372

Original research

Triple antithrombotic therapy versus dual antiplatelet therapy in patients with atrial fibrillation undergoing drug-eluting stent implantation Dong Oh Kanga,*, Cheol Woong Yua,*, Hee Dong Kima, Jae Young Choa, Hyung Joon Jooa, Rak Kyong Choib, Jin Sik Parkb, Hyun Jong Leeb, Je Sang Kimb, Jae Hyung Parka, Soon Jun Honga and Do-Sun Lima Background The optimal antithrombotic regimen in patients with atrial fibrillation (AF) undergoing drug-eluting stent (DES) implantation for complex coronary artery disease is unclear. We compared the net clinical outcomes of triple antithrombotic therapy (TAT; aspirin, thienopyridine, and warfarin) and dual antiplatelet therapy (DAPT; aspirin and thienopyridine) in AF patients who had undergone DES implantation. Methods A total of 367 patients were enrolled and analyzed retrospectively; 131 patients (35.7%) received TAT and 236 patients (64.3%) received DAPT. DAPT and warfarin were maintained for a minimum of 12 and 24 months, respectively. The primary endpoint was the 2-year net clinical outcomes, a composite of major bleeding and major adverse cardiac and cerebral events (MACCE). Propensity score-matching analysis was carried out in 99 patient pairs.

ratio 3.54, 95% confidence interval 1.65–7.58). After propensity score matching, the TAT group still had worse net clinical outcomes and a higher incidence of major bleeding compared with the DAPT group. Conclusion In AF patients undergoing DES implantation, prolonged administration of TAT may be harmful due to the substantial increase in the risk for major bleeding without any reduction in MACCE. Coron Artery Dis 26:372–380 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Coronary Artery Disease 2015, 26:372–380 Keywords: atrial fibrillation, drug-eluting stent, dual antiplatelet therapy, triple antithrombotic therapy, warfarin a Cardiovascular Center, Korea University Anam Hospital, Korea University College of Medicine, Seoul and bSejong General Hospital, Sejong Heart Institute, Kyunggido, Republic of Korea

Results The 2-year net clinical outcomes of the TAT group were worse than those of the DAPT group (34.3 vs. 21.1%, P = 0.006), which was mainly due to the higher incidence of major bleeding (16.7 vs. 4.6%, P < 0.001), without any significant increase in MACCE (22.1 vs. 17.7%, P = 0.313). In the multivariate analysis, TAT was an independent predictor of worse net clinical outcomes (odds ratio 1.63, 95% confidence interval 1.06–2.50) and major bleeding (odds

Correspondence to Do-Sun Lim, MD, PhD, Cardiovascular Center, Korea University Anam Hospital, Korea University College of Medicine, 126-1, 5ka, Anam-dong Sungbuk-gu, Seoul 136-705, Republic of Korea Tel: + 82 2 920 5445; fax: + 82 2 927 1478; e-mail: [email protected]

Introduction

guidelines and expert opinions suggest concomitant administration of DAPT and OAC for a short duration, the so-called triple antithrombotic therapy (TAT), to effectively prevent both thromboembolism and late stent thrombosis [5–8].

After placement of a drug-eluting stent (DES), maintenance of dual antiplatelet therapy (DAPT) with aspirin and thienopyridine is strongly recommended for minimizing thrombotic major adverse cardiac events [1,2]. Among the patients undergoing DES implantation, ∼ 5–10% are candidates for prolonged anticoagulation therapy because they have concomitant atrial fibrillation (AF) [3]. In AF patients at moderate to high risk of stroke, substitution of oral anticoagulation (OAC) with DAPT is insufficient for preventing stroke and thromboembolic vascular events [4]. The issue of an optimal antithrombotic strategy arises in AF patients with DES implantation, as both DAPT and OAC need to be administered simultaneously in this population. The Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.coronary-artery.com). 0954-6928 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

*Dong Oh Kang and Cheol Woong Yu contributed equally to the writing of this article. Received 4 December 2014 Revised 2 February 2015 Accepted 15 February 2015

Although TAT has potential beneficial effects, prolonged administration of TAT may increase the risk of bleeding. Currently, the most frequently recommended duration of TAT after DES implantation is a minimum of 3–6 months, and it is often increased up to 12 months in patients at high risk for thromboembolism [5–8]. However, the optimal duration of TAT has not been established, and supporting evidences for TAT are significantly limited, mostly based on the results of nonrandomized observational studies with short-term follow-up [9–12]. Furthermore, only a few studies have been conducted so far exclusively in AF patients when coronary stenting is strictly confined to the use of a DOI: 10.1097/MCA.0000000000000242

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Antithrombotic strategies in AF with DES implants Kang et al. 373

DES [11,13]. In this study, we investigated the net clinical outcomes of TAT, compared with DAPT, over a long-term follow-up period in AF patients who had undergone DES implantation.

