risk of thromboembolic events in atrial fibrillation with...

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Atrial fibrillation (AF) has gained much attention as an independent risk factor for ischemic stroke and its asso-

ciation with increased mortality and morbidity.1 Chronic kid-ney disease (CKD), defined as reduced glomerular filtration rate or proteinuria, markedly increases the risk of stroke by 2.1-folds,2 risk of myocardial infarction by 2.0-folds,3 and risk of combined cardiovascular events by 2.3-folds in the general population.4 AF frequently coexists with CKD: about one-third of outpatients with AF have CKD, and 15% of patients with CKD have AF. There was an almost 4-fold increase in risk of AF in patients with stage 4 CKD compared with age-matched and sex-matched patients without CKD.5–7

CKD is a well-established risk factor for atherosclerotic disease,8 but conflicting data exist about the incremental effect of CKD and its severity on the risk of ischemic stroke in the setting of AF. Although several latest studies have reported that CKD is associated with increased risk of stroke among patients with AF,5,9,10 patients with renal disease were under-represented in most trials that validated stroke risk stratifica-tion schemes, and current risk scores, such as CHADS

2 and

CHA2DS

2-VASc, do not include CKD as a potential risk fac-

tor for thromboembolic events.11,12 Therefore, there is limited information on whether moderate–severe CKD improves the

predictive value of stroke risk stratification. To help resolve this uncertainty of CKD as a prognostic tool, we conducted a meta-analysis to evaluate the effect of renal function on the risk of thromboembolic events in nonvalvular AF patients and, second, to assess the additive prognostic value of moderate–severe CKD on CHADS

2 scores.

MethodsSearch Strategy and Selection CriteriaWe did a computerized search of English-language publications listed in the electronic databases MEDLINE (source PUBMED, 1966 to July 2014) and EMBASE (1980 to July 2014) using the following text and key words in combination both as MeSH terms and text words: renal, kidney, atrial fibrillation, ischemic stroke, thromboembolic events, randomized controlled trial, cohort studies, andprospective studies.

To minimize differences between studies, we imposed the follow-ing methodological restrictions for the inclusion criteria: (1) Studies that contained the minimum information necessary to estimate the relative risk (RR) associated with CKD, including case–control, co-hort studies and randomized controlled trials published as original articles; (2) Studies in which populations were representative of pa-tients with CKD and not those limited exclusively to patients with end-stage renal disease. In instances of multiple publications, the most up-to-date or comprehensive information was used. Citations initially selected by systematic search were first retrieved as a title

Background and Purpose—Chronic kidney disease may increase the risk for ischemic stroke or systemic embolism in patients with nonvalular atrial fibrillation (AF). We conducted a meta-analysis to summarize all published studies to investigate the link between chronic kidney disease and risk of thromboembolic events in AF.

Methods—We performed a literature search using MEDLINE (source PubMed, 1966 to July, 2014) and EMBASE (1980 to July 2014) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis.

Results—Eighteen studies involving 538 479 patients and 41 719 incident thromboembolic events were identified. From the pooled analysis, AF patients with estimated glomerular filtration rate <60 mL/min compared with those with estimated glomerular filtration rate ≥60 mL/min experienced a significantly increased risk for developing thromboembolic events (relative risk, 1.62 [95% confidence interval, 1.40–1.87; P<0.001]). The annual rate of thromboembolic events increased by 0.41% (95% confidence interval, 0.17%–0.65%) for a 10 mL/min decrease in renal function. Addition of renal impairment to CHADS

2 slightly improved the stroke risk stratification.

Conclusions—Impaired renal function is an independent predictor of stroke or systemic embolism in patients with nonvalvular AF. Consideration of renal function may improve stroke risk stratification in patients with AF. (Stroke. 2015;46:157-163. DOI: 10.1161/STROKEAHA.114.006881.)

Key Words: atrial fibrillation ◼ chronic kidney disease ◼ ischemic stroke

Risk of Thromboembolic Events in Atrial Fibrillation With Chronic Kidney Disease

Wu-Tao Zeng, MD, PhD*; Xiu-Ting Sun, MD*; Kai Tang, MD, PhD*; Wei-Yi Mei, MD, PhD; Li-Juan Liu, MD, PhD; Qing Xu, MD; Yun-Jiu Cheng, MD

Received July 24, 2014; final revision received October 15, 2014; accepted October 28, 2014.From the Department of Cardiology, the Eastern Hospital of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.*Drs Zeng, Sun, and Tang contributed equally.The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.

006881/-/DC1.Correspondence to Yun-Jiu Cheng, MD, Department of Cardiology, the Eastern Hospital of The First Affiliated Hospital, Sun Yat-Sen University, No.

