Polypharmacy in atrial fibrillation: A prospective analysis of mortality and ischemic stroke using the Clinical Practice Research Datalink
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SUBMITTER: Slater N
PROVIDER: S-EPMC10848617 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Background Atrial fibrillation (AF) is a major, often undetected, cardiac cause of stroke. Markers of atrial cardiopathy, including left atrial enlargement (LAE) or excessive atrial ectopy (EAE) increase the risk of AF and have shown associations with stroke. We sought to determine whether these markers improve stroke risk prediction beyond traditional vascular risk factors (eg CHA2DS2-VASc score). Methods and Results Retrospective longitudinal cohort of 32 454 consecutive community-dwelling adults aged ≥65 years referred for outpatient echocardiogram or Holter in Ontario, Canada (2010-2017). Moderate-severe LAE was defined as men >47 mm and women >43 mm, and EAE was defined as >30 APBs per hour. Cause-specific competing risks Cox proportional hazards used to estimate risk of ischemic stroke (primary), incident AF, and death (secondary). C-statistics, incremental discrimination improvement and net reclassification were used to compare CHA2DS2-VASc with LAE and EAE to CHA2DS2-VASc alone. Each 10 mm increase in left atrial diameter increased 2- and 5-year adjusted cause-specific stroke hazard almost 2-fold (LAE: 2-year hazard ratio (HR), 1.72; P=0.007; 5-year HR, 1.87; P<0.0001), while EAE showed no significant associations with stroke (2-year HR, 1.00; P=0.99; 5-year HR, 1.08, P=0.70), adjusting for incident AF. Stroke risk estimation improved significantly at 2 (C-statistics=0.68-0.75, P=0.008) and 5 years (C-statistics=0.70-0.76, P=0.003) with LAE and EAE. Conclusions LAE was independently associated with an increased risk of ischemic stroke in the absence of AF and both LAE and EAE improved stroke risk prediction. These findings have implications for stroke risk stratification, AF screening, and stroke prevention before the onset of AF.
| S-EPMC7428995 | biostudies-literature
Project description:BackgroundStroke prevention guidance for patients with atrial fibrillation (AF) uses evidence generated from randomised controlled trials (RCTs). However, applicability to patient groups excluded from trials remains unknown. Real-world patient data provide an opportunity to evaluate outcomes in a trial analogous population of direct oral anticoagulants (DOACs) users and in patients otherwise excluded from RCTs; however, there remains uncertainty on the validity of methods and suitability of the data. Successful reference trial emulation can support the generation of evidence around treatment effects in groups excluded or underrepresented in trials. We used linked United Kingdom primary care data to investigate whether we could emulate the pivotal ARISTOTLE trial (apixaban versus warfarin) and extend the analysis to investigate the impact of warfarin time in therapeutic range (TTR) on results.Methods and findingsPatients with AF in the UK Clinical Practice Research Datalink (CPRD Aurum) prescribed apixaban or warfarin from 1 January 2013 to 31 July 2019 were selected. ARISTOTLE eligibility criteria were applied to this population and matched to the RCT apixaban arm on baseline characteristics creating a trial-analogous apixaban cohort; this was propensity-score matched to warfarin users in the CPRD Aurum. ARISTOTLE outcomes were assessed using Cox proportional hazards regression stratified by prior warfarin exposure status during 2.5 years of patient follow-up and results benchmarked against the trial results before treatment effectiveness was further evaluated based on (warfarin) TTR. The dataset comprised 8,734 apixaban users and propensity-score matched 8,734 warfarin users. Results [hazard ratio (95% confidence interval)] confirmed apixaban noninferiority for stroke or systemic embolism (SE) [CPRD 0.98 (0.82,1.19) versus trial 0.79 (0.66,0.95)] and death from any cause [CPRD 1.03 (0.93,1.14) versus trial 0.89 (0.80,0.998)] but did not indicate apixaban superiority. Absolute event rates for stroke/SE were similar for apixaban in CPRD Aurum and ARISTOTLE (1.27%/year), whereas a lower event rate was observed for warfarin (CPRD Aurum 1.29%/year, ARISTOTLE 1.60%/year). Analysis by TTR suggested similar effectiveness of apixaban compared with poorly controlled warfarin (TTR < 0.75) for stroke/SE [0.91 (0.73, 1.14)], all-cause death [0.94 (0.84, 1.06)], and superiority for major bleeding [0.74 (0.63, 0.86)]. However, when compared with well-controlled warfarin (TTR ≥ 0.75), apixaban was associated with an increased hazard for all-cause death [1.20 (1.04, 1.37)], and there was no significant benefit for major bleeding [1.08 (0.90, 1.30)]. The main limitation of the study's methodology are the risk of residual confounding, channelling bias and attrition bias in the warfarin arm, and selection bias and misclassification in the analysis by TTR.ConclusionsAnalysis of noninterventional data generated results demonstrating noninferiority of apixaban versus warfarin consistent with prespecified benchmarking criteria. Unlike in ARISTOTLE, superiority of apixaban versus warfarin was not seen, possible due to the lower proportion of Asian patients and higher proportion of patients with well-controlled warfarin compared to ARISTOTLE. This methodological template can be used to investigate treatment effects of oral anticoagulants in patient groups excluded from or underrepresented in trials and provides a framework that can be adapted to investigate treatment effects for other conditions.
