Comparison Between Long-Term Clinical Outcomes of Vitamin K Antagonist and Direct Oral Anticoagulants in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

Abstract

Background: Whether direct oral anticoagulants (DOACs) are safer and more effective than vitamin K antagonist (VKA) for preventing thrombotic events in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) remains unknown.

Methods and Results: Between April 2011 and March 2014, data from 2,045 consecutive patients who underwent PCI were retrospectively examined. Of them, 129 patients treated with oral anticoagulants (OACs) and antiplatelet agents because of AF were enrolled. Primary bleeding outcome was a composite of major and minor bleeding, as per the Thrombolysis in Myocardial Infarction criteria. Secondary efficacy outcome was a composite outcome of death, myocardial infarction (MI), stroke, and target-lesion revascularization (TLR). Of the 129 patients, VKA was used in 84 and DOACs in 45. The mean time in the therapeutic range for the VKA group was 52.6%. The ratio of CHA₂D₂-VASC and HAS-BLED scores ≥3 was similar between the groups (VKA, 90.5%; DOAC, 84.4%; P=0.31 and VKA, 79.8%; DOAC, 68.9%; P=0.17, respectively). During follow-up (median, 1,080 days), the primary bleeding outcome tended to occur less (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.24–1.11, P=0.10) and the composite secondary efficacy outcome significantly less frequently (HR, 0.40; 95% CI, 0.14–0.91; P=0.03) in the DOAC group.

Conclusions: Compared with DOACs, VKA with poorly controlled INR and antiplatelet agents correlated with adverse outcomes of death, MI, stroke, and TLR in patients undergoing PCI.

Long-term oral anticoagulant agents (OACs) are mandatory for patients with atrial fibrillation (AF)^1–3 and 5–10% of patients undergoing percutaneous coronary intervention (PCI) have concomitant AF.^3–5 A combination of antiplatelet therapy and OACs is indicated for patients who undergo PCI, but there is great concern regarding bleeding complications (4–16% of cases) has with such combination therapy.^6–12 Direct OACs (DOACs) have been associated with a lower risk for stroke and systemic embolism than the vitamin K antagonist (VKA) warfarin among patients with AF, with similar or lower rates of major bleeding.^13–15 The PIONEER AF-PCI trial¹⁶ found that a combination of low-dose rivaroxaban and antiplatelet agent reduced the frequency of significant bleeding compared with standard therapy using VKA in patients with AF undergoing PCI. However, there are no comparative data available from daily practice for VKA and DOACs in these patients. Therefore, we investigated the bleeding and thrombotic events associated VKA and DOAC usage in AF patients who underwent PCI and required OAC therapy.

Methods

Patient Population

This retrospective cohort study was conducted at Ogaki Municipal Hospital from April 2011 to March 2014. Inclusion criteria were: (1) long-term indication for OAC treatment because of AF; (2) indication for PCI of a severe coronary lesion, defined as ≥75% stenosis on angiography or fractional flow reserve <0.80; and (3) aged ≥18 years. Exclusion criteria were: history of intracranial bleeding; cardiogenic shock; contraindication to aspirin, clopidogrel, or both; peptic ulcer in the previous 6 months; thrombocytopenia (platelet count, <50×10⁹/L); and major bleeding [according to the Thrombolysis in Myocardial Infarction (TIMI) criteria] in the previous 12 months. The indication for PCI was based on established European, US and Japanese guidelines. This study was approved by the Research Review Board of Ogaki Municipal Hospital.

Treatment

All patients received at least 1 antiplatelet agent [thienopyridine (200 mg ticlopidine or 75 mg clopidogrel daily) and/or 81–100 mg aspirin daily] and an OAC (VKA or DOAC). Although the standard antiplatelet regimen for PCI was both thienopyridine and aspirin for at least 1 month, the type and timing of discontinuation of the antiplatelet agents were at the discretion of each attending physician. The selection of OAC (VKA or DOAC) was also left to the discretion of the attending physician. In order to reduce the risk of bleeding, proton-pump inhibitors were administrated and access-site-closure devices (when PCI was conducted through a femoral access site) were used in all patients. In the periprocedural period, OAC was continued whenever possible.

