Divergence Between Clinical Trial Evidence and Actual Practice in Use of Dual Antiplatelet Therapy After Transient Ischemic Attack and Minor Stroke.

BACKGROUND: Randomized controlled trials (RCTs) proved that short-term (21-90 days) dual antiplatelet therapy (DAPT) reduces the risk of early ischemic recurrences after a noncardioembolic minor stroke or high-risk transient ischemic attack (TIA) without substantially increasing the hemorrhagic risk. We aimed at understanding whether and how real-world use of DAPT differs from RCTs. METHODS: READAPT (Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or TIA) is a prospective cohort study including >18-year-old patients treated with DAPT after a noncardioembolic minor ischemic stroke or high-risk TIA from 51 Italian centers. The study comprises a 90-day follow-up from symptom onset. In the present work, we reported descriptive statistics of baseline data of patients recruited up to July 31, 2022, and proportions of patients who would have been excluded from RCTs. We compared categorical data through the χ² test. RESULTS: We evaluated 1070 patients, who had 72 (interquartile range, 62-79) years median age, were mostly Caucasian (1045; 97.7%), and were men (711; 66.4%). Among the 726 (67.9%) patients with ischemic stroke, 226 (31.1%) did not meet the RCT inclusion criteria because of National Institutes of Health Stroke Scale score >3 and 50 (6.9%) because of National Institutes of Health Stroke Scale score >5. Among the 344 (32.1%) patients with TIA, 69 (19.7%) did not meet the RCT criteria because of age, blood pressure, clinical features, duration of TIA, presence of diabetes score <4 and 252 (74.7%) because of age, blood pressure, clinical features, duration of TIA, presence of diabetes score <6 and no symptomatic arterial stenosis. Additionally, 144 (13.5%) patients would have been excluded because of revascularization procedures. Three hundred forty-five patients (32.2%) did not follow the RCT procedures because of late (>24 hours) DAPT initiation; 776 (72.5%) and 676 (63.2%) patients did not take loading doses of aspirin and clopidogrel, respectively. Overall, 84 (7.8%) patients met the RCT inclusion/exclusion criteria. CONCLUSIONS: The real-world use of DAPT is broader than RCTs. Most patients did not meet the RCT criteria because of the severity of ischemic stroke, lower risk of TIA, late DAPT start, or lack of antiplatelet loading dose. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT05476081.

Clinical RoPE (cRoPE) score predicts patent foramen ovale detection among stroke patients: a multicenter observational study.

BACKGROUD: The role of patent foramen ovale (PFO) in cryptogenic stroke (CS) is debated. Tools to predict PFO occurrence and attributable fraction are needed to guide cost-effective diagnostics and treatment. Risk of Paradoxical Embolism (RoPE) score relies on neuroimaging findings, which might be inconclusive in up to 30% of cases. METHODS: We developed a clinical-based easy tool to predict the presence and attributable fraction of PFO in CS patients, without using neuroimaging. The clinical RoPE (cRoPE) score, ranging 1-10, was elaborated through Delphi method from the original RoPE score, replacing cortical infarction with the Oxfordshire Community Stroke Project (OCSP) classification (lacunar stroke = 0 points, other subtypes = 1 point). Then, from the SISIFO (Studio Italiano di prevalenza nello Stroke Ischemico di pervietà del Forame Ovale, or Prevalence of Patent Foramen Ovale in Ischemic Stroke in Italy) study, a multicenter, prospective study on consecutive acute ischemic stroke patients (n = 1130) classified by Trial of Org 10172 in Acute Stroke Treatment (TOAST) and OCSP criteria and undergoing PFO testing, we selected the VV-CDC cohort (Vibo Valentia, Città di Castello, n = 323) to test the accuracy of cRoPE in predicting PFO detection. We compared cRoPE with RoPE to verify cRoPE reliability. Finally, we tested, through ROC analysis, the performance of cRoPE depending on TOAST classification. RESULTS: Overall, PFO was detected in 21% in VV-CDC and in 23.4% in remaining SISIFO cohort (n = 807). cRoPEAUC and RoPEAUC were similar in VV-CDC. cRoPE performance was comparable with RoPE among CS (cRoPEAUC 0.76, 95%CI 0.67-0.85, RoPEAUC 0.75, 95%CI 0.66-0.84). Moving to the remaining SISIFO cohort, cRoPE confirmed satisfactory accuracy in predicting PFO detection in CS patients (cRoPEAUC 0.71, 95%CI 0.66-0.78, p = 0.032). CONCLUSIONS: Conclusions: cRoPE might help in stratification of patients with CS, allowing accurate esteem of the likelihood of PFO to be found, especially in cases when neuroimaging is inconclusive.

Defining short-term outcomes of minor ischemic stroke due to small artery occlusion in the era of dual antiplatelet treatment: A READAPT study sub-analysis.

