Publications

Background Since its approval, the use of alteplase had been limited to patients aged ≤80 years. Aims TESPI trial had been designed to evaluate whether alteplase treatment within 3 h in patients with acute ischemic stroke aged >80 years resulted in favorable benefit/risk ratio compared with standard care. The meta-analysis of randomized controlled trials was updated to put findings in the context of all available evidence. Methods TESPI was a multicenter, open-label with blinded outcome evaluation, randomized, controlled trial. Main clinical endpoints were 90-day favorable functional outcome (mRS score 0–2) and mortality and symptomatic intracerebral hemorrhage. The trial was prematurely terminated for ethical reasons after publication of IST-3 trial which provided evidence of treatment benefit in elderly. Results Of the planned 600 patients, 191 (88 assigned to alteplase) were enrolled. Overall, 24/83 (28.9%) alteplase patients had a favorable outcome compared to 22/95 (23.2%) controls (non-significant absolute difference of 5.7% for alteplase; OR 1.35, 95% CI 0.69–2.64, P = 0.381). Rates of death were non-significantly lower in the alteplase patients (18.1% vs. 26.5%); rates of symptomatic intracerebral hemorrhage were similar between the two groups (5.9% vs. 5.1%). The updated meta-analysis showed consistent results with prior estimates and add weights. Conclusions The effects of alteplase observed in this interrupted trial did not reach statistical significance, probably for the small numbers, but are consistent with and add weight to the sum total of the randomized evidence demonstrating that alteplase is beneficial in patients with acute ischemic stroke aged over 80 years, particularly if given within 3 h.

Introduction: Ischaemic stroke patients with atrial fibrillation (AF) are at high risk of stroke recurrence despite oral anticoagulation therapy. Patients with cardiovascular comorbidities may take both antiplatelet and oral anticoagulation therapy (OAC/AP). Our study aims to evaluate the safety and efficacy of OAC/AP therapy as secondary prevention in people with AF and ischaemic stroke. Patients and methods: We performed a post-hoc analysis of pooled individual data from multicenter prospective cohort studies and compared outcomes in the OAC/AP cohort and patients on DOAC/VKA anticoagulation alone (OAC cohort). Primary outcome was a composite of ischaemic stroke, systemic embolism, intracranial bleeding, and major extracranial bleeding, while secondary outcomes were ischaemic and haemorrhagic events considered separately. A multivariable logistic regression analysis was performed to identify independent predictors for outcome events. To compare the risk of outcome events between the two cohorts, the relation between the survival function and the set of explanatory variables were calculated by Cox proportional hazard models and the results were reported as adjusted hazard ratios (HR). Finally another analysis was performed to compare the overall risk of outcome events in both OAC/AP and OAC cohorts after propensity score matching (PSM). Results: During a mean follow-up time of 7.5 ± 9.1 months (median follow-up time 3.5 months, interquartile range ±3), 2284 stroke patients were on oral anticoagulants and 215 were on combined therapy. The multivariable model demonstrated that the composite outcome is associated with age (OR: 1.03, 95% CI: 1.01–1.04 for each year increase) and concomitant antiplatelet therapy (OR: 2.2, 95% CI: 1.48–3.27), the ischaemic outcome with congestive heart failure (OR: 1.55, 95% CI: 1.02–2.36) and concomitant antiplatelet therapy (OR: 1.93, 95% CI: 1.19–3.13) and the haemorrhagic outcome with age (OR: 1.03, 95% CI: 1.01–1.06 for each year increase), alcoholism (OR: 2.15, 95% CI: 1.06–4.39) and concomitant antiplatelet therapy (OR: 2.22, 95% CI: 1.23–4.02). Cox regression demonstrated a higher rate of the composite outcome (hazard ratio of 1.93 [95% CI, 1.35–2.76]), ischaemic events (HR: 2.05 [95% CI: 1.45–2.87]) and bleeding outcomes (HR: 1.90 [95% CI, 1.06–3.40]) in OAC/AP cohort. After PSM analysis, the composite outcome remained more frequent in people treated with OAC + AP (RR: 1.70 [95% CI, 1.05–2.74]). Discussion: Secondary prevention with combination of oral anticoagulant and antiplatelet therapy after ischaemic stroke was associated with worse outcomes in our cohort. Conclusion: Further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischaemic stroke in patients with atrial fibrillation.