Assessments and Follow-up

Demographic, angiographic and procedural data were collected from hospital charts or databases. Follow-up data were obtained from hospital charts or by contacting patients by telephone for up to 3 years.

The primary bleeding outcome was defined as a composite of major and minor bleeding according to the TIMI criteria during the follow-up period. The composite secondary efficacy outcome consisted of the incidence of death, non-procedural myocardial infarction (MI), stroke, and target-lesion revascularization (TLR). From this secondary efficacy outcome, a hard outcome was separately defined as a composite of death, non-procedural MI, and stroke. Each individual outcome comprising the primary and secondary outcomes was evaluated. MI was defined as the presence of pathologic and new Q waves on ECG, or an increase in the creatine-kinase myocardial band level to >3-fold the upper limit of the normal range; we excluded periprocedural MI from the composite secondary efficacy outcome in this study. Stent thrombosis was defined according to the Academic Research Consortium definitions.¹⁷

Stroke was assessed by the attending neurologist and defined as focal loss of neurologic function caused by an ischemic or hemorrhagic event.

Time in the Therapeutic Range

Data for the international normalized ratio (INR) during follow-up in patients with AF receiving VKA were collected from hospital charts. Time in the therapeutic range (TTR) in the VKA group was calculated by the Rosendaal method,¹⁸ according to a therapeutic INR range of 2.0–3.0 in patients aged <70 years, or 1.6–2.6, which is recommended for elderly patients (aged ≥70 years) in the Japanese guidelines.¹⁹

DOAC Treatment Dosage

The 3 DOACs were initially administered according to the instructions provided by the manufacturer/supplier of the respective drug. Briefly, dabigatran was administered twice daily at 150 mg per dose. Dose reduction to 110 mg was considered if the patient’s serum creatinine clearance was <50 mL/min, if older than 70 years, or with a history of gastrointestinal bleeding. Rivaroxaban was administered once daily at 15 mg. A 10 mg dose was used for patients whose serum creatinine clearance was 30–49 mL/min. Apixaban was administered twice daily at 5 mg, but a 2.5 mg dose was used for patients who met 2 or more of the following criteria: aged >80 years; body weight <60 kg; and serum creatinine level >1.5 mg/dL.

Statistical Analysis

Continuous variables are summarized as means and standard deviation (SD) or median and interquartile range (IQR), and categorical variables are shown as proportions. Continuous variables were compared using Student’s t-test or the Wilcoxon rank-sum test based on their distributions. Categorical variables were compared with chi-squared tests.

Primary and secondary outcomes based on time to first event were assessed by comparison of Kaplan-Meier-based cumulative incidence rates with the log-rank test. The primary analysis was assessed using the intention-to-treat principle. As a measure of the strength of the treatment effect, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for the VKA and DOAC groups using Cox’s proportional hazards regression analysis.

A propensity score indicating the predicted probability of receiving a specific treatment that was conditional on the observed covariates was calculated for each patient from the logistic equation. The following variables were included in the logistic regression model to calculate the propensity score: age, prior coronary artery bypass graft (CABG), dual antiplatelet therapy (DAPT) usage, the ratio of ST-elevation MI, and the 2 scores that excluded the component of age from the CHA₂D₂-VASC score and HAS-BLED score. The C-statistic was 0.81. We performed an adjustment for significant differences in the baseline characteristics of patients matched by propensity score. Clinical outcomes in the matched population were analyzed by Cox proportional hazards regression analysis.

All statistical analyses were performed using JMP software version 13.1 (SAS, Cary NC, USA). A P value <0.05 was considered statistically significant.