183, Huangpu East Rd, Guangzhou 510700, China. E-mail [email protected]© 2014 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.114.006881

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158 Stroke January 2015

or abstract and preliminarily screened. Potentially suitable citations were then retrieved as complete manuscripts and assessed for compli-ance to inclusion criteria.

Data AbstractionArticles were reviewed and cross-checked independently by 2 au-thors (W.T. Zeng, X.T. Sun). Data on the following characteristics were independently extracted: author identification, year of publica-tion, type of study design, study population, study location, numbers of disease outcomes of interest; mean duration of follow-up; type of thromboembolic event; RR with 95% confidence interval (CI), and reported adjustment for potential confounders. Corresponding author was contacted to verify the extracted data and to request data where it was unavailable from the published article. Any disagreements were resolved by consensus.

Data AnalysisSummary RRs (95% CI) and area under the curve (AUC or C-statistic) were calculated by pooling the study-specific estimates using a random-effects model that included between-study heterogeneity because sig-nificant heterogeneity was anticipated among studies. Pooled RRs were expressed with 95% CIs. We calculated the I2 (95% CI) statistic to assess heterogeneity across studies,13 applying the following interpretation for I2: <50%, low heterogeneity; 50% to 75%, moderate heterogeneity; and >75%, high heterogeneity.14,15 Sensitivity analyses were performed to evaluate whether the results could have been affected markedly by us-ing fixed-effect model, trim and fill method, and different inclusion and exclusion criteria. Subgroup analyses and meta-regression models were performed to investigate potential sources of between-study heteroge-neity. Small study bias, consistent with publication bias, was assessed with funnel plot by Begg’s adjusted rank correlation test and by Egger’s regression asymmetry test.16 Restricted cubic spline regression model was used to test the linearity in the relationship between renal function and the outcomes. Interations with estimated glomerular filtration rate (eGFR) were illustrated by plotting the estimated probability of 1-year events.17 We used STATA, version 11.0 (Stata Corp), for all analyses. Statistical tests were 2-sided and used a significance level of P<0.05.

ResultsStudy SelectionWith the search strategy, 1021 unique citations were initially retrieved. Of these, 261 articles were considered of inter-est, and full text was retrieved for detailed evaluation. Two hundred forty-three of these 261 articles were subsequently excluded because they included only patients with end-stage renal disease or did not provide enough data to estimate rela-tive risk. Finally, 18 articles were eligible for inclusion (Figure I in the online-only Data Supplement).

Study CharacteristicsEighteen independent eligible studies reporting 538 479 patients and 41 719 incident thromboembolic events were identified. Six studies were based in Europe, 6 in Asia, 1 in North America, and 5 were multinational. Studies were published between March 2009 and April 2014. There were 10 prospective cohort studies,5,18–26 2 retrospective studies,9,27 and 6 randomized con-trolled trials.17,28–32 Of the primary studies, 100% had described independent, consecutive sampling of their cohort. Average fol-low-up duration ranged from 11 to 144 months. Patients were followed up for an average of over 2 years in 50% of the studies. The sizes of the cohorts ranged from 387 to 283 969, with 7 largest studies recruiting over 10 000 participants.

Of all the studies, 6 included only patients off anticoagula-tion5,23,27,32–34 and 6 investigated only patients taking oral antico-agulants (OACs).17,19,28–31 Fourteen studies reported the incidence of a composite outcome (ischemic stroke or systematic embo-lism) as an outcome of interest and 4 studies only reported the incidence of ischemic stroke. Fourteen studies (77.8%) provided ≥1 adjusted risk estimate, and 11 (78.6%) of them reported an adjusted estimate for CHADS

2: congestive heart failure, hyper-

tension, age, diabetes mellitus, stroke/transient ischemic attack. Detailed information on adjustments is reported in Table 1.

CKD and Risk of Thromboembolic Events in Atrial FibrillationFigure 1 showed the results from the random effects model combining the RRs for thromboembolic events. Overall, patients with eGFR <60 mL/min compared with those with eGFR ≥60 mL/min experienced a significantly increased risk for developing thromboembolic events (RR, 1.62 [95% CI, 1.40–1.87; P<0.001]; Figure 1). There was evidence of mod-erate heterogeneity of RRs across these studies (I2, 70.85% [95% CI, 67.19–86.37; P<0.001]). These measurements of heterogeneity were likely driven by the extremely large over-all number of participants in our analysis (>500 000). The point estimates of the RRs were consistently >1 in all studies, and study subgroups were more homogeneous.

