Patients with atrial fibrillation (AF) have a high risk for recurrent clinical events after an ischemic stroke. Direct oral anticoagulants (DOAC) are prescribed for secondary prevention. Adherence to ...DOAC is crucial mainly because of their short elimination half-life. Non-adherence to DOAC can negatively impact patients' outcomes. The relationship between (non-)adherence and recurrent clinical events is unknown in AF patients after initial stroke. We investigated adherence to DOAC in stroke survivors with AF who were included in the MAAESTRO study at the University Hospital Basel, Switzerland, between 2008 and 2022.
This study is a secondary analysis of data from MAAESTRO with a matched nested case-control design and 1:2 ratio. DOAC intake was measured with a small electronic device (Time4MedTM). We defined two arbitrary intervals of 17 days and 95 days as the longest time spans with electronic monitoring data per patient to maximize the number of participants with adequate amount of observation time available for analysis. Taking and timing adherence were calculated retrospectively i.e., prior to the recurrent event for cases. Trendline analysis of adherence over 95 days was calculated. Linear regression analysis was performed after adjusting for the co-variables age and daily pill burden. Sensitivity analysis was performed with controls for intervals in the reverse direction (prospectively).
We analyzed 11 cases and 22 matched controls (mean age: 75.9 ± 9.2 years vs. 73.1 ± 8.4 years; n.s.) with similar stroke characteristics (NIHSS, mRS, MoCA) and 36.4% women in each group. Mean adherence values were high and similar between cases and controls (95 days taking: 87.0 ± 18.9% (cases) vs. 90.8 ± 9.8% (controls), n.s.; similar values for timing adherence). Six hemorrhagic and five ischemic events had occurred. Compared to controls, a significantly higher 95 days taking adherence was observed for hemorrhagic events (96.0 ± 5.0% (cases) vs. 88.1 ± 11.5% (controls); p<0.01) and a significantly lower 95 days taking adherence was observed for ischemic events (75.7 ± 24.8% (cases) vs. 94.2 ± 6.2% (controls), p = 0.024). Values for timing adherence were similar. A non-significant downward linear trend of adherence was observed over 95 days independently of the clinical events. The sensitivity analysis showed that the direction of the interval had negligible impact on the 95 days adherence.
Because recurrent ischemic events after an AF-related stroke were associated with low adherence to DOAC <76%, adherence enhancing interventions seem crucial in anticoagulated AF-patients. However, AF-patients with high adherence might benefit from a regular re-assessment of the bleeding risk as hemorrhagic complications were associated with adherence to DOAC >96%.
ClinicalTrials.gov NCT03344146.
It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary ...prevention should be managed.
We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists VKA or direct oral anticoagulants DOAC) prior to index event (OAC
) with those without prior oral anticoagulation (OAC
). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OAC
) with those who continued the same anticoagulation as secondary prevention (OAC
). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine-Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).
We included 5,413 patients (median age = 78 years interquartile range (IQR) = 71-84 years; 5,136 96.7% had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 IQR = 2-12). The median CHA
DS
-Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) was 5 (IQR = 4-6) and was similar for OAC
(n = 1,195) and OAC
(n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2-5.3%). OAC
was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OAC
(n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OAC
(n = 585).
Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA
DS
-Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group. ANN NEUROL 2020.
Objective
We compared outcomes after treatment with direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and a recent cerebral ischemia.
...Methods
We conducted an individual patient data analysis of seven prospective cohort studies. We included patients with AF and a recent cerebral ischemia (<3 months before starting oral anticoagulation) and a minimum follow‐up of 3 months. We analyzed the association between type of anticoagulation (DOAC versus VKA) with the composite primary endpoint (recurrent ischemic stroke AIS, intracerebral hemorrhage ICH, or mortality) using mixed‐effects Cox proportional hazards regression models; we calculated adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs).