Results

Patients’ Characteristics

Of 2,045 patients who underwent PCI during the study period, we identified 184 eligible subjects who were taking OACs. Of those 184 patients, 84 in the VKA group and 45 in the DOAC group were taking OACs because of AF (Figure 1). The clinical characteristics of the recruited patients are summarized in Table 1. Median length of follow-up was 1,080 (IQR=627.5, 1,080) days for the VKA group and 1,080 (IQR=825.5, 1,080) days for the DOAC group. The mean age of the patients was higher in the VKA than in the DOAC group [74.9 (SD=8.5) years vs. 69.9 (SD=9.7) years; P=0.003]. The ratio of CHA₂D₂-VASC and HAS-BLED scores ≥3 was similar between the 2 groups (VKA: 90.5%, DOAC: 84.4%, P=0.31; VKA: 79.8%, DOAC: 68.9%, P=0.17, respectively). Drug-eluting stents (DES) were used in 67.9% of patients in the VKA group and in 55.6% of those in the DOAC group (P=0.21).

Figure 1.

Flowchart of the study. AF, atrial fibrillation; DOACs, direct OACs; OACs, oral anticoagulants; PCI, percutaneous coronary intervention; Pt., patient; VKA, vitamin K antagonist.

Table 1. Patient’s Clinical Characteristics, Medications, Lesion and Procedural Characteristics, and Echocardiographic Findings at Baseline

	Patient OAC groups
	VKA (n=84)	DOAC (n=45)	P value
Clinical baseline characteristics
Mean (SD) age (years)	74.9 (8.5)	69.9 (9.7)	0.003
Male sex	66 (78.6)	37 (82.2)	0.62
Duration of follow-up (days)	1,080 [627.5, 1,080]	1,080 [825.5, 1,080]	0.93
Mean (SD) BMI (kg/m2)	23.3 (4.0)	23.5 (3.3)	0.73
Diabetes	36 (42.9)	18 (40.0)	0.75
Hypertension	60 (71.4)	23 (51.1)	0.61
Hypercholesterolemia	48 (57.1)	29 (63.0)	0.51
Smoking history	50 (59.5)	30 (66.7)	0.43
History of MI	21 (25.3)	11 (24.4)	0.92
History of HF	50 (59.5)	22 (48.9)	0.25
History of stroke	16 (19.1)	4 (8.9)	0.13
History of PCI	37 (44.1)	17 (37.8)	0.49
History of CABG	14 (16.7)	1 (2.2)	0.02
Ccr ≥60	36 (42.9)	29 (64.4)	0.02
CHA2DS2-VASC score			0.01
0	0 (0.0)	0 (0.0)
1	0 (0.0)	3 (6.67)
2	8 (9.5)	4 (8.9)
3	8 (9.5)	7 (15.6)
4	20 (23.8)	15 (33.3)
5	21 (25.0)	9 (20.0)
6	16 (19.1)	4 (8.9)
7	7 (8.3)	2 (4.4)
8	4 (4.8)	1 (2.2)
9	0 (0.0)	0 (0.0)
HAS-BLED score			0.02
0	0 (0.0)	0 (0.0)
1	3 (3.6)	3 (6.7)
2	14 (16.7)	11 (24.4)
3	28 (33.3)	21 (46.7)
4	31 (36.9)	7 (15.6)
5	7 (8.3)	3 (6.7)
6	1 (1.2)	0 (0.0)
7	0 (0.0)	0 (0.0)
8	0 (0.0)	0 (0.0)
Mean (SD) TTR (%) for VKA	52.6 (31.5)	–	–
Medications at discharge
Aspirin	81 (96.4)	42 (93.3)	0.43
Clopidogrel	80 (95.2)	37 (82.2)	0.02
DAPT	77 (91.7)	34 (75.6)	0.01
PPI	125 (91.9)	46 (95.8)	0.36
ACEI/ARB	56 (66.7)	33 (73.3)	0.43
Statin	77 (91.7)	42 (93.3)	0.73
β-blocker	45 (53.6)	25 (55.6)	0.83
Type of DOAC
Rivaroxaban	–	22 (48.8)
Dabigatran	–	11 (24.4)
Apixaban	–	12 (26.6)
Lesion characteristics
ACS	24 (28.6)	23 (51.1)	0.01
STEMI	14 (16.7)	18 (40.0)	0.003
MVD	38 (45.2)	17 (37.8)	0.41
Peak CK in ACS	607 [306, 2,069]	1,528 [913.5, 5,992.5]	0.09
Peak CKMB in ACS	120 [40, 196]	149 [81.5, 378]	0.14
Procedural characteristics
DES	58 (69.1)	25 (55.6)	0.13
2nd-generation DES	52 (61.9)	24 (53.3)	0.35
Stent length (mm)	32.6 (21.8)	38.8 (26.0)	0.15
Stent number	1.47 (0.83)	1.71 (1.08)	0.17
Echocardiography findings
Mean (SD) LVDd (mm)	50.4 (7.5)	52.3 (5.6)	0.14
Mean (SD) LVEDV (mL)	124.4 (44.0)	133.5 (33.6)	0.22
Mean (SD) LVEF (%)	59.0 (12.3)	59.4 (10.9)	0.87
Mean (SD) LVFS (%)	33.2 (8.0)	34.0 (6.6)	0.59