The findings from the sensitivity analyses based on different inclusion and exclusion criteria are presented in Table 2. Risk estimates changed little after analyses with fixed-effects mod-els, trim and fill method, or exclusion of the 2 largest and the outlier studies. Even the analysis was confined to those studies adjusted for CHADS

2, and the overall combined RR did not

materially change (RR, 1.69 [95% CI, 1.36–2.12; P<0.001]).Visual inspection of the Begg funnel plot did not identify

substantial asymmetry. The Begg rank correlation test and Egger linear regression test also indicated no evidence of pub-lication bias (Begg, P=0.20; Egger, P=0.09; Figure II in the online-only Data Supplement).

Stratified AnalysesTo explore the study heterogeneity, we performed stratified analyses across several key study characteristics and clinical fac-tors (Figure 2). We observed no significant differences across subgroups according to study type (RR, 1.75; 1.47–2.08 for ran-domized controlled trials and 1.55, 1.30–1.85 for cohort stud-ies; P=0.67), sample size (RR 1.48, 1.28–1.71 for studies with patients >10 000 and 1.98, 1.40–2.79 for studies with patients <10 000; P=0.21), duration of follow-up (RR 1.56, 1.25–1.94 for studies with average follow-up >2 years and 1.71, 1.42–2.07 for studies with average follow-up <2 years; P=0.66), level of adjust-ment (RR 1.69, 1.36–2.11 for studies adjusted for risk profiles and 1.56, 1.27–1.98 for studies unadjusted for risk profiles; P=0.75) or OACs treatment (RR 1.51, 1.29–1.77 for patients taking OACs and 1.54, 1.35–1.75 for patients not taking OACs; P=0.56). Significant heterogeneity between pooled analyses were noted for studies with ≥400 thromboembolic events compared with those with <400 events (RR 1.44, 1.26–1.64 versus 2.31, 1.49–3.59; P=0.03) and stroke compared with stroke plus systemic thrombo-embolism (RR 1.23, 1.09–1.38 versus 1.73, 1.46–2.06; P=0.03).


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Zeng et al CKD and Stroke Risk in AF 159

Renal Function and Rate of Thromboembolic EventsIn the cubic spline model that included 8 studies reporting infor-mation on event rates in varying levels of renal function, we did not find evidence suggesting any nonlinear relation between eGFR and thromboembolic risk (P for nonlinearity =0.31). A linear increase was observed in annual rate of thromboembolic events with decreasing renal function (Figure 3). The rate increased by 0.41% (95% CI, 0.17–0.65) for a 10 mL/min decrease in renal

function. According to the Cockcroft–Gault equation, patients with eGFR ≥80 mL/min had annual stroke or systemic embolism rates of 2.11% compared with 2.94% in patients with eGFR 50 to <80 mL/min and 4.54% in patients with eGFR <50 mL/min.

Risk Discrimination ModelsEight studies reported on changes in measures of risk dis-crimination on the addition of CKD to CHADS

2 predic-

tion model.5,9,19,22,24,25,30,31 These studies comprised a total of

Table 1. Summary of Available Studies Included in the Present Meta-Analysis

Study, year CountryType of Study

Average Follow-Up (months)

