Alexandros Polymeris

Early start of DOAC after ischemic stroke: Risk of intracranial hemorrhage and recurrent events

Objective: In patients with recent acute ischemic stroke (AIS) and atrial fibrillation, we assessed the starting time of direct, non–vitamin K antagonist oral anticoagulants (DOACs) for secondary prevention, the rate of intracranial hemorrhage (ICH), and recurrent ischemic events during follow-up. Methods: We included consecutive patients with nonvalvular atrial fibrillation admitted to our hospital for AIS or TIA (index event) who received secondary prophylaxis with DOAC or vitamin K antagonists (VKAs). Follow-up was at least 3 months. In the primary analysis, we compared rates of ICH and recurrent ischemic events (AIS or TIA) between patients with early (≤7 days since event; DOACearly) and those with late (>7 days, DOAClate) start of DOAC. Results: Two hundred four patients were included (median age 79 years, 89% AIS) and total follow-up time was 78.25 patient-years. One hundred fifty-five patients received DOAC with a median delay of 5 days after the index event (interquartile range 3–11) and 49 received VKA. DOAC was started early in 100 patients (65%). We observed one ICH (1.3%/y) and 6 recurrent AIS (7.7%/y). The ICH occurred in a patient taking VKA. No significant difference in the rate of recurrent AIS between DOACearly (5.1%/y) and DOAClate (9.3%/y, p = 0.53) was observed. Conclusions: Even if DOACs are often started early after an index event, the risk of ICH appears to be low. Among all patients receiving anticoagulation, the rate of recurrent events was 6 times higher than the rate of ICH.

Sex Differences and Functional Outcome After Intravenous Thrombolysis

Background and Purpose— Women have a worse outcome after stroke compared with men, although in intravenous thrombolysis (IVT)–treated patients, women seem to benefit more. Besides sex differences, age has also a possible effect on functional outcome. The interaction of sex on the functional outcome in IVT-treated patients in relation to age remains complex. The purpose of this study was to compare outcome after IVT between women and men with regard to age in a large multicenter European cohort reflecting daily clinical practice of acute stroke care. Methods— Data were obtained from IVT registries of 12 European tertiary hospitals. The primary outcome was poor functional outcome, defined as a modified Rankin scale score of 3 to 6 at 3 months. We stratified outcome by age in decades. Safety measures were symptomatic intracranial hemorrhage and mortality at 3 months. Results— In this cohort, 9495 patients were treated with IVT, and 4170 (43.9%) were women with a mean age of 71.9 years. After adjustments for baseline differences, female sex remained associated with poor functional outcome (odds ratio, 1.15; 95% confidence interval, 1.02–1.31). There was no association between sex and functional outcome when data were stratified by age. Symptomatic intracranial hemorrhage rate was similar in both sexes (adjusted odds ratio, 0.93; 95% confidence interval, 0.73–1.19), whereas mortality was lower among women (adjusted odds ratio, 0.83; 95% confidence interval, 0.70–0.99). Conclusions— In this large cohort of IVT-treated patients, women more often had poor functional outcome compared with men. This difference was not dependent on age.

Intravenous Thrombolysis in Patients with Stroke Taking Rivaroxaban Using Drug Specific Plasma Levels: Experience with a Standard Operation Procedure in Clinical Practice

Background and Purpose Standard operating procedures (SOP) incorporating plasma levels of rivaroxaban might be helpful in selecting patients with acute ischemic stroke taking rivaroxaban suitable for IVthrombolysis (IVT) or endovascular treatment (EVT). Methods This was a single-center explorative analysis using data from the Novel-Oral-Anticoagulants-in-Stroke-Patients-registry (clinicaltrials.gov:NCT02353585) including acute stroke patients taking rivaroxaban (September 2012 to November 2016). The SOP included recommendation, consideration, and avoidance of IVT if rivaroxaban plasma levels were <20 ng/mL, 20‒100 ng/mL, and >100 ng/mL, respectively, measured with a calibrated anti-factor Xa assay. Patients with intracranial artery occlusion were recommended IVT+EVT or EVT alone if plasma levels were ≤100 ng/mL or >100 ng/mL, respectively. We evaluated the frequency of IVT/EVT, door-to-needle-time (DNT), and symptomatic intracranial or major extracranial hemorrhage. Results Among 114 acute stroke patients taking rivaroxaban, 68 were otherwise eligible for IVT/EVT of whom 63 had plasma levels measured (median age 81 years, median baseline National Institutes of Health Stroke Scale 6). Median rivaroxaban plasma level was 96 ng/mL (inter quartile range [IQR] 18‒259 ng/mL) and time since last intake 11 hours (IQR 4.5‒18.5 hours). Twenty-two patients (35%) received IVT/EVT (IVT n=15, IVT+EVT n=3, EVT n=4) based on SOP. Median DNT was 37 (IQR 30‒60) minutes. None of the 31 patients with plasma levels >100 ng/mL received IVT. Among 14 patients with plasma levels ≤100 ng/mL, the main reason to withhold IVT was minor stroke (n=10). No symptomatic intracranial or major extracranial bleeding occurred after treatment. Conclusions Determination of rivaroxaban plasma levels enabled IVT or EVT in one-third of patients taking rivaroxaban who would otherwise be ineligible for acute treatment. The absence of major bleeding in our pilot series justifies future studies of this approach.

Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage.

Information about rivaroxaban plasma level (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban.

Impact of body mass index on outcome in stroke patients treated with intravenous thrombolysis.

The impact of body mass index (BMI) on outcome in stroke patients treated with intravenous thrombolysis (IVT) was investigated.

Intracerebral Hemorrhage and Outcome After Thrombolysis in Stroke Patients Using Selective Serotonin-Reuptake Inhibitors

Background and Purpose— Selective serotonin-reuptake inhibitors (SSRIs) impair platelet function and have been linked to a higher risk of spontaneous intracerebral hemorrhage—an association that may be augmented by oral anticoagulants (OAC). We aimed to assess whether preadmission treatment with SSRIs in patients with acute ischemic stroke is associated with post-thrombolysis symptomatic intracerebral hemorrhage (sICH) and functional outcome. Methods— A multicenter retrospective analysis was conducted in prospective registries of patients treated by thrombolysis within 4.5 hours of stroke onset. The association between preadmission treatment with SSRIs and sICH (ECASS II definition [European Cooperative Acute Stroke Study]) or unfavorable 3-month outcome (modified Rankin Scale >2) was assessed by logistic regression, taking into account potential interaction with concomitant use of antithrombotics. Results— Six thousand two hundred forty-two patients were included (mean age, 70.1±14.0 years; median National Institutes of Health Stroke Scale, 9 [5–16]). Preadmission treatment with SSRIs was present in 4.3% (n=266) of patients. Overall, SICH rate was 3.9% (95% confidence interval [CI], 3.5%–4.4%; n=244), and SSRI use was not significantly associated with sICH in unadjusted (odds ratio [OR], 1.28; 95% CI, 0.72–2.27) or adjusted (OR, 1.30; 95% CI, 0.71–2.40) analysis. However, there was a significant interaction of concomitant use of OACs (international normalized ratio <1.7) and SSRI for occurrence of sICH (P=0.01). SICH was significantly more frequent in patients taking both OAC and SSRI (23.1%; 95% CI, 8.2%–50.3%) than in patients taking OAC but not SSRI (adjusted OR, 9.04; 95% CI, 1.95–41.89). Preadmission use of SSRI was associated with unfavorable 3-month outcome (unadjusted OR, 1.90; 95% CI, 1.48–2.46; adjusted OR, 1.59; 95% CI, 1.15–2.19). Conclusions— Preadmission treatment with SSRIs was not significantly associated with an increased risk of post-thrombolysis sICH in this cohort study. However, subgroup analysis suggested an increased risk of sICH in patients taking both SSRI and OAC. Preadmission treatment with SSRIs was associated with unfavorable outcome, which may reflect the prognostic significance of prestroke depression.

Intravenous thrombolysis and platelet count

Objective To study the effect of platelet count (PC) on bleeding risk and outcome in stroke patients treated with IV thrombolysis (IVT) and to explore whether withholding IVT in PC < 100 × 109/L is supported. Methods In this prospective multicenter, IVT register–based study, we compared PC with symptomatic intracranial hemorrhage (sICH; Second European-Australasian Acute Stroke Study [ECASS II] criteria), poor outcome (modified Rankin Scale score 3–6), and mortality at 3 months. PC was used as a continuous and categorical variable distinguishing thrombocytopenia (<150 × 109/L), thrombocytosis (>450 × 109/L), and normal PC (150–450 × 109/L [reference group]). Moreover, PC < 100 × 109/L was compared to PC ≥ 100 × 109/L. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) from the logistic regression models were calculated. Results Among 7,533 IVT-treated stroke patients, 6,830 (90.7%) had normal PC, 595 (7.9%) had thrombocytopenia, and 108 (1.4%) had thrombocytosis. Decreasing PC (every 10 × 109/L) was associated with increasing risk of sICH (ORadjusted 1.03, 95% CI 1.02–1.05) but decreasing risk of poor outcome (ORadjusted 0.99, 95% CI 0.98–0.99) and mortality (ORadjusted 0.98, 95% CI 0.98–0.99). The risk of sICH was higher in patients with thrombocytopenic than in patients with normal PC (ORadjusted 1.73, 95% CI 1.24–2.43). However, the risk of poor outcome (ORadjusted 0.89, 95% CI 0.39–1.97) and mortality (ORadjusted 1.09, 95% CI 0.83–1.44) did not differ significantly. Thrombocytosis was associated with mortality (ORadjusted 2.02, 95% CI 1.21–3.37). Forty-four (0.3%) patients had PC < 100 × 109/L. Their risks of sICH (ORunadjusted 1.56, 95% CI 0.48–5.07), poor outcome (ORadjusted 1.63, 95% CI 0.82–3.24), and mortality (ORadjusted 1.38, 95% CI 0.64–2.98) did not differ significantly from those of patients with PC ≥ 100 × 109/L. Conclusion Lower PC was associated with increased risk of sICH, while higher PC indicated increased mortality. Our data suggest that PC modifies outcome and complications in individual patients, while withholding IVT in all patients with PC < 100 × 109/L is challenged.