Values are mean±standard deviation (SD), n (%), or median (interquartile range) as appropriate. ACEI, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin-receptor blocker; BMI, body mass index; CABG, coronary artery bypass graft; Ccr, creatinine clearance; CK, creatine kinase; CKMB, creatine-kinase myocardial band; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; DOAC, direct oral anticoagulant; HF, heart failure; LVDd, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVEDV, left ventricular end-diastolic volume; LVFS, left ventricular fractional shortening; MI, myocardial infarction; MVD, multivessel disease; PCI, percutaneous coronary intervention; PPI, proton-pump inhibitor; STEMI, ST-elevation MI; TTR, time in the therapeutic range; VKA, vitamin K antagonist.

After propensity score-matching, 36 pairs were compared. Baseline clinical and lesion characteristics for the matched groups are shown in Table S1.

Primary Bleeding Outcome

During the entire follow-up period, the primary outcome (TIMI major or minor bleeding) occurred in 29 patients (34.5%) in the VKA group and in 9 patients (20.0%) in the DOAC group. Table 2 shows the location of the worst bleeding site, including intracranial and gastrointestinal bleeds. Table 3 shows the 3-year risk estimates comparing the groups in terms of TIMI major bleeding and TIMI major or minor bleeding. Results for the VKA and DOAC groups, respectively were: major bleeding in 12.2% and 4.7% (HR 0.40, 95% CI 0.06–1.56, P=0.20), and major or minor bleeding in 38.9% and 21.4% (HR 0.55, 95% CI 0.24–1.11, P=0.10) (Figure 2A, Table 3). However, in the propensity score-matched analysis, there was no difference between the 2 groups (adjusted HR 0.72, 95% CI 0.25–1.93, P=0.51) (Figure 2B).

Table 2. Location of Worst Bleeding Event per Patient

	Patient OAC groups
	VKA (n=84)	DOAC (n=45)
TIMI major bleeding	9 (10.7)	2 (4.4)
TIMI minor bleeding	20 (23.8)	7 (15.6)
Location of worst bleeding event
Intracranial	4 (4.8)	1 (2.2)
Access site	5 (6.0)	1 (2.2)
Retroperitoneal	1 (1.2)	1 (2.2)
Gastrointestinal	10 (11.9)	3 (6.7)
Skin hematoma requiring medical attention	2 (2.4)	0 (0.0)
Nose	2 (2.4)	0 (0.0)
Urogenital	1 (1.2)	1 (2.2)
Respiratory tract	2 (2.4)	1 (2.2)
Mouth	1 (1.2)	1 (2.2)
Muscle	1 (1.2)	0 (0.0)

Values are n (%). DOAC, direct oral anticoagulant; VKA, vitamin K antagonist.