BACKGROUND: The outcomes of minor ischemic stroke resulting from small artery occlusion (SAO-MIS) have not yet been characterized after dual antiplatelet treatment (DAPT) has become the standard of care. We provided updated figures on the short-term prognosis of SAO-MIS treated with early short-term DAPT and compared the outcomes of SAO-MIS versus non-SAO-MIS patients. METHODS: This is a prespecified sub-analysis from a prospective multicentric real-world study (READAPT, NCT05476081) including patients with minor (NIHSS≤5) non-cardioembolic ischemic stroke treated with DAPT. The primary outcome was a composite of 90-day symptomatic ischemic stroke or major cardiovascular events. Secondary outcomes were the 90-day ordinal distribution of modified Rankin Scale (mRS) scores, 90-day excellent functional outcome (mRS of 0 to 1), and 24-h early neurological deterioration (END). Safety outcomes were 90-day intracerebral hemorrhage, moderate-to-severe and any bleedings. All outcomes were compared between SAO-MIS and non-SAO-MIS patients. RESULTS: We included 678 MIS, of whom 253 (37.3 %) were SAO-related. At 90 days, 3 patients with SAO-MIS had primary outcome (1.2 % [95 % CI 0.2 %-3.5 %]), which were all SAO-related ischemic strokes. For the secondary outcomes, most SAO-MIS patients (n = 191, 75.5 %) had 90-day excellent functional outcome and 12 had 24-h END (4.7 % [95 % CI 2.5 %-8.3 %]). Referring to safety outcomes, 90-day intracerebral hemorrhage occurred only in one patient with SAO-MIS (0.4 % [95 % CI 0.0 %- 2.2 %]). Compared to non-SAO-MIS, the 90-day risk of recurrent vascular events was significantly lower among SAO-MIS (aHR 0.24 [95 % CI 0.08-0.68]; p = 0.007), while there were not significant differences in other secondary outcomes, nor in the risk of safety events. CONCLUSIONS: Our findings show overall favorable short-term prognosis after SAO-MIS treated with DAPT. Future studies should investigate factors associated with residual stroke risk and long-term outcomes of SAO-MIS.

Beyond RCTs: Short-term dual antiplatelet therapy in secondary prevention of ischemic stroke and transient ischemic attack.

BACKGROUND AND PURPOSE: Randomized controlled trials (RCTs) proved the efficacy of short-term dual antiplatelet therapy (DAPT) in secondary prevention of minor ischemic stroke or high-risk transient ischemic attack (TIA). We aimed at evaluating effectiveness and safety of short-term DAPT in real-world, where treatment use is broader than in RCTs. METHODS: READAPT (REAl-life study on short-term Dual Antiplatelet treatment in Patients with ischemic stroke or Transient ischemic attack) (NCT05476081) was an observational multicenter real-world study with a 90-day follow-up. We included patients aged 18+ receiving short-term DAPT soon after ischemic stroke or TIA. No stringent NIHSS and ABCD2 score cut-offs were applied but adherence to guidelines was recommended. Primary effectiveness outcome was stroke (ischemic or hemorrhagic) or death due to vascular causes, primary safety outcome was moderate-to-severe bleeding. Secondary outcomes were the type of ischemic and hemorrhagic events, disability, cause of death, and compliance to treatment. RESULTS: We included 1920 patients; 69.9% started DAPT after an ischemic stroke; only 8.9% strictly followed entry criteria or procedures of RCTs. Primary effectiveness outcome occurred in 3.9% and primary safety outcome in 0.6% of cases. In total, 3.3% cerebrovascular ischemic recurrences occurred, 0.2% intracerebral hemorrhages, and 2.7% bleedings; 0.2% of patients died due to vascular causes. Patients with NIHSS score ⩽5 and those without acute lesions at neuroimaging had significantly higher primary effectiveness outcomes than their counterparts. Additionally, DAPT start >24 h after symptom onset was associated with a lower likelihood of bleeding. CONCLUSIONS: In real-world, most of the patients who receive DAPT after an ischemic stroke or a TIA do not follow RCTs entry criteria and procedures. Nevertheless, short-term DAPT remains effective and safe in this population. No safety concerns are raised in patients with low-risk TIA, more severe stroke, and delayed treatment start.

Combining Intravenous Thrombolysis and Dual Antiplatelet Treatment in Patients With Minor Ischemic Stroke: A Propensity Matched Analysis of the READAPT Study Cohort.