Methods Study population and definition

The retrospective registry data were collected from the percutaneous coronary intervention database of Korea University Anam Hospital (Seoul, Republic of Korea) and Sejong General Hospital (Bucheon, Kyunggi-do, Republic of Korea). From June 2007 through March 2012, AF patients who had undergone DES implantation for complex coronary artery disease at both cardiovascular centers were enrolled. Implantation of a DES rather than a bare-metal stent was mostly selected for treating conditions associated with a higher risk for in-stent restenosis, such as diffuse lesions (>20 mm), small vessels (< 2.5 mm), highly calcified lesions, bifurcation lesions, chronic total occlusion, multivessel disease, chronic kidney disease, and diabetes mellitus [14–16]. AF was classified as paroxysmal, persistent, or permanent nonvalvular AF. Among these AF patients, those who had received either DAPT or TAT after DES implantation were identified. Selection of DAPT or TAT was mostly at the discretion of the attending physician after assessing the individual’s thromboembolic risk with the congestive heart failure, hypertension, age at least 75 years, diabetes mellitus, prior stroke or transient ischemic attack (CHADS2) [17] or congestive heart failure, hypertension, age at least 75 years, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex (CHA2DS2VASc) [18] score and the bleeding risk with the hypertension, abnormal renal and liver function, stroke, bleeding, labile INRs, age at least 65 years, drugs or alcohol (HAS-BLED) [19] score. DAPT was maintained for the minimum of 12 months in both groups and OAC was administered continuously in the TAT group unless an adverse event occurred. Antiplatelet drugs and OAC at discharge were administered in standard doses, and OAC with warfarin was adjusted at regular intervals to a target prothrombin time international normalized ratio (PT-INR) of 2.0–3.0. Assessment for adequate intensity of OAC was carried out during follow-up by calculating the time in the therapeutic range (TTR) using the Rosendaal method [20]. The duration within the suboptimal PT-INR level (< 2.0) was also calculated. The exclusion criteria included contraindication to the use of antiplatelet drugs or OAC, a recent episode of active bleeding or a history of major surgery within the last 3 months, and nonavailability of 2-year clinical outcomes because of an unexpected follow-up loss. The baseline demographic parameters were recorded from the initial hospital admission records. Using baseline parameters, CHADS2, CHA2DS2-VASc, and HASBLED scores were calculated. The labile INR factor was omitted from the HAS-BLED score as data were not available in the DAPT group and were insufficient in the

TAT group. Angiographic and procedural parameters related to the severity of coronary artery disease and DES implantation were also recorded. The study protocol was approved by the Ethics Committee of Korea University Anam Hospital, Seoul, Republic of Korea. Definition and analysis of study outcomes

The primary outcome measure was the 2-year net clinical outcomes, a composite of major bleeding and major adverse cardiac and cerebral events (MACCE). Major bleeding was defined as moderate or severe bleeding according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria [21]. MACCE was defined as a quadruple composite of all-cause mortality, nonfatal myocardial infarction, repeat revascularization, and ischemic cerebrovascular events. Mortality was classified as cardiovascular and noncardiovascular death. Repeat revascularization was defined as reperfusion of previously treated vessels by percutaneous coronary intervention or bypass surgery. Ischemic cerebrovascular events included both transient ischemic attack and ischemic cerebral infarction. The severity of functional impairment after a cerebrovascular event was graded using the modified Rankin’s scale (mRS) under inspection by an experienced neurologist [22]. The TTR was analyzed exclusively in the TAT group and was compared according to the development of a specific adverse event or composite endpoint. To investigate a temporal relationship between the adverse clinical outcomes and the intensity of treatment, the administered antithrombotic medications at the time of event development were verified in the TAT group. All study outcomes were adjudicated by the attending physician. Statistical analysis

Continuous variables are expressed as mean ± SD and categorical variables as frequency (percentage). The difference between the groups was analyzed using Student’s t-test for continuous variables and Pearson’s χ2-test or Fisher’s exact test for categorical variables. The cumulative incidence rate was analyzed on the basis of the time to the first adverse event, estimated using the Kaplan–Meier method with the log-rank test. The Cox proportional hazards regression model was used to examine the chief contributing factor toward outcome measures. To adjust for additional confounding factors, a multilevel propensity score was calculated using the logistic regression model. Besides the risk factors included in the Cox proportional hazards regression, the following potential relevant confounders were included in the logistic regression model: dyslipidemia, diagnosis at DES implantation, the extent of coronary artery involvement, the number of lesions with significant stenosis, the number of stents used, and underlying congestive heart failure. The logistic model, which estimated the propensity score, revealed a good predictive value (C = 0.722). A significant difference was defined as a

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374 Coronary Artery Disease 2015, Vol 26 No 5

P-value of less than 0.05, and all analyses were two-tailed. Statistical analysis was carried out using SPSS ver. 21.0 (SPSS-PC Inc., Chicago, Illinois, USA).

