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Department of Medicine, McMaster University, Hamilton, Ontario, CanadaPopulation Health Research Institute, McMaster University, Hamilton, Ontario, CanadaDepartment of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, Ontario, Canada
Department of Medicine, McMaster University, Hamilton, Ontario, CanadaPopulation Health Research Institute, McMaster University, Hamilton, Ontario, CanadaDepartment of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, Ontario, Canada
Population Health Research Institute, McMaster University, Hamilton, Ontario, CanadaDepartment of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, Ontario, CanadaDepartment of Surgery, McMaster University, Hamilton, Ontario, Canada
Department of Medicine, McMaster University, Hamilton, Ontario, CanadaPopulation Health Research Institute, McMaster University, Hamilton, Ontario, CanadaDepartment of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, Ontario, Canada
Department of Medicine, McMaster University, Hamilton, Ontario, CanadaPopulation Health Research Institute, McMaster University, Hamilton, Ontario, CanadaDepartment of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, Ontario, Canada
Department of Medicine, McMaster University, Hamilton, Ontario, CanadaPopulation Health Research Institute, McMaster University, Hamilton, Ontario, Canada
Population Health Research Institute, McMaster University, Hamilton, Ontario, CanadaDepartment of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, Ontario, CanadaDepartment of Surgery, McMaster University, Hamilton, Ontario, Canada
Department of Medicine, McMaster University, Hamilton, Ontario, CanadaPopulation Health Research Institute, McMaster University, Hamilton, Ontario, CanadaDepartment of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, Ontario, Canada
Perioperative atrial fibrillation (POAF) after cardiac surgery has been associated with an increased risk of stroke in some studies. However, the exact magnitude of this association during short-term and long-term follow-up remains unclear.
Methods
We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) for the time period from database inception to October 2020. We included observational studies with ≥ 100 patients that reported data on short-term or long-term stroke risk in patients with and without POAF after cardiac surgery. Data were pooled using random-effects models. We reported summary risk ratios (RRs) for studies reporting multivariable adjusted results and calculated absolute risk differences (ARDs) with 95% confidence intervals (CIs).
Results
A total of 55 studies with 540,209 patients were included. POAF was associated with both an increased relative risk (RR 1.69; 95% CI, 1.41-2.03; I2 = 82%; 9 studies) and absolute risk of short-term stroke (4.5% vs 2.5%; ARD 2.0%; 95% CI, 1.28-2.89). POAF was associated with an increased relative risk (RR 1.20; 95% CI, 1.12-1.29; I2 = 16%; 10 studies) and absolute risk of long-term stroke (1.06 vs 0.88 per 100 patient-years; ARD 0.18 per 100 patient-years; 95% CI, 0.07-0.26). Sensitivity analyses of high-quality studies and studies reporting either ischemic or embolic strokes yielded similar findings.
Conclusions
POAF after cardiac surgery was associated with an increased risk of both short-term and long-term stroke. However, the long-term stroke ARD was small, and whether these patients will benefit from long-term oral anticoagulation therapy is unclear.
Résumé
Contexte
La fibrillation auriculaire périopératoire (FAPO) après une chirurgie cardiaque a été associée à un risque accru d’accident vasculaire cérébral (AVC) dans certaines études. Cependant, l’ampleur exacte de cette association durant le suivi à court et à long terme reste incertaine.
Méthodologie
Nous avons effectué des recherches dans les bases de données PubMed, Embase et CENTRAL (Cochrane Central Register of Controlled Trials) pour la période allant de la création de ces bases à octobre 2020. Nous avons inclus des études d’observation comptant ≥ 100 patients et rapportant des données sur le risque d’AVC à court ou à long terme chez les patients ayant présenté ou non une FAPO après une chirurgie cardiaque. Les données ont été regroupées à l’aide de modèles à effets aléatoires. Nous avons consigné les rapports de risque (RR) sommaires pour les études rapportant des résultats corrigés multivariables et calculé les différences de risque absolu (DRA) avec des intervalles de confiance (IC) à 95 %.
