASO.Clinical trial registration: The REVAMP trial was prospectively registered in the Japan Registry of Clinical Trials (jRCTs051230013) on April 13, 2023.

A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit. Objective: The AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL. Sample size: Overall, 60 patients will be recruited. Methods: The AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180. Study outcomes: The primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t-test will be used for analysis. Conclusion: The AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition. Clinical Trial Registration: jRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117).

Effect of Eicosapentaenoic Acid/Docosahexaenoic Acid on Coronary High-Intensity Plaques Detected Using Noncontrast T1-weighted Imaging: The AQUAMARINE EPA/DHA Randomized Study.

AIM: Omega-3 fatty acids have emerged as a new option for controlling the residual risk for coronary artery disease (CAD) in the statin era. Eicosapentaenoic acid (EPA) is associated with reduced CAD risk in the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention trial, whereas the Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia trial that used the combination EPA/docosahexaenoic acid (DHA) has failed to derive any clinical benefit. These contradictory results raise important questions about whether investigating the antiatherosclerotic effect of omega-3 fatty acids could help to understand their significance for CAD-risk reduction. METHODS: The Attempts at Plaque Vulnerability Quantification with Magnetic Resonance Imaging Using Noncontrast T1-weighted Technic EPA/DHA study is a single-center, triple-arm, randomized, controlled, open-label trial used to investigate the effect of EPA/DHA on high-risk coronary plaques after 12 months of treatment, detected using cardiac magnetic resonance (CMR) in patients with CAD receiving statin therapy. Eligible patients were randomly assigned to no-treatment, 2-g/day, and 4-g/day EPA/DHA groups. The primary endpoint was the change in the plaque-to-myocardium signal intensity ratio (PMR) of coronary high-intensity plaques detected by CMR. Coronary plaque assessment using computed tomography angiography (CTA) was also investigated. RESULTS: Overall, 84 patients (mean age: 68.2 years, male: 85%) who achieved low-density lipoprotein cholesterol levels of ＜100 mg/dL were enrolled. The PMR was reduced in each group over 12 months. There were no significant differences in PMR changes among the three groups in the primary analysis or analysis including total lesions. The changes in CTA parameters, including indexes for detecting high-risk features, also did not differ. CONCLUSION: The EPA/DHA therapy of 2 or 4 g/day did not significantly improve the high-risk features of coronary atherosclerotic plaques evaluated using CMR under statin therapy.

Recurrent pulmonary hypertension after balloon pulmonary angioplasty for inoperable chronic thromboembolic pulmonary hypertension.

BACKGROUND: Balloon pulmonary angioplasty improves the hemodynamics of patients with inoperable chronic thromboembolic pulmonary hypertension; however, the clinical impact of recurrent pulmonary hypertension after balloon pulmonary angioplasty remains unclear. METHODS: We retrospectively reviewed 262 consecutive patients with chronic thromboembolic pulmonary hypertension who underwent balloon pulmonary angioplasty between July 2009 and December 2020; 158 (65 ± 12 years; males, 20%; median follow-up period, 45 [26, 66] months) with follow-up right heart catheterization and no residual pulmonary hypertension were included. Recurrent pulmonary hypertension was defined as mean pulmonary arterial pressure <25 mm Hg at the first evaluation after balloon pulmonary angioplasty and ≥25 mm Hg at follow-up evaluation requiring additional treatment with balloon pulmonary angioplasty or pulmonary vasodilators. RESULTS: Recurrent pulmonary hypertension was observed in 11 patients; the state occupation probability of recurrence at 5 years was 9.0% (95% confidence interval: 5.0%-18.9%). Only 1 case (0.6%) of recurrent pulmonary hypertension showed vascular restenosis and reocclusion of previously treated lesions, with more significant hemodynamic and exercise capacity deterioration than the other cases. Additional treatments for recurrent pulmonary hypertension (balloon pulmonary angioplasty in 9 patients, pulmonary vasodilators in 4 patients) improved the mean pulmonary arterial pressure from 27 [26, 29] to 22 [19, 23] mm Hg (p < 0.01). Recurrence had a low probability of transitioning to death in an illness-death model. No specific risk factors for recurrent pulmonary hypertension were identified. CONCLUSIONS: Symptomatic recurrent pulmonary hypertension due to vascular restenosis or reocclusion after balloon pulmonary angioplasty was extremely rare. Most cases of recurrent pulmonary hypertension were mild, did not worsen clinically, and had favorable prognoses.