No. of Patients, n

No. of Events, n End Points

Variables Adjusted for

Swedish Atrial Fibrillation Cohort, 20149

Sweden Retrospective cohort study

25 283 969 19 493 Ischemic stroke or systemic embolism

Age and sex

Nakagawa K, 201118 Japan Prospective cohort study

67 387 7 Ischemic stroke Age and sex

Roldán V, 201319 Spain Prospective cohort study

29 978 39 Ischemic stroke or systemic embolism

Age, sex, hypertension, DM, CHF, CHD, stroke

RE-LY Trial, 201317 Multinational Randomized controlled trial

24 17 951 516 Ischemic stroke or systemic embolism

None

ARISTOTLE trial, 201228 Multinational Randomized controlled trial


None

ATRIA Study, 20095 USA Prospective cohort study


Age, sex, race, hypertension, DM, CHF,

CHD, stroke

Lin WY, 201420 China Prospective cohort study


Age, hypertension

J-ROCKET AF, 201329 Japan Randomized controlled trial


None

SWEDEHEART registry, 201421 Sweden Prospective cohort study

12 24 314 1145 Ischemic stroke None

Loire Valley Atrial Fibrillation Project, 201122

France Prospective cohort study



Guo Y, 201323 China Prospective cohort study

23 1034 78 Ischemic stroke Age, hypertension, DM, CHF, CHD, stroke

Chao TF, 201434 China Prospective cohort study



ROCKET AF, 201330 Multinational Randomized controlled trial



Leipzig Heart Center AF Ablation Registry, 201325

Germany Prospective cohort study



AMADEUS trial, 201331 Multinational Randomized controlled trial



Taiwan NHI program, 201127 China Retrospective cohort study

55 7920 472 Ischemic stroke Age, sex, hypertension, DM, CHF, CHD, stroke

Danish national registries, 201226 Denmark Prospective cohort study

144 132 372 17 654 Ischemic stroke or systemic embolism

Age, sex, hypertension, DM, CHF, CHD, stroke, sex, vascular disease

Eikelboom JW, 201232 Multinational Randomized controlled trial



AMADEUS indicates Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; ATRIA, Anticoagulation and Risk Factors in Atrial Fibrillation; CHD, coronary heart disease; CHF, congestive heart failure; DM, diabetes mellitus; J-ROCKET, Japanese Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; NHI, national health insurance; ROCKET, Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy; and SWEDEHEART, Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies.


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328 889 patients and 21 307 incident outcomes recorded dur-ing a weighted mean follow-up duration of ≈2 years. Studies reported findings in relation to thromboembolic risk discrimina-tion as AUC or C-statistic. The pooled AUCs of the CHADS

2,

CHA2DS2-VASc, and CHADS

2-CKD scores in predicting

thromboembolic events were 0.66 (95% CI, 0.62–0.70), 0.68 (95% CI, 0.64–0.71), and 0.69 (95% CI, 0.65–0.73), respectively. There was a slightly significant improvement of CHADS

2 score

by the addition of CKD (pooled AUC difference, 0.03 [95% CI, 0.01–0.05]), but the AUC for CHADS

2-CKD and CHA2DS

2-

VASc scores were not statistically different (Table 3).

DiscussionThe present meta-analysis, involving >500 000 patients and >40 000 patients with thromboembolic events from 18 stud-ies, found a significantly increased risk of thromboembolic events associated with renal impairment in patients with AF, even after reported adjustment for CHADS

2 risk factors.

The association seemed to be similar in patients taking or

not taking OACs. Incidence of thromboembolic events was inversely associated with renal function, and the addition of renal impairment to CHADS

2 scores yielded a slight improve-

ment in risk discrimination (0.03 point estimate).Recent studies have suggested that nonvalvular AF patients

with heart failure (RR=1.4), hypertension (RR=1.6), older age (RR=1.4), diabetes mellitus (RR=1.7), and previous ischemic stroke (RR=2.5) were at risk of developing thromboembolic events, whereas conflicting results were reported for renal impairment.35 This meta-analysis is the first to our knowledge to confirm CKD to be an independent risk factor for thromboem-bolism in patients with nonvalvular AF. Although the risk mag-nitude seems to be less robust than previous ischemic stroke, it is at least as strong as other well-established major risk factors, such as heart failure, hypertension, older age, diabetes mellitus.35 However, CKD is common in AF patients, and the combination of end-stage renal disease and AF in patients treated with chronic hemodialysis may confer significantly greater thromboembolic risk. For example, Vazquez et al demonstrated that approximately

Figure 1. Forrest plot showing relative risk of thromboembolic events associated with renal impairment in atrial fibrillation (AF) patients. The size of each square is proportional to the study’s weight (inverse of variance). AMADEUS indicates Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; ATRIA, Anticoagulation and Risk Factors in Atrial Fibrillation; CI, confidence interval; J-ROCKET, Japanese Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; NHI, national health insurance; ROCKET, Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy; RR, relative risk; and SWEDEHEART, Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies.


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one third of hemodialysis patients with AF have thromboembolic complications within 1 year of follow-up.36 Thus, given the mul-tifactorial nature of thromboembolism, it is highly likely that the concomitant action of CKD may be responsible for a proportion of thromboembolic events in the AF patients.

Understanding the mechanisms that underlie the associa-tion between kidney dysfunction and the risk of stroke in AF is of particular importance to help frame appropriate therapeutic

decisions. First, AF per se confers a hypercoagulable state through various pathways.37 Disorganized contraction of the atria with a decrease in atrial blood flow, endothelial and endocardial dam-age and dysfunction, and increased expression of tissue factor and von Willebrand factor, increased platelet activation and fibri-nolysis may predispose to thrombus formation and subsequent systemic emboli.37 Second, patients with CKD without AF is associated with a prothrombotic state, including endothelial dam-age, alteration in protein C metabolism, defects in the expression of glycoprotein Ib, elevated levels of various plasminogen activa-tor inhibitor-1 and von Willebrand factor, abnormalities in various coagulation factor levels and activity, as well as inflammation.38–41 Third, CKD is further associated with abnormality of neurohor-monal (eg, renin–angiotensin–aldosterone system), inflammatory, and oxidative pathways or mineral metabolism (eg, hyperparathy-roidism), which may result in atherosclerosis and thus greater risk of thromboembolic events.42 Therefore, CKD may contribute to an increased risk of ischemic stroke and other thromboembolism in AF patients by augmenting the underlying prothrombotic state through several different pathophysiological pathways.

