- Email: [email protected]
Postoperative Atrial Fibrillation Following Noncardiac Surgery Increases Risk of Stroke
Journal Pre-proof Post-operative Atrial Fibrillation following Noncardiac Surgery Increases Risk of Stroke
Anoop N. Koshy, Garry Hamilton, James Theuerle, Andrew W Teh, Hui-Chen Han, Paul J. Gow, Han S Lim, Vincent Thijs, Omar Farouque PII:
S0002-9343(19)30702-8
DOI:
https://doi.org/10.1016/j.amjmed.2019.07.057
Reference:
AJM 15359
To appear in:
The American Journal of Medicine
Please cite this article as: A.N. Koshy, G. Hamilton, J. Theuerle, et al., Post-operative Atrial Fibrillation following Noncardiac Surgery Increases Risk of Stroke, The American Journal of Medicine(2019), https://doi.org/10.1016/j.amjmed.2019.07.057
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© 2019 Published by Elsevier.
Journal Pre-proof Post-operative Atrial Fibrillation following Noncardiac Surgery Increases Risk of Stroke
Anoop N. Koshy MBBS (Hons)1,2; Garry Hamilton MBBS1; James Theuerle MBBS1; Andrew W Teh MBBS, PhD1,2; Hui-Chen Han MBBS1,2; Paul J. Gow MBBS, MD 2,3; Han S Lim MBBS, PhD1,2; Vincent Thijs MD, PhD2,4; Omar Farouque MBBS, PhD
Author Affiliations Department of Cardiology, Austin Health, Melbourne, Victoria, Australia
2
Department of Medicine, The University of Melbourne, Victoria, Australia
3
Victorian Liver Transplant Unit, Austin Health, Melbourne, Victoria, Australia
4
Stroke Division, Florey Institute of Neuroscience and Mental Health and
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1
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Department of Neurology, Austin Health, Melbourne, Victoria, Australia
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Corresponding author: A/Prof. Omar Farouque MBBS, PhD, FRACP, FACC Department of Cardiology, Austin Hospital
T|: +61 3 94963034 F|: +61 3 94590971
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145 Studley Road, Heidelberg 3084, Victoria, Australia
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Email: [email protected]
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All authors had access to the data and a role in writing the manuscript. Word Count: 2978 Conflicts of interest: None Running head: Post-operative atrial fibrillation and stroke Article Type: Clinical Research Study Funding: Dr. Koshy is a recipient of the National Health and Medical Research Council of Australia/National Heart Foundation Post-Graduate Scholarship and Royal Australasian College of Physicians Blackburn Scholarship. Dr. Teh is a recipient of the Early Career Fellowship from the National Health and Medical Research Council of Australia. Key Words: perioperative; arrhythmias; surgery; cerebrovascular events; metaanalysis
Journal Pre-proof Abstract
Background New-onset post-operative atrial fibrillation is well recognized to be an adverse prognostic marker in patients undergoing noncardiac surgery. Whether postoperative atrial fibrillation confers an increased risk of stroke remains unclear.
Methods A systematic review and meta-analysis was performed to assess the risk of stroke
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after post-operative atrial fibrillation in noncardiac surgery. MEDLINE, Cochrane and EMBASE databases were searched for articles published up to May 2019 for studies of patients undergoing noncardiac surgery that reported incidence of new atrial
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fibrillation and stroke. Event rates from individual studies were pooled and risk ratios
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(RR) were pooled using a random-effects model
Results
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Fourteen studies of 3,536,291 patients undergoing noncardiac surgery were included in the quantitative analysis (mean follow-up 1.4 ±1 year). New atrial fibrillation
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occurred in 26,046 (0.74%) patients with a higher incidence following thoracic surgery. Stroke occurred in 279 (1.5%) and 6199 (0.4%) patients, with and without
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post-operative atrial fibrillation, respectively. On pooled analysis, post-operative atrial fibrillation was associated with a significantly increased risk of stroke (RR 2.51,
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95%CI 1.76-3.59) with moderate heterogeneity. The stroke risk was significantly higher with atrial fibrillation following non-thoracic compared to thoracic surgery (RR 3.09 vs RR 1.95; p=0.01). Conclusion New post-operative atrial fibrillation following noncardiac surgery was associated with a 2.5-fold increase in the risk of stroke. This risk was highest among patients undergoing non-thoracic noncardiac surgery. Given the documented efficacy of newer anticoagulants, randomized controlled trials are warranted to assess whether they can reduce the risk of stroke in these patients.
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New-onset post-operative atrial fibrillation is the most common cardiac arrhythmia in patients undergoing noncardiac surgery. 1 The incidence of atrial fibrillation varies depending on the type of noncardiac surgery and ranges between 0.4-15%.2, 3 Although traditionally thought to be a self-limiting entity, mounting evidence suggests that post-operative atrial fibrillation is associated with a greater risk of perioperative
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complications, healthcare costs and mortality.4, 5 As over 200 million noncardiac surgery are performed worldwide each year, this represents an issue of
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significance.6
While it is well established that nonvalvular atrial fibrillation carries up to a 5-fold
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increased risk of ischemic stroke, it is unclear whether atrial fibrillation after
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noncardiac surgery confers a similar hazard.7 This relationship is important to ascertain due to the proven efficacy of non-vitamin K antagonist oral anticoagulants
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(NOACs) in mitigating risk of stroke in nonvalvular atrial fibrillation and a lack of
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evidence cited in international guidelines about appropriate stroke prevention strategies in this target population.8-14 Although recent studies have suggested an increased risk of stroke with post-operative atrial fibrillation, some have been more circumspect with their findings.15, 16 Evidence from individual studies is limited by the uncertainty surrounding risk estimates, both as a result of a limited number of outcomes and the differences in the patient populations evaluated. Therefore, we conducted a systematic review and meta-analysis to elucidate the link between postoperative atrial fibrillation and stroke in patients undergoing noncardiac surgery.
Journal Pre-proof Methods Data Sources A literature search limited to full-text English language articles was performed through the MEDLINE, EMBASE and Cochrane Central Register of controlled trials up to May 2019 using the keywords “stroke” AND “perioperative complications” AND “atrial fibrillation” with associated MeSH headings. The search was not limited by date of publication and adhered to the PRISMA (Preferred Reporting Items for
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Systematic Reviews and Meta-Analyses) statement.17 MeSH terms used for the
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MEDLINE search strategy are presented in Table S1 in the Data Supplement.
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Study Selection
Studies were included if they reported outcomes in patients undergoing noncardiac
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surgery and reported incidence of new atrial fibrillation and risk of stroke. We
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excluded studies that reported stroke among patients with a pre-existing history of atrial fibrillation or when details about the onset of atrial fibrillation were not specified.
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Studies enrolling patients who underwent cardiac or carotid vascular surgery were
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excluded. Carotid vascular surgeries were excluded as strokes in this population are primarily carotid-embolic and procedure related.18 Where multiple studies reported on the same cohort of patients, we included articles with the largest cohort size.
Data Extraction Two investigators (J.T. and G.H.) independently searched and extracted relevant articles which were subsequently verified by the senior investigator (O.F.) with discrepancies resolved by consensus. The following variables were extracted: study design and characteristics, inclusion and exclusion criteria, sample size, type of
Journal Pre-proof operations and follow-up duration. As we predicted a predominant number of studies to be of retrospective cohort design, quality ascertainment of atrial fibrillation was adjudicated in a similar manner as previously published.19 This involved assessment of three domains including: ascertainment of atrial fibrillation-free status at baseline, ascertainment of atrial fibrillation incidence in-hospital and atrial fibrillation recurrence after hospital discharge.
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Outcome Assessment
The primary end-point of this study was the association between new post-operative
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atrial fibrillation and stroke. In secondary analyses, we sought to (a) pool the
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prevalence of atrial fibrillation based on type of surgery; (b) assess the recurrence rate of atrial fibrillation in studies with longitudinal follow-up; and (c) identify the
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proportion with atrial fibrillation treated with therapeutic anticoagulation on discharge.
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Early adverse outcome was defined as stroke occurring within 30 days of operation. Late adverse outcome was defined as stroke occurring after 30 days of operation.
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We collected event counts and/or effect size data where available. Where effect
adjustment.
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sizes were reported as an adjusted metric, we extracted the variables used in this
Quality Assessment Methodological quality was assessed by two independent investigators using the Newcastle-Ottawa Scale (NOS) for quality assessment of observational studies in meta-analyses.20 Assessment of quality on this instrument was judged on study group selection, study-group comparability and outcome assessment. Studies meeting ≥5 criteria were considered to be high quality.
