Safety and Efficacy of Low-Dose Prasugrel as Part of Triple Therapy With Aspirin and Oral Anticoagulants in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention　― From the TWMU-AF PCI Registry ―

Abstract

Background: Using the standard maintenance dose of prasugrel (10 mg/day) as part of triple therapy with aspirin and an oral anticoagulant (OAC) is not recommended in the current guidelines because it increases the risk of bleeding compared with clopidogrel. However, the safety and efficacy of low-dose prasugrel (3.75 mg/day) as part of triple therapy has not been reported.

Methods and Results: We registered 816 consecutive patients with atrial fibrillation (AF) who underwent percutaneous coronary intervention (PCI) from January 2011 to June 2016 at 8 hospitals in Japan. We examined the clinical outcomes of patients who received either low-dose prasugrel (n=57) or clopidogrel (n=451) as part of triple therapy after PCI. The incidences of bleeding (TIMI major and minor) and major adverse cerebrocardiovascular events (MACCE; all-cause death, nonfatal myocardial infarction, stent thrombosis, unplanned revascularization, and stroke) were evaluated. The cumulative 1-year incidence of bleeding was not significantly different (prasugrel 5.6% vs. clopidogrel 8.1%, log-rank P=0.55). In addition, the cumulative 1-year incidence of MACCE was also not significantly different (prasugrel 11.5% vs. clopidogrel 12.3%, log-rank P=0.88).

Conclusions: Low-dose prasugrel, as part of triple therapy, did not increase the risk of bleeding compared with clopidogrel. Therefore, it can be an alternative to clopidogrel for patients with AF undergoing PCI.

The management of patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) remains a concern. Approximately 5–10% of patients undergoing PCI have concomitant AF¹ and require long-term oral anticoagulation (OAC) therapy. Additionally, dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 receptor inhibitor is essential for preventing thrombotic adverse events, such as stent thrombosis (ST), after stent implantation. Thus, patients indicated for OAC because of AF who undergo PCI are recommended to receive triple therapy consisting of aspirin, a P2Y12 receptor inhibitor, and an OAC, if they are not at high risk for bleeding. However, triple therapy is associated with a 3- to 5-fold increase in total bleeding complications compared with other antithrombotic therapy combinations,^2–4 so the current guidelines and consensus documents recommend shortening the duration of triple therapy after PCI.^5–8

Editorial p 963

Previous studies of triple therapy have mainly focused on clopidogrel, which has been the most widely studied P2Y12 receptor inhibitor.^9,10 Prasugrel is a 3rd-generation P2Y12 receptor inhibitor that rapidly and potently inhibits platelet aggregation with less pharmacological variability than clopidogrel. However, using prasugrