Bleeding risk with triple antithrombotic therapy in patients with atrial fibrillation and drug-eluting stents

  • Yoshinari Enomoto
  • Raisuke Iijima
  • Masahide Tokue
  • Naoshi Ito
  • Yoshinori Nagashima
  • Tadashi Araki
  • Kenji Yamazaki
  • Makoto Utsunomiya
  • Masaki Hori
  • Hideki Itaya
  • Masanori Shiba
  • Hidehiko Hara
  • Masato Nakamura
  • Kaoru Sugi
Original Article

Abstract

In the era of drug-eluting stents (DES), a long-term dual antiplatelet therapy is required to prevent late stent thrombosis. However, in patients with atrial fibrillation (AF), there is a concern that combining warfarin with dual antiplatelet therapy may increase the risk of bleeding. We analyzed 1274 consecutive patients with coronary artery disease who were treated with coronary intervention from January 2006 through January 2009. Of these, we enrolled 74 AF patients treated with DES and dual antiplatelet therapy as well as warfarin. The primary endpoint was the incidence of major bleeding within 3 years; the predictive factor of major bleeding was also analyzed. To evaluate the efficacy of anticoagulant therapy, time in therapeutic range (TTR) was also measured. The 3-year incidence of major bleeding was 12.2 % (nine of 74 patients). The average observation period was 25.7 ± 20.2 months. Mean TTR value was 44.6 ± 33.0 % and was maintained at a relatively low level. Multivariate analysis revealed that a higher CHADS2 score (2-point more) was an independent predictor of increased risk of major bleeding. Major bleeding in the patients with triple antithrombotic therapy including warfarin occurred at a relatively high rate. Although the higher CHADS2-score indicates a high risk of thrombotic events, it was strongly associated with bleeding complications.

Keywords

Drug-eluting stent Triple antithrombotic therapy Time in the therapeutic range CHADS2 score 

Introduction

Currently, drug-eluting stent (DES) technology and dual antiplatelet therapy play a central role in the field of percutaneous coronary intervention (PCI) for coronary artery disease, although the risk of late stent thrombosis remains a troublesome issue [1, 2]. With regard to the concern about the development of late stent thrombosis, the guidelines recommend that dual antiplatelet therapy should be administered for at least the first 12 months following DES implantation, although further continuation is desirable [3]. In real-world practice, DES has been used for patients with atrial fibrillation (AF). AF is the most commonly sustained cardiac arrhythmia. Life-long anticoagulant therapy with warfarin, rather than antiplatelet treatment, is recommended to reduce the risk of stroke and thromboembolic events [4, 5]. According to the AFFIRM and RACE trials, 26–48 % AF patients have coronary artery disease [6, 7]. This raises a clinical concern. If AF patients are treated with DES for coronary artery disease, a triple antithrombotic therapy (TAT) with a dual antiplatelet regimen plus warfarin would be needed to prevent both thromboembolism and late stent thrombosis. However, contrary to a beneficial effect, this regimen has a negative aspect; it may increase the risk of bleeding complications. The aim of this study was to investigate the incidence and predictive factors of major bleeding in AF patients with DES who are treated with TAT.

Methods

We retrospectively analyzed 1274 consecutive coronary artery disease patients treated with PCI from January 2006 through January 2009. Of these, AF patients who had received oral anticoagulant therapy with warfarin were enrolled in the present study. Patients with hemodynamic instability, malignancies, or increased risk of bleeding (stroke within the previous 3 months, active bleeding, recent trauma or major surgery in the last month) and those who received direct thrombin inhibitors (dabigatran) or who had contraindication to the antiplatelet drugs were excluded from the study.

Antiplatelet therapy

All patients were pretreated with thienopyridine derivatives and aspirin. Patients scheduled for PCI were administered aspirin (100 mg) plus ticlopidine (200 mg) or clopidogrel (75 mg) daily for at least 3 days before the procedure. In case of unstable angina or urgent PCI within 48 h after admission, a 300-mg clopidogrel loading dose was administered before the procedure. A heparin bolus (100 U/Kg) was administered before the procedure, with a repeat bolus of 5000 U, as needed, to maintain an activated clotting time of >250 s throughout the procedure. After the procedure, a dual antiplatelet therapy [aspirin (100 mg) plus ticlopidine (200 mg) or clopidogrel 75 mg daily] was continued for at least 12 months; continuation of dual antiplatelet therapy after the procedure was left to the discretion of the patients’ physicians.