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Statistical Analysis
Descriptive statistics are presented as mean and standard deviation for continuous variables and absolute and relative frequencies for categorical variables. To determine the pooled risk associated with post-operative atrial fibrillation and stroke, summary estimates for relative risk (RR) with 95% confidence intervals (CI) were
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calculated using the Der Simonian and Laird random-effects model.21 As stroke following noncardiac surgery is a rare event, the assumption was made that hazard ratio (HR) and relative risk (RR) would converge with negligible difference, enabling
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data pooling across studies.22 Publication bias was assessed graphically through the
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creation of funnel plots of study point estimates against precision and explored
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further for small study effects using Egger’s test. Statistical heterogeneity was quantified using the I2 statistic. An I2 ≥80% was considered to be significant inter-
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study heterogeneity.23 We undertook pre-specified sensitivity analyses to explore
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potential sources of heterogeneity including study quality, type of surgery (thoracic and non-thoracic) and whether routine cardiac monitoring or electrocardiograms
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were performed. Stratification by surgery type was performed by thoracic and nonthoracic surgeries as thoracic operations are well recognized to carry higher rates of post-operative atrial fibrillation.24 Statistical analyses were performed using Comprehensive Meta-Analysis software (Version 3, Biostat, Englewood, NJ). Results The initial search yielded 7814 studies. We eliminated 7688 after initial screening. Details of the literature search and excluded studies are reported in Figure 1. Eighteen studies with a total of 3,758,541 patients were included in the qualitative
Journal Pre-proof analysis.3, 15, 16, 25-39 This included sixteen observational cohort studies3, 15, 16, 25-37 and two randomized controlled trials.38, 39 Four studies were excluded from the metaanalysis due to stroke outcome being reported as a composite of adverse cardiovascular events26, 27 and due to significant atrial fibrillation ascertainment bias (Table S2).3, 31 Among the fourteen studies included in the quantitative analysis (n=3,536,291), six reported early (<30-day)16, 25, 28, 29, 38, 39 while eight reported late (≥30 day) outcomes.15, 26, 30, 32-34, 36, 37 Individual study details including baseline
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characteristics and duration of follow-up are presented in Table 1 and Table S3,
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Methodological Quality of Data
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respectively.
Overall, the methodological quality of studies varied. On assessment of study quality
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based on the NOS (Table S4), fifteen studies were of high quality (median score 6,
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IQR 5-7) (Table S4). Overall atrial fibrillation ascertainment quality was deemed high
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in eight studies (Table 2, S2).
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Incidence of Post-Operative Atrial Fibrillation Reporting of post-operative atrial fibrillation was limited to the index hospitalisation. Among studies included in the quantitative analysis, 26,046 patients experienced new atrial fibrillation. The overall pooled incidence rate across studies was 13.6% (95%CI 11.5-15.9) with substantial heterogeneity (I2=99%, p<0.001) (Figure 2). The pooled incidence rate of atrial fibrillation was significantly higher after thoracic surgery when compared with non-thoracic surgery (16.2% vs 3.9%; p <0.001 for comparison between groups) (Figure 2, S2). A trend to higher atrial fibrillation incidence was observed in studies with continuous as opposed to opportunistic post-
Journal Pre-proof operative cardiac monitoring (13.4% vs 8.2%; p=0.07 for comparison between groups).
Risk Factors for Post-Operative Atrial Fibrillation Thirteen studies reported multivariable analyses that assessed predictors of postoperative atrial fibrillation and are summarized in Table S5. Although predictors tested varied across studies, older age, post-operative complications and thoracic
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surgery were commonly associated with atrial fibrillation.
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Recurrence of Atrial Fibrillation following Discharge & Anticoagulation
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Both recurrence rates and anticoagulation use in the studies were poorly reported. Only seven studies reported on anticoagulation use on discharge which ranged from
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1.5% to 74% (Table 2).16, 25, 31, 32, 37-39 Rates of anticoagulation use with post-
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operative atrial fibrillation was proportionally higher following non-thoracic noncardiac surgery compared to thoracic surgery (mean 38.4% (range 16-74%) vs 7.6% (range
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1.5-15%). Three studies reported rates of AF recurrence (range 3.6-16.6%) at
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varying time-intervals with no pre-specified methods.16, 36, 39
Risk of Stroke with Post-operative Atrial Fibrillation Among studies included in the quantitative analysis, the primary end-point of stroke occurred in 6,478 patients. Excluding two studies33, 37 that reported only the computed effect size, stroke occurred in 279 (1.5%) patients with post-operative atrial fibrillation compared to 6199 (0.4%) patients without, at maximal follow-up reported in each study. Atrial fibrillation was associated with a significantly higher risk of stroke (RR 2.51 95% CI 1.76-3.59) with moderate heterogeneity (I2= 78%; Figure
Journal Pre-proof 3). The hazard of stroke conferred by atrial fibrillation was lower following thoracic surgery when compared with non-thoracic noncardiac surgery (RR 1.95 95%CI 1.263.02 vs RR 3.09 95%CI 1.88-5.06; respectively, p=0.01 for comparison between groups). Heterogeneity was low in the thoracic surgery cohort (I 2=18%, p=0.32) although high in the non-thoracic noncardiac surgery cohort (I2=86%, p<0.001).
Subgroup Analyses
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Sub-group analyses to further evaluate potential sources of heterogeneity are presented in Figure 4. No significant differences in effect sizes were noted in the
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sub-group comparisons (p=ns), although studies with low sample size and those
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reporting only early outcomes had wider dispersion in the computed effect size.
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Publication Bias
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The funnel plot demonstrated slight asymmetry suggesting possible publication bias (Figure S2). However, no evidence of publication bias was demonstrated on
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calculation of the Egger’s test for small-study effects (p=0.29). Analysis to assess the
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influence of single studies on the effect estimate demonstrated a persistent significant association between post-operative atrial fibrillation and risk of stroke.
Discussion Occurrence of post-operative atrial fibrillation is well recognized to be an adverse prognostic marker in patients undergoing noncardiac surgery. However, the risk of stroke, particularly in the long-term, is unclear. The key findings of this meta-analysis are as follows: (1) the incidence of post-operative atrial fibrillation varied significantly across studies with non-uniform reporting of both anticoagulation use as well as
Journal Pre-proof atrial fibrillation recurrence; (2) new atrial fibrillation was associated with over a twofold increased risk of stroke; and (3) the hazard of stroke conferred by post-operative atrial fibrillation was significantly higher in patients with atrial fibrillation after nonthoracic noncardiac surgery. These results highlight the need for prospective, systematic screening for atrial fibrillation recurrence after noncardiac surgery and to assess whether the long-term risk of stroke can be mitigated with anticoagulation.
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A recent systematic review and meta-analysis by Lin et al. reported on the risk of mortality and stroke in patients undergoing surgery. 40 However, only two of the
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included studies reported the risk of stroke following noncardiac surgery. Our study
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focussed on a cohort of patients with atrial fibrillation after noncardiac surgery and included a larger cohort of patients from fourteen studies. Further, we made a
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targeted effort to exclude studies of patients with pre-existing non-valvular atrial
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fibrillation by rigorously appraising the methodology for ascertainment of atrial fibrillation. This was important as the thromboembolic risk from a paroxysmal
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well described.7
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episode of atrial fibrillation in someone with known non-valvular atrial fibrillation is
On pooled estimates of patients undergoing noncardiac surgery, post-operative atrial fibrillation was associated with a 2.5-fold increased risk of stroke. This risk was significantly lower when comparing thoracic versus non-thoracic noncardiac surgery (RR 1.95 vs 3.09, p=0.01). Prior studies evaluating the risk of stroke following cardiac surgery estimated an even lower risk of stroke (RR 1.36 [1.12-1.65]).41 The reasons for differences in stroke risk across surgeries are likely multifactorial. Mechanistically, as atrial fibrillation in cardiac and thoracic surgery occurs following
Journal Pre-proof direct manipulation of the heart, pulmonary veins or the lung hilum; it is therefore thought to be a direct and possibly short-lived trigger.24, 42 In noncardiac surgery, however, exact reasons for atrial fibrillation occurrence are less clear with some evidence suggesting that a pre-existing substrate may be accountable.4, 42 This is supported by studies that demonstrate recurrence rates of atrial fibrillation following noncardiac surgery to be as high as 64%.43 In these patients, it is postulated that the underlying substrate for atrial fibrillation was unmasked by the occurrence of acute
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triggers and pro-arrhythmic factors in the perioperative period. Following on, the potential risk of thromboembolism following noncardiac surgery may also be higher,
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also promote thrombogenesis.5, 11, 42
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as risk factors that predispose to atrial fibrillation (eg: age, hypertension, diabetes)
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Whether a link exists between perioperative atrial fibrillation burden, symptoms and
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long-term thrombogenic risk remains unclear. Although current risk prediction algorithms do not incorporate atrial fibrillation pattern to assessing the risk of
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thromboembolism, some population-based studies have demonstrated up to a 25%
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lower risk of stroke with non-permanent atrial fibrillation.44 In contrast, others have demonstrated a substantial risk of stroke even in patients with silent or undetected AF.45 Further, reports from the Framingham Heart study demonstrated that stroke can be the first manifestation of AF in 2 to 5% of patients. 46 The burden of atrial fibrillation, symptoms and timing of stroke was not well described in the studies included in this meta-analysis. As noncardiac surgical patients are less likely to be monitored post-operatively, it is conceivable that detected episodes of atrial fibrillation in this cohort would also be prolonged and more clinically apparent. 13, 14 Future studies with more effective surveillance for atrial fibrillation recurrence are
Journal Pre-proof warranted to better inform clinicians about the natural history of post-operative atrial fibrillation following noncardiac surgery.