Results
We included 4,912 patients (median age, 78 years interquartile range {IQR}, 71–84; 2,331 47.5% women; median National Institute of Health Stroke Severity Scale at onset, 5 IQR, 2–12); 2,256 (45.9%) patients received VKAs and 2,656 (54.1%) DOACs. Median time from index event to starting oral anticoagulation was 5 days (IQR, 2–14) for VKAs and 5 days (IQR, 2–11) for DOACs (p = 0.53). There were 262 acute ischemic strokes (AISs; 4.4%/year), 71 intracranial hemorrrhages (ICHs; 1.2%/year), and 439 deaths (7.4%/year) during the total follow‐up of 5,970 patient‐years. Compared to VKAs, DOAC treatment was associated with reduced risks of the composite endpoint (HR, 0.82; 95% CI, 0.67–1.00; p = 0.05) and ICH (HR, 0.42; 95% CI, 0.24–0.71; p < 0.01); we found no differences for the risk of recurrent AIS (HR, 0.91; 95% CI, 0.70–1.19; p = 0.5) and mortality (HR, 0.83; 95% CI, 0.68–1.03; p = 0.09).
Interpretation
DOAC treatment commenced early after recent cerebral ischemia related to AF was associated with reduced risk of poor clinical outcomes compared to VKA, mainly attributed to lower risks of ICH. ANN NEUROL 2019;85:823–834.
Background
Direct oral anticoagulants (DOAC) effectively prevent recurrent ischaemic events in atrial fibrillation (AF) patients with recent stroke. However, excellent adherence to DOAC is mandatory ...to guarantee sufficient anticoagulation as the effect quickly subsides.
Aim
To investigate the effect of intake reminders on adherence to DOAC.
Methods
MAAESTRO was a randomised, cross-over study in DOAC-treated AF patients hospitalised for ischaemic stroke. Adherence was measured by electronic monitoring for 12 months. After an observational phase, patients were randomised to obtain an intake reminder either in the first or the second half of the subsequent 6-month interventional phase. The primary outcome was
100%-timing adherence
. Secondary outcomes were
100%-taking adherence
, and overall timing and taking adherence. We analysed adherence outcomes using McNemar’s test or mixed-effects logistic models.
Results
Between January 2018 and March 2022, 130 stroke patients were included, of whom 42 dropped out before randomisation. Analysis was performed with 84 patients (mean age: 76.5 years, 39.3% women). A
100%-timing adherence
was observed in 10 patients who were using the reminder, and in zero patients without reminder (
p
= 0.002). The reminder significantly improved adherence to DOAC, with study participants having 2.7-fold increased odds to achieve an alternative threshold of
90%-timing adherence
(OR 2.65; 95% CI 1.05–6.69;
p
= 0.039). A similar effect was observed for
90%-taking adherence
(OR 3.06; 95% CI 1.20–7.80;
p
= 0.019). Overall timing and taking adherence increased significantly when using the reminder (OR 1.70; 95% CI 1.55–1.86,
p
< 0.01; and OR 1.67; 95% CI 1.52–1.84;
p
< 0.01).
Conclusion
Intake reminders increased adherence to DOAC in patients with stroke attributable to atrial fibrillation.
Trial registration
ClinicalTrials.gov: NCT03344146.
To investigate the aetiology, subsequent preventive strategies and outcomes of stroke despite anticoagulation in patients with atrial fibrillation (AF).
We analysed consecutive patients with AF with ...an index imaging-proven ischaemic stroke despite vitamin K-antagonist (VKA) or direct oral anticoagulant (DOAC) treatment across 11 stroke centres. We classified stroke aetiology as: (i) competing stroke mechanism other than AF-related cardioembolism; (ii) insufficient anticoagulation (non-adherence or low anticoagulant activity measured with drug-specific assays); or, (iii) AF-related cardioembolism despite sufficient anticoagulation. We investigated subsequent preventive strategies with regard to the primary (composite of recurrent ischaemic stroke, intracranial haemorrhage, death) and secondary endpoint (recurrent ischaemic stroke) within 3 months after index stroke.