Table 3. Kaplan-Meier 3-Year Estimates by Intention-to-Treat Analysis

	Patient OAC groups
	VKA (n=84)	DOAC (n=45)	HR (95% CI)	P value
TIMI major bleeding	12.2%	4.7%	0.40 (0.06–1.56)	0.20
TIMI major or minor bleeding (Primary outcome)	38.9%	21.4%	0.55 (0.24–1.11)	0.10
Combined secondary outcome	32.9%	15.2%	0.40 (0.15–0.91)	0.03
Hard outcome (secondary outcome except TLR)	29.5%	13.1%	0.37 (0.13–0.87)	0.02
Death	19.5%	10.4%	0.48 (0.14–1.32)	0.17
Non-procedural MI	1.6%	0.0%	–	0.35
TLR	5.6%	2.4%	0.44 (0.02–3.01)	0.45
Stroke
Any stroke	14.5%	5.2%	0.34 (0.05–1.31)	0.13
Ischemic stroke	9.1%	2.9%	0.18 (0.02–1.67)	0.18
Hemorrhagic stroke	5.9%	2.3%	0.44 (0.02–2.99)	0.43

Values are Kaplan-Meier estimates (%). CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; TLR, target-lesion revascularization.

Figure 2.

Cumulative incidence of the primary outcome (composite of major bleeding and minor bleeding according to Thrombolysis in Myocardial Infarction criteria). Cumulative incidence of the primary outcome in (A) all patients and (B) the propensity score-matched groups. AF, atrial fibrillation; DOACs, direct oral anticoagulants; HR, hazard ratio; VKA, vitamin K antagonist.

Secondary Efficacy Outcome

The combined secondary outcome of death, MI, stroke, and TLR was significantly lower in the DOAC group (HR 0.40, 95% CI 0.14–0.91, P=0.03) (Figure 3A). In the propensity score-matched analysis also, the use of DOACs was associated with a significantly lower risk of the combined secondary outcome (adjusted HR 0.24, 95% CI 0.06–0.78, P=0.02) (Figure 3C).

Figure 3.

Cumulative incidence of the secondary efficacy outcome (composite of death, myocardial infarction, stroke, and TLR). Cumulative incidence of (A) the secondary efficacy outcome and (B) the hard outcome excluding TLR (composite of death, myocardial infarction and stroke) in all patients. Cumulative incidence of (C) the secondary efficacy outcome and (D) hard outcome excluding TLR in the propensity score-matched groups. AF, atrial fibrillation; DOACs, direct oral anticoagulants; HR, hazard ratio; TLR, target-lesion revascularization; VKA, vitamin K antagonist.

Kaplan-Meier 3-year estimates of the secondary outcome using the intention-to-treat principle were 32.9% for the VKA group and 15.2% for the DOAC group (Figure 3A, Table 3). The risk of hard outcome (excluding TLR) was also significantly lower in the DOAC group (HR 0.37, 95% CI 0.13–0.87, P=0.02) (Figure 3B). In the propensity score-matched analysis, the use of DOACs tended to be associated with a lower risk of the hard outcome (adjusted HR 0.31, 95% CI 0.01–1.03, P=0.06) (Figure 3D). The incidence of each individual outcome comprising the hard outcome tended to be lower in the DOAC group (Table 3).

TTR in Patients Who Received VKA

Figure 4 shows the INR control of each patient who received VKA. TTR was only 52.6%, and most of the remaining time (44.3%) was spent below the therapeutic INR range. TTR was not different between patients aged ≥70 years and those aged <70 years (TTR in aged ≥70 years, 52.4%; TTR in aged <70 years, 53.2%). Only 30 patients (35.7%) had TTR ≥65%.

Figure 4.

Percentages of time spent below, within, and above the therapeutic INR range in each patient taking VKA. INR, international normalized ratio; VKA, vitamin K antagonist.

Of the 29 patients who had TIMI major or minor bleeding during follow-up, INR data within 60 days before and at the time of bleeding were available for 23 patients. In them, INR control tended to increase more at the time of bleeding than before bleeding; the INR was below the therapeutic range in 6 (26.1%) patients, within the therapeutic range in 9 (39.1%) patients, and above the therapeutic range in 8 (34.8%) patients at the time of bleeding; the respective values before bleeding were 6 (26.1%), 16 (69.6%), and 1 (4.3%). However, the mean TTR was similar between bleeding and non-bleeding patients [54.1% (SD=30.6); 51.8% (SD=32.3); P=0.76].