Effect of cyborg-type robot Hybrid Assistive Limb on patients with severe walking disability in acute stroke: A randomized controlled study.

OBJECTIVES: To investigate whether early gait training using Hybrid Assistive Limb (HAL) is feasible and improves walking and independency compared with conventional physical therapy (CPT) in patients with severe walking disability after stroke. METHODS: We conducted a single-center, randomized controlled study. Patients with first-ever stroke who had severe walking disability were included. All patients started gait training within 10 days post-stroke onset. Twenty-four patients were randomly assigned into HAL or CPT groups. Outcome measures were collected at three time points, at baseline, completion of 20 sessions of gait training (second assessment), and 3 months after the initiation of gait training. The primary outcomes were changes in motor sub-scores of the Functional Independence Measure or Functional Ambulation Category at the completion of the second assessment from baseline. RESULTS: Twenty-two patients (median age, 68 years; 12 patients in the HAL group and 10 patients in the CPT group) completed the study. There were no significant differences in primary outcomes. Apathy scale, one of the secondary outcomes, showed a decreasing trend in the HAL group (mean change of -3.8, 95% CI -8.14 to 0.475), and a slight increasing trend in the CPT group (mean change of 1.2, 95% CI -2.66 to 5.06) at the second assessment. Patients in the HAL group experienced no adverse events. CONCLUSIONS: Early gait training in patients with severe walking disability after stroke using HAL was feasible. Walking ability and independency were not improved at the completion of 20 sessions of gait training.

Area under the curve-optimized synthesis of prediction models from a meta-analytical perspective.

The number of clinical prediction models sharing the same prediction task has increased in the medical literature. However, evidence synthesis methodologies that use the results of these prediction models have not been sufficiently studied, particularly in the context of meta-analysis settings where only summary statistics are available. In particular, we consider the following situation: we want to predict an outcome Y, that is not included in our current data, while the covariate data are fully available. In addition, the summary statistics from prior studies, which share the same prediction task (i.e., the prediction of Y), are available. This study introduces a new method for synthesizing the summary results of binary prediction models reported in the prior studies using a linear predictor under a distributional assumption between the current and prior studies. The method provides an integrated predictor combining all predictors reported in the prior studies with weights. The vector of the weights is designed to achieve the hypothetical improvement of area under the receiver operating characteristic curve (AUC) on the current available data under a practical situation where there are different sets of covariates in the prior studies. We observe a counterintuitive aspect in typical situations where a part of weight components in the proposed method becomes negative. It implies that flipping the sign of the prediction results reported in each individual study would improve the overall prediction performance. Finally, numerical and real-world data analysis were conducted and showed that our method outperformed conventional methods in terms of AUC.

Dual antiplatelet therapy with cilostazol in stroke patients with extracranial arterial stenosis or without arterial stenosis: A subgroup analysis of the CSPS.com trial.