In spite of the clear association between kidney dysfunction and thromboembolism in AF population, CKD has not been formally included in any of the current stroke stratification schemes, although it was previously proposed that the small c in CHA

2DS

2-VASc score could represent informally chronic

renal impairment.43 There is 1 factor that may confound the interpretation of renal impairment in AF patients. It has been proposed that renal impairment does not add much predictive value to current schemes, especially because the components of clinical scores are themselves related to renal dysfunction. For example, increasing age and heart failure are independently associated with low eGFR.44 However, our result found that

Table 2. Sensitivity and Heterogeneity Analysis of Pooled Relative Risks of Thromboembolic Events in Atrial Fibrillation Patients With CKD

n, Studies

RR (95% CI)

I2 (95% CI)

Statistical model

Random effects 18 1.62 (1.40–1.87) 70.85 (67.19–86.37)

Fixed effect 18 1.43 (1.35–1.51) 70.85 (67.19–86.37)

Trim and fill method

Random effects 26 1.35 (1.15–1.18) 84.20 (77.91–88.70)

Fixed effect 26 1.33 (1.26–1.40) 84.20 (77.91–88.70)

Analysis of all studies with

Adjustment for CHADS2

11 1.69 (1.36–2.12) 79.15 (63.30–88.15)

Analysis of all studies except

Two largest studies* 16 1.69 (1.42–2.00) 78.13 (64.98–86.34)

Two outlier studies† 16 1.49 (1.33–1.66) 66.25 (42.85–80.06)

CI indicates confidence interval; CHADS2, congestive heart failure,

hypertension, age, diabetes mellitus, stroke/transient ischemic attack; CKD, chronic kidney disease; and RR, relative risk.

*Studies with patients over 100 000: Danish national registries and Swedish Atrial Fibrillation Cohort.21,26

†Studies with largest relative risk by Chao and Lin.20,34

Figure 2. Stratified analysis of relative risk of thromboembolic events associated with renal impairment in atrial fibrillation (AF) patients and heterogeneity analysis. CI indicates confidence interval; OAC, oral anticoagulant drug; RCT, randomized controlled trial; RR, relative risk; and TE, thromboembolic events.


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renal dysfunction further increases the risk of ischemic stroke significantly after accounting for other known thromboembolic risk factors. In addition, our study demonstrated that adding renal dysfunction to the CHADS

2 score yields a small but sta-

tistically significant improvement in c-statistic. Given these findings, further studies are warranted to elucidate the additive predictive value of renal dysfunction to CHA

2DS

2-VASc score.

Strengths of this meta-analysis include the strict inclusion crite-ria, the large number of patients analyzed, the robustness of the find-ings in sensitivity analyses, and the fact that all subgroup analyses

were prespecified a priori. The absence of important publication bias supports the robustness of the study findings. A possible limita-tion of our study is the heterogeneity of the studies with regard to adjustment of the estimates for potential confounders. Although dif-ferences in number of events and the outcomes of interest, at least in part, explain this finding, the specific mechanism remains unclear. Inclusion of different types of studies into one meta-analysis may also introduce heterogeneity into the results. Despite this, the con-sistency of the finding of an increased thromboembolic risk among cohort studies and randomized controlled trials suggests that the association is valid. Another limitation was the lack of individual participant data, which precluded determining the independent associations of individual variables with study outcomes. Instead, we used between-study meta-regressions, when possible.

In conclusion, impaired renal function is a predictor of incident stroke and systemic embolism in patients with non-valvular AF taking and not taking OACs, independent of conventional thromboembolic risk factors. Adding CKD to the CHADS

2 stroke risk scores slightly improved the risk dis-

crimination, and consideration of renal function may improve stroke risk stratification in patients with AF.

DisclosuresNone.