Strokes that occur in patients with atrial fibrillation are known to be more disabling and confer significantly worse prognosis. 47 Therapeutic anticoagulation is proven to mitigate the risk of stroke with atrial fibrillation, particularly with the improved efficacy and safety profile of NOACs.8, 10 Results of a nationwide registry study included in
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the meta-analysis demonstrated a halving of the rate of stroke and systemic embolism in those prescribed anticoagulation for post-operative atrial fibrillation.37
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Despite this, aggregate results from studies included in this meta-analysis suggest
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that anticoagulation was under-prescribed in those with post-operative atrial fibrillation (range 1.5-74%). Butt et al. in a large national-registry study compared a
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matched cohort of patients with post-operative atrial fibrillation following noncardiac
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surgery and non-valvular atrial fibrillation. Utilizing data on anticoagulation prescription at 30-days following discharge, this study reported almost double the
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rate of anticoagulant use in patients with non-valvular atrial fibrillation (41.3 vs 24.3
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%).37 This disparity may in part have resulted from clinicians deeming the risk of post-operative and long-term bleeding to outweigh risks of thrombosis. However, the lack of guideline recommendations on anticoagulation use as well as standardized strategies to systematically screen for atrial fibrillation recurrence in this population is a significant gap in current practice.13, 14 The findings from this study are important in informing the clinician about the hazard conferred by post-operative atrial fibrillation in increasing long-term risk of stroke. However, future trials assessing the safety and efficacy as well as the timing and duration of oral anticoagulant therapy in this target population are imperative.
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To our knowledge, this is the largest pooled study that reports the risk of stroke with post-operative AF following noncardiac surgery. Other strengths of this study include the systematic screening for pre-existing AF and well as a comparative assessment of the risk of stroke stratified by surgery type, type of cardiac monitoring and study design. However, certain limitations of our study warrant discussion. First, as most studies included were of a retrospective design, an important limitation is the
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possibility of misclassifying an episode as post-operative atrial fibrillation which may in fact represent an episode of paroxysmal nonvalvular atrial fibrillation. To address
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this ascertainment bias, we rigorously appraised the methodology for confirmation of
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atrial fibrillation at baseline. Second, different non-cardiac operations are associated with a varied risk of stroke.3, 39 Whilst we report differences in hazard for stroke in
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thoracic and non-thoracic noncardiac surgery, we were unable to compare other
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surgical sub-types due to stroke incidence not being stratified by type of surgery. From a therapeutic standpoint, we are unable to comment on the safety of
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anticoagulation in the postoperative setting as bleeding outcomes were not reported.
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Third, there was a paucity of data on both atrial fibrillation duration, recurrence and prescription of anticoagulation following surgery. Longer atrial fibrillation duration or recurrence may have led to increased recognition and treatment with anticoagulation. Fourth, the generalizability of our findings could also be affected by the variability in definition of stroke and a lack of differentiation between ischemic and hemorrhagic outcomes- which were not uniformly reported across studies. Lastly, it is important not to infer causation from this pooled cohort of observational studies. It is increasingly recognized that the risk of stroke with atrial fibrillation is not entirely related to the presence of atrial thrombus. 48
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Conclusion New post-operative atrial fibrillation following noncardiac surgery was associated with a 2.5-fold increase in risk of stroke. This risk was highest among patients undergoing non-thoracic noncardiac surgery. Given the efficacy of NOACs for stroke prophylaxis, prospective studies are warranted to assess whether they can reduce
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the risk of stroke in patients with post-operative atrial fibrillation.
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Lin MH, Kamel H, Singer DE, Wu YL, Lee M, Ovbiagele B. Perioperative/Postoperative Atrial Fibrillation and Risk of Subsequent Stroke and/or Mortality. Stroke. 2019:STROKEAHA118023921.
41.
Megens MR, Churilov L, Thijs V. New-Onset Atrial Fibrillation After Coronary Artery Bypass Graft and Long-Term Risk of Stroke: A Meta-Analysis. J Am Heart Assoc. 2017;6.
Journal Pre-proof 42.
Dobrev D, Aguilar M, Heijman J, Guichard JB, Nattel S. Postoperative atrial fibrillation: mechanisms, manifestations and management. Nat Rev Cardiol. 2019.
43.
Lubitz SA, Yin X, Rienstra M, et al. Long-term outcomes of secondary atrial fibrillation in the community: the Framingham Heart Study. Circulation. 2015;131:1648-1655.
44.
Ganesan AN, Chew DP, Hartshorne T, et al. The impact of atrial fibrillation type on
analysis. Eur Heart J. 2016;37:1591-1602. 45.
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the risk of thromboembolism, mortality, and bleeding: a systematic review and meta-
Flaker GC, Belew K, Beckman K, et al. Asymptomatic atrial fibrillation:
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demographic features and prognostic information from the Atrial Fibrillation Follow-
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up Investigation of Rhythm Management (AFFIRM) study. Am Heart J. 2005;149:657-663.
Lubitz SA, Yin X, McManus DD, et al. Stroke as the Initial Manifestation of Atrial
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46.
47.
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Fibrillation: The Framingham Heart Study. Stroke. 2017;48:490-492. Steger C, Pratter A, Martinek-Bregel M, et al. Stroke patients with atrial fibrillation
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have a worse prognosis than patients without: data from the Austrian Stroke registry.
48.
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Eur Heart J. 2004;25:1734-1740. Calenda BW, Fuster V, Halperin JL, Granger CB. Stroke risk assessment in atrial fibrillation: risk factors and markers of atrial myopathy. Nat Rev Cardiol. 2016;13:549-559.
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Figure 1: PRISMA Flow Diagram
Figure 2: Incidence of new postoperative atrial fibrillation stratified by thoracic and non-thoracic surgery
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The blue diamond indicates the summary estimate for the incidence of postoperative atrial fibrillation in the thoracic and non-thoracic surgical sub-groups. The red
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diamond represents the pooled estimate from the entire cohort.
Figure 3: Risk of stroke with post-operative atrial fibrillation following thoracic and
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non-thoracic noncardiac surgery
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POAF, post-operative atrial fibrillation
atrial fibrillation
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Figure 4: Sub-group Analyses evaluating the risk of stroke with new postoperative
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Table 1. List of Studies included in Review Ye ar
Type of Surgery
Study design
Locatio n
n
Key Inclusion criteria
Polanczyk et al.*
19 98
All major noncardiac procedures
Prospecti ve cohort study
Boston, USA
4,181
Sinus rhythm at pre-op evaluation.
Amar et al.
20 00
Pneumonec tomy or lobectomy
Randomi sed, doubleblind, placebocontrolle d trial of IV diltiazem
New York, USA
330
Sinus rhythm, >60yo if undergoing lobectomy.
Chronic atrial arrhythmia , second degree AV block, taking class I or III antiarrhyth mics or a CCB.
30 days
Murthy et al.
20 03
Esophagect omy for cancer
Retrospe ctive cohort study
POISE study group.
20 08
All noncardiac surgery
Winkel et al.*
20 09
Vascular surgery#
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Author
F/U durati on Inpatie nt stay
921
Esophagect omy for oesophagus or gastric cardia Ca
Abdominal resection of gastric cardia cancer, staged resections.
Minim um 3 years
Randomi sed controlle d trial of preoperat ive metoprol ol
Multinational
8,351
≥45yo, had or at risk of atherosclero tic heart disease
HR <50, 2nd or 3rd deg heart block, asthma, already on a betablocker, on verapamil, CABG in the last 5 years and no ischaemia since.