Abstract Introduction The APULEIO study was designed to describe the psychological effects of apixaban in Italian elderly patients with non-valvular atrial fibrillation (NVAF), deep vein thrombosis (DVT) or pulmonary embolism (PE). The existence of implications of treatment on health-related quality of life (HRQL) and mood is among the most important knowledge gaps in cardiovascular care of older subjects. Real-world data on these issues, essential to improve therapy adherence, are lacking. Aim of the present analysis was to evaluate the presence of a different response to oral anticoagulation in the disabled, frail and robust subjects enrolled in the study. Methods APULEIO was a multicenter, prospective, observational study including apixaban eligible patients. The 12-Item Short Form Health Survey (SF-12), the Beck Depression Inventory-II (BDI-II) and the Frail non-Disabled (FiND) questionnaire were used to evaluate, respectively, HRQL, depressive symptoms and the presence of disability and frailty. The findings of the baseline and the 6-month evaluation - end of the study - will be presented. Results Overall, 376 patients had complete data. Of these, 163 (43.4%), 111 (29.5%) and 102 (27.1%) subjects were, respectively, defined disabled, frail and robust. No differences for reason to anticoagulate were observed by FiND category (p=0.797; overall, AF: 77.1%; DVT/PE: 22.9%). Patients with disability were older (Disabled – D: 79±11; Frail - F: 72±12; Robust – R: 72±12 years; p<0.0001), more frequently women (D: 66.9; F: 43.2; R: 24.5%; p<0.0001), with a greater clinical complexity, as expressed by the CHA2DS2-VASc score (D: 4.3±1.5; F: 3.2±1.5; R: 2.9±1.6; p<0.0001), and showed a higher heart rate (D: 82±17; F: 77±14; R: 77±15 bpm; p=0.0414). BMI (overall, 27.5±4.7 Kg/m2; p=0.328), left ventricular ejection fraction (overall, 53±10%; p=0.453), and systolic (overall, 129±15 mmHg; p=0.219) and diastolic (overall, 76±10 mmHg; p=0.285) arterial pressure were similar among groups. The incidence of any adverse event was higher in those with disability (D: 14.1; F: 8.1; R: 3.9%; p=0.0190), but the proportion of those with serious adverse events was similar among categories (overall, 6.9%; p=0.105). When studying HRQL, at enrollment, the Physical Health composite score of the SF-12 was significantly different among groups (D: 32.7±7.9; F: 42.4±9.3; R: 45.6±8.0; p<0.0001). At the 6-month evaluation (D: 37.0±10.1; F: 43.9±8.8; R: 47.2±7.3; p<0.0001), only the improvement for disabled subjects was significant (p=0.0020). At Baseline, the Mental Health composite score of the SF-12 was lower in disabled and frail patients, when compared to robust ones (D: 46.8±9.8; F: 47.7±9.2; R: 51.4±8.6; p<0.0001). After 6 months, once again, only the improvement for disabled subjects (D: 37.0±10.1; F: 43.9±8.8; R: 47.2±7.3; p=0.0004) was significant (p<0.0001) and statistically greater than that observed for frail and robust patients. Regarding depressive symptoms, at enrollment, the BDI-II score was worse in the disabled and frail groups (D: 14.7±9.8; F: 9.0±8.1; R: 4.7±4.5; p<0.0001). At the 6-month assessment, it was possible to observe an improvement (D: 10.5±8.5; F: 6.8±7.8; R: 4.2±4.5; p<0.0001) in disabled (p<0.0001) and frail subjects (p=0.0112), but not in robust ones (p=0.1705). Conclusions The APULEIO study demonstrates that disability and frailty are common conditions in older subjects anticoagulated for AF and DVT/PE. Disabled patients present a higher clinical complexity than frail and robust ones. After 6 months of therapy, the use of apixaban is associated with a significant improvement of HRQL in disabled individuals and of depressive symptoms in disabled and frail ones. No changes were found in robust subjects. No differences by group were observed in the incidence of serious adverse events. These findings confirm the efficacy and safety of apixaban also when applying a multidimensional approach to high-risk geriatric populations.

To assess whether smoking cessation after an ischemic stroke or TIA improves outcomes compared to continued smoking. We conducted a prospective observational cohort study of 3,876 nondiabetic men and women enrolled in the Insulin Resistance Intervention After Stroke (IRIS) trial who were randomized to pioglitazone or placebo within 180 days of a qualifying stroke or TIA and followed up for a median of 4.8 years. A tobacco use history was obtained at baseline and updated during annual interviews. The primary outcome, which was not prespecified in the IRIS protocol, was recurrent stroke, myocardial infarction (MI), or death. Cox regression models were used to assess the differences in stroke, MI, and death after 4.8 years, with correction for adjustment variables prespecified in the IRIS trial: age, sex, stroke (vs TIA) as index event, history of stroke, history of hypertension, history of coronary artery disease, and systolic and diastolic blood pressures. At the time of their index event, 1,072 (28%) patients were current smokers. By the time of randomization, 450 (42%) patients had quit smoking. Among quitters, the 5-year risk of stroke, MI, or death was 15.7% compared to 22.6% for patients who continued to smoke (adjusted hazard ratio 0.66, 95% confidence interval 0.48-0.90). Cessation of cigarette smoking after an ischemic stroke or TIA was associated with significant health benefits over 4.8 years in the IRIS trial cohort.