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Table 3. AUC Analysis for 3 Risk Stratification Models in Predicting Thromboembolic Events in AF Patients

CHADS2

CHA2DS

2−VASc CHADS

2+CKD

Study AUC (95% CI)c AUC (95% CI) AUC (95% CI)

Swedish Atrial Fibrillation Cohort study

0.72 (0.72–0.73) 0.71 (0.71–0.72) 0.72 (0.71–0.72)

Roldan V 0.65 (0.62–0.68) 0.62 (0.59–0.65) 0.64 (0.61–0.67)

Chao TF NA 0.83 (0.73–0.93) 0.87 (0.79–0.95)

ROCKET AF 0.57 (0.55–0.60) 0.58 (0.55–0.60) 0.59 (0.56–0.61)

Leipzig Heart Center AF Ablation Registry

0.72 (0.70–0.74) 0.74 (0.72–0.75) 0.74 (0.72–0.75)

AMADEUS Trial 0.64 (0.56–0.73) 0.67 (0.60–0.75) 0.69 (0.62–0.76)

The Loire Valley Atrial Fibrillation Project

0.64 (0.61–0.67) 0.64 (0.62–0.67) 0.64 (0.61–0.67)

ATRIA Study 0.66 (0.62–0.70) 0.69 (0.67–0.71) 0.71 (0.69–0.74)

Pooled AUC estimates 0.66 (0.62–0.70) 0.68 (0.64–0.71) 0.69 (0.65–0.73)

AF indicates atrial fibrillation; AMADEUS, Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation; ATRIA, Anticoagulation and Risk Factors in Atrial Fibrillation; AUC, area under the curve; CHADS

2, congestive heart failure, hypertension, age, diabetes mellitus,

stroke/transient ischemic attack; CHA2DS

2-VASc, congestive heart failure,

hypertension, age (>75 y), diabetes mellitus, stroke/transient ischemic attack, vascular disease, age (65–74 y), sex (female); and ROCKET, Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.

Figure 3. Annual rates of stroke or systemic embolism accord-ing to renal function estimated by Cockcroft–Gault. The solid line represents point estimates of rate of thromboembolic events; dashed lines are 95% confidence interval (CIs). Circles pres-ent the estimated glomerular filtration rate (eGFR)–specific rate estimates reported in each study. The area of each circle is pro-portional to the sample size. The dotted line represents the null hypothesis of no association.


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Wu-Tao Zeng, Xiu-Ting Sun, Kai Tang, Wei-Yi Mei, Li-Juan Liu, Qing Xu and Yun-Jiu ChengRisk of Thromboembolic Events in Atrial Fibrillation With Chronic Kidney Disease

Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 2014 American Heart Association, Inc. All rights reserved.

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27

Abstract 6

만성신장질환을 동반한 심방세동에서 혈전색전 사건의 위험

Risk of Thromboembolic Events in Atrial Fibrillation With Chronic Kidney DiseaseWu-Tao Zeng, MD, PhD*; Xiu-Ting Sun, MD*; Kai Tang, MD, PhD*; Wei-Yi Mei, MD, PhD; Li-Juan Liu, MD, PhD;

Qing Xu, MD; Yun-Jiu Cheng, MD

(Stroke. 2015;46:157-163.)

Key Words: atrial fibrillation ■ chronic kidney disease ■ ischemic stroke

배경과 목적

만성신장질환은 비판막성 심방세동(atrial fibrillation, AF) 환자

에서 허혈뇌졸중이나 전신색전증의 위험을 증가시킬 수 있다. 본

연구에서는 AF에서 만성신장질환과 혈전색전 사건 위험도 간의

관계를 발표한 연구들을 요약하기 위해 메타분석을 시행하였다.

방법

MEDLINE (source PubMed, 1966년-2014년 7월)과 EMBASE

(1980년-2014년 7월)를 이용해서 제한 없이 문헌을 검색하였다.

통합 효과 추정치(pooled effect estimates)는 변량효과(random-

effects) 메타분석에 의해 구하였다.

결과

538479명의 환자를 대상으로 한 18개의 연구에서 41719례의 혈전

색전 사건이 확인되었다. 통합분석에서, 추정 사구체여과율 ＜60

mL/min인 AF 환자가 ≥60 mL/min인 AF 환자에 비해 혈전색전

사건이 발생할 위험이 유의하게 증가하였다(relative risk, 1.62

[95% CI, 1.40-1.87; P＜0.001]). 혈전색전 사건의 연간 발생률은

신장기능이 10 mL/min 감소할 때 0.41% (95% CI, 0.17%-

0.65%) 증가하였다. CHADS2에 신장 장애를 추가했을 때 뇌졸중

위험도 계층화가 약간 개선되었다.

결론

신장기능의 장애는 비판막성 AF 환자에서 뇌졸중이나 전신색전증

의 독립적인 예측 인자이다. 신장기능을 고려하는 것이 AF 환자의

뇌졸중 위험도 계층화를 개선하는데 도움이 될 것이다.