30 days
Prospecti ve cohort study
Rotterda m, The Netherla
317
Elective AAA repair or
History or arrhythmia ,
12 Month s (IQR
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Hong Kong
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Key exclusion Criteria
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pacemaker, 2-28) LVH, LBBB/RB BB. Previous atrial arrhythmia .
20 10
Thoracic surgery
Retrospe ctive cohort study
USA
13,906
Lobectomy “or greater”.
Henri et al.
20 11
Lung transplant
Retrospe ctive cohort study
Montrea l, Canada
224
Consecutiv e patients undergoing lung transplant in database.
Imperatori 20 et al. 12
Lobectomy for lung Cancer
Prospecti ve cohort study
Varese, Italy
Rao et al.
20 12
Oesophagec Retrospe tomy for ctive cancer cohort study
Notting ham, United Kingdo m
Gialdini et al.
20 14
All noncardiac surgery
Retrospe ctive cohort study
Mc Cormack et al.
20 14
Oesophagea l Surgery
Chaikrian gkrai et al.
20 15
Giambron e et al.
20 15
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Onaitis et al.
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nds
Inpatie nt stay
Chronic AF, pacemaker devices.
Media n 36 month s
997
Oesophagec tomy
Preoperative arrhythmia .
Inpatie nt stay
Californ ia, USA
1,655, 817
Patients undergoing “major surgery”
Preexisting AF, previous cerebrovas cular disease.
Mean 2.1 years
Retrospe ctive cohort study
Dublin, Ireland
473
Surgery for oesophagea l or junctional Cancer
Preexisting AF
Media n 39 month s (IQR 7-104)
Lung transplant
Retrospe ctive cohort study
Houston , USA
293
Lung transplant
Preexisting atrial arrhythmia
28 ± 17 month s
Lobectomy for Lung cancer
Retrospe ctive cohort study
Californ ia, Florida & New York,
20,695
Lobectomy for lung cancer
Previous atrial arrhythmia , preexisting
Minim um 90 days
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Not specifically stated.
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454
Minim um 30 days
>18yo
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supraventri cular tachycardi a, missing data
20 16
Lung Cancer Surgery
Retrospe ctive cohort study
Kyoto, Japan
593
Lung cancer operation
Chronic AF, previous ablation for AF.
30 days
Butt et al.
20 18
All noncardiac surgery
Retrospe ctive cohort study
Denmar k
1,520, 109
>30yo, first time surgery, no recent cancer diagnosis,
<30yo, previous AF, previous antiarrhythmic drugs
3.2 Years (IQR 0.9-7)
Khormaee et al.
20 18
Total hip or knee replacement
Retrospe ctive cohort study
New York, USA
>18yo
Previous Diagnosis of atrial fibrillation
Minim um 1 year
Sholte et al.*
20 18
Liver transplant
Retrospe ctive cohort study
Yoshida et al.
20 18
All noncardiac surgery
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Muranishi et al.*
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528,24 6
916
Liver transplant
Died within 30 days of transplant
Media n 4.9 (IQR 1.310) years
Kyoto, Japan
1,718
≥18yo, admitted to ICU and stayed longer then 24 hrs
Prior history of AF, cardiac surgery, rhythm abnormalit y other than AF..
Inpatie nt stay
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Rotterda m, The Netherla nds
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Retrospe ctive cohort study
* Denotes studies not included in meta-analyses, but part of systemic review. F/U, follow-up, AF, atrial fibrillation, AAA, abdominal aortic aneurysm, IQR, interquartile range.
Table 2. Atrial Fibrillation Definition, Timing and Anticoagulation use Author, year AF AF AF Anticoagulati Definition Ascertainme Timing on on * nt quality Discharge
% AF on Dischar ge
AF Recurren ce
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Onaitis, 2010
Henri, 2011
Imperatori, 2012
Rao, 2012
Gialdini, 2014
Mc Cormack, 2014 Chaikriangkr ai, 2015 Giambrone, 2016 Muranishi, 2016
New AF requiring treatment New AF or flutter for >30 seconds Any AF on ECG or telemetry
9 (15%)
2 (3.3%)
NR
Low
NR
NR
NR
NR
High
NR
35 (16.6%)
NR
20 (16.6%)
High
Peak incidence day 1 (85%) NR
NR
3 (23%)
NR
NR
NR
NR
7 ± 11 days
1 (1.5%)
1 (1.5%)
8 (3.6%)
NR
2 (4.4%)
NR
High
Peak incidence day 2 (69%) NR
0
NR
NR
Low
NR
NR
NR
NR
Low
71 (74%)
8 (8.3%)
NR
NR
NR
42 (14%)
Low
Median 3 (IQR 120) days Median 5 (IQR 3-9) days NR
NR
NR
NR
Low
NR
4 (9.8%)
NR
NR
Low
New AF confirmed on 12-lead ECG ICD-9 codes, not present on prior encounters Any new AF confirmed on 12-lead ECG New AF or flutter for >30 seconds ICD-9 codes not present on admission New AF confirmed on 12-lead ECG
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NR
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Winkel, 2009
NR
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POISE, 2017
NR
High
Peak incidence day 2/3 postoperative ly (44% of cases) 3 ±2 days
High
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Murthy, 2003
Low
High
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Amar, 2000
New AF, flutter, multifocal atrial tachycardia or supraventricul ar tachycardia New sustained AF ≥15 minutes or clinically significant Any new AF on ECG or telemetry New clinically important AF (AF with symptoms or requiring therapy) New AF confirmed on 12-lead ECG
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Polanczyk, 1998
High
Journal Pre-proof ICD-10 Low NR 859 (24.3%) NR NR codes; AF not present previously Khormaee ICD-9 codes Low NR NR NR NR 2018 not present on admission Scholte 2018 De-novo AF Low NR NR NR NR not recorded in past medical history Yoshida New AF not High Median 6 (4.3%) NR NR 2018 present on 1.5 (0.5prior history 2.1) days that persisted >6 hours * Quality of attainment of atrial fibrillation data as determined by assessment proposed by Mcintyre et al. – see supplementary table S2 AF, atrial fibrillation; AF, atrial fibrillation, ECG, electrocardiogram, IQR, interquartile range, ICD, international classification of diseases, NR, not reported
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Butt, 2018
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Total n
n
Strokes
n
Strokes
Calculated Stroke Risk
Polanczyk et al. (1998)*
4,181
222
2 (0.9%)
39,59
NR
-
Amar et al. (2000)
330
60
1 (1.7%)
270
0 (0%)
-
Murthy et al. (2003)
921
144
1 (0.7%)
144 §
0 (0%)
-
POISE (2008)
8,351
211
6 (2.8%)
Winkel et al. (2009)†
317
15
NR*
Onaitis et al (2010)
13,906
1,755
23 (1.3%)
Henri et al. (2011)
224
65
1 (1.5%)
Imperatori et al. (2012)
454
45
Rao et al. (2012)
997
209
1,655,817
54 (0.7%)
-
302
NR
HR 4.2, 95% CI (2.1‡ 8.8)
61 (0.5%)
-
159
7 (4.4%)
-
2 (4.4%)
409
7( 1.7%)
-
2 (1.0%)
788
4 (0.5%)
-
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8,140
12,151
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Gialdini et al. (2014)
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Author, (year)
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Table 3. Individual Study breakdown of Postoperative Atrial Fibrillation and Stroke Rates Post-operative No Post-operative Atrial Fibrillation Atrial Fibrillation
12874
189 (1.0%)
1,642,943
5,914 (0.4%)
-
96
4 (4.2%)
377
0 (0%)
-
473
Chaikriangkrai et al. (2015)
293
73
2 (2.7%)
220
1 (0.5%)
-
20,695
2,449
37 (1.5%)
18,246
146 (0.8%)
-
593
38
3 (8%)
555
NR
-
1,520,109
6,048
NR
1,514,061
NR
HR 1.89 (95% CI 1.56-2.29)
528,246
3,646
NR
524,600
NR
OR 2.7 (95% CI 1.54.8)
Sholte et al.*
916
NR
NR
NR
NR
OR 2.2 (95%CI 0.875.54) ‡
Yoshida et al. (2018)§
1,718
151
11 (7.3%)
1,567
5 (0.3%)
Muranishi et al. † (2016) Butt et al. (2018) Khormaee et al. (2018)
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Giambrone et al. (2015)
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Mc Cormack et al. (2014)
*Not included in meta-analysis as atrial fibrillation ascertainment bias determined to be too high.