Résultats
Au total, 55 études portant sur 540 209 patients ont été incluses. La FAPO était associée à une augmentation tant du risque relatif (RR : 1,69; IC à 95 % : 1,41 à 2,03; I2 = 82 %; 9 études) que du risque absolu d’AVC à court terme (4,5 % vs 2,5 %; DRA : 2,0 %; IC à 95 % : 1,28 à 2,89). La FAPO était également associée à une augmentation du risque relatif (RR : 1,20; IC à 95 % : 1,12 à 1,29; I2 = 16 %; 10 études) et du risque absolu d’AVC à long terme (1,06 vs 0,88 par 100 années-patients; DRA : 0,18 par 100 années-patients; IC à 95 % : 0,07 à 0,26). Les analyses de sensibilité des études de haute qualité et des études rapportant des AVC ischémiques ou emboliques ont donné des résultats similaires.
Conclusions
La FAPO après une chirurgie cardiaque a été associée à un risque accru d’AVC à court et à long terme. Cependant, comme la différence de risque absolu d’AVC à long terme était faible, la possibilité qu’une anticoagulothérapie orale à long terme soit bénéfique pour ces patients est incertaine.
The incidence of perioperative atrial fibrillation (POAF) after cardiac surgery ranges between 20% and 40%.
Postoperative atrial fibrillation is not associated with an increased risk of stroke or the type and number of grafts: a single-center retrospective analysis.
However, whether the observed increase in stroke risk persists beyond the immediate perioperative period is unclear. Although most observational studies have shown an association between POAF and short-term stroke risk,
Long-term thromboembolic risk in patients with postoperative atrial fibrillation after coronary artery bypass graft surgery and patients with nonvalvular atrial fibrillation.
Compared with matched controls, patients with postoperative atrial fibrillation (POAF) have increased long-term AF after CABG, and POAF is further associated with increased ischemic stroke, heart failure and mortality even after adjustment for AF.
New-onset perioperative atrial fibrillation after coronary artery bypass grafting and long-term risk of adverse events: an analysis from the coronary trial.
Defining the exact magnitude of the excess stroke risk in patients with POAF is crucial in order to determine whether anticoagulation has a meaningful effect that outweighs the risks of bleeding. To address these issues, we performed a systematic review and meta-analysis evaluating the short-term and long-term relative and absolute risks of stroke in patients with POAF after cardiac surgery.
Methods
This systematic review and meta-analysis is reported according to the Meta-analyses of Observational Studies in Epidemiology (MOOSE) reporting guidelines.
Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42020170568).
Search methods
Relevant studies were identified through a systematic literature search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from the time of database inception until October 26, 2020. Eligible studies were identified using a search strategy combining keywords and terms related to cardiac surgery, AF, and stroke (Supplemental Appendix S1). Additional articles were identified through reviewing reference lists from relevant studies and consulting experts in the field.
Study selection and outcome assessment
Observational studies and observational analyses from randomized controlled trials were considered eligible for inclusion. Studies were included if they (i) had patients undergoing cardiac surgery; (ii) reported stroke outcomes stratified by the presence or absence of POAF; (iii) defined POAF as a new-onset AF episode; (iv) had ≥ 100 participants; and (v) only included patients ≥ 18 years of age. The following were excluded: (i) studies of transcatheter valve implantation procedures; (ii) studies that did not distinguish between short-term and long-term strokes; and (iii) studies not published as full-text articles (eg, meeting abstracts). Studies were not excluded on the basis of publication language. Screening and full-text review were conducted independently and in duplicate by 6 of the authors (M.K.W., P.M., R.H., L.B., Y.C.P.C., M.Z.A), with discrepancies resolved through consensus or by consulting with a third independent reviewer.
The primary outcome was stroke. Acceptable definitions of stroke included any stroke, ischemic stroke, and embolic stroke. When multiple types of stroke were reported, we used the outcome of ischemic stroke. We collected information on short-term and long-term stroke risk separately. Short-term strokes were defined as events occurring either in-hospital or within the first 30 days after surgery. Long-term strokes were events occurring either after discharge or more than 30 days after surgery.