Results Baseline clinical characteristics

Among the 404 AF patients who had undergone DES implantation, 37 (9.2%) patients were excluded because of unexpected follow-up loss, with nonavailability of 2-year clinical outcomes: 25 patients from the DAPT group and 12 patients from the TAT group. Finally, a total of 367 patients from both cardiovascular centers were included in the analysis, and the mean follow-up duration was 20.6 ± 7.4 months (median 24 months). DAPT was prescribed to 236 patients (64.3%; DAPT group) and TAT, including warfarin, was administered to 131 patients (35.7%; TAT group). Baseline clinical, angiographic, and procedural characteristics are shown in Tables 1 and 2. The proportion of patients with persistent AF, congestive heart failure, and high thromboembolic risk (CHADS2 score ≥ 2 or CHA2DS2-VASc score ≥ 2) was significantly higher in the TAT group compared with the DAPT group. The HAS-BLED score and the proportion of patients with high bleeding risk (HAS-BLED score ≥ 3) were similar in both groups. In the TAT group, the average duration of TAT was Table 1

352.4 ± 144.0 days (Supplementary Table S1, Supplemental digital content 1, http://links.lww.com/MCA/ A37) and the TTR (mean 29.20 ± 24.88%) was maintained at a relatively low level. After the discontinuation of TAT, the majority of patients in the TAT group continued antithrombotic medications with warfarin plus a single antiplatelet agent (80.9% of the TAT group; Supplementary Table S1, Supplemental digital content 1, http://links.lww.com/MCA/A37). Other baseline and angiographic characteristics were relatively comparable between the two groups. Clinical outcomes within the 2-year follow-up period

Cumulative 2-year clinical outcomes are shown in Table 3. The incidence of 2-year net clinical outcomes was significantly higher in the TAT group compared with the DAPT group (34.3 vs. 21.1%, P = 0.006). This difference was mostly due to the higher incidence of 2-year major bleeding (16.7 vs. 4.6%, P < 0.001) in the TAT group, without any definite increase in 2-year MACCE (22.1% in the TAT group vs. 17.7% in the DAPT group, P = 0.313). During the 2-year follow-up, 74 (20.1%) cases of overall bleeding and 71 (19.3%) cases of MACCE were reported. Among the cases of overall bleeding events, 33 (44.6% of overall bleeding events) cases manifested with major bleeding and 45 (60.8% of overall bleeding events)

Baseline clinical characteristics Unmatched overall population

Sex (male) Age (years) Persistent AF (%) Smoking history (%) Hypertension (%) Diabetes (%) Dyslipidemia (%) Congestive heart failure (%) LVEF < 40% (%) Chronic kidney disease (%) Previous ischemic cerebrovascular disease (%) Previous MI (%) Previous PUD (%) Previous GI bleeding (%) Risk stratification parameter CHADS2 score CHADS2 ≥ 2 (%) CHA2DS2-VASc score CHA2DS2-VASc ≥ 2 (%) HAS-BLED score HAS-BLED ≥ 3 (%) TTR (%) Time in PT-INR below 2.0 (%) Antiplatelet drugs at discharge Aspirin (%) Clopidogrel (%) Ticlopidine (%) Cilostazol (%)

PSM-matched population

DAPT (n = 236)

TAT (n = 131)

P-value

DAPT (n = 99)

TAT (n = 99)

P-value

152 (64.4) 67.52 ± 9.73 145 (61.4) 92 (38.9) 177 (75.0) 72 (30.5) 109 (46.1) 44 (18.6) 38 (16.1) 24 (10.1) 28 (11.8) 20 (8.4) 10 (4.2) 2 (0.8)

87 (66.4) 69.06 ± 8.20 112 (85.4) 52 (39.6) 97 (74.0) 43 (32.8) 52 (39.6) 52 (39.6) 34 (25.9) 12 (9.1) 24 (18.3) 9 (6.8) 5 (3.8) 3 (2.2)

0.699 0.126 < 0.001 0.894 0.840 0.647 0.230 < 0.001 0.023 0.755 0.089 0.585 0.845 0.253

65 (65.6) 68.00 ± 8.28 79 (79.7) 36 (36.3) 76 (76.7) 38 (38.3) 48 (48.4) 33 (33.3) 23 (23.2) 7 (7.0) 14 (14.1) 11 (11.1) 4 (4.0) 1 (1.0)

64 (64.6) 69.03 ± 7.49 82 (82.8) 39 (39.3) 74 (74.7) 34 (34.3) 44 (44.4) 26 (26.2) 20 (20.2) 10 (10.1) 13 (13.1) 7 (7.0) 4 (4.0) 3 (3.0)

0.881 0.360 0.584 0.660 0.740 0.555 0.569 0.277 0.605 0.447 0.836 0.323 1.000 0.621