BACKGROUND: We previously reported that dual antiplatelet therapy (DAPT) with cilostazol was superior to aspirin or clopidogrel for the prevention of recurrent stroke and vascular events in a subgroup analysis of intracranial arterial stenosis in the Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com), a randomized controlled trial. AIMS: We conducted another subgroup analysis to investigate the benefit of DAPT with cilostazol in patients with extracranial arterial stenosis (ECAS) and those without arterial stenosis. METHODS: We compared the risk of recurrent ischemic stroke, vascular events, and major bleeding between DAPT with cilostazol plus aspirin or clopidogrel and aspirin or clopidogrel alone in patients with ischemic stroke between 8 and 180 days before starting trial treatment and ECAS or without arterial stenosis. RESULTS: The median follow-up period was 1.4 years. The risk of recurrent ischemic stroke (hazard ratio (HR): 1.04, 95% confidence interval (CI): 0.42-2.57) and vascular events (HR: 0.97, 95% CI: 0.42-2.24) did not differ between the two groups for the 253 patients with ECAS, whereas they were lower (HR: 0.36, 95% CI: 0.18-0.74 and HR: 0.47, 95% CI: 0.26-0.85, respectively) in the DAPT group for the 944 patients without arterial stenosis. The risk of major bleeding did not differ between the groups in patients with ECAS (HR: 0.58, 95% CI: 0.05-6.39) or without arterial stenosis (HR: 0.79, 95% CI: 0.27-2.26). CONCLUSION: DAPT with cilostazol might be beneficial for prevention of recurrent stroke and vascular events in patients without arterial stenosis but not in those with ECAS. DATA ACCESS STATEMENT: We will make the deidentified participant data from this research available to the scientific community with as few restrictions as feasible, while retaining exclusive use until the publication of major output.

Sex Difference in the Impact of Dual Antiplatelet Therapy using Cilostazol for Secondary Stroke Prevention: A Sub-Analysis of CSPS.com.

AIM: Although some sex differences in stroke have been reported, differences in the effects of antiplatelet therapy for secondary stroke prevention have not been clarified. METHODS: In the Cilostazol Stroke Prevention Study combination trial, patients with high-risk, non-cardioembolic ischemic stroke between 8 and 180 days after onset treated with aspirin or clopidogrel alone were recruited and randomly assigned to receive either monotherapy or dual antiplatelet therapy (DAPT) using cilostazol and followed up for 0.5-3.5 years. The primary efficacy outcome was recurrence of ischemic stroke. The safety outcome was severe or life-threatening hemorrhage. Outcomes were analyzed by sex. RESULTS: A total of 1,320 male patients and 558 female patients were included. The male patients had more risk factors than the female patients. In male patients, the primary endpoint occurred at a rate of 2.0 per 100 patient-years in the DAPT group and 5.1 per 100 patient-years in the monotherapy group (hazard ratio (HR), 0.40; 95% confidence interval (CI), 0.23-0.68). In male patients, DAPT prolonged the time to recurrent stroke by 4.02-fold (95% CI, 1.63-9.96) compared with monotherapy. In female patients, the average annual event rates were 2.7 per 100 patient-years in the DAPT group and 3.3 per 100 patient-years in the monotherapy group (HR, 0.82; 95% CI, 0.37-1.84). Safety outcomes did not differ significantly in both male and female patients. CONCLUSIONS: Long-term DAPT using cilostazol reduced the recurrence of ischemic stroke and prolonged the recurrence-free time in male patients, but not in female patients.

DAPagliflozin for the attenuation of albuminuria in Patients with hEaRt failure and type 2 diabetes (DAPPER study): a multicentre, randomised, open-label, parallel-group, standard treatment-controlled trial.