Anticoagulant therapy and time in therapeutic range

Anticoagulant therapy with warfarin was adjusted monthly using the prothrombin time international normalized ratio (PT-INR), and a target PT-INR range of 2.0–3.0 was set [8]. However, there were limitations regarding the evaluation of the optimal achieved anticoagulant therapy intensity; the control of PT-INR values was left to the discretion of the patients’ physicians. Furthermore, the PT-INR value at a single time point does not always reflect the long-term anticoagulant therapy intensity in some patients on warfarin. Therefore, the optimal intensity of anticoagulant therapy achieved was evaluated by analyzing the time in the therapeutic range (TTR) [9]. The notion of TTR is based on the assumption that anticoagulation intensity during warfarin therapy shifts linearly between any two consecutive measurements, and the TTR is calculated for the entire duration of observation. The optimal achieved intensity of anticoagulant therapy was defined as TTR >65 %, which is associated with a reduced risk of stroke [10].

Stent and post-procedural management

DES was used at our hospital unless contraindicated, for example, in patients with malignancies or those scheduled for surgery. Target lesions were predilatated with conventional angioplasty balloons; after stent implantation, high-pressure balloon inflation was performed to achieve a satisfactory angiographic result of <25 % residual stenosis by visual estimate [11].

Definitions and follow-up

The primary endpoint was the incidence of major bleeding within 3 years. According to the REPLACE-2 trial, [12] major bleeding events were defined as follows: intracranial, intraocular, or retroperitoneal hemorrhage; hematoma related to the procedure; clinically overt blood loss resulting in a decrease in hemoglobin of more than 4 g/dL; gastrointestinal bleeding; or transfusion of two or more units of packed red blood cells. The secondary endpoints were cardiac death, stroke, and myocardial infarction related to stent thrombosis. The risk of embolic events was stratified using the CHADS2 score, which takes into account the presence of heart failure, hypertension and diabetes, the patient’s age, and history of stroke; the CHADS2 score is widely used in clinical practice for predicting stroke risk in patients with AF [13].

Statistical analysis

The data are presented as mean ± SD or counts (%). Categorical data were compared with the Chi-square test or Fisher’s exact test when cell values were <5. Continuous data were compared using a two-tailed unpaired t test. Event-free analysis was performed by applying the Kaplan–Meier method. Differences in the major bleeding event rates were assessed with the log-rank test, which allowed the calculation of odds ratios (OR) [95 % confidence intervals (CI)]. The Cox proportional hazards model was used to assess the association between major bleeding and the CHADS2 score or TTR value, while adjusting for other confounding factors. A probability value <0.05 was considered statistically significant.

Results

Seventy-four patients were receiving TAT for AF and DES implantation. The mean follow-up time was 36 ± 19 months. During this period, nine of the 74 patients (12.2 %) experienced a major bleeding event, including two cases of blood loss, three cases of hematoma related to procedure, one case of gastrointestinal bleeding, and three cases of intracranial hemorrhage cases. The mean time of bleeding developed after DES implantation was 12 ± 13 months. On the other hand, there were two cardiac deaths (2.7 %), and myocardial infarction related with very late stent thrombosis occurred in one patient (1.4 %). No patients with embolic stroke were observed during this period. As shown in Table 1, 74 patients were divided into a bleeding group (n = 9) and a nonbleeding group (n = 65). Patients who experienced bleeding events were older (p = 0.042) and had a higher mean CHADS2 score (p < 0.001) than those who did not experience bleeding events. The mean CHADS2 score of all patients was 2.0 ± 1.2 points. Table 2 shows the clinical profile of patients with major bleeding. When a cut-off value was set at a score of 2, the incidence of major bleeding was significantly higher in patients with high CHADS2 score than those with low CHADS2 score (Fig. 1). Multivariate analysis indicated that a high CHADS2 score was an independent predictive factor of major bleeding in patients on TAT (Table 3). The average TTR value in our patients was 44.6 ± 33.0 %; only 22 patients (29.7 %) achieved the optimal intensity of anticoagulant therapy. Consequently, fifty-two remaining patients were controlled with the low levels of PT-INR. To evaluate the influence of TTR on the incidence of major bleeding, the patients were divided into 4 groups based on a CHADS2 cut-off point of 2.0 (high CHADS2 score >2 vs. low CHADS2 score ≤2) and a TTR cut-off point of 65 % (optimal TTR ≥65 % vs. suboptimal TTR <65 %). Figure 2 shows that 3-year major bleeding rates were 2.3 % (n = 1), 15.4 % (n = 2), 33.3 % (n = 3), and 37.5 % (n = 3) in the low-CHADS2/suboptimal TTR, low-CHADS2/optimal TTR, high-CHADS2/suboptimal TTR, and high-CHADS2/optimal TTR, respectively. After adjusting for age, patients with high-CHADS2/optimal TTR had a markedly increased risk of major bleeding compared with those with low-CHADS2/suboptimal TTR [adjusted hazard ratio 12.65 (95 % Cl 1.21–132.06), p = 0.03]. (Fig. 3).
Table 1