1.68 ± 1.15 123 (52.1) 3.02 ± 1.84 181 (76.6) 2.127 ± 0.744 58 (24.5)

2.06 ± 1.18 90 (68.7) 3.47 ± 1.66 118 (90) 2.244 ± 0.755 43 (32.8) 29.20 ± 24.88 63.85 ± 29.05

0.003 0.002 0.022 0.002 0.152 0.090

1.98 ± 1.20 63 (63.6) 3.41 ± 1.80 87 (87.8) 2.181 ± 0.705 26 (26.2)

1.82 ± 1.10 60 (60.6) 3.22 ± 1.63 86 (86.8) 2.212 ± 0.746 30 (30.3) 27.09 ± 24.69 66.85 ± 28.40

0.324 0.660 0.432 0.831 0.769 0.528

236 222 16 40

(100.0) (94) (6.7) (16.9)

124 123 5 19

(94.6) (93.8) (3.8) (14.5)

0.001 0.946 0.242 0.541

99 92 8 18

(100) (92.9) (8.0) (18.1)

93 93 4 14

(93.9) (93.9) (4.0) (14.1)

0.013 0.774 0.234 0.440

Data are expressed as n (%) or mean ± SD. AF, atrial fibrillation; CHADS2, congestive heart failure, hypertension, age at least 75 years, diabetes mellitus, prior stroke or transient ischemic attack; CHA2DS2-VASc, congestive heart failure, hypertension, age at least 75 years, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex; DAPT, dual antiplatelet therapy; GI, gastrointestinal; HAS-BLED, hypertension, abnormal renal and liver function, stroke, bleeding, labile INRs, age at least 65 years, drugs or alcohol; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PSM, propensity score matched; PT-INR, prothrombin time international normalized ratio; PUD, peptic ulcer disease; TAT, triple antithrombotic therapy; TTR, time in the therapeutic range.

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Antithrombotic strategies in AF with DES implants Kang et al. 375

Table 2

Baseline angiographic and procedural characteristics Unmatched overall population

Number of lesions with significant stenosis (%) Total number of stents Average stent diameter (mm) Total stent length (mm) Diagnosis at DES implantation Myocardial infarction (%) Unstable angina (%) Stable angina (%) Ischemic CMP (%) Others (%) Extent of vessel involvement One-vessel disease (%) Two-vessel disease (%) Three-vessel disease (%) Left main disease (%)

PSM-matched population

DAPT (n = 236)

TAT (n = 131)

P-value

DAPT (n = 99)

TAT (n = 99)

P-value

2.17 ± 1.04 1.63 ± 0.88 2.96 ± 0.41 37.13 ± 23.54

2.05 ± 0.96 1.52 ± 0.77 2.94 ± 0.45 35.93 ± 20.81

0.248 0.221 0.722 0.626

2.18 ± 1.01 1.55 ± 0.72 3.01 ± 0.49 34.41 ± 19.12

2.04 ± 0.94 1.49 ± 0.77 2.96 ± 0.48 35.15 ± 21.00

0.309 0.635 0.470 0.796

53 130 46 4 3

(22.4) (55.0) (19.4) (1.6) (1.2)

34 68 24 4 1

(25.9) (51.9) (18.3) (3.0) (0.7)

0.810

21 52 24 1 1

(21.2) (52.5) (24.2) (1.0) (1.0)

25 51 19 3 1

(25.2) (51.5) (19.1) (3.0) (1.0)

0.774

109 71 36 20

(46.1) (30.0) (15.2) (8.4)

66 36 20 9

(50.3) (27.4) (15.2) (6.8)

0.854

43 31 17 8

(43.4) (31.3) (17.1) (8.0)

49 28 16 6

(49.4) (28.2) (16.1) (6.0)

0.835

Data are expressed as n (%) or mean ± SD. CMP, cardiomyopathy; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; PCI, percutaneous coronary intervention; PSM, propensity score matched; TAT, triple antithrombotic therapy.

Table 3

Cumulative 2-year clinical outcomes after DES implantation Unmatched overall population

PSM-matched population

DAPT (n = 236)

TAT (n = 131)

P-value

DAPT (n = 99)

TAT (n = 99)

P-value

11 (4.6) 9 (3.8) 20 (8.4)

22 (16.7) 36 (27.4) 54 (41.2)

< 0.001 < 0.001 < 0.001

3 (3.0) 6 (6.0) 9 (9.0)

18 (18.1) 28 (28.2) 44 (44.4)

0.001 < 0.001 < 0.001

11 2 9 15 5 15 42 50

9 4 5 6 4 12 29 45

Bleeding events Major bleeding (%) Minor bleeding (%) Overall bleeding (%) MACCE Death (%) CV death (%) Non-CV death (%) Nonfatal MI (%) Ischemic CVA (%) Repeat revascularization (%) MACCE (%) Net clinical outcome (major bleeding + MACCE)