Among 2946 patients (median age 81 years; 48% women; 43% VKA, 57% DOAC), stroke aetiology was competing mechanism in 713 patients (24%), insufficient anticoagulation in 934 (32%) and cardioembolism despite sufficient anticoagulation in 1299 (44%). We found high rates of the primary (27% of patients; completeness 91.6%) and secondary endpoint (4.6%; completeness 88.5%). Only DOAC (vs VKA) treatment after index stroke showed lower odds for both endpoints (primary: adjusted OR (aOR) (95% CI) 0.49 (0.32 to 0.73); secondary: 0.44 (0.24 to 0.80)), but not switching between different DOAC types. Adding antiplatelets showed higher odds for both endpoints (primary: aOR (95% CI) 1.99 (1.25 to 3.15); secondary: 2.66 (1.40 to 5.04)). Only few patients (1%) received left atrial appendage occlusion as additional preventive strategy.
Stroke despite anticoagulation comprises heterogeneous aetiologies and cardioembolism despite sufficient anticoagulation is most common. While DOAC were associated with better outcomes than VKA, adding antiplatelets was linked to worse outcomes in these high-risk patients. Our findings indicate that individualised and novel preventive strategies beyond the currently available anticoagulants are needed.
ISRCTN48292829.
Correction of hyponatremia might represent an additional treatment for improving stroke patients' clinical outcomes.
Admission hyponatremia is associated with worse clinical outcome in stroke ...patients, but whether normalization of hyponatremia improves outcome is unknown. We investigated whether normalization of hyponatremia affects patients' disability, mortality, and stroke recurrence within 3 months; length of hospitalization; and discharge destination.
This was a registry-based analysis of data collected between January 2016 and December 2018. We linked data from Swiss Stroke Registry (SSR) with electronic patients' records for extracting sodium values.
We analyzed data of hospitalized patients treated at University Hospital of Basel.
Stroke patients whose data and informed consent were available.
Modified Rankin Scale (mRS) score at 3 months. The tested hypothesis was formulated after SSR data collection but before linkage with electronic patients' records.
Of 1995 patients, 144 (7.2%) had hyponatremia on admission; 102 (70.8%) reached normonatremia, and 42 (29.2%) remained hyponatremic at discharge. An increase of initial sodium was associated with better functional outcome at 3 months (odds ratio OR 0.94; 95% CI, 0.90-0.99, for a shift to higher mRS per 1 mmol/L sodium increase). Compared with normonatremic patients, patients who remained hyponatremic at discharge had a worse functional outcome at 3 months (odds ratio 2.46; 95% CI, 1.20-5.03, for a shift to higher mRS). No effect was found on mortality, recurrence, or length of hospitalization.
In hospitalized acute stroke patients, persistent hyponatremia is associated with worse functional outcome. Whether active correction of hyponatremia improves outcome remains to be determined in prospective studies.
Serum neurofilament light chain (sNfL) is increasingly used as a neuroaxonal injury biomarker in the elderly. Besides age, little is known about how other physiological factors like renal function ...and body mass index (BMI) alter its levels. Here, we investigated the association of estimated glomerular filtration rate (eGFR) and BMI with sNfL in a large sample of elderly patients with atrial fibrillation (AF).
This is a cross-sectional analysis from the Swiss-AF Cohort (NCT02105844). We measured sNfL using an ultrasensitive single-molecule array assay. We calculated eGFR using the chronic kidney disease epidemiology collaboration (CKD-EPI) creatinine (eGFR
) and creatinine-cystatin C (eGFR
) formulas, and BMI from weight and height measurements. We evaluated the role of eGFR and BMI as determinants of sNfL levels using multivariable linear regression and the adjusted R
(R
).
Among 2,277 Swiss-AF participants (mean age 73.3 years), eGFR
showed an inverse curvilinear association with sNfL after adjustment for age and cardiovascular comorbidities. BMI also showed an independent, inverse linear association with sNfL. The R
of models with age, eGFR
, and BMI alone was 0.26, 0.35, and 0.02, respectively. A model with age and eGFR
combined explained 45% of the sNfL variance. Sensitivity analyses (i) further adjusting for vascular brain lesions (
= 1,402 participants with MRI) and (ii) using eGFR
yielded consistent results.