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the urinary albumin-to-creatinine ratio (UACR) in patients with elevated levels of albuminuria in the presence or absence of heart failure (HF) or type 2 diabetes mellitus (T2D). However, these effects have not yet been reported in the presence of both HF and T2D. This lack of evidence prompted us to conduct a clinical trial on the effects of dapagliflozin on UACR in patients with HF and T2D. Methods: DAPPER is a multicentre, randomised, open-labeled, parallel-group, standard treatment-controlled trial that enrolled patients at 18 medical facilities in Japan. Eligible participants with both HF and T2D and aged between 20 and 85 years were randomly assigned to a dapagliflozin or control (anti-diabetic drugs other than SGLT 2 inhibitors) group with a 1:1 allocation. The primary outcome was changes in UACR from baseline after a two-year observation, and secondary endpoints were cardiovascular (CV) events and parameters related to HF. This trial was registered with the UMIN-CTR registry, UMIN000025102 and the Japan Registry of Clinical Trials, jRCTs051180135. Findings: Between 12 May 2017 and 31 March 2020, 294 patients were randomly assigned to the dapagliflozin group (n = 146) or control group (n = 148). The mean age of patients was 72.1 years and 29% were female. The mean glycated hemoglobin value was 6.9%, mean NT-proBNP was 429.1 pg/mL, mean estimated GFR was 65.7 mL/min/1.73 m2, and median UACR was 25.0 (8.8-74.6) mg/g Cr in the dapagliflozin group and 25.6 (8.2-95.0) mg/g Cr in the control group. Of the 146 patients in the dapagliflozin group, 122 completed the study, and 107 (87.7%) were taking 5 mg of dapagliflozin daily at the end of the observation period. The primary outcome did not significantly differ between the dapagliflozin and control groups. Among the secondary endpoints, the mean decrease in left ventricular end-diastolic dimensions as one of the echocardiographic parameters was larger in the dapagliflozin group than in the control group. The composite endpoint, defined as CV death or hospitalisation for CV events, hospitalisation for HF events, hospitalisation for all causes, and an additional change in prescriptions for heart failure in a two-year observation, was less frequent in the dapagliflozin group than in the control group. Interpretation: Although dapagliflozin at a dose of 5 mg daily did not reduce urinary albumin excretion in patients with HF and T2D from that in the controls, our findings suggest that dapagliflozin decreased CV events and suppressed left ventricular remodeling. Funding: AstraZeneca KK, Ono Pharmaceutical Co., Ltd.

Tenecteplase versus alteplase for large vessel occlusion recanalization (T-FLAVOR): Trial protocol.

Background: Tenecteplase has higher fibrin specificity with a longer half-life and the potential to achieve higher rates of recanalization than alteplase. A critical limitation of tenecteplase is no commercial use in Japan and no experience with its administration to Japanese patients. Hypothesis: Tenecteplase is superior to alteplase in achieving recanalization on the initial angiogram when administered ≤4.5-hour of stroke onset in patients planned for mechanical thrombectomy (MT) in Japan where alteplase at the unique dose of 0.6mg/kg is officially used. Methods: The Tenecteplase versus alteplase For LArge Vessel Occlusion Recanalization (T-FLAVOR) trial is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, masked-endpoint, superiority study. Eligibility criteria include acute ischemic stroke with pre-stroke modified Rankin Scale score ≤3 and large vessel occlusion (internal carotid artery, middle cerebral artery, or basilar artery) eligible for intravenous thrombolysis ≤4.5-hour and MT ≤6-hour of stroke onset. After completing the safety confirmation phase involving three patients who received non-masked tenecteplase (0.25 mg/kg), 220 patients will be randomized to two groups (1:1), intravenous alteplase (0.6mg/kg, n = 110) or tenecteplase (0.25mg/kg, n = 110), prior to MT. Outcomes: In the safety confirmation phase, the primary outcome is symptomatic intracranial hemorrhage (sICH) ≤24-36-hour. In the randomized, comparative phase, the primary efficacy outcome is substantial angiographic reperfusion (mTICI grade 2b/2c/3) or absence of retrievable thrombus on the initial angiogram. The primary safety outcome is sICH ≤24-36-hour and 90-day mortality. Discussion: T-FLAVOR may help determine if tenecteplase should be recommended as a routine clinical strategy before MT for Japanese stroke patients. Trial registration: jRCTs051210055.

Association of Timing for Starting Dual Antiplatelet Treatment With Cilostazol and Recurrent Stroke: A CSPS.com Trial Post Hoc Analysis.

BACKGROUND AND OBJECTIVES: Long-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. METHODS: In 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. RESULTS: Of 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). DISCUSSION: Long-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 INFORMATION: ClinicalTrials.gov NCT01995370; UMIN Clinical Trials Registry 000012180. CLASSIFICATION OF EVIDENCE: This 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.

Efficacy of vonoprazan against bleeding from endoscopic submucosal dissection-induced gastric ulcers under antithrombotic medication: A cross-design synthesis of randomized and observational studies.