A Score for Risk of Thrombolysis-Associated Hemorrhage Including Pretreatment with Statins

Background Symptomatic intracranial hemorrhage (sICH) after intravenous thrombolysis with recombinant tissue-plasminogen activator (rt-PA) for acute ischemic stroke is associated with a poor functional outcome. We aimed to develop a score assessing risk of sICH including novel putative predictors—namely, pretreatment with statins and severe renal impairment. Methods We analyzed our local cohort (Berlin) of patients receiving rt-PA for acute ischemic stroke between 2006 and 2016. Outcome was sICH according to ECASS-III criteria. A multiple regression model identified variables associated with sICH and receiver operating characteristics were calculated for the best discriminatory model for sICH. The model was validated in an independent thrombolysis cohort (Basel). Results sICH occurred in 53 (4.0%) of 1,336 patients in the derivation cohort. Age, baseline National Institutes of Health Stroke Scale, systolic blood pressure on admission, blood glucose on admission, and prior medication with medium- or high-dose statins were associated with sICH and included into the risk of intracranial hemorrhage score. The validation cohort included 983 patients of whom 33 (3.4%) had a sICH. c-Statistics for sICH was 0.72 (95% CI 0.66–0.79) in the derivation cohort and 0.69 (95% CI 0.60–0.77) in the independent validation cohort. Inclusion of severe renal impairment did not improve the score. Conclusion We developed a simple score with fair discriminating capability to predict rt-PA-related sICH by adding prior statin use to known prognostic factors of sICH. This score may help clinicians to identify patients with higher risk of sICH requiring intensive monitoring.

Frequency and Determinants of Adherence to Oral Anticoagulants in Stroke Patients with Atrial Fibrillation in Clinical Practice

Background: Vitamin K antagonists (VKAs) and non-VKA oral anticoagulants (NOACs) are beneficial in patients with stroke and atrial fibrillation (AF). However, little is known about frequency and determinants of adherence to NOACs/VKAs in clinical practice. Methods: This is a single-center explorative study from the Novel Oral Anticoagulants in Stroke Patients (NOACISP)-LONGTERM registry. We included consecutive AF-stroke patients treated with NOACs/VKAs and followed up for 3-24 months. Adherence was assessed at follow-up using structured interviews and quantified as the proportion of prescribed doses taken (PDT). Outcome measures were (i) full adherence, (ii) ≥95% adherence and (iii) ≥80% adherence (i.e., PDT 100/≥95/≥80%). To explore determinants of full adherence, we compared characteristics of fully and non-fully adherent patients. Results: A total of 218 of 251 (86.9%) patients (48% female, mean age 77.9 ± 9.1 years, 78% NOACs; 22% VKAs) were eligible for analysis with a median follow-up of 12 months: fully adherent were 78.4% patients (NOACs 77.1%, VKAs 83.3%, p = 0.35), ≥95% adherent were 95.4% and ≥80% adherent were 97.2%. Fully adherent patients took more pills daily (median (interquartile range) 7 (5-10) vs. 6 (4-8), p = 0.039), had more often previous antithrombotic treatment (70.8 vs. 53.2%, p = 0.023), caregiver-assisted medication administration (54.2 vs. 19.1%, p < 0.001) and functional dependency (32.8 vs. 15%, p = 0.011) than non-fully adherent patients. Conclusions: Full adherence was frequent. Patients naïve to antithrombotics, taking few pills, which they self-administer, were at the highest risk of non-adherence and may benefit most from adherence-enhancing interventions.

Management of patients with stroke treated with direct oral anticoagulants

Since their market approval, direct oral anticoagulants (DOACs) are being increasingly used for stroke prevention in patients with atrial fibrillation. However, the management of DOAC-treated patients with stroke poses several challenges for physicians in everyday clinical practice, both in the acute setting and in long-term care. This has spurred extensive research activity in the field over the past few years, which we review here.