(4.6) (0.8) (3.8) (6.3) (2.1) (6.3) (17.7) (21.1)

(6.8) (3.0) (3.8) (4.5) (3.0) (9.1) (22.1) (34.3)

0.372 0.192 1.000 0.483 0.727 0.324 0.313 0.006

3 2 1 6 0 11 17 21

(3.0) (2.0) (1.0) (6.0) (0) (11.1) (17.1) (21.2)

7 4 3 5 4 9 22 35

(7.0) (4.0) (3.0) (5.0) (4.0) (9.0) (22.2) (35.3)

0.331 0.683 0.621 0.756 0.121 0.637 0.372 0.027

Data are expressed as n (%). CV, cardiovascular; CVA, cerebrovascular accident; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; MACCE, major adverse cardiovascular and cerebrovascular event; MI, myocardial infarction; PSM, propensity score matched; TAT, triple antithrombotic therapy.

Clinical manifestations of the bleeding events within the 2-year follow-up

Table 4

Major bleeding patients only (n = 33) Intracranial (%) Gastrointestinal bleeding (%) Retroperitoneal hemorrhage (%) Decrease in Hgb > 4 g/dl (%) Transfusion > 2 pints (%) Hemodynamic instability (%) Minor bleeding patients only (n = 45) Hematuria (%) Epistaxis (%) Anal bleeding (%) Oral/gum bleeding (%) Easy bruising (%) Miscellaneous (%)

DAPT (n = 11) 1 0 0 2 4 4

(9.0) (0) (0) (18.1) (36.3) (36.3)

DAPT (n = 9) 4 2 0 0 0 3

(44.4) (22.2) (0) (0) (0) (33.3)

TAT (n = 22) 3 6 3 1 6 3

(13.6) (27.2) (13.6) (4.5) (27.2) (13.6)

TAT (n = 36) 11 7 2 8 3 5

(30.5) (19.4) (5.5) (22.2) (8.3) (13.8)

Data are expressed as n (%). DAPT, dual antiplatelet therapy; Hgb, hemoglobin; TAT, triple antithrombotic therapy.

cases manifested with minor bleeding. The incidence of 2-year minor bleeding (27.4 vs. 3.8%, P < 0.001) was also significantly higher in the TAT group. The specific etiology of each bleeding event is provided in Table 4. There was no significant difference between both groups in the 2-year incidence of each adverse event constituting MACCE. Although the incidence of ischemic cerebrovascular events was similar in both groups, moderate to severe functional impairment (mRS > 2) was more frequent in the DAPT group (86.6 vs. 16.6%, P = 0.006; Table 5). The proportion of patients with mRS greater than 2 was still higher in the DAPT group when hemorrhagic cerebrovascular events were included in the analysis (87.5 vs. 22.2%, P = 0.002; Table 5). In subgroup analysis of the TAT group, a higher proportion of 2-year adverse clinical events including both MACCE and major bleeding was found to develop under the administration of TAT

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376

Coronary Artery Disease 2015, Vol 26 No 5

Severity of functional impairment after ischemic and hemorrhagic cerebrovascular events

Table 5

Ischemic and hemorrhagic CVA (n = 25)

DAPT (n = 16)

TAT (n = 9)

P-value

Modified Rankin’s scale Score 0 (%) Score 1 (%) Score 2 (%) Score 3 (%) Score 4 (%) Score 5 (%) Moderate to severe (mRS > 2) (%)

0 0 2 6 4 4 14

Ischemic CVA patients only (n = 20)

DAPT (n = 15)

TAT (n = 5)

P-value

Moderate to severe (mRS > 2) (%)

13 (86.6)

1 (16.6)

0.006

(0) (0) (12.5) (37.5) (25.0) (25.0) (87.5)

1 2 4 1 1 0 2

(11.1) (22.2) (44.4) (11.1) (11.1) (0) (22.2)

Propensity score-matching analysis

0.002

Data are expressed as n (%). CVA, cerebrovascular accidents; DAPT, dual antiplatelet therapy; mRS, modified Rankin’s scale; TAT, triple antithrombotic therapy.

Table 6 Time in the therapeutic range of the triple antithrombotic therapy group according to the development of each adverse outcome

Two-year net clinical outcome TTR (%) Two-year overall bleeding TTR (%) Two-year major bleeding TTR (%) Two-year minor bleeding TTR (%) Two-year ischemic CVA TTR (%)

Event group

Control group

n = 45 25.13 ± 21.26 n = 54 28.80 ± 22.93 n = 22 29.23 ± 21.18 n = 36 27.99 ± 24.13 n=6 16.80 ± 8.02

n = 86 32.21 ± 27.12 n = 77 29.61 ± 27.04 n = 109 29.2 ± 25.97 n = 95 29.81 ± 25.49 n = 125 30.00 ± 25.41

explanatory factor for bleeding events, the coadministration of OAC with DAPT (OR 3.54, 95% CI 1.65–7.58; P = 0.001) was the most important predicting factor for 2-year major bleeding.