328 889 patients and 21 307 incident outcomes recorded dur-ing a weighted mean follow-up duration of ≈2 years. Studies reported findings in relation to thromboembolic risk discrimina-tion as AUC or C-statistic. The pooled AUCs of the CHADS

2,

CHA2DS2-VASc, and CHADS

2-CKD scores in predicting

thromboembolic events were 0.66 (95% CI, 0.62–0.70), 0.68 (95% CI, 0.64–0.71), and 0.69 (95% CI, 0.65–0.73), respectively. There was a slightly significant improvement of CHADS

2 score

by the addition of CKD (pooled AUC difference, 0.03 [95% CI, 0.01–0.05]), but the AUC for CHADS

2-CKD and CHA2DS

2-

VASc scores were not statistically different (Table 3).

DiscussionThe present meta-analysis, involving >500 000 patients and >40 000 patients with thromboembolic events from 18 stud-ies, found a significantly increased risk of thromboembolic events associated with renal impairment in patients with AF, even after reported adjustment for CHADS

2 risk factors.

The association seemed to be similar in patients taking or

not taking OACs. Incidence of thromboembolic events was inversely associated with renal function, and the addition of renal impairment to CHADS

2 scores yielded a slight improve-

ment in risk discrimination (0.03 point estimate).Recent studies have suggested that nonvalvular AF patients

with heart failure (RR=1.4), hypertension (RR=1.6), older age (RR=1.4), diabetes mellitus (RR=1.7), and previous ischemic stroke (RR=2.5) were at risk of developing thromboembolic events, whereas conflicting results were reported for renal impairment.35 This meta-analysis is the first to our knowledge to confirm CKD to be an independent risk factor for thromboem-bolism in patients with nonvalvular AF. Although the risk mag-nitude seems to be less robust than previous ischemic stroke, it is at least as strong as other well-established major risk factors, such as heart failure, hypertension, older age, diabetes mellitus.35 However, CKD is common in AF patients, and the combination of end-stage renal disease and AF in patients treated with chronic hemodialysis may confer significantly greater thromboembolic risk. For example, Vazquez et al demonstrated that approximately

Figure 1. Forrest plot showing relative risk of thromboembolic events associated with renal impairment in atrial fibrillation (AF) patients. The size of each square is proportional to the study’s weight (inverse of variance). AMADEUS indicates Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; ATRIA, Anticoagulation and Risk Factors in Atrial Fibrillation; CI, confidence interval; J-ROCKET, Japanese Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; NHI, national health insurance; ROCKET, Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy; RR, relative risk; and SWEDEHEART, Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies.

28 Stroke 한국어판 Vol. 8, No. 2

Abstract 7

증상성 주요 대뇌동맥질환 환자에서의 극단적 관류 저하, 혈압 조절 및 5년 뇌졸중 위험성

Misery Perfusion, Blood Pressure Control, and 5-Year Stroke Risk in Symptomatic Major Cerebral Artery Disease

Hiroshi Yamauchi, MD, PhD; Shinya Kagawa, MS; Yoshihiko Kishibe, RT; Masaaki Takahashi, RT; Tatsuya Higashi, MD, PhD

(Stroke. 2015;46:265-268.)

Key Words: blood pressure ■ cerebrovascular disease ■ positron emission tomography ■ prognosis

배경과 목적

증상성대뇌동맥질환 및 극단적 관류저하(misery perfusion, MP)

가 있는 고위험 환자에서, 엄격한 혈압(blood pressure, BP) 조절

의 유용성은 아직 논란의 여지가 있다. 연구자들은 (1) MP가 5년

뇌졸중 위험도의 예측 인자인지, (2) 추적 관찰 기간의 BP, MP 및

뇌졸중 위험도 사이의 상호 관계를 분석하고자 하는 목적을 갖고

본 연구를 진행하였다.

방법

증상성 주요 대뇌동맥 질환을 갖고 어느 정도 일상 생활이 가능한

130명의 환자를 수집하였다. 초기 혈역학적 측정은 15O-기체 양전

자방출단층영상(positron emission tomography)을 이용하여 측

정하였으며, 대상 환자들을 의학적 치료를 받으며 5년 간 혹은 뇌

졸중 재발 또는 사망이 발생할 시점까지 추적 관찰하였다.

결과

5년의 추적 관찰 기간 동안, 뇌졸중은 MP가 있는 환자 16명 중 6

명 그리고 MP가 없는 환자 114명 중 15명에서 발생하였다(로그-

순위 검정; P＜0.01). MP가 있는 환자에서 4건(25%)의 동측 허혈

뇌졸중이 발생하였고, MP가 없는 환자에서는 4건이 발생하였다

(P＜0.001). 동측의 허혈뇌졸중 발생 위험은 2년이 지나면서 급격

히 감소하였고, MP가 없는 환자에서는 단 한 건의 동측 허혈뇌졸

중만 발생하였다. 관류가 저하된 환자(MP 포함)에서 정상적인 수

축기 BP(＜130 mmHg)을 유지할 때 동측 허혈뇌졸중의 위험이 증

가하였으나, MP가 없는 환자에서 수축기 BP가 130-149 mmHg

범위 밖으로 유지되면 모든 종류의 뇌졸중 위험도가 증가하였다.