Journal Pre-proof †Excluded from metanalysis as result is a composite endpoint of adverse cardiovascular events, not stroke alone ‡ Composite risk for adverse cardiovascular events § Post-operative Atrial fibrillation cases matched to patients without Post-operative Atrial fibrillation in study
Clinical Significance
Although new post-operative atrial fibrillation confers an adverse prognosis following noncardiac surgery, it is unclear whether it increases the risk of
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stroke Post-operative AF following noncardiac surgery was associated with a 2.5-fold increased risk of stroke. This risk was highest following non-thoracic surgery.
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Whether anticoagulation can mitigate the risk of stroke in patients with post-
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operative atrial fibrillation warrants further study
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Figure 1
Figure 2
Figure 3
Figure 4
Anoop N. Koshy, Garry Hamilton, James Theuerle, Andrew W Teh, Hui-Chen Han, Paul J. Gow, Han S Lim, Vincent Thijs, Omar Farouque PII:
S0002-9343(19)30702-8
DOI:
https://doi.org/10.1016/j.amjmed.2019.07.057
Reference:
AJM 15359
To appear in:
The American Journal of Medicine
Please cite this article as: A.N. Koshy, G. Hamilton, J. Theuerle, et al., Post-operative Atrial Fibrillation following Noncardiac Surgery Increases Risk of Stroke, The American Journal of Medicine(2019), https://doi.org/10.1016/j.amjmed.2019.07.057
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© 2019 Published by Elsevier.
Journal Pre-proof Post-operative Atrial Fibrillation following Noncardiac Surgery Increases Risk of Stroke
Anoop N. Koshy MBBS (Hons)1,2; Garry Hamilton MBBS1; James Theuerle MBBS1; Andrew W Teh MBBS, PhD1,2; Hui-Chen Han MBBS1,2; Paul J. Gow MBBS, MD 2,3; Han S Lim MBBS, PhD1,2; Vincent Thijs MD, PhD2,4; Omar Farouque MBBS, PhD
Author Affiliations Department of Cardiology, Austin Health, Melbourne, Victoria, Australia
2
Department of Medicine, The University of Melbourne, Victoria, Australia
3
Victorian Liver Transplant Unit, Austin Health, Melbourne, Victoria, Australia
4
Stroke Division, Florey Institute of Neuroscience and Mental Health and
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Department of Neurology, Austin Health, Melbourne, Victoria, Australia
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Corresponding author: A/Prof. Omar Farouque MBBS, PhD, FRACP, FACC Department of Cardiology, Austin Hospital
T|: +61 3 94963034 F|: +61 3 94590971
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145 Studley Road, Heidelberg 3084, Victoria, Australia
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Email: [email protected]
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All authors had access to the data and a role in writing the manuscript. Word Count: 2978 Conflicts of interest: None Running head: Post-operative atrial fibrillation and stroke Article Type: Clinical Research Study Funding: Dr. Koshy is a recipient of the National Health and Medical Research Council of Australia/National Heart Foundation Post-Graduate Scholarship and Royal Australasian College of Physicians Blackburn Scholarship. Dr. Teh is a recipient of the Early Career Fellowship from the National Health and Medical Research Council of Australia. Key Words: perioperative; arrhythmias; surgery; cerebrovascular events; metaanalysis
Journal Pre-proof Abstract
Background New-onset post-operative atrial fibrillation is well recognized to be an adverse prognostic marker in patients undergoing noncardiac surgery. Whether postoperative atrial fibrillation confers an increased risk of stroke remains unclear.
Methods A systematic review and meta-analysis was performed to assess the risk of stroke
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after post-operative atrial fibrillation in noncardiac surgery. MEDLINE, Cochrane and EMBASE databases were searched for articles published up to May 2019 for studies of patients undergoing noncardiac surgery that reported incidence of new atrial
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fibrillation and stroke. Event rates from individual studies were pooled and risk ratios
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(RR) were pooled using a random-effects model
Results
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Fourteen studies of 3,536,291 patients undergoing noncardiac surgery were included in the quantitative analysis (mean follow-up 1.4 ±1 year). New atrial fibrillation
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occurred in 26,046 (0.74%) patients with a higher incidence following thoracic surgery. Stroke occurred in 279 (1.5%) and 6199 (0.4%) patients, with and without
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post-operative atrial fibrillation, respectively. On pooled analysis, post-operative atrial fibrillation was associated with a significantly increased risk of stroke (RR 2.51,
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95%CI 1.76-3.59) with moderate heterogeneity. The stroke risk was significantly higher with atrial fibrillation following non-thoracic compared to thoracic surgery (RR 3.09 vs RR 1.95; p=0.01). Conclusion New post-operative atrial fibrillation following noncardiac surgery was associated with a 2.5-fold increase in the risk of stroke. This risk was highest among patients undergoing non-thoracic noncardiac surgery. Given the documented efficacy of newer anticoagulants, randomized controlled trials are warranted to assess whether they can reduce the risk of stroke in these patients.
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New-onset post-operative atrial fibrillation is the most common cardiac arrhythmia in patients undergoing noncardiac surgery. 1 The incidence of atrial fibrillation varies depending on the type of noncardiac surgery and ranges between 0.4-15%.2, 3 Although traditionally thought to be a self-limiting entity, mounting evidence suggests that post-operative atrial fibrillation is associated with a greater risk of perioperative
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complications, healthcare costs and mortality.4, 5 As over 200 million noncardiac surgery are performed worldwide each year, this represents an issue of
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significance.6
While it is well established that nonvalvular atrial fibrillation carries up to a 5-fold
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increased risk of ischemic stroke, it is unclear whether atrial fibrillation after
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noncardiac surgery confers a similar hazard.7 This relationship is important to ascertain due to the proven efficacy of non-vitamin K antagonist oral anticoagulants
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(NOACs) in mitigating risk of stroke in nonvalvular atrial fibrillation and a lack of
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evidence cited in international guidelines about appropriate stroke prevention strategies in this target population.8-14 Although recent studies have suggested an increased risk of stroke with post-operative atrial fibrillation, some have been more circumspect with their findings.15, 16 Evidence from individual studies is limited by the uncertainty surrounding risk estimates, both as a result of a limited number of outcomes and the differences in the patient populations evaluated. Therefore, we conducted a systematic review and meta-analysis to elucidate the link between postoperative atrial fibrillation and stroke in patients undergoing noncardiac surgery.
Journal Pre-proof Methods Data Sources A literature search limited to full-text English language articles was performed through the MEDLINE, EMBASE and Cochrane Central Register of controlled trials up to May 2019 using the keywords “stroke” AND “perioperative complications” AND “atrial fibrillation” with associated MeSH headings. The search was not limited by date of publication and adhered to the PRISMA (Preferred Reporting Items for
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Systematic Reviews and Meta-Analyses) statement.17 MeSH terms used for the
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MEDLINE search strategy are presented in Table S1 in the Data Supplement.
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Study Selection
Studies were included if they reported outcomes in patients undergoing noncardiac
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surgery and reported incidence of new atrial fibrillation and risk of stroke. We
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excluded studies that reported stroke among patients with a pre-existing history of atrial fibrillation or when details about the onset of atrial fibrillation were not specified.
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Studies enrolling patients who underwent cardiac or carotid vascular surgery were
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excluded. Carotid vascular surgeries were excluded as strokes in this population are primarily carotid-embolic and procedure related.18 Where multiple studies reported on the same cohort of patients, we included articles with the largest cohort size.
Data Extraction Two investigators (J.T. and G.H.) independently searched and extracted relevant articles which were subsequently verified by the senior investigator (O.F.) with discrepancies resolved by consensus. The following variables were extracted: study design and characteristics, inclusion and exclusion criteria, sample size, type of
Journal Pre-proof operations and follow-up duration. As we predicted a predominant number of studies to be of retrospective cohort design, quality ascertainment of atrial fibrillation was adjudicated in a similar manner as previously published.19 This involved assessment of three domains including: ascertainment of atrial fibrillation-free status at baseline, ascertainment of atrial fibrillation incidence in-hospital and atrial fibrillation recurrence after hospital discharge.
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Outcome Assessment
The primary end-point of this study was the association between new post-operative
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atrial fibrillation and stroke. In secondary analyses, we sought to (a) pool the
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prevalence of atrial fibrillation based on type of surgery; (b) assess the recurrence rate of atrial fibrillation in studies with longitudinal follow-up; and (c) identify the
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proportion with atrial fibrillation treated with therapeutic anticoagulation on discharge.
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Early adverse outcome was defined as stroke occurring within 30 days of operation. Late adverse outcome was defined as stroke occurring after 30 days of operation.
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We collected event counts and/or effect size data where available. Where effect
adjustment.