Baseline and procedural characteristics of patients with or without major bleeding

 

Major bleeding (+)

Major bleeding (−)

p value

n = 9 (%)

n = 65 (%)

Age (years)

76 ± 7

68 ± 10

0.042

Male

6 (67)

54 (83)

0.40

Hypertension

9 (100)

49 (75)

0.19

Diabetes mellitus

4 (44)

26 (40)

0.99

Insulin user

1 (11)

4 (6)

0.49

Dyslipidemia

4 (44)

35 (54)

0.72

Killip ≥2

3 (33)

7 (11)

0.1

CHADS2 score

3.4 ± 1.6

1.8 ± 1.0

<0.001

CHADS2 score >2

6 (67)

11 (17 %)

0.004

e-GFR (ml/min)

64.1 ± 34.9

71.5 ± 29.8

0.49

Chronic kidney disease

3 (33)

21 (32)

0.99

Hemodialysis

2 (22)

6 (9)

0.25

Acute coronary syndromes

6 (67)

33 (51)

0.48

Prior coronary artery bypass surgery

2 (22)

11 (17)

0.66

Left ventricular ejection fraction (%)

52.0 ± 15.9

50.3 ± 14.8

0.75

Multivessel disease

8 (89)

40 (62)

0.15

Mean TTR

58.8 ± 39.9

42.2 ± 31.6

0.16

Medications

 Statins

8 (89)

51 (78)

0.67

 Proton pump inhibitors

7 (78)

28 (44)

0.07

 Angiotensin receptor blockers

7 (78)

37 (57)

0.30

 ACE inhibitor

0

17 (26)

0.11

 β-blocker

0

21 (32)

0.05

Target lesion

 Left main coronary artery

1 (11)

5 (8)

0.6

 Left anterior descending

6 (67)

34 (52)

 

 Right coronary artery

2 (22)

16 (25)

 

 Left circumflex

0

10 (15)

 

Type B2/C lesions

7 (78)

49 (75)

0.99

Chronic total occluded lesion

1 (11)

14 (22)

0.67

Vessel size (mm)

2.68 ± 0.98

2.80 ± 0.58

0.71

MLD before intervention, mm

0.88 ± 0.37

0.61 ± 0.57

0.44

Diameter stenosis (%)

62 ± 7

77 ± 22

0.23

Lesion length (mm)

27.1 ± 28.5

26.4 ± 17.9

0.94

Trans radial intervention

3 (33)

15 (23)

0.68

Sirolimus-eluting stent

3 (33)

30 (46)

0.5

Paclitaxel-eluting stent

3 (33)

25 (38)

 

Zotarolimus-eluting stent

1 (11)

5 (8)

 

Everolimus-eluting stent

2 (22)

5 (8)

 

Stent diameter (mm)

3.2 ± 0.4

3.1 ± 0.3

0.67

Number of stent

1.8 ± 1.0

1.7 ± 0.9

0.81

Stent length (mm)

37 ± 27

38 ± 23

0.87

Data are presented as number of patients (%) or mean ± SD

e-GFR estimated glomerular filtration rate, MLD minimal lumen diameter

Table 2

Clinical profile of patients with major bleeding

 

Age

Sex

Type of bleeding

HAS-BLED score

CHADS2 score

Duration of TAT (months)