Data extraction
Data extraction was performed independently and in duplicate (M.K.W., P.M., R.H., L.B., Y.C.P.C., M.Z.A) using structured forms. Information was collected on study design, sample size, types of surgical procedures, baseline demographics, definitions for POAF and stroke, number of patients with POAF and stroke, reported associations between POAF and stroke, covariates used for multivariable adjustment, and anticoagulation use. If several multivariable models were available, results were extracted from the most adjusted model. We contacted study authors to obtain missing data, unpublished data with multivariable adjustment, and clarifications regarding the number and timing of strokes.
Assessment of the quality of evidence
The Newcastle–Ottawa Scale (NOS) was used to assess the quality of observational studies. This scale assigns a maximum of 9 points in 3 domains: selection of study groups, comparability of groups, and ascertainment of exposures and outcomes.
Quality assessment was completed independently and in duplicate. Disagreements were resolved through consensus, consistent with the process outlined for study eligibility. Studies were considered high quality if they received ≥ 7 points.
Statistical analysis
Separate meta-analyses were constructed for short-term and long-term stroke risk. For our main meta-analyses, we included only studies reporting multivariable adjusted data. Pooled risk ratios (RRs) and their corresponding 95% confidence intervals (CIs) were estimated using the inverse variance method with random-effects models. We used tests of interaction to determine whether there were significant differences between subgroups of studies with and without multivariable adjustment. We additionally reported the pooled RRs across all studies when no significant differences were reported between adjusted and unadjusted subgroups. Between-study statistical heterogeneity was quantified using the I2 value. Heterogeneity was considered to be important when I2 was greater than 30%.
Deeks J, Higgins J, Altman D. Analysing data and undertaking meta-analyses. In: Cochrane Handbook for Systematic Reviews of Interventions. Vol 2020. Cochrane: 2019. Available at: https://training.cochrane.org/handbook. Accessed December 8, 2021.
The absolute risk difference (ARD) and its corresponding 95% CIs were calculated for short-term and long-term stroke using methods described in the Cochrane Handbook for Systematic Reviews of Interventions.
Schünemann HJ, Viste GE, Higgings JPT, et al. Interpreting results and drawing conclusions. In: Higgins JPT, Santesso N, Deesk JJ, Glasziou P, eds. Cochrane Handbook for Systematic Reviews of Interventions. city: Cochrane; 2020. Available at: www.training.cochrane.org/handbook. Accessed December 8, 2021.
We estimated the baseline short-term and long-term absolute risks of stroke by calculating an overall weighted incidence of stroke in patients without POAF across all included studies. We estimated the absolute risk of stroke and its corresponding 95% CIs in patients with POAF by adding the absolute risk difference and its corresponding 95% CIs to the baseline risk estimate.
We planned several analyses a priori to identify potential sources of heterogeneity. We performed subgroup analyses based on the type of surgical procedure performed (ie, isolated coronary artery bypass surgery (CABG) vs valvular procedures) for short-term and long-term risks of stroke. For studies reporting long-term risk of stroke, we performed univariable meta-regression analyses using a series of predetermined variables that were reported by at least 10 studies, including anticoagulation use, length of follow-up, study size, mean age, and female sex (%). To assess the robustness of our findings, we performed sensitivity analyses by limiting analyses to studies deemed to be of high quality, studies reporting either ischemic or embolic strokes, studies published in the year 2010 or later, and studies that reported the method by which POAF was detected. All analyses were conducted using Review Manager (Cochrane Collaboration, London, UK), version 5.4, or Stata (StataCorp, LLC, College Station, TX), version 16. Analyses were 2-tailed with statistical significance set at P < 0.05.
Results
Study selection
Through database searching, reviewing the bibliographies of relevant literature, and consulting with field experts, 14,535 unique citations were identified. After review of the full text of 578 articles, 55 studies were identified as meeting eligibility criteria.
Postoperative atrial fibrillation is not associated with an increased risk of stroke or the type and number of grafts: a single-center retrospective analysis.
Long-term thromboembolic risk in patients with postoperative atrial fibrillation after coronary artery bypass graft surgery and patients with nonvalvular atrial fibrillation.
Compared with matched controls, patients with postoperative atrial fibrillation (POAF) have increased long-term AF after CABG, and POAF is further associated with increased ischemic stroke, heart failure and mortality even after adjustment for AF.
Postoperative atrial fibrillation in patients undergoing aortocoronary bypass surgery carries an eightfold risk of future atrial fibrillation and a doubled cardiovascular mortality.