Vonoprazan, a potassium-competitive acid blocker, is expected to be superior to proton pump inhibitors (PPIs) in preventing post-endoscopic submucosal dissection (ESD)-induced gastric bleeding. However, the results of randomized controlled trials (RCTs) and observational studies on the efficacy of vonoprazan have been inconsistent. This study aimed to evaluate the effectiveness of vonoprazan in antithrombotic drug users, a population that has been excluded from RCTs. Treatment effects were assessed using cross-design synthesis, which can be adjusted for differences in study design and patient characteristics. We used data from an RCT in Japan (70 patients in the vonoprazan group and 69 in the PPI group) and an observational study (408 patients in the vonoprazan group and 870 in the PPI group). After matching, among the antithrombotic drug users in the observational study, post-ESD bleeding was noted in 8 out of 86 patients in the vonoprazan group and 18 out of 86 patients in the PPI group. After pooling the data from the RCT and observational study, the risk difference for antithrombotic drug users was -14.6% (95% CI: -22.0 to -7.2). CDS analysis suggested that vonoprazan is more effective than PPIs in preventing post-ESD bleeding among patients administered antithrombotic medications.

Dual Antiplatelet Therapy Using Cilostazol in Patients With Stroke and Intracranial Arterial Stenosis.

Background Long-term benefit of dual antiplatelet therapy (DAPT) over single antiplatelet therapy (SAPT) for the prevention of recurrent stroke has not been established in patients with intracranial arterial stenosis. We compared the efficacy and safety of DAPT with cilostazol and clopidogrel or aspirin to those of SAPT with clopidogrel or aspirin in patients with intracranial arterial stenosis, who were recruited to the Cilostazol Stroke Prevention Study for Antiplatelet Combination trial, a randomized controlled trial in high-risk Japanese patients with ischemic stroke. Methods and Results We compared the vascular and hemorrhagic events between DAPT and SAPT in patients with ischemic stroke and symptomatic or asymptomatic intracranial arterial stenosis of at least 50% in a major intracranial artery. Patients were placed in two groups: 275 were assigned to receive DAPT and 272 patients SAPT. The risks of ischemic stroke (hazard ratio [HR], 0.47; 95% CI, 0.23-0.95); and composite of stroke, myocardial infarction, and vascular death (HR, 0.48; 95% CI, 0.26-0.91) were lower in DAPT than SAPT, whereas the risk of severe or life-threatening bleeding (HR, 0.72; 95% CI, 0.12-4.30) did not differ between the 2 treatment groups. Conclusions DAPT using cilostazol was superior to SAPT with clopidogrel or aspirin for the prevention of recurrent stroke and vascular events without increasing bleeding risk among patients with intracranial arterial stenosis after stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01995370.

Dual Antiplatelet Therapy Using Cilostazol With Aspirin or Clopidogrel: Subanalysis of the CSPS.com Trial.

Background and Purpose: Although dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the recurrence of ischemic stroke while significantly increasing the bleeding events compared with monotherapy, the CSPS.com trial (Cilostazol Stroke Prevention Study combination) showed that DAPT using cilostazol was more effective without the bleeding risk. In the CSPS.com trial, aspirin or clopidogrel was used as the underlying antiplatelet drug. The effectiveness and safety of each combination were examined and clarified. Methods: In the CSPS.com trial, a multicenter, open-label, randomized controlled study, patients with high-risk, noncardioembolic ischemic stroke 8 to 180 days after onset treated with aspirin or clopidogrel alone at the discretion of the physician in charge were recruited. Patients were randomly assigned to receive either monotherapy or DAPT using cilostazol and followed for 0.5 to 3.5 years. The primary efficacy outcome was first recurrence of ischemic stroke. The safety outcome was severe or life-threatening bleeding. The analysis was based on the underlying antiplatelet agents. Results: A total of 763 patients taking aspirin and 1116 taking clopidogrel were included in the intention-to-treat analysis. Although the clopidogrel group had more risk factors than the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the 2 groups. In the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the DAPT group and the aspirin-monotherapy group. In the clopidogrel group, the primary end point occurred at a rate of 2.31 per 100 patient-years in the DAPT group and 5.19 per 100 patient-years in the clopidogrel-monotherapy group (hazard ratio, 0.447 [95% CI, 0.258­0.774]). Safety outcome did not differ significantly between groups (0.51 per 100 patient-years versus 0.71 per 100 patient-years, respectively; hazard ratio, 0.730 [95% CI, 0.206­2.588]). Conclusions: The combination of cilostazol and clopidogrel significantly reduced the recurrence of ischemic stroke without increasing the bleeding risk in noncardioembolic, high-risk patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012180.