PT-INRa

Case1

72

M

Gastrointestinal bleeding

5

2

1

1.23

Case2

67

M

Hematoma related procedure

4

3

4

1.44

Case3

85

M

Hemorrhagic shock

5

3

1

1.49

Case4

80

F

Hematoma related procedure

4

3

1

2.71

Case5

62

M

Hematoma related procedure

4

6

8

2.4

Case6

81

F

Intracranial bleeding

5

2

28

2.59

Case7

80

M

Intracranial bleeding

5

2

46

1.23

Case8

78

M

Intracranial bleeding

6

4

24

3.65

Case9

77

M

Hemorrhagic shock

7

6

1

3.4

TAT triple antithrombotic therapy

aPT-INR levels at the time of major bleeding

Fig. 1

Kaplan–Meier estimates of free from major bleeding events. Low CHADS2 score vs. high CHADS2 score

Table 3

Predictive factors of major bleeding

 

Univariate

Multivariate

p value

Odd ratio

95 % Cl

p value

CHADS2 score >2

0.002

2.97

1.45–6.07

0.003

Age

0.05

1.10

0.97–1.24

0.13

Fig. 2

Kaplan–Meier curves of free from major bleeding according to the CHADS2 score and TTR value. Cut-off points were set as follows: CHADS2 score >2 = high, CHADS2 score ≤2 = low, TTR value ≥65 % = optimal, and TTR value <65 % = suboptimal

Fig. 3

Risk of major bleeding after age adjustment among groups divided based on the CHADS2 score and TTR values. Hazard ratio (HR) (squares) and 95 % confidence interval (Cl) (horizontal bars) are shown. TTR time in the therapeutic range

Discussion

The present study was summarized by the following points: (1) AF patients on warfarin constituted 5.8 % of patients treated with DES and dual antiplatelet therapy. Furthermore, the incidence of major bleeding was 12.2 % among AF patients on TAT. (2) Although the CHADS2 score is commonly used for evaluating thrombotic events in AF patients, a higher CHADS2 score was an independent predictor of increased risk of major bleeding. (3) In clinical practice, AF patients on warfarin was controlled with a relatively low level of TTR, whereas there was a significantly higher incidence of major bleeding events in AF patients with higher CHADS2 score when they were treated with an optimal achieved intensity of anticoagulant therapy.

Many trials have demonstrated that DES use results in excellent outcomes with low rates of clinical restenosis and major adverse cardiac events compared with bare-metal stents [1, 2]. Consequently, the use of DES has become widespread among patients with comorbidities, including AF patients receiving warfarin treatment [14].

In recent years, aggressive antiplatelet regimens and prolonged dual antiplatelet therapy have been used with the objective of reducing the incidence of thrombotic events, especially the risk of very late stent thrombosis, following DES implantation [3].

On the other hand, AF is the most common cardiac arrhythmia, and its incidence is increasing in clinical practice. In addition, AF patients require life-long anticoagulant therapy with warfarin to prevent stroke and thromboembolic events [4, 5]. For this reason, the duration of TAT is still an unresolved issue. Extending TAT prevents stroke and stent thrombosis, but is associated with increased risk of bleeding events and the requirement for blood transfusion. Major bleeding is one of the most frequent complications of PCI and antithrombotic therapy [15]. Therefore, current antiplatelet regimens need to be administered with caution, given the heightened bleeding risk. As previously shown, the bleeding rate in our study was 12.2 %, which is considered quite frequent. Previous studies reported that the rate of major bleeding in patients receiving TAT was 5.9–12.3 % [16, 17, 18, 19]. This discrepancy may possibly be related to differences in bleeding definition, aspirin dose, racial differences, and intensity of anticoagulant therapy with warfarin. There is no doubt about the value of optimal anticoagulant therapy, which maintains “PT-INR 2.0–3.0” and “TTR >65 %,” to reduce the risk of stroke in AF patients [10]. However, there is a lack of definitive evidence regarding the optimal intensity of anticoagulant therapy in patients receiving TAT. Intuitively, a higher intensity of anticoagulant therapy would be related to an increased risk of major bleeding. In the present study, the average TTR value was 44.6 ± 33.0 % and optimal intensity of anticoagulation was achieved in only 22 patients (30.1 %). This means that, in real clinical practice, attending physicians who were concerned about bleeding complications controlled this risk with warfarin at lower levels of TTR if the AF patients also had a dual antiplatelet therapy after DES implantation. To adequately balance major bleeding and thrombotic events after DES implantation, the intensity and duration of TAT should be tailored to the individual patients.