In an elderly AF cohort, both renal function and BMI were associated with sNfL, but only renal function explained a substantial proportion of the sNfL variance. This should be taken into account when using sNfL in elderly patients or patients with cardiovascular disease.
Objective
We assessed whether hematoma expansion (HE) and favorable outcome differ according to type of intracerebral hemorrhage (ICH).
Methods
Among participants with ICH enrolled in the TICH‐2 ...(Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) trial, we assessed baseline scans for hematoma location and presence of cerebral amyloid angiopathy (CAA) using computed tomography (CT, simplified Edinburgh criteria) and magnetic resonance imaging (MRI; Boston criteria) and categorized ICH as lobar CAA, lobar non‐CAA, and nonlobar. The main outcomes were HE and favorable functional outcome. We constructed multivariate regression models and assessed treatment effects using interaction terms.
Results
A total of 2,298 out of 2,325 participants were included with available CT (98.8%; median age = 71 years, interquartile range = 60‐80 years; 1,014 female). Additional MRI was available in 219 patients (9.5%). Overall, 1,637 participants (71.2%) had nonlobar ICH; the remaining 661 participants (28.8%) had lobar ICH, of whom 202 patients had lobar CAA‐ICH (8.8%, 173 participants according to Edinburgh and 29 participants according to Boston criteria) and 459 did not (lobar non‐CAA, 20.0%). For HE, we found a significant interaction of lobar CAA ICH with time from onset to randomization (increasing risk with time, pinteraction < 0.001) and baseline ICH volume (constant risk regardless of volume, pinteraction < 0.001) but no association between type of ICH and risk of HE or favorable outcome. Tranexamic acid significantly reduced the risk of HE (adjusted odds ratio = 0.7, 95% confidence interval = 0.6–1.0, p = 0.020) without statistically significant interaction with type of ICH (pinteraction = 0.058). Tranexamic acid was not associated with favorable outcome.
Interpretation
Risk of HE in patients with lobar CAA‐ICH was not independently increased but seems to have different dynamics compared to other types of ICH. The time window for treatment of CAA‐ICH to prevent HE may be longer. ANN NEUROL 2022;92:921–930
Background
The negative impact of the COVID-19 outbreak on stroke care has been reported, but no data exist on the influence of the lockdown on medication adherence to antithrombotic treatment for ...stroke prevention. We present a comparison of electronic adherence data of stroke patients treated with direct oral anticoagulants (DOAC) prior to and during the COVID-19 lockdown in spring 2020 in Switzerland.
Methods
This is a secondary analysis using data from the ongoing MAAESTRO study, in which stroke patients with atrial fibrillation electronically monitor their adherence to DOAC treatment. Eligible patients for this analysis had at least four weeks of adherence data prior to and during the COVID-19 lockdown. Three adherence metrics (
taking adherence, timing adherence, drug holidays
) were calculated and compared descriptively.
Results
The analysis included eight patients (median age 81.5 years, IQR 74.8–84.5). Five patients had a pre-lockdown
taking adherence
over 90% (mean 96.8% ± 2.9), with no change during lockdown, high
timing adherence
in both periods and no
drug holidays
. The remaining three patients had pre-lockdown
taking
and
timing adherence
below 90%. Of those, two patients showed a moderate decline either in
taking
or
timing adherence
compared to pre-lockdown. One showed a substantial increase in
taking
and
timing adherence
during lockdown (both + 25.8%).
Conclusion
Our data suggest that a major disruption of social life (i.e., the imposed COVID-19 lockdown) is unlikely to relevantly affect the medication intake behaviour of patients with high pre-established adherence, but might have an impact in patients with previously suboptimal adherence.
Trial registration number
MAAESTRO: electronic Monitoring and improvement of Adherence to direct oral Anticoagulant treatment—a randomized crossover study of an Educational and reminder-based intervention in ischaemic STROke patients under polypharmacy, NCT03344146.
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