P-value 0.257 0.896 0.996 0.781 0.307

Data are expressed as n (%) or mean ± SD. CVA, cerebrovascular accidents; TTR, time in the therapeutic range.

rather than after its discontinuation (Supplementary Table S2, Supplemental digital content 1, http://links.lww.com/ MCA/A37). The TTR showed no significant difference between the groups according to the development of each adverse outcome (Table 6). Survival curve analysis and multivariate analysis for the 2-year clinical outcomes

On Kaplan–Meier survival curve analysis, the cumulative incidence of 2-year net clinical outcome events (log-rank test, P = 0.006; Fig. 1a) and 2-year major bleeding events (log-rank test, P < 0.001; Fig. 1e) was found to be significantly higher in the TAT group compared with the DAPT group. The cumulative incidence of 2-year MACCE showed no significant difference over the followup period (log-rank test, P = 0.255; Fig. 1c). On multivariate Cox regression analysis, coadministration of OAC with DAPT [odds ratio (OR) 1.63, 95% confidence interval (CI) 1.06–2.50, P = 0.025], a previous diagnosis of hypertension (OR 2.61, 95% CI 1.35–5.02, P = 0.004), and a HAS-BLED score ≥ 3 (OR 1.83, 95% CI 1.12–2.97, P = 0.014) were found to be independent predictors for worse 2-year net clinical outcomes (Table 7). In the analysis of 2-year major bleeding, regarding HAS-BLED score ≥ 3 (OR 2.50, 95% CI 1.12–5.55; P = 0.024) as an

The propensity score-matching analysis yielded 99 pairs of study participants who presented with similar angiographic and procedural profiles, as well as baseline characteristics (Tables 1 and 2). The TAT group was still associated with worse 2-year net clinical outcomes (35.3 vs. 21.2%, P = 0.027), which was also due to the higher incidence of 2-year major bleeding (18.1 vs. 3.0%, P = 0.001), without any difference in 2-year MACCE (22.2 vs. 17.1%, P = 0.372), as in the unmatched analysis (Table 3). The survival curve analysis revealed a higher cumulative incidence of 2-year net clinical outcome events (log-rank test, P = 0.014; Fig. 1b) and 2-year major bleeding (log-rank test, P < 0.001; Fig. 1f) in the TAT group. On multivariate Cox regression analysis, the administration of TAT was found to be the most important predictor for both worse 2-year net clinical outcomes (OR 2.08, 95% CI 1.20–3.60, P = 0.009) and 2-year major bleeding (OR 6.84, 95% CI 1.98–23.6, P = 0.002; Table 7). A HAS-BLED score of 3 or higher was also found to be associated with an increased risk for 2-year net clinical outcome events (OR 1.91, 95% CI 1.03–3.56, P = 0.040) and 2-year major bleeding (OR 2.93, 95% CI 1.10–7.81, P = 0.031).

Discussion The current study demonstrated that TAT was associated with worse net clinical outcomes and a higher incidence of major bleeding within the 2-year follow-up in AF patients who had undergone DES implantation. Although the use of TAT could potentially reduce the risk for thromboembolic events, it is uncertain whether this therapeutic benefit surpasses the risk for bleeding. In previous studies, an increased risk for bleeding associated with the use of TAT has been commonly reported; however, study results on the reduced incidence of MACCE and the impact on net clinical outcomes have been widely inconsistent [10–12,23–27]. Most of the previous studies have analyzed the safety and efficacy outcomes separately [10,12,23–28], and a limited number of studies have focused on the net clinical outcomes [11]. The current study evaluated the net clinical outcomes of each antithrombotic regimen to estimate the overall therapeutic benefit. Assessment of the net clinical outcomes was carried out by propensity score-matching analysis to provide more convincing evidence, and these features made our study result more relevant compared with those of other previous retrospective studies. The results of the present study indicate that long-term administration of TAT significantly increases the risk for bleeding without a definite reduction in MACCE. The net clinical outcomes were found to be even worse when treatment outcomes were analyzed as a composite endpoint.