There was no statistically significant difference in the cumulative 3-year incidence of ischemic stroke between those with TTR ≥65% (3.3%) and those with TTR <65% (9.3%; P=0.31). However, the INR was below the therapeutic range in 5 of 6 patients who experienced ischemic stroke, and it was almost at the lower limit (INR of 1.69) in the remaining patients.

DOACs Treatment Dosage

DOACs were administered at an insufficient dose in 6 patients (dabigatran was administered twice daily at 75 mg/dose in 2 patients, rivaroxaban at 10 mg/dose in 3 patients, and apixaban twice daily at 2.5 mg/dose in 1 patient), but there were no cases of overdose.

Only 1 patient experienced ischemic stroke, and in that case rivaroxaban was administered at an appropriate dose.

Discussion

In this study, we compared DOACs and VKA in Asian patients with AF who underwent PCI and we performed long-term follow-up of these patients. Our study had a longer follow-up period (median=1,080 days) than did the PIONEER AF-PCI trial with a follow-up period of 1 year.¹⁶ Furthermore, we provided precise data for VKA control. The main findings of our study are as follows. (1) Treatment including DOACs in patients with AF who underwent PCI was associated with a significantly lower risk of the secondary efficacy outcome than treatment including VKA with poor INR control. (2) The rate of the primary bleeding outcome did not differ between the DOAC and VKA groups. (3) Only 35.7% of patients achieved TTR ≥65%, and the INR was below the therapeutic range in 5 of 6 patients who experienced ischemic stroke.

Our finding that the risk of the bleeding outcome did not differ between the 2 groups was inconsistent with that of PIONEER AF-PCI, which was a randomized trial comparing the safety and efficacy of rivaroxaban treatment plus antiplatelet therapy with the standard triple-therapy including VKA among 2,124 patients with AF undergoing PCI.¹⁶ The groups receiving rivaroxaban in PIONEER AF-PCI had significantly lower rates of bleeding at 1 year after PCI than did the group receiving standard therapy. However, there are rigorous differences between PIONEER AF-PCI and our study on the issue of TTR: it was 65%in PIONEER AF-PCI and 51% in our study. As Jones et al showed, their poor INR control group had higher rates of major bleeding compared with their moderate and good control group;²⁰ poor INR control in our study led to a higher incidence of bleeding in the VKA group. On the other hand, other studies have indicated that patients with high INR control were at risk of hemorrhage while patients with low INR control did not have an increased occurrence of bleeding events.^21,22 In our study, the VKA group spent 97.9% of time within or below the therapeutic range, so it was uncertain how the low TTR value affected the rate of the bleeding outcome in the VKA group. Also, the doses of the DOACs were different between our study and PIONEER AF-PCI. The dose of rivaroxaban used in PIONEER AF-PCI was reduced from the standard dose to prevent ischemic stroke in the AF patients, whereas the doses of the DOACs in our study were the standard doses for Japanese AF patients.^23–25 This might also affect the incidence of bleeding outcomes in the 2 studies.

In our study, the composite secondary outcome was significantly lower in the DOAC group, although the rates of major adverse cardiovascular event (MACCE), defined as a composite of death from cardiovascular causes, MI, or stroke, in PIONEER AF-PCI were similar among the 3 groups. The MACCE rate (6%) in the PIONEER AF-PCI may have been very low because the MACCE rates in other trials were notably higher; for instance, the MACCE rates at 1 year in the WOEST trial were 11.1% and 17.6% in the double- and triple-therapy groups, respectively.²⁶ The MACCE rate in our study was similar to that in the WOEST trial in DOACs group (15.2%) and much higher in the VKA group (32.9%). In the SPORTIFF 3 trial, the poor anticoagulation control group had a significantly higher annual mortality rate than the moderate and good anticoagulation control groups (4.2% vs. 1.84%, P<0.01; vs. 1.69%, P<0.01).²⁰ In another study, the poor anticoagulation control group had a significantly higher cumulative risk of major adverse cardiovascular events than the moderate and good anticoagulation control groups (P<0.001, by log-rank test).²⁷ It was the most important factor in the higher incidence of MACCE in the VKA group in our study, because the TTR rate in the VKA group was low in our study. Another explanation of the differences in the MACCE rate between PIONEER AF-PCI, WOEST and our study might be differences in the patients’ baseline characteristics. Patients with a prior history of MI and CABG were included in relatively large numbers in our study and in the WOEST trial, but not in PIONEER AF-PCI. Prior history of CABG might represent progression of atherosclerosis, not only leading to a higher rate of TLR, but possibly to stroke, MI, or even death.