결론

MP가 있는 환자는 5년 뇌졸중 재발 위험도가 증가하는데, 그러한

추가 위험의 상당수는 2년이 지나면서 감소한다. MP를 비롯하여

관류가 저하된 환자에서 적극적인 BP 조절은 위해를 입힐 가능성

이 있다.


renal dysfunction further increases the risk of ischemic stroke significantly after accounting for other known thromboembolic risk factors. In addition, our study demonstrated that adding renal dysfunction to the CHADS

2 score yields a small but sta-

tistically significant improvement in c-statistic. Given these findings, further studies are warranted to elucidate the additive predictive value of renal dysfunction to CHA

2DS

2-VASc score.

Strengths of this meta-analysis include the strict inclusion crite-ria, the large number of patients analyzed, the robustness of the find-ings in sensitivity analyses, and the fact that all subgroup analyses

were prespecified a priori. The absence of important publication bias supports the robustness of the study findings. A possible limita-tion of our study is the heterogeneity of the studies with regard to adjustment of the estimates for potential confounders. Although dif-ferences in number of events and the outcomes of interest, at least in part, explain this finding, the specific mechanism remains unclear. Inclusion of different types of studies into one meta-analysis may also introduce heterogeneity into the results. Despite this, the con-sistency of the finding of an increased thromboembolic risk among cohort studies and randomized controlled trials suggests that the association is valid. Another limitation was the lack of individual participant data, which precluded determining the independent associations of individual variables with study outcomes. Instead, we used between-study meta-regressions, when possible.

In conclusion, impaired renal function is a predictor of incident stroke and systemic embolism in patients with non-valvular AF taking and not taking OACs, independent of conventional thromboembolic risk factors. Adding CKD to the CHADS

2 stroke risk scores slightly improved the risk dis-

crimination, and consideration of renal function may improve stroke risk stratification in patients with AF.

DisclosuresNone.

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Table 3. AUC Analysis for 3 Risk Stratification Models in Predicting Thromboembolic Events in AF Patients

CHADS2

CHA2DS

2−VASc CHADS

2+CKD

Study AUC (95% CI)c AUC (95% CI) AUC (95% CI)

Swedish Atrial Fibrillation Cohort study

0.72 (0.72–0.73) 0.71 (0.71–0.72) 0.72 (0.71–0.72)

Roldan V 0.65 (0.62–0.68) 0.62 (0.59–0.65) 0.64 (0.61–0.67)

Chao TF NA 0.83 (0.73–0.93) 0.87 (0.79–0.95)

ROCKET AF 0.57 (0.55–0.60) 0.58 (0.55–0.60) 0.59 (0.56–0.61)

Leipzig Heart Center AF Ablation Registry

0.72 (0.70–0.74) 0.74 (0.72–0.75) 0.74 (0.72–0.75)

AMADEUS Trial 0.64 (0.56–0.73) 0.67 (0.60–0.75) 0.69 (0.62–0.76)

The Loire Valley Atrial Fibrillation Project

0.64 (0.61–0.67) 0.64 (0.62–0.67) 0.64 (0.61–0.67)

ATRIA Study 0.66 (0.62–0.70) 0.69 (0.67–0.71) 0.71 (0.69–0.74)

Pooled AUC estimates 0.66 (0.62–0.70) 0.68 (0.64–0.71) 0.69 (0.65–0.73)

AF indicates atrial fibrillation; AMADEUS, Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation; ATRIA, Anticoagulation and Risk Factors in Atrial Fibrillation; AUC, area under the curve; CHADS

2, congestive heart failure, hypertension, age, diabetes mellitus,

stroke/transient ischemic attack; CHA2DS

2-VASc, congestive heart failure,

hypertension, age (>75 y), diabetes mellitus, stroke/transient ischemic attack, vascular disease, age (65–74 y), sex (female); and ROCKET, Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.

Figure 3. Annual rates of stroke or systemic embolism accord-ing to renal function estimated by Cockcroft–Gault. The solid line represents point estimates of rate of thromboembolic events; dashed lines are 95% confidence interval (CIs). Circles pres-ent the estimated glomerular filtration rate (eGFR)–specific rate estimates reported in each study. The area of each circle is pro-portional to the sample size. The dotted line represents the null hypothesis of no association.

risk of thromboembolic events in atrial fibrillation with...

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