Patterns of management of atrial fibrillation complicating coronary artery bypass grafting: results from the PRoject of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT-IV) Trial.
Risk factors of atrial fibrillation following off-pump coronary artery bypass graft surgery: predictive value of C-reactive protein and transfusion requirement.
Statins reduce short- and long-term mortality associated with postoperative atrial fibrillation after coronary artery bypass grafting: impact of postoperative atrial fibrillation and statin therapy on survival.
Transoesophageal echocardiography for prediction of postoperative atrial fibrillation after isolated aortic valve replacement: two-dimensional speckle tracking for intraoperative assessment of left ventricular longitudinal strain.
Usefulness of postoperative atrial fibrillation as an independent predictor for worse early and late outcomes after isolated coronary artery bypass grafting (multicenter Australian study of 19,497 patients).
Of the 539,520 participants included, 151,856 (28.1%) had POAF. A flow diagram of the study selection process is shown in Figure 1. Three studies with a total of 443 participants reported no strokes,
leaving 52 studies eligible for inclusion in the meta-analysis. Three primary study authors provided unpublished information on the number of short-term and long-term strokes.
Long-term thromboembolic risk in patients with postoperative atrial fibrillation after coronary artery bypass graft surgery and patients with nonvalvular atrial fibrillation.
The characteristics of the 55 included studies are outlined in Table 1. The average participant age was 65.8 years (standard deviation: 11.4), and 29.8% were female. Most studies were conducted in North America (33%), Europe (28%), and Asia (19%). Short-term stroke risk was reported in 48 studies, of which 9 reported multivariable adjusted results. Long-term stroke risk was reported in 19 studies, of which 10 reported multivariable adjusted results. In the studies reporting long-term stroke risk, follow-up ranged from 1 to 17.8 years (median: 2.4 years). Studies included patients undergoing isolated CABG surgery (35 studies), valvular surgery with or without a concomitant procedure (11 studies), or a combination of different cardiac procedures (9 studies). A total of 36 studies made the diagnosis of POAF, using either continuous telemetry monitoring or an electrocardiogram. Of the remaining studies, 10 used database records, 2 used medical records, and 7 did not specify how the diagnosis was obtained. A total of 46 studies reported a composite of all strokes; 8 reported ischemic strokes; and 1 reported embolic strokes. For the diagnosis of stroke, 6 studies required imaging findings, 8 studies required compatible clinical findings, 23 studies used diagnoses registered in databases, and 12 studies did not specify a data source.
Postoperative atrial fibrillation in patients undergoing aortocoronary bypass surgery carries an eightfold risk of future atrial fibrillation and a doubled cardiovascular mortality.
Patterns of management of atrial fibrillation complicating coronary artery bypass grafting: results from the PRoject of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT-IV) Trial.
Long-term thromboembolic risk in patients with postoperative atrial fibrillation after coronary artery bypass graft surgery and patients with nonvalvular atrial fibrillation.
Risk factors of atrial fibrillation following off-pump coronary artery bypass graft surgery: predictive value of C-reactive protein and transfusion requirement.
Risk factors of atrial fibrillation following off-pump coronary artery bypass graft surgery: predictive value of C-reactive protein and transfusion requirement.
New-onset perioperative atrial fibrillation after coronary artery bypass grafting and long-term risk of adverse events: an analysis from the coronary trial.
Statins reduce short- and long-term mortality associated with postoperative atrial fibrillation after coronary artery bypass grafting: impact of postoperative atrial fibrillation and statin therapy on survival.
Transoesophageal echocardiography for prediction of postoperative atrial fibrillation after isolated aortic valve replacement: two-dimensional speckle tracking for intraoperative assessment of left ventricular longitudinal strain.
Postoperative atrial fibrillation is not associated with an increased risk of stroke or the type and number of grafts: a single-center retrospective analysis.
Usefulness of postoperative atrial fibrillation as an independent predictor for worse early and late outcomes after isolated coronary artery bypass grafting (multicenter Australian study of 19,497 patients).
Compared with matched controls, patients with postoperative atrial fibrillation (POAF) have increased long-term AF after CABG, and POAF is further associated with increased ischemic stroke, heart failure and mortality even after adjustment for AF.