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Antithrombotic strategies in AF with DES implants Kang et al. 377

Fig. 1

Cumulative incidence rate

(a) 0.5

Unmatched analysis : 2-year net clinical outcomes Log-rank test DAPT group P-value = 0.006 TAT group

0.4

(b) 0.5

PSM-analysis : 2-year net clinical outcomes DAPT group TAT group

0.4 35.3%

34.3%

0.3

0.3 21.2%

21.1%

0.2

0.2

0.1

0.1

0.0

∗OR 1.63, 95% CI 1.06−2.50, P-value = 0.025

0 (c) 0.3

180

360

540

Unmatched analysis : 2-year MACCE

0.0

720

Log-rank test P-value = 0.255

∗OR 2.08, 95% CI 1.20−3.60, P-value = 0.009

0 (d) 0.3

Cumulative incidence rate

180

360

PSM-analysis : 2-year MACCE

DAPT group TAT group

540

0.2

17.7%

0.1

Log-rank test P-value = 0.301

22.2%

0.2 17.1%

0.1

∗OR 1.15, 95% CI 0.69−1.91, P-value = 0.573

0 (e) 0.3

720

DAPT group TAT group 22.1%

0.0

180

360

540

Unmatched analysis : 2-year major bleeding DAPT group TAT group

Cumulative incidence rate

Log-rank test P-value = 0.014

720

Log-rank test P-value < 0.001

0.2

0.0

16.7%

0.1

∗OR 1.57, 95% CI 0.82−2.99, P-value = 0.167

0 (f) 0.3

180

360

PSM-analysis : 2-year major bleeding DAPT group TAT group

540

720

Log-rank test P-value < 0.001

18.1%

0.2

0.1 4.6% 3.0%

0.0

∗OR 3.54, 95% CI 1.65−7.58, P-value = 0.001

0

180

360 540 Follow-up period

720

0.0

∗OR 6.84, 95% CI 1.98−23.6, P-value = 0.002

0

180

360 540 Follow-up period

720

Cumulative incidence of each 2-year clinical outcome event according to the prescribed antithrombotic regimen. Results of the (a, c, e) unmatched analysis and (b, d, f) propensity score-matching analysis are shown: (a, b) 2-year net clinical outcomes, (c, d) 2-year MACCE, and (e, f) 2-year major bleeding. CI, confidence interval; DAPT, dual antiplatelet therapy; MACCE, major adverse cardiac and cerebral events; OR, odds ratio; PSM, propensity score matching; TAT, triple antithrombotic therapy.

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Coronary Artery Disease 2015, Vol 26 No 5

Table 7

Predictive factors for 2-year net clinical outcomes and major clinical adverse events Unmatched overall population Adjusted OR (95% CI)

Two-year net clinical outcome Triple antithrombotic therapy Hypertension CHA2DS2-VASc ≥ 2 (%) HAS-BLED ≥ 3 (%) Two-year MACCE Triple antithrombotic therapy Hypertension CHA2DS2-VASc ≥ 2 (%) HAS-BLED ≥ 3 (%) Two-year major bleeding Triple antithrombotic therapy Hypertension CHA2DS2-VASc ≥ 2 (%) HAS-BLED ≥ 3 (%)

PSM-matched population

a

P-value

Adjusted ORa (95% CI)

P-value

1.63 2.61 1.16 1.83

(1.06–2.50) (1.35–5.02) (0.49–2.76) (1.12–2.97)

0.025 0.004 0.728 0.014

2.08 2.84 1.26 1.91

(1.20–3.60) (1.14–7.07) (0.36–4.37) (1.03–3.56)

0.009 0.025 0.713 0.040

1.15 2.62 0.70 1.51

(0.69–1.91) (1.22–5.66) (0.26–1.86) (0.85–2.68)

0.573 0.014 0.485 0.157

1.57 2.92 0.55 1.48

(0.82–2.99) (0.93–9.14) (0.12–2.43) (0.69–3.16)

0.167 0.064 0.436 0.307

3.54 2.92 1.08 2.50

(1.65–7.58) (0.92–9.26) (0.23–4.92) (1.12–5.55)

0.001 0.068 0.918 0.024

6.84 3.99 1.94 2.93

(1.98–23.6) (0.80–19.8) (0.30–12.5) (1.10–7.81)

0.002 0.091 0.486 0.031

CHA2DS2-VASc, congestive heart failure, hypertension, age at least 75 years, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex; CI, confidence interval; HAS-BLED, hypertension, abnormal renal and liver function, stroke, bleeding, labile INRs, age at least 65 years, drugs or alcohol; MACCE, major adverse cardiovascular and cerebrovascular event; OR, odds ratio; PSM, propensity score matched. a Adjusted for age, sex, diabetes mellitus, congestive heart failure, previous ischemic cerebrovascular disease, types of atrial fibrillation.