| S-EPMC11361421 | biostudies-literature
Project description:Background Our objective was to investigate stroke severity and subsequent rate of mortality among patients with and without atrial fibrillation (AF). Contemporary data on stroke severity and prognosis in patients with AF are lacking. Methods and Results First-time ischemic stroke patients from the Danish Stroke Registry (January 2005-December 2016) were included in an observational study. Patients with AF were matched 1:1 by sex, age, calendar year, and CHA2DS2-VASc score with patients without AF. Stroke severity was determined by the Scandinavian Stroke Scale (0-58 points). The rate of death was estimated by Kaplan-Meier plots and multivariable Cox regression. Among 86 458 identified patients with stroke, 17 205 had AF. After matching, 14 662 patients with AF and 14 662 patients without AF were included (51.8% women; median age, 79.6 years [25th-75th percentile, 71.8-86.0]). More patients with AF had very severe stroke (0-14 points) than patients without AF (13.7% versus 7.9%, P<0.01). The absolute rates of 30-day and 1-year mortality were significantly higher for patients with AF (12.1% and 28.4%, respectively) versus patients without AF (8.7% and 21.8%, respectively). This held true in adjusted models for 30-day mortality (hazard ratio [HR], 1.40 [95% CI, 1.30-1.51]). However, this association became nonsignificant when additionally adjusting for stroke severity (HR, 1.10 [95% CI, 1.00-1.23]). AF was associated with a higher rate of 1-year mortality (HR, 1.39 [95% CI, 1.32-1.46]), although it was mediated by stroke severity (HR, 1.15 [95% CI, 1.09-1.23], model including stroke severity). Conclusions In a contemporary nationwide cohort of patients with ischemic stroke, patients with AF had more severe strokes and higher mortality than patients without AF. The difference in mortality was mainly driven by stroke severity.
| S-EPMC9245802 | biostudies-literature
Project description:Background There is little evidence on how the occurrence of a bleed in individuals on vitamin K antagonists (VKAs) impacts the risk of subsequent bleeds, and thromboembolic and ischemic events. Such information would help to inform treatment decisions following bleeds. Objective To estimate the impact of bleeding events on the risk of subsequent bleeds, venous thromboembolism (VTE), stroke, and myocardial infarction (MI) among patients initiating VKA treatment for new-onset nonvalvular atrial fibrillation (NVAF). Methods We conducted an observational cohort study using a linked Clinical Practice Research Datalink-Hospital Episode Statistics dataset. Among a cohort of individuals with NVAF, the risk of clinically relevant bleeding, VTE, stroke, and MI was compared between the period prior to the first bleed and the periods following each subsequent bleed. The rate and cost of general practitioner (GP) consultations, prescriptions, and hospitalizations were also compared across these periods. Results The risk of clinically relevant bleeding events was observed to be elevated at least twofold in all periods following the first bleeding event. The risk of VTE, stroke, and MI was not found to differ according to the number of clinically relevant bleeding events. The rate and cost of GP consultations, GP prescriptions, and hospitalizations were increased in all periods relative to the period prior to the first bleed. Conclusions The doubling in the risk of bleeding following the first bleed, taken alongside the stable risk of MI, VTE, and stroke, suggests that the risk-benefit balance for VKA treatment should be reconsidered following the first clinically relevant bleed.