Outcome (-): outcome not reported. Outcome (∗): outcome reported. Multivariable adjustment (-): no data or adjustment results not used in meta-analysis. Multivariable adjustment (∗): multivariable adjusted results used in meta-analysis.
Among all 55 studies included in the review, 8 of 48 studies (17%) that reported short-term stroke and 13 of 19 studies (68%) that reported long-term stroke were determined to be high-quality studies (Supplemental Table S1). Fourteen studies (25%) reported follow-up data that were at least 90% complete, and 18 studies (33%) used diagnostic criteria that demonstrated recorded strokes were new events. Among studies that reported multivariable adjusted results, 6 of 9 studies (67%) that reported short-term stroke, and 10 of 10 studies (100%) that reported long-term stroke were determined to be high-quality studies.
Risk of short-term stroke
Among studies that reported short-term stroke risk, 30.1% of participants had POAF (48 studies; Supplemental Table S2). The incidence of POAF was higher among participants undergoing valvular procedures (49.0%; 9 studies), compared to those undergoing isolated CABG (24.3%; 31 studies).
Among studies that reported multivariable adjusted results, the relative risk of short-term stroke was significantly higher in patients with POAF (RR 1.69; 95% CI, 1.41-2.03; 9 studies). Substantial heterogeneity was detected across study results (I2 = 82%). There was no evidence of publication bias (Egger test, P = 0.48). Studies reporting unadjusted results had a higher pooled relative risk (RR 2.22; 95% CI, 1.87-2.63; I2 = 61%; 39 studies) compared to studies with multivariable adjustment (test for interaction, P = 0.03; Fig. 2). The estimated incidence of short-term stroke was 4.5% vs 2.5% in patients with and without POAF (ARD 2.0%; 95% CI, 1.28-2.89; Fig. 3).
Figure 2Forest plot for short-term risk of stroke. Forest plot for short-term stroke risk in patients with vs without perioperative atrial fibrillation (POAF), stratified by studies with vs without multivariable adjustment. Results are reported as an overall risk ratio. Short-term stroke is defined as in-hospital events or events occurring within 30 days of surgery. AVR, aortic valve replacement; CABG, coronary artery bypass graft; df, degrees of freedom; IV, inverse variance; MV, mitral valve; MVR, mitral valve replacement; SE, standard error.
Figure 3Estimated absolute risks for short-term and long-term stroke. Estimated absolute risks of short-term and long-term stroke stratified by perioperative atrial fibrillation (POAF) status and type of surgery. The number of included studies used to estimate the baseline risk is indicated in brackets. Absolute risks are estimated in the POAF group using the relative risks calculated from the study meta-analyses. Error bars represent 95% confidence intervals (CIs).
Among studies that reported long-term stroke risk, 19.7% of participants had POAF (18 studies; Supplemental Table S2). The incidence of POAF was higher among patients undergoing valvular procedures (44.9%; 3 studies), compared with those undergoing isolated CABG (27.3%; 13 studies).
Among studies that reported multivariable adjusted results, the overall risk of long-term stroke was significantly increased in patients with POAF (RR 1.20; 95% CI, 1.12-1.29; 10 studies; Fig. 4). Although between-study heterogeneity was low (I2 = 16%), we found evidence of publication bias (Egger test, P = 0.05). The RR after study imputation by the trim-and-fill method was 1.18 (95% CI, 1.10-1.26; Supplemental Fig. S1). Results remained similar after pooling both unadjusted and adjusted studies (RR 1.24; 95% CI, 1.13-1.35; 18 studies; Fig. 4). The estimated incidence of long-term stroke was 1.06 vs 0.88 per 100 patient-years in patients with and without POAF (ARD 0.18 per 100 patient-years; 95% CI, 0.07-0.26; Fig. 2).
Figure 4Forest plot for long-term risk of stroke. Forest plot for long-term stroke risk in patients with vs without perioperative atrial fibrillation (POAF), stratified by studies with vs without multivariable adjustment. Results are reported as an overall risk ratio. Long-term stroke is defined as strokes occurring > 30 days after surgery or after hospital discharge. CI, confidence interval; df, degrees of freedom; IV, inverse variance; SE, standard error.