Optimal intensity of TAT

The present study also identified a CHADS2 score >2 as an independent predictor of major bleeding. Although the CHADS2 score is a well-known scoring system for stroke events, it was also associated with an increased risk of major bleeding in patients receiving TAT. The reason remains unclear, but it may be associated with the fact that the CHADS2 score takes into consideration both age and a history of stroke, which are recognized risk factors of bleeding [13]. Interestingly, incidence of major bleeding was significantly high in patients with a high CHADS2 score (score >2) and an optimal level of TTR. This finding may indicate an increased risk of bleeding complications if patients with high CHADS2 score were administered at an optimal dose (INR 2.0–3.0) and dual antiplatelet therapy. Recently, WOEST study reported that in patients taking oral anticoagulants, use of clopidogrel without aspirin was significantly associated with a reduction in bleeding events and no increase in the rate of thrombotic events [20]. Therefore, anticoagulant therapy with warfarin plus clopidogrel may be feasible strategy in such a patient with bleeding risk.

Optimal duration of TAT

The guideline shows that the risk of stent thrombosis reduces significantly after 3–6 months following DES implantation [21]. Therefore, TAT might need to continue only during the high-risk periods and only among patients at higher risk of stroke. On the other hand, very late stent thrombosis that occurs after 12 months following DES implantation still remains an important issue. To avoid bleeding complications, for example, AF patients on TAT may have to switch from a dual antiplatelet therapy to a mono antiplatelet therapy, such as low dose of aspirin, as soon as possible. With regard to the risk of thrombotic events, such as stent thrombosis and myocardial infarction, registries and observational studies have produced data suggesting that dual antiplatelet therapy is not required beyond 6 months [22, 23]. However, these data should be interpreted with care because of possible patient-selection bias. As a matter of fact, low-risk patients should be included in a dual antiplatelet therapy group for a 6-month duration. Currently, many randomized clinical trials testing the optimal duration of dual antiplatelet therapy after DES implantation are underway [24, 25, 26]. If the ongoing clinical trials could provide the safety which the duration of dual antiplatelet therapy does not need to continue beyond 6 months after PCI, anticoagulant regimen of AF patients should be reconsidered regarding the duration and combination with antiplatelet drugs.

The present study has several limitations. First, it was a single-center study with a small sample size. The levels of PT-INR also varied considerably, because the intensity of anticoagulation with warfarin depended on the patients’ physicians. HAS-BLED score is well-known risk score for bleeding in AF patients. However, “taking antiplatelet-drugs” is calculated as a factor of bleeding in the HAS-BLED score. Our population has already higher HAS-BLED score because all patients received dual antiplatelet therapy. Therefore, we did not use the HAS-BLED score in this study.

In conclusion, we found the dilemma that higher CHADS2 scores were strongly associated with bleeding complications in AF patients if a target PT-INR range of 2.0–3.0 was maintained. Although the present study did not provide insights regarding the optimal intensity and duration of TAT after DES implantation, ongoing randomized clinical trials will help resolve this issue. At the moment, TAT in AF patients should be administered after careful consideration of the balance between the risks of thrombotic events and major bleeding at an individual patient level.

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Copyright information

© Japanese Association of Cardiovascular Intervention and Therapeutics 2013

Authors and Affiliations

  • Yoshinari Enomoto
    • 1
  • Raisuke Iijima
    • 1
  • Masahide Tokue
    • 1
  • Naoshi Ito
    • 1
  • Yoshinori Nagashima
    • 1
  • Tadashi Araki
    • 1
  • Kenji Yamazaki
    • 1
  • Makoto Utsunomiya
    • 1
  • Masaki Hori
    • 1
  • Hideki Itaya
    • 1
  • Masanori Shiba
    • 1
  • Hidehiko Hara
    • 1
  • Masato Nakamura
    • 1
  • Kaoru Sugi
    • 1
  1. 1.Division of Cardiovascular Medicine, Ohashi HospitalToho University Medical CenterTokyoJapan

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