| S-EPMC6777986 | biostudies-literature
Project description:The Clinical Practice Research Datalink (CPRD) is a widely used data resource, representative in demographic profile, with accurate death recordings but it is unclear if mortality rates within CPRD GOLD are similar to rates in the general population. Rates may additionally be affected by selection bias caused by the requirement that a cohort have a minimum lookback window, i.e. observation time prior to start of at-risk follow-up. Standardised Mortality Ratios (SMRs) were calculated incorporating published population reference rates from the Office for National Statistics (ONS), using Poisson regression with rates in CPRD GOLD contrasted to ONS rates, stratified by age, calendar year and sex. An overall SMR was estimated along with SMRs presented for cohorts with different lookback windows (1, 2, 5, 10 years). SMRs were stratified by calendar year, length of follow-up and age group. Mortality rates in a random sample of 1 million CPRD GOLD patients were slightly lower than the national population [SMR = 0.980 95% confidence interval (CI) (0.973, 0.987)]. Cohorts with observational lookback had SMRs below one [1 year of lookback; SMR = 0.905 (0.898, 0.912), 2 years; SMR = 0.881 (0.874, 0.888), 5 years; SMR = 0.849 (0.841, 0.857), 10 years; SMR = 0.837 (0.827, 0.847)]. Mortality rates in the first two years after patient entry into CPRD were higher than the general population, while SMRs dropped below one thereafter. Mortality rates in CPRD, using simple entry requirements, are similar to rates seen in the English population. The requirement of at least a single year of lookback results in lower mortality rates compared to national estimates.
| S-EPMC9352072 | biostudies-literature
Project description:Background To clarify differences in clinical significance of intracardiac thrombi in nonvalvular atrial fibrillation-associated stroke as identified by transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE). Methods and Results Using patient data on nonvalvular atrial fibrillation-associated ischemic stroke between 2011 and 2014 from 15 South Korean stroke centers (n=4841) and 18 Japanese centers (n=1192), implementation rates of TEE/TTE, and detection rates of intracardiac thrombi at each center were correlated. The primary outcome was recurrent ischemic stroke at 1 year after the onset. A total of 5648 patients (median age, 75 years; 2650 women) were analyzed. Intracardiac thrombi were detected in 75 patients (1.3%) overall. Thrombi were detected in 7.8% of patients with TEE (either TEE alone or TEE+TTE: n=679) and in 0.6% of those with TTE alone (n=3572). Thrombus detection rates varied between 0% and 14.3% among centers. As TEE implementation rates at each center increased from 0% to 56.7%, thrombus detection rates increased linearly (detection rate [%]=0.11×TEE rate [%]+1.09 [linear regression], P<0.01). TTE implementation rates (32.3%-100%) were not associated with thrombus detection rates (P=0.53). Intracardiac thrombi were associated with risk of recurrent ischemic stroke overall (adjusted hazard ratio [aHR] 2.35, 95% CI, 1.07-5.16). Thrombus-associated ischemic stroke risk was high in patients with TEE (aHR, 3.13; 95% CI, 1.17-8.35), but not in those with TTE alone (aHR, 0.89; 95% CI, 0.12-6.51). Conclusions Our data suggest clinical relevance of TEE for accurate detection and risk stratification of intracardiac thrombi in nonvalvular atrial fibrillation-associated stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01581502.
| S-EPMC8751927 | biostudies-literature
Project description:Patients with atrial fibrillation (AF) experiencing ischemic stroke despite oral anticoagulation (OAC), i.e., breakthrough strokes, are not uncommon, and represent an important clinical subgroup in view of the consistently high risk of stroke recurrence and mortality. The understanding of the heterogenous potential mechanism underlying OAC failure is essential in order to implement specific therapeutic measures aimed at reducing the risk of recurrent ischemic stroke. However, due to the incomplete comprehension of this phenomenon and the limited available data, secondary stroke prevention in such high-risk patients represents a clinical dilemma. There are several available strategies to prevent ischemic stroke recurrence in AF patients with breakthrough stroke in the absence of competing causes unrelated to AF, and these include continuation or change in the type of OAC, addition of antiplatelet therapy, left atrial appendage closure, or any combination of the above options. However, due to the limited available data, the latest guidelines do not provide any specific recommendations about which of the above strategies may be preferred. This review describes the incidence, the clinical impact and the potential mechanisms underlying OAC failure in AF patients. Furthermore, the evidence supporting each of the above therapeutic options for secondary stroke prevention and the potential future directions will be discussed.