Patients with POAF were more frequently discharged on anticoagulation, compared with those without POAF (11 studies; n = 50,522; 17.7% vs 4.4%; Supplemental Table S3). The average level of use of long-term anticoagulation in patients with vs without POAF was 6.3% and 2.5%, respectively (2 studies; mean follow-up 5.1 years).
New-onset perioperative atrial fibrillation after coronary artery bypass grafting and long-term risk of adverse events: an analysis from the coronary trial.
Postoperative atrial fibrillation in patients undergoing aortocoronary bypass surgery carries an eightfold risk of future atrial fibrillation and a doubled cardiovascular mortality.
In the subgroup analysis comparing the risk of short-term stroke across different types of surgery, isolated CABG was associated with a higher relative risk of short-term stroke (RR 2.17; 95% CI, 1.89-2.49) than valvular surgery (RR 1.52; 95% CI, 1.15-2.02) (P for interaction = 0.03). This difference was not seen among studies reporting long-term stroke risk (P for interaction = 0.13; Supplemental Table S4). Univariable meta-regression analyses did not demonstrate differential associations in the risk of long-term stroke according to follow-up duration or study size (Supplemental Table S5). A post hoc analysis of long-term stroke studies found that the absolute risk of stroke per 100 patient-years was greater in studies reporting a higher prevalence of previous stroke among patients with POAF (upper vs lower tertile of studies; independent t-test P = 0.02; Supplemental Fig. S2).
Sensitivity analyses of high-quality studies, studies reporting only ischemic or embolic strokes, studies published in the year 2010 or later, and studies that specified the method by which POAF was detected demonstrated consistent results (Supplemental Table S6).
Discussion
In this systematic review and meta-analysis of 55 studies with over 500,000 participants undergoing cardiac surgery, we found that POAF was associated with an increased risk of short-term and long-term stroke. Patients with POAF had a 2% higher absolute risk of short-term stroke, compared to patients without POAF. In contrast, the absolute risk of stroke was only 0.18 per 100 patient-years higher in patients with POAF during long-term follow-up. These differences in risk suggest that short-term and long-term stroke prevention in POAF patients should be approached separately.
Although anticoagulation is the cornerstone of stroke prevention in patients with chronic nonoperative AF, its routine use in patients with POAF after cardiac surgery is controversial. Although guidelines suggest that clinicians should consider anticoagulation in this scenario,
2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS): The Task Force for the Diagnosis and Management of Atrial Fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
no high-quality evidence supports these recommendations. Some groups have recommended a limited treatment duration of 4 weeks after sinus rhythm restoration.
Our meta-analysis found that the increased risk of stroke with POAF was concentrated in the early postoperative period, suggesting that such a strategy may be beneficial.
In the absence of high-quality data, however, there are several important knowledge gaps associated with such an approach. First, many short-term strokes occur during or shortly after surgery, and therefore cannot be prevented with anticoagulation therapy. A retrospective cohort study by Kollar et al. that included 2964 patients undergoing CABG found that 4 of 9 early strokes occurred intraoperatively.
In our meta-analysis, we found that patients with POAF undergoing valvular procedures had a higher absolute risk increase in short-term stroke than those undergoing isolated CABG surgery. A plausible possibility is that intraoperative factors specific to valvular procedures, such as longer cross-clamping times and embolization risk during surgical excision,
contributed to the higher stroke risk. Second, alternate pathophysiologic mechanisms may mediate the short-term risk of postoperative stroke in POAF, for which the effectiveness of anticoagulation is uncertain. Kollar et al. found that 2 of the 4 postoperative strokes occurring after POAF were caused by atherosclerotic disease in the carotid and vertebral arteries.
Third, excess bleeding from early anticoagulation use may outweigh any potential reduction in stroke. A retrospective study of 166,747 post-CABG patients with POAF found that anticoagulation use on discharge was associated with a significant increase in re-hospitalization rates for major bleeding at 30 days after surgery (0.98% vs 0.23%; adjusted odds ratio 4.30; 95% CI, 3.69-5.03) without a reduction in hospitalizations for stroke.