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sizes were reported as an adjusted metric, we extracted the variables used in this
Quality Assessment Methodological quality was assessed by two independent investigators using the Newcastle-Ottawa Scale (NOS) for quality assessment of observational studies in meta-analyses.20 Assessment of quality on this instrument was judged on study group selection, study-group comparability and outcome assessment. Studies meeting ≥5 criteria were considered to be high quality.
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Statistical Analysis
Descriptive statistics are presented as mean and standard deviation for continuous variables and absolute and relative frequencies for categorical variables. To determine the pooled risk associated with post-operative atrial fibrillation and stroke, summary estimates for relative risk (RR) with 95% confidence intervals (CI) were
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calculated using the Der Simonian and Laird random-effects model.21 As stroke following noncardiac surgery is a rare event, the assumption was made that hazard ratio (HR) and relative risk (RR) would converge with negligible difference, enabling
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data pooling across studies.22 Publication bias was assessed graphically through the
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creation of funnel plots of study point estimates against precision and explored
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further for small study effects using Egger’s test. Statistical heterogeneity was quantified using the I2 statistic. An I2 ≥80% was considered to be significant inter-
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study heterogeneity.23 We undertook pre-specified sensitivity analyses to explore
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potential sources of heterogeneity including study quality, type of surgery (thoracic and non-thoracic) and whether routine cardiac monitoring or electrocardiograms
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were performed. Stratification by surgery type was performed by thoracic and nonthoracic surgeries as thoracic operations are well recognized to carry higher rates of post-operative atrial fibrillation.24 Statistical analyses were performed using Comprehensive Meta-Analysis software (Version 3, Biostat, Englewood, NJ). Results The initial search yielded 7814 studies. We eliminated 7688 after initial screening. Details of the literature search and excluded studies are reported in Figure 1. Eighteen studies with a total of 3,758,541 patients were included in the qualitative
Journal Pre-proof analysis.3, 15, 16, 25-39 This included sixteen observational cohort studies3, 15, 16, 25-37 and two randomized controlled trials.38, 39 Four studies were excluded from the metaanalysis due to stroke outcome being reported as a composite of adverse cardiovascular events26, 27 and due to significant atrial fibrillation ascertainment bias (Table S2).3, 31 Among the fourteen studies included in the quantitative analysis (n=3,536,291), six reported early (<30-day)16, 25, 28, 29, 38, 39 while eight reported late (≥30 day) outcomes.15, 26, 30, 32-34, 36, 37 Individual study details including baseline
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characteristics and duration of follow-up are presented in Table 1 and Table S3,
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Methodological Quality of Data
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respectively.
Overall, the methodological quality of studies varied. On assessment of study quality
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based on the NOS (Table S4), fifteen studies were of high quality (median score 6,
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IQR 5-7) (Table S4). Overall atrial fibrillation ascertainment quality was deemed high
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in eight studies (Table 2, S2).
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Incidence of Post-Operative Atrial Fibrillation Reporting of post-operative atrial fibrillation was limited to the index hospitalisation. Among studies included in the quantitative analysis, 26,046 patients experienced new atrial fibrillation. The overall pooled incidence rate across studies was 13.6% (95%CI 11.5-15.9) with substantial heterogeneity (I2=99%, p<0.001) (Figure 2). The pooled incidence rate of atrial fibrillation was significantly higher after thoracic surgery when compared with non-thoracic surgery (16.2% vs 3.9%; p <0.001 for comparison between groups) (Figure 2, S2). A trend to higher atrial fibrillation incidence was observed in studies with continuous as opposed to opportunistic post-
Journal Pre-proof operative cardiac monitoring (13.4% vs 8.2%; p=0.07 for comparison between groups).
Risk Factors for Post-Operative Atrial Fibrillation Thirteen studies reported multivariable analyses that assessed predictors of postoperative atrial fibrillation and are summarized in Table S5. Although predictors tested varied across studies, older age, post-operative complications and thoracic
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surgery were commonly associated with atrial fibrillation.
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Recurrence of Atrial Fibrillation following Discharge & Anticoagulation
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Both recurrence rates and anticoagulation use in the studies were poorly reported. Only seven studies reported on anticoagulation use on discharge which ranged from
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1.5% to 74% (Table 2).16, 25, 31, 32, 37-39 Rates of anticoagulation use with post-
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operative atrial fibrillation was proportionally higher following non-thoracic noncardiac surgery compared to thoracic surgery (mean 38.4% (range 16-74%) vs 7.6% (range
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1.5-15%). Three studies reported rates of AF recurrence (range 3.6-16.6%) at
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varying time-intervals with no pre-specified methods.16, 36, 39
Risk of Stroke with Post-operative Atrial Fibrillation Among studies included in the quantitative analysis, the primary end-point of stroke occurred in 6,478 patients. Excluding two studies33, 37 that reported only the computed effect size, stroke occurred in 279 (1.5%) patients with post-operative atrial fibrillation compared to 6199 (0.4%) patients without, at maximal follow-up reported in each study. Atrial fibrillation was associated with a significantly higher risk of stroke (RR 2.51 95% CI 1.76-3.59) with moderate heterogeneity (I2= 78%; Figure
Journal Pre-proof 3). The hazard of stroke conferred by atrial fibrillation was lower following thoracic surgery when compared with non-thoracic noncardiac surgery (RR 1.95 95%CI 1.263.02 vs RR 3.09 95%CI 1.88-5.06; respectively, p=0.01 for comparison between groups). Heterogeneity was low in the thoracic surgery cohort (I 2=18%, p=0.32) although high in the non-thoracic noncardiac surgery cohort (I2=86%, p<0.001).
Subgroup Analyses
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Sub-group analyses to further evaluate potential sources of heterogeneity are presented in Figure 4. No significant differences in effect sizes were noted in the
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sub-group comparisons (p=ns), although studies with low sample size and those
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reporting only early outcomes had wider dispersion in the computed effect size.
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Publication Bias
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The funnel plot demonstrated slight asymmetry suggesting possible publication bias (Figure S2). However, no evidence of publication bias was demonstrated on
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calculation of the Egger’s test for small-study effects (p=0.29). Analysis to assess the
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influence of single studies on the effect estimate demonstrated a persistent significant association between post-operative atrial fibrillation and risk of stroke.
Discussion Occurrence of post-operative atrial fibrillation is well recognized to be an adverse prognostic marker in patients undergoing noncardiac surgery. However, the risk of stroke, particularly in the long-term, is unclear. The key findings of this meta-analysis are as follows: (1) the incidence of post-operative atrial fibrillation varied significantly across studies with non-uniform reporting of both anticoagulation use as well as
Journal Pre-proof atrial fibrillation recurrence; (2) new atrial fibrillation was associated with over a twofold increased risk of stroke; and (3) the hazard of stroke conferred by post-operative atrial fibrillation was significantly higher in patients with atrial fibrillation after nonthoracic noncardiac surgery. These results highlight the need for prospective, systematic screening for atrial fibrillation recurrence after noncardiac surgery and to assess whether the long-term risk of stroke can be mitigated with anticoagulation.