| S-EPMC10532406 | biostudies-literature
Project description:Background and purposeAtrial fibrillation (AF) is a leading cause of cardioembolic stroke, but the relationship between AF and noncardioembolic stroke subtypes are unclear. Because AF may be unrecognized, and because AF has a substantial genetic basis, we assessed for predisposition to AF across ischemic stroke subtypes.MethodsWe examined associations between AF genetic risk and Trial of Org 10172 in Acute Stroke Treatment stroke subtypes in 2374 ambulatory individuals with ischemic stroke and 5175 without from the Wellcome Trust Case-Control Consortium 2 using logistic regression. We calculated AF genetic risk scores using single-nucleotide polymorphisms associated with AF in a previous independent analysis across a range of preselected significance thresholds.ResultsThere were 460 (19.4%) individuals with cardioembolic stroke, 498 (21.0%) with large vessel, 474 (20.0%) with small vessel, and 814 (32.3%) individuals with strokes of undetermined cause. Most AF genetic risk scores were associated with stroke, with the strongest association (P=6×10-4) attributed to scores of 944 single-nucleotide polymorphisms (each associated with AF at P<1×10-3 in a previous analysis). Associations between AF genetic risk and stroke were enriched in the cardioembolic stroke subset (strongest P=1.2×10-9, 944 single-nucleotide polymorphism score). In contrast, AF genetic risk was not significantly associated with noncardioembolic stroke subtypes.ConclusionsComprehensive AF genetic risk scores were specific for cardioembolic stroke. Incomplete workups and subtype misclassification may have limited the power to detect associations with strokes of undetermined pathogenesis. Future studies are warranted to determine whether AF genetic risk is a useful biomarker to enhance clinical discrimination of stroke pathogeneses.
| S-EPMC7438180 | biostudies-literature
Project description:BackgroundAtrial fibrillation (AF) screening after ischemic stroke or transient ischemic attack (TIA) is given high priority in clinical guidelines. However, patient selection, electrocardiogram (ECG) modality and screening duration remains undecided and current recommendations vary.MethodsThe aim of this study was to investigate the clinical practice of AF screening after ischemic stroke or TIA at Swedish stroke units. In collaboration with the stakeholders of the Swedish Stroke Register (Riksstroke) a digital survey was drafted, then tested and revised by three stroke consultants. The survey consisted of 17 multiple choice/ free text questions and was sent by e-mail to the medical directors at all stroke units in Sweden.ResultsAll 72 stroke units in Sweden responded to the survey. Most stroke units reported that ≥ 75% of ischemic stroke (69/72 stroke units) or TIA patients (67/72 stroke units), without previously known AF, were screened for AF. Inpatient telemetry ECG was the method of first-choice in 81% of the units, but 7% reported lack of access. A variety of standard monitoring durations were used for inpatient telemetry ECG. The second most common choice was Holter ECG (17%), also with considerable variations in monitoring duration. Other AF screening modalities were used as a first-choice method (handheld and patch ECG) but less frequently.ConclusionsClinical practice for AF screening after ischemic stroke or TIA differed between Swedish stroke units, both in choice of AF screening methods as well as in monitoring durations. There is an urgent need for evidence and evidence-based recommendations in this field.Trial registrationNot applicable.
| S-EPMC11007877 | biostudies-literature
Project description:BackgroundAtrial myopathy-characterized by changes in left atrial function and size-may precede and promote atrial fibrillation (AF) and cardiac thromboembolism. In people without prior AF or stroke, whether analysis of left atrial function and size can improve ischemic stroke prediction is unknown.ObjectiveTo evaluate the association of echocardiographic left atrial function (reservoir, conduit, and contractile strain) and left atrial size (left atrial volume index) with ischemic stroke and determine whether these measures can improve the stroke prediction achieved by CHA2DS2-VASc score variables.DesignProspective cohort study.SettingARIC (Atherosclerosis Risk in Communities) study.Participants4917 ARIC participants without prevalent stroke or AF.MeasurementsIschemic stroke events (2011 to 2019) were adjudicated by physicians. Left atrial strain was measured using speckle-tracking echocardiography.ResultsOver 5 years, the cumulative incidences of ischemic stroke in the lowest quintiles of left atrial reservoir, conduit, and contractile strain were 2.99% (95% CI, 1.89% to 4.09%), 3.18% (CI, 2.14% to 4.22%), and 2.15% (CI, 1.09% to 3.21%), respectively, and that of severe left atrial enlargement was 1.99% (CI, 0.23% to 3.75%). On the basis of the Akaike information criterion, left atrial reservoir strain plus CHA2DS2-VASc variables was the best predictive model. With the addition of left atrial reservoir strain to CHA2DS2-VASc variables, 11.6% of the 112 participants with stroke after 5 years were reclassified to higher risk categories and 1.8% to lower risk categories. Among the 4805 participants who did not develop stroke, 12.2% were reclassified to lower and 12.7% to higher risk categories. Decision curve analysis showed a predicted net benefit of 1.34 per 1000 people at a 5-year risk threshold of 5%.LimitationUnderascertainment of subclinical AF.ConclusionIn people without prior AF or stroke, when added to CHA2DS2-VASc variables, left atrial reservoir strain improves stroke prediction and yields a predicted net benefit, as shown by decision curve analysis.Primary funding sourceNational Heart, Lung, and Blood Institute of the National Institutes of Health.
| S-EPMC11793084 | biostudies-literature