Anticoagulation and amiodarone for new atrial fibrillation after coronary artery bypass grafting: prescription patterns and 30-day outcomes in the United States and Canada.
The results of an ongoing clinical trial randomizing patients to either warfarin or standard antiplatelet therapy for 3 months after CABG will inform clinicians on the best management strategy for preventing short-term strokes.
Until these results become available, short-term use of anticoagulation remains an unproven strategy.
It has been hypothesized that POAF may represent the first manifestation of sustained AF, and that long-term strokes may be caused by subsequent AF recurrences.
However, several key differences between POAF and nonoperative AF suggest that the 2 may be separate entities. First, many patients with POAF do not have documented AF recurrence. One randomized controlled trial of cardiac surgery patients with POAF found that less than 5% of participants had clinical evidence of AF at their 2-month follow-up visit.
Second, our meta-analysis found that the estimated long-term stroke risk in patients with POAF was low (1.06 events per 100 patient-years). For patients with nonoperative AF who are at a similar stroke risk, there is no universal recommendation for anticoagulation use.
2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS): The Task Force for the Diagnosis and Management of Atrial Fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Third, given that the long-term difference in stroke risk was very small (0.18 per 100 patient-years) between patients with vs without POAF, the benefit of long-term anticoagulation in POAF patients is likely small. This is apparent when the risk increase is compared to that seen with other stroke risk factors. For example, the presence of asymptomatic carotid stenosis (60% or greater) conveys a much larger absolute risk increase of 2.3% per year for long-term stroke.
The causes and risk of stroke in patients with asymptomatic internal-carotid-artery stenosis. North American Symptomatic Carotid Endarterectomy Trial collaborators.
Finally, even if anticoagulation were an effective therapy for reducing stroke, the risks of bleeding need to be considered. For instance, in a registry study of 7368 cardiac surgery patients with POAF, use of anticoagulation led to more bleeding events (adjusted HR 1.4; 95% CI, 1.08-1.81), with no long-term differences in thromboembolism.
New-onset atrial fibrillation after coronary artery bypass grafting and long-term outcome: a population-based nationwide study from the SWEDEHEART Registry.
Therefore, until better evidence is available, anticoagulation cannot be universally recommended in patients with POAF after cardiac surgery. However, our data suggest that it would be difficult to show a net clinical benefit for all POAF patients in a randomized controlled trial of long-term anticoagulation. A benefit may nevertheless be achievable in higher-risk subgroups. Our post hoc analysis suggests that patients with POAF and a prior history of stroke have a higher absolute risk of subsequent stroke, providing a potential target population for a future anticoagulation trial in patients with POAF after cardiac surgery.
The current systematic review and meta-analysis provides significant methodological improvements over previous publications. First, we included all types of cardiac surgeries. Second, we strictly separated the analyses for short-term and long-term risks of stroke. Third, we obtained additional unpublished data. Fourth, we used more-stringent eligibility criteria compared to previous meta-analyses.
POAF had to be described as new in onset and reported independently from other tachyarrhythmias, and individual studies were not eligible if they omitted transient AF events or nonfatal strokes.
Our systematic review has limitations. A high degree of heterogeneity was detected among individual studies reporting short-term risk of stroke. Therefore, cautious interpretation of the summary estimate is warranted. Most studies reporting short-term stroke did not confirm whether strokes occurred after the onset of POAF, limiting the establishment of causality. However, the vast majority of long-term studies clearly specified that POAF occurred prior to stroke occurrence. Publication bias was detected in the analysis for long-term risk of stroke, suggesting that small studies demonstrating no association or an inverse association of POAF with stroke may not be published. Nevertheless, our results remained robust after replacing these studies using the trim-and-fill method. Postoperative anticoagulation use may have lowered the observed magnitude of association between POAF and stroke. This lowering is unlikely to have had a significant effect on the overall risk estimates, given that the reported rates of anticoagulation use were generally low. However, there may be certain subgroups of patients, such as those with persistent or recurrent AF, who may still benefit from anticoagulation. As our study did not assess the duration of AF, we could not determine its effect on stroke risk.