Impact of Renal Impairment on Intensive Blood-Pressure-Lowering Therapy and Outcomes in Intracerebral Hemorrhage: Results From ATACH-2.

BACKGROUND AND OBJECTIVE: The clinical effect of renal impairment on intracerebral hemorrhage (ICH) is unknown. This study sought to assess whether estimated glomerular filtration rate (eGFR) affects clinical outcomes or modifies the efficacy of intensive systolic blood pressure (BP) control (target, 110-139 mm Hg) against the standard (target, 140-179 mm Hg) among patients with ICH. METHODS: We conducted post hoc analyses of ATACH-2, a randomized, 2-group, open-label trial. The baseline eGFR of each eligible patient was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. The outcome of interest was death or disability at 90 days. Multivariate logistic regression models were used for analysis. RESULTS: Among the 1,000 patients randomized, 974 were analyzed. The median baseline eGFR was 88 (interquartile range, 68, 99) mL/min/1.73 m2; 451 (46.3%), 363 (37.3%), and 160 (16.4%) patients had baseline eGFR values of ≥90, 60-89, and <60 mL/min/1.73 m2, respectively. Compared with normal eGFR (≥90 mL/min/1.73 m2), higher odds of death or disability were noted among those with eGFR values of <60 mL/min/1.73 m2 (adjusted odds ratio [OR], 2.02; 95% confidence interval [CI], 1.25-3.26) but not among those with eGFR values of 60-89 mL/min/1.73 m2 (OR, 1.01; 95% CI, 0.70-1.46). The odds of death or disability were significantly higher in the intensive arm among patients with decreased eGFR; the ORs were 0.89 (95% CI, 0.55-1.44), 1.13 (0.68-1.89), and 3.60 (1.47-8.80) in patients with eGFR values of ≥90, 60-89, and <60 mL/min/1.73 m2, respectively (p for interaction = 0.02). DISCUSSION: Decreased eGFR is associated with unfavorable outcomes following ICH. The statistically significant interaction between the eGFR group and treatment assignment raised safety concerns for the intensive BP-lowering therapy among patients with renal impairment. TRIAL REGISTRATION INFORMATION: Clinicaltrials.gov identifier: NCT01176565. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in spontaneous ICH, decreased eGFR identifies patients at risk of death or disability following intensive BP control.

Study Protocol for a Randomized, Double-Blind, Placebo-Controlled, Phase-II Trial: AdrenoMedullin for Ischemic Stroke Study.

OBJECTIVES: Adrenomedullin (AM), a vasoactive peptide, has strong anti-inflammatory and angiogenic properties, which have been reported to ameliorate the consequences of ischemic stroke in several animal models. After a phase I study in healthy volunteers, two phase II trials of AM for inflammatory bowel diseases have been recently completed. The current AdrenoMedullin For Ischemic Stroke (AMFIS) study aims to assess the safety and efficacy of AM in patients with acute ischemic stroke. MATERIALS AND METHODS: The AMFIS study is an investigator-initiated, randomized, double-blind, phase-II trial. AM or placebo will be administered to patients with non-cardioembolic ischemic stroke within 24 h after stroke onset. In the first cohort of the AMFIS study, patients will be randomly allocated to the investigation treatment A (30 µg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10). In the second cohort, patients will be assigned to the investigation treatment B (56 µg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10). RESULTS: Serious adverse events related to the protocol treatment will be evaluated as the primary outcome. All adverse events will be analyzed as the secondary outcome. Regarding efficacy endpoints, the change in National Institutes of Health Stroke Scale and modified Rankin Scale scores will be compared between investigation treatment and placebo groups. CONCLUSIONS: AM is expected to be a safe and effective treatment for ischemic stroke.