According to the CHADS2 and CHA2DS2-VASc scoring systems, the majority of patients in the current study were at intermediate or high risk for thromboembolism, requiring long-term administration of OAC. Although the DAPT group showed better net clinical outcomes in the current study, the administration of DAPT alone without OAC in this population cannot be justified on the basis of the results of the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVEW) trial [4]. Furthermore, the current data suggest that DAPT alone could result in more severe functional impairment (mRS >2) from thromboembolic cerebrovascular events. Therefore, neither long-term administration of DAPT alone nor TAT can be solely recommended as an optimal antithrombotic strategy after DES implantation in AF patients at intermediate or high risk for thromboembolism. However, the current study results cannot be directly applied to AF patients at lower thromboembolic risk. DAPT alone without OAC in such a population after coronary stenting could possibly provide more benefits compared with the use of TAT [29], and this is currently under investigation in the ongoing MUSICA-II trial [30]. As an alternative antithrombotic strategy for AF patients at intermediate or high risk for thromboembolism, modulating the duration and components of TAT can be a plausible option. Currently, an open-label multicenter randomized trial [Intracoronary Stenting and Antithrombotic Regimen – Testing of a sixweek versus a six-month clopidogrel treatment Regimen In Patients with concomitant aspirin and oraL anticoagulant therapy following drug-Eluting stenting (ISARTRIPLE)] is underway to prove the general efficacy and safety of the shortened duration of 6-week TAT compared with 6-month TAT, especially in AF patients implanted with a DES [31]. Another strategy included administration of OAC with single thienopyridine, which

demonstrated reduced overall bleeding and MACCE compared with TAT in the recently reported What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting (WOEST) trial [27,28]. In addition to these strategies, an interventional technique that eliminates the need for OAC, for example, left atrial appendage occlusion, can be considered in suitable patients [32]. Besides the use of TAT, HAS-BLED scores of 3 or higher and hypertension were other chief contributing factors toward worse net clinical outcomes and a higher incidence of major bleeding. As originally used as a parameter for bleeding risk stratification [19], a HAS-BLED score of 3 or higher was closely associated with the increased incidence of major bleeding. Hypertension has been a well-known conventional risk factor for adverse clinical outcomes including bleeding complications, and the scoring systems for risk stratification in AF patients already include hypertension as a major component [17–19]. Therefore, hypertension should not be considered an ordinary factor and blood pressure should preferably be maintained within its normal limits. In the subgroup analysis, the TTR was maintained at a suboptimal level in most cases because of the PT-INR levels being lower than a targeted minimum of 2.0 (Table 1). In ‘real-world’ practice, there are profound concerns about bleeding complications with the use of TAT; therefore, physicians are likely to show a tendency to maintain PT-INR at a relatively lower range. Although a monitored PT-INR level was mostly unsatisfactory for stroke prevention, this showed no significant correlation with the development of either thromboembolic or bleeding events. When compared with the DAPT group, the use of OAC itself rather than the obtained suboptimal TTR in the TAT group was likely to be a chief contributing factor toward worsened net clinical outcomes and increased bleeding risk. Subgroup analysis of the

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Antithrombotic strategies in AF with DES implants Kang et al. 379

TAT group also revealed that the majority of 2-year net clinical outcomes including both MACCE and major bleeding was mostly attributed to the addition of OAC to DAPT. The present study provides special perspectives compared with previous studies. The study population of the present study included AF patients who had undergone DES implantation, without the use of a bare-metal stent; thus, the patients had more homogeneous characteristics compared with those included in previous studies [10,12,23–28]. Because only a few studies have been conducted in AF patients treated with the use of DES exclusively [11,13], the results of the present study could help determine the optimal antithrombotic strategy in such a group of patients. Another important feature of the current study is the analysis of the temporal relationship between the 2-year adverse clinical outcomes and the administered antithrombotic regimens at the time of event development. This feature enabled us to highlight the marked correlation between worsened 2-year net clinical outcomes and concurrent use of TAT. The present study has some limitations. First, the sample size of 367 patients from retrospective registry data from two centers was not very small compared with that in previous studies [11–13,23–26,28]; however, it was not large enough to draw solid conclusions. Stent thrombosis merely occurred as an adverse outcome in the current study, and this low rate of occurrence could probably be related to the small sample size. Future prospective randomized studies with a larger sample size are required to overcome the limitations of the registry data and to confirm the reproducibility of the results. Second, because of the inherent limitations of nonrandomized registry data, the difference in treatment groups could have affected the clinical outcomes. Although we included the potential confounding factors into both multivariate analysis and propensity score-matched analysis to minimize such biases, it is still possible that the remaining confounders might have been included in the analysis. Third, the current study compared between the TAT group and the DAPT group only; thus, the safety and efficacy of other treatment strategies such as OAC with a single antiplatelet agent were not assessed. In AF patients undergoing DES implantation, prolonged administration of TAT is associated with worse 2-year net clinical outcomes, with a substantial increase in the risk for major bleeding without any definite reduction in MACCE. In AF patients who require long-term administration of TAT after DES implantation, alternative treatment strategies should be considered for balancing the risk for thromboembolism and major bleeding.

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Acknowledgements Conflicts of interest

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There are no conflicts of interest.

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Triple antithrombotic therapy versus dual antiplatelet therapy in patients with atrial fibrillation undergoing drug-eluting stent implantation.

The optimal antithrombotic regimen in patients with atrial fibrillation (AF) undergoing drug-eluting stent (DES) implantation for complex coronary art...
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