Conclusion
In this systematic review and meta-analysis, POAF after cardiac surgery was associated with an increased risk of short-term and long-term stroke. Although a potentially relevant ARD in short-term stroke was observed, the role of early anticoagulation use in this setting remains unknown and is currently being investigated in clinical trials. Given the small ARD in long-term stroke for patients with vs without POAF, it is uncertain whether POAF patients benefit from long-term anticoagulation therapy.
Funding Sources
The authors have no sources of funding to declare.
Disclosures
Dr Devereaux has received grants from Abbott Diagnostics, Boehringer Ingelheim, Philips Healthcare, Roche Diagnostics, and Siemens, outside the submitted work. Dr Devereaux has participated in advisory board meetings for Boehringer Ingelheim, Bayer, and Quidel Canada, and has attended an expert panel meeting with Boehringer Ingelheim, outside the submitted work. Dr Whitlock has received grants from Bayer, Roche, and Boehringer Ingelheim, and consultancy fees from PhaseBio, Atricure, and Boehringer Ingelheim, outside the submitted work. Dr Healey has received grants and speaking fees from BMS/Pfizer and Servier, outside the submitted work. Dr McIntyre has received speaking fees from Bayer and Servier, outside the submitted work. Dr Belley-Côté has received grants from Bayer and Roche, outside the submitted work. Dr Conen has received consultancy fees from Servier Canada, and Roche Diagnostics, outside the submitted work. All the other authors have no conflicts of interest to disclose.
Postoperative atrial fibrillation is not associated with an increased risk of stroke or the type and number of grafts: a single-center retrospective analysis.
Long-term thromboembolic risk in patients with postoperative atrial fibrillation after coronary artery bypass graft surgery and patients with nonvalvular atrial fibrillation.
Compared with matched controls, patients with postoperative atrial fibrillation (POAF) have increased long-term AF after CABG, and POAF is further associated with increased ischemic stroke, heart failure and mortality even after adjustment for AF.
New-onset perioperative atrial fibrillation after coronary artery bypass grafting and long-term risk of adverse events: an analysis from the coronary trial.
Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
Deeks J, Higgins J, Altman D. Analysing data and undertaking meta-analyses. In: Cochrane Handbook for Systematic Reviews of Interventions. Vol 2020. Cochrane: 2019. Available at: https://training.cochrane.org/handbook. Accessed December 8, 2021.
Schünemann HJ, Viste GE, Higgings JPT, et al. Interpreting results and drawing conclusions. In: Higgins JPT, Santesso N, Deesk JJ, Glasziou P, eds. Cochrane Handbook for Systematic Reviews of Interventions. city: Cochrane; 2020. Available at: www.training.cochrane.org/handbook. Accessed December 8, 2021.
Postoperative atrial fibrillation in patients undergoing aortocoronary bypass surgery carries an eightfold risk of future atrial fibrillation and a doubled cardiovascular mortality.
Patterns of management of atrial fibrillation complicating coronary artery bypass grafting: results from the PRoject of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT-IV) Trial.
Risk factors of atrial fibrillation following off-pump coronary artery bypass graft surgery: predictive value of C-reactive protein and transfusion requirement.
Statins reduce short- and long-term mortality associated with postoperative atrial fibrillation after coronary artery bypass grafting: impact of postoperative atrial fibrillation and statin therapy on survival.
Transoesophageal echocardiography for prediction of postoperative atrial fibrillation after isolated aortic valve replacement: two-dimensional speckle tracking for intraoperative assessment of left ventricular longitudinal strain.
Usefulness of postoperative atrial fibrillation as an independent predictor for worse early and late outcomes after isolated coronary artery bypass grafting (multicenter Australian study of 19,497 patients).
2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS): The Task Force for the Diagnosis and Management of Atrial Fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Anticoagulation and amiodarone for new atrial fibrillation after coronary artery bypass grafting: prescription patterns and 30-day outcomes in the United States and Canada.
The causes and risk of stroke in patients with asymptomatic internal-carotid-artery stenosis. North American Symptomatic Carotid Endarterectomy Trial collaborators.
New-onset atrial fibrillation after coronary artery bypass grafting and long-term outcome: a population-based nationwide study from the SWEDEHEART Registry.
Ethics Statement: This systematic review and meta-analysis was conducted in accordance to the ethical principles described in the Declaration of Helsinki.
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