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A recent systematic review and meta-analysis by Lin et al. reported on the risk of mortality and stroke in patients undergoing surgery. 40 However, only two of the
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included studies reported the risk of stroke following noncardiac surgery. Our study
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focussed on a cohort of patients with atrial fibrillation after noncardiac surgery and included a larger cohort of patients from fourteen studies. Further, we made a
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targeted effort to exclude studies of patients with pre-existing non-valvular atrial
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fibrillation by rigorously appraising the methodology for ascertainment of atrial fibrillation. This was important as the thromboembolic risk from a paroxysmal
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well described.7
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episode of atrial fibrillation in someone with known non-valvular atrial fibrillation is
On pooled estimates of patients undergoing noncardiac surgery, post-operative atrial fibrillation was associated with a 2.5-fold increased risk of stroke. This risk was significantly lower when comparing thoracic versus non-thoracic noncardiac surgery (RR 1.95 vs 3.09, p=0.01). Prior studies evaluating the risk of stroke following cardiac surgery estimated an even lower risk of stroke (RR 1.36 [1.12-1.65]).41 The reasons for differences in stroke risk across surgeries are likely multifactorial. Mechanistically, as atrial fibrillation in cardiac and thoracic surgery occurs following
Journal Pre-proof direct manipulation of the heart, pulmonary veins or the lung hilum; it is therefore thought to be a direct and possibly short-lived trigger.24, 42 In noncardiac surgery, however, exact reasons for atrial fibrillation occurrence are less clear with some evidence suggesting that a pre-existing substrate may be accountable.4, 42 This is supported by studies that demonstrate recurrence rates of atrial fibrillation following noncardiac surgery to be as high as 64%.43 In these patients, it is postulated that the underlying substrate for atrial fibrillation was unmasked by the occurrence of acute
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triggers and pro-arrhythmic factors in the perioperative period. Following on, the potential risk of thromboembolism following noncardiac surgery may also be higher,
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also promote thrombogenesis.5, 11, 42
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as risk factors that predispose to atrial fibrillation (eg: age, hypertension, diabetes)
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Whether a link exists between perioperative atrial fibrillation burden, symptoms and
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long-term thrombogenic risk remains unclear. Although current risk prediction algorithms do not incorporate atrial fibrillation pattern to assessing the risk of
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thromboembolism, some population-based studies have demonstrated up to a 25%
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lower risk of stroke with non-permanent atrial fibrillation.44 In contrast, others have demonstrated a substantial risk of stroke even in patients with silent or undetected AF.45 Further, reports from the Framingham Heart study demonstrated that stroke can be the first manifestation of AF in 2 to 5% of patients. 46 The burden of atrial fibrillation, symptoms and timing of stroke was not well described in the studies included in this meta-analysis. As noncardiac surgical patients are less likely to be monitored post-operatively, it is conceivable that detected episodes of atrial fibrillation in this cohort would also be prolonged and more clinically apparent. 13, 14 Future studies with more effective surveillance for atrial fibrillation recurrence are
Journal Pre-proof warranted to better inform clinicians about the natural history of post-operative atrial fibrillation following noncardiac surgery.
Strokes that occur in patients with atrial fibrillation are known to be more disabling and confer significantly worse prognosis. 47 Therapeutic anticoagulation is proven to mitigate the risk of stroke with atrial fibrillation, particularly with the improved efficacy and safety profile of NOACs.8, 10 Results of a nationwide registry study included in
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the meta-analysis demonstrated a halving of the rate of stroke and systemic embolism in those prescribed anticoagulation for post-operative atrial fibrillation.37
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Despite this, aggregate results from studies included in this meta-analysis suggest
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that anticoagulation was under-prescribed in those with post-operative atrial fibrillation (range 1.5-74%). Butt et al. in a large national-registry study compared a
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matched cohort of patients with post-operative atrial fibrillation following noncardiac
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surgery and non-valvular atrial fibrillation. Utilizing data on anticoagulation prescription at 30-days following discharge, this study reported almost double the
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rate of anticoagulant use in patients with non-valvular atrial fibrillation (41.3 vs 24.3
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%).37 This disparity may in part have resulted from clinicians deeming the risk of post-operative and long-term bleeding to outweigh risks of thrombosis. However, the lack of guideline recommendations on anticoagulation use as well as standardized strategies to systematically screen for atrial fibrillation recurrence in this population is a significant gap in current practice.13, 14 The findings from this study are important in informing the clinician about the hazard conferred by post-operative atrial fibrillation in increasing long-term risk of stroke. However, future trials assessing the safety and efficacy as well as the timing and duration of oral anticoagulant therapy in this target population are imperative.
Journal Pre-proof
To our knowledge, this is the largest pooled study that reports the risk of stroke with post-operative AF following noncardiac surgery. Other strengths of this study include the systematic screening for pre-existing AF and well as a comparative assessment of the risk of stroke stratified by surgery type, type of cardiac monitoring and study design. However, certain limitations of our study warrant discussion. First, as most studies included were of a retrospective design, an important limitation is the
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possibility of misclassifying an episode as post-operative atrial fibrillation which may in fact represent an episode of paroxysmal nonvalvular atrial fibrillation. To address
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this ascertainment bias, we rigorously appraised the methodology for confirmation of
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atrial fibrillation at baseline. Second, different non-cardiac operations are associated with a varied risk of stroke.3, 39 Whilst we report differences in hazard for stroke in
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thoracic and non-thoracic noncardiac surgery, we were unable to compare other
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surgical sub-types due to stroke incidence not being stratified by type of surgery. From a therapeutic standpoint, we are unable to comment on the safety of
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anticoagulation in the postoperative setting as bleeding outcomes were not reported.
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Third, there was a paucity of data on both atrial fibrillation duration, recurrence and prescription of anticoagulation following surgery. Longer atrial fibrillation duration or recurrence may have led to increased recognition and treatment with anticoagulation. Fourth, the generalizability of our findings could also be affected by the variability in definition of stroke and a lack of differentiation between ischemic and hemorrhagic outcomes- which were not uniformly reported across studies. Lastly, it is important not to infer causation from this pooled cohort of observational studies. It is increasingly recognized that the risk of stroke with atrial fibrillation is not entirely related to the presence of atrial thrombus. 48
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Conclusion New post-operative atrial fibrillation following noncardiac surgery was associated with a 2.5-fold increase in risk of stroke. This risk was highest among patients undergoing non-thoracic noncardiac surgery. Given the efficacy of NOACs for stroke prophylaxis, prospective studies are warranted to assess whether they can reduce
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the risk of stroke in patients with post-operative atrial fibrillation.
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Khormaee S, Do HT, Mayr Y, et al. Risk of Ischemic Stroke After Perioperative Atrial Fibrillation in Total Knee and Hip Arthroplasty Patients. J Arthroplasty. 2018;33:3016-3019.
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New Clinically Important Atrial Fibrillation After Noncardiac Surgery: A Prospective Cohort Study. Anesth Analg. 2017;125:162-169. 40.
Lin MH, Kamel H, Singer DE, Wu YL, Lee M, Ovbiagele B. Perioperative/Postoperative Atrial Fibrillation and Risk of Subsequent Stroke and/or Mortality. Stroke. 2019:STROKEAHA118023921.
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analysis. Eur Heart J. 2016;37:1591-1602. 45.
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have a worse prognosis than patients without: data from the Austrian Stroke registry.
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Journal Pre-proof Figure Legend
Figure 1: PRISMA Flow Diagram
Figure 2: Incidence of new postoperative atrial fibrillation stratified by thoracic and non-thoracic surgery
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The blue diamond indicates the summary estimate for the incidence of postoperative atrial fibrillation in the thoracic and non-thoracic surgical sub-groups. The red
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diamond represents the pooled estimate from the entire cohort.
Figure 3: Risk of stroke with post-operative atrial fibrillation following thoracic and
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non-thoracic noncardiac surgery
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POAF, post-operative atrial fibrillation
atrial fibrillation
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Figure 4: Sub-group Analyses evaluating the risk of stroke with new postoperative
Journal Pre-proof
Table 1. List of Studies included in Review Ye ar
Type of Surgery
Study design
Locatio n
n
Key Inclusion criteria
Polanczyk et al.*
19 98
All major noncardiac procedures
Prospecti ve cohort study
Boston, USA
4,181
Sinus rhythm at pre-op evaluation.
Amar et al.
20 00
Pneumonec tomy or lobectomy
Randomi sed, doubleblind, placebocontrolle d trial of IV diltiazem
New York, USA
330
Sinus rhythm, >60yo if undergoing lobectomy.
Chronic atrial arrhythmia , second degree AV block, taking class I or III antiarrhyth mics or a CCB.
30 days
Murthy et al.
20 03
Esophagect omy for cancer
Retrospe ctive cohort study
POISE study group.
20 08
All noncardiac surgery
Winkel et al.*
20 09
Vascular surgery#
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ro of
Author
F/U durati on Inpatie nt stay
921
Esophagect omy for oesophagus or gastric cardia Ca
Abdominal resection of gastric cardia cancer, staged resections.
Minim um 3 years
Randomi sed controlle d trial of preoperat ive metoprol ol
Multinational
8,351
≥45yo, had or at risk of atherosclero tic heart disease
HR <50, 2nd or 3rd deg heart block, asthma, already on a betablocker, on verapamil, CABG in the last 5 years and no ischaemia since.
30 days
Prospecti ve cohort study
Rotterda m, The Netherla
317
Elective AAA repair or
History or arrhythmia ,
12 Month s (IQR
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Hong Kong
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Key exclusion Criteria
Journal Pre-proof peripheral artery bypass.
pacemaker, 2-28) LVH, LBBB/RB BB. Previous atrial arrhythmia .
20 10
Thoracic surgery
Retrospe ctive cohort study
USA
13,906
Lobectomy “or greater”.
Henri et al.
20 11
Lung transplant
Retrospe ctive cohort study
Montrea l, Canada
224
Consecutiv e patients undergoing lung transplant in database.
Imperatori 20 et al. 12
Lobectomy for lung Cancer
Prospecti ve cohort study
Varese, Italy
Rao et al.