Previous observational studies have shown that the prevalence of OAC ranges from 9% to 85%, with an average of 51% in patients with an indication for OAC undergoing PCI.^{10–12,28–30} Thus, in real-world patients with AF undergoing PCI, OACs are underused and the intensity of VKA administration could be shifting to lower INR control because of physicians’ concern about bleeding complications. In a large Japanese PCI registry (the Coronary Revascularization Demonstrating Outcome Study in Kyoto), only 37.7% of patients had TTR ≥65% even when the therapeutic INR range was set at 1.6–2.6. That result was similar to our study, in which TTR ≥65% was achieved in only 35.7% of patients. Furthermore, instability of VKA dosing seemed to be associated with a high rate of bleeding in our study. In another study, the risk of admission for a bleeding-related event was associated with greater variability in INR values.²¹

The correct dose of DOACs for AF patients undergoing PCI remains controversial. The dose of DOACs used in the management of AF may differ from that used in the management of acute coronary syndrome (ACS). Among trials exploring the effect of adding DOACs to DAPT for secondary prevention of MACCE in ACS patients, standard doses of DOACs were associated with a significantly increased risk of bleeding.^31–33 The rate of bleeding in our study was similar to that of the standard dose group in those other trials (i.e., 21.4% 3-year estimated risk of bleeding in the DOAC group in our study and 15.3% at 20 mg dose of rivaroxaban for 180 days³¹) and much higher than that in the reduced dose groups.³¹ Therefore, to prevent bleeding, lower doses of DOACs are recommended in the ESC guidelines.³⁴ However, there is no evidence regarding a reduced dose of DOACs in patients with AF requiring PCI. Because AF patients requiring OAC have a much higher risk of stroke than ACS patients,³⁵ further dedicated research comparing reduced and standard doses of DOACs in patients undergoing PCI with AF is necessary.

Study Limitations

First, the study was performed at a single medical center and had a non-randomized, retrospective design. Accordingly, because there were limited numbers of patients enrolled in this study, regimens of antiplatelet therapy, age, HAS-BLED scores and CHA₂DS₂-VASC scores were inconsistent between the VKA and DOAC groups. Second, the duration of DAPT was not considered in our analysis because of the small numbers. Third, the DOAC group tended to include patients from more recent years. There may also have been changes in the PCI technique during the study period. Furthermore, there are no data about patients with AF and a coronary stent but without anticoagulant therapy, and we compared only the DOAC and VKA groups. The reason why physicians have decided not to prescribe any anticoagulant drug to some patients were not investigated. Further dedicated studies with large sample sizes and long-term follow-up are, therefore, necessary.

Conclusions

In this retrospective study of patients receiving OACs and undergoing PCI, the use of DOACs in conjunction with antiplatelet agents was associated with decreased risk of composite secondary efficacy outcome (death, MI, stroke and TLR) compared with VKA, without increasing the bleeding complications. Additional prospective studies with a larger sample size are necessary to evaluate the safety and effectiveness of DOACs.

Research Funding

This study was not supported by any funding.

Supplementary Files

Supplementary File 1

Table S1. Patient’s clinical characteristics, medications, lesion and procedural characteristics, and echocardiographic findings at baseline in the propensity score-matched groups

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-17-1171

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