BACKGROUND: The optimal treatment for acute minor ischemic stroke is still undefined. and options include dual antiplatelet treatment (DAPT), intravenous thrombolysis (IVT), or their combination. We aimed to investigate benefits and risks of combining IVT and DAPT versus DAPT alone in patients with MIS. METHODS AND RESULTS: This is a prespecified propensity score-matched analysis from a prospective multicentric real-world study (READAPT [Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or Transient Ischemic Attack]). We included patients with MIS (National Institutes of Health Stroke Scale score at admission ≤5), without prestroke disability (modified Rankin scale [mRS] score ≤2). The primary outcomes were 90-day mRS score of 0 to 2 and ordinal mRS distribution. The secondary outcomes included 90-day risk of stroke and other vascular events and 24-hour early neurological improvement or deterioration (≥2-point National Institutes of Health Stroke Scale score decrease or increase from the baseline, respectively). From 1373 patients with MIS, 240 patients treated with IVT plus DAPT were matched with 427 patients treated with DAPT alone. At 90 days, IVT plus DAPT versus DAPT alone showed similar frequency of mRS 0 to 2 (risk difference, 2.3% [95% CI -2.0% to 6.7%]; P=0.295; risk ratio, 1.03 [95% CI 0.98-1.08]; P=0.312) but more favorable ordinal mRS scores distribution (odds ratio, 0.57 [95% CI 0.41-0.79]; P<0.001). Compared with patients treated with DAPT alone, those combining IVT and DAPT had higher 24-hour early neurological improvement (risk difference, 20.9% [95% CI 13.1%-28.6%]; risk ratio, 1.59 [95% CI 1.34-1.89]; both P<0.001) and lower 90-day risk of stroke and other vascular events (hazard ratio, 0.27 [95% CI 0.08-0.90]; P=0.034). There were no differences in safety outcomes. CONCLUSIONS: According to findings from this observational study, patients with MIS may benefit in terms of better functional outcome and lower risk of recurrent events from combining IVT and DAPT versus DAPT alone without safety concerns. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05476081.

European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke.

Intravenous thrombolysis is the only approved systemic reperfusion treatment for patients with acute ischaemic stroke. These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist physicians in their clinical decisions with regard to intravenous thrombolysis for acute ischaemic stroke. These guidelines were developed based on the ESO standard operating procedure and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and wrote recommendations. Expert consensus statements were provided if not enough evidence was available to provide recommendations based on the GRADE approach. We found high quality evidence to recommend intravenous thrombolysis with alteplase to improve functional outcome in patients with acute ischemic stroke within 4.5 h after symptom onset. We also found high quality evidence to recommend intravenous thrombolysis with alteplase in patients with acute ischaemic stroke on awakening from sleep, who were last seen well more than 4.5 h earlier, who have MRI DWI-FLAIR mismatch, and for whom mechanical thrombectomy is not planned. These guidelines provide further recommendations regarding patient subgroups, late time windows, imaging selection strategies, relative and absolute contraindications to alteplase, and tenecteplase. Intravenous thrombolysis remains a cornerstone of acute stroke management. Appropriate patient selection and timely treatment are crucial. Further randomized controlled clinical trials are needed to inform clinical decision-making with regard to tenecteplase and the use of intravenous thrombolysis before mechanical thrombectomy in patients with large vessel occlusion.

Performance of aß1-40, aß1-42, total tau, and phosphorylated tau as predictors of dementia in a cohort of patients with mild cognitive impairment.

Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimer's disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid-ß 1-42 (Aß1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Aß1-40, Aß1-42, t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without dementia (OND) followed up for four years. Aß1-42 levels were significantly lower in AD and MCI-AD than in MCI-MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Aß1-42/Aß1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aß1-42/t-tau and Aß1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aß1-42/p-tau ratio was the best parameter for discriminating MCI-AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination annual change rate score (MMSE-ACR, rS = -0.71, p < 0.0001). Survival analysis showed that 81% of MCI with a low Aß1-42/p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Aß1-42 and p-tau (sensitivity 75%, 95%CI: 70-80%; specificity 96%, 95%CI: 94-98%). We can conclude that Aß1-42 and p-tau reliably predict conversion to AD in MCI patients.

Cerebrospinal fluid biomarkers in Parkinson's disease with dementia and dementia with Lewy bodies.

BACKGROUND: Clinical criteria for differentiating Parkinson's disease (PD) with dementia (PDD) from dementia with Lewy bodies (DLB) are unsatisfactory. Their existence as distinct clinicopathologic entities is still debated, although the burden of Alzheimer's disease (AD) pathology seems higher in DLB. Thus, analysis of cerebrospinal fluid (CSF) biomarkers (beta-amyloid(1-42) [Abeta42], total tau, and hyperphosphorylated tau [p-tau]) in living subjects might provide significant pathophysiological information on these diseases. METHODS: Cerebrospinal fluid biomarkers were measured in DLB (n = 19), PDD (n = 18), and AD (n = 23) subjects matched for age, sex, and dementia severity, as well as in PD (n = 20) and normal control subjects (n = 20). RESULTS: DLB showed the lowest mean CSF Abeta42 levels, with a negative association to dementia duration (rho = -.42, p = .07). In DLB patients, mean CSF total tau levels were significantly lower than in AD patients (508 +/- 387 vs. 960 +/- 619, respectively) but twofold to threefold higher than in PDD (286 +/- 184), PD (160 +/- 64), or normal control subjects (177 +/- 76), with a positive association to dementia severity (Mini-Mental State Examination: rho = -.54, p = .02; Milan Overall Dementia Assessment: rho = -.66, p = .002). PDD patients had mean CSF Abeta42 and total tau levels similar to those seen in PD patients. Hyperphosphorylated tau was significantly increased in the AD group only. CONCLUSIONS: Cerebrospinal fluid Abeta42 and total tau have a different behavior in DLB and PDD, being related to duration and severity of dementia in DLB alone. Hyperphosphorylated tau is not significantly altered in these conditions.