20 12
Oesophagec Retrospe tomy for ctive cancer cohort study
Notting ham, United Kingdo m
Gialdini et al.
20 14
All noncardiac surgery
Retrospe ctive cohort study
Mc Cormack et al.
20 14
Oesophagea l Surgery
Chaikrian gkrai et al.
20 15
Giambron e et al.
20 15
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Onaitis et al.
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nds
Inpatie nt stay
Chronic AF, pacemaker devices.
Media n 36 month s
997
Oesophagec tomy
Preoperative arrhythmia .
Inpatie nt stay
Californ ia, USA
1,655, 817
Patients undergoing “major surgery”
Preexisting AF, previous cerebrovas cular disease.
Mean 2.1 years
Retrospe ctive cohort study
Dublin, Ireland
473
Surgery for oesophagea l or junctional Cancer
Preexisting AF
Media n 39 month s (IQR 7-104)
Lung transplant
Retrospe ctive cohort study
Houston , USA
293
Lung transplant
Preexisting atrial arrhythmia
28 ± 17 month s
Lobectomy for Lung cancer
Retrospe ctive cohort study
Californ ia, Florida & New York,
20,695
Lobectomy for lung cancer
Previous atrial arrhythmia , preexisting
Minim um 90 days
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Not specifically stated.
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454
Minim um 30 days
>18yo
Journal Pre-proof USA
supraventri cular tachycardi a, missing data
20 16
Lung Cancer Surgery
Retrospe ctive cohort study
Kyoto, Japan
593
Lung cancer operation
Chronic AF, previous ablation for AF.
30 days
Butt et al.
20 18
All noncardiac surgery
Retrospe ctive cohort study
Denmar k
1,520, 109
>30yo, first time surgery, no recent cancer diagnosis,
<30yo, previous AF, previous antiarrhythmic drugs
3.2 Years (IQR 0.9-7)
Khormaee et al.
20 18
Total hip or knee replacement
Retrospe ctive cohort study
New York, USA
>18yo
Previous Diagnosis of atrial fibrillation
Minim um 1 year
Sholte et al.*
20 18
Liver transplant
Retrospe ctive cohort study
Yoshida et al.
20 18
All noncardiac surgery
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Muranishi et al.*
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528,24 6
916
Liver transplant
Died within 30 days of transplant
Media n 4.9 (IQR 1.310) years
Kyoto, Japan
1,718
≥18yo, admitted to ICU and stayed longer then 24 hrs
Prior history of AF, cardiac surgery, rhythm abnormalit y other than AF..
Inpatie nt stay
na
lP
Rotterda m, The Netherla nds
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Retrospe ctive cohort study
* Denotes studies not included in meta-analyses, but part of systemic review. F/U, follow-up, AF, atrial fibrillation, AAA, abdominal aortic aneurysm, IQR, interquartile range.
Table 2. Atrial Fibrillation Definition, Timing and Anticoagulation use Author, year AF AF AF Anticoagulati Definition Ascertainme Timing on on * nt quality Discharge
% AF on Dischar ge
AF Recurren ce
Journal Pre-proof
Onaitis, 2010
Henri, 2011
Imperatori, 2012
Rao, 2012
Gialdini, 2014
Mc Cormack, 2014 Chaikriangkr ai, 2015 Giambrone, 2016 Muranishi, 2016
New AF requiring treatment New AF or flutter for >30 seconds Any AF on ECG or telemetry
9 (15%)
2 (3.3%)
NR
Low
NR
NR
NR
NR
High
NR
35 (16.6%)
NR
20 (16.6%)
High
Peak incidence day 1 (85%) NR
NR
3 (23%)
NR
NR
NR
NR
7 ± 11 days
1 (1.5%)
1 (1.5%)
8 (3.6%)
NR
2 (4.4%)
NR
High
Peak incidence day 2 (69%) NR
0
NR
NR
Low
NR
NR
NR
NR
Low
71 (74%)
8 (8.3%)
NR
NR
NR
42 (14%)
Low
Median 3 (IQR 120) days Median 5 (IQR 3-9) days NR
NR
NR
NR
Low
NR
4 (9.8%)
NR
NR
Low
New AF confirmed on 12-lead ECG ICD-9 codes, not present on prior encounters Any new AF confirmed on 12-lead ECG New AF or flutter for >30 seconds ICD-9 codes not present on admission New AF confirmed on 12-lead ECG
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NR
re
Winkel, 2009
NR
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POISE, 2017
NR
High
Peak incidence day 2/3 postoperative ly (44% of cases) 3 ±2 days
High
na
Murthy, 2003
Low
High
ur
Amar, 2000
New AF, flutter, multifocal atrial tachycardia or supraventricul ar tachycardia New sustained AF ≥15 minutes or clinically significant Any new AF on ECG or telemetry New clinically important AF (AF with symptoms or requiring therapy) New AF confirmed on 12-lead ECG
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Polanczyk, 1998
High
Journal Pre-proof ICD-10 Low NR 859 (24.3%) NR NR codes; AF not present previously Khormaee ICD-9 codes Low NR NR NR NR 2018 not present on admission Scholte 2018 De-novo AF Low NR NR NR NR not recorded in past medical history Yoshida New AF not High Median 6 (4.3%) NR NR 2018 present on 1.5 (0.5prior history 2.1) days that persisted >6 hours * Quality of attainment of atrial fibrillation data as determined by assessment proposed by Mcintyre et al. – see supplementary table S2 AF, atrial fibrillation; AF, atrial fibrillation, ECG, electrocardiogram, IQR, interquartile range, ICD, international classification of diseases, NR, not reported
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Butt, 2018
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Total n
n
Strokes
n
Strokes
Calculated Stroke Risk
Polanczyk et al. (1998)*
4,181
222
2 (0.9%)
39,59
NR
-
Amar et al. (2000)
330
60
1 (1.7%)
270
0 (0%)
-
Murthy et al. (2003)
921
144
1 (0.7%)
144 §
0 (0%)
-
POISE (2008)
8,351
211
6 (2.8%)
Winkel et al. (2009)†
317
15
NR*
Onaitis et al (2010)
13,906
1,755
23 (1.3%)
Henri et al. (2011)
224
65
1 (1.5%)
Imperatori et al. (2012)
454
45
Rao et al. (2012)
997
209
1,655,817
54 (0.7%)
-
302
NR
HR 4.2, 95% CI (2.1‡ 8.8)
61 (0.5%)
-
159
7 (4.4%)
-
2 (4.4%)
409
7( 1.7%)
-
2 (1.0%)
788
4 (0.5%)
-
-p
8,140
12,151
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na
Gialdini et al. (2014)
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Author, (year)
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Table 3. Individual Study breakdown of Postoperative Atrial Fibrillation and Stroke Rates Post-operative No Post-operative Atrial Fibrillation Atrial Fibrillation
12874
189 (1.0%)
1,642,943
5,914 (0.4%)
-
96
4 (4.2%)
377
0 (0%)
-
473
Chaikriangkrai et al. (2015)
293
73
2 (2.7%)
220
1 (0.5%)
-
20,695
2,449
37 (1.5%)
18,246
146 (0.8%)
-
593
38
3 (8%)
555
NR
-
1,520,109
6,048
NR
1,514,061
NR
HR 1.89 (95% CI 1.56-2.29)
528,246
3,646
NR
524,600
NR
OR 2.7 (95% CI 1.54.8)
Sholte et al.*
916
NR
NR
NR
NR
OR 2.2 (95%CI 0.875.54) ‡
Yoshida et al. (2018)§
1,718
151
11 (7.3%)
1,567
5 (0.3%)
Muranishi et al. † (2016) Butt et al. (2018) Khormaee et al. (2018)
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Giambrone et al. (2015)
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Mc Cormack et al. (2014)
*Not included in meta-analysis as atrial fibrillation ascertainment bias determined to be too high.
Journal Pre-proof †Excluded from metanalysis as result is a composite endpoint of adverse cardiovascular events, not stroke alone ‡ Composite risk for adverse cardiovascular events § Post-operative Atrial fibrillation cases matched to patients without Post-operative Atrial fibrillation in study
Clinical Significance
Although new post-operative atrial fibrillation confers an adverse prognosis following noncardiac surgery, it is unclear whether it increases the risk of
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stroke Post-operative AF following noncardiac surgery was associated with a 2.5-fold increased risk of stroke. This risk was highest following non-thoracic surgery.
-p
Whether anticoagulation can mitigate the risk of stroke in patients with post-
ur
na
lP
re
operative atrial fibrillation warrants further study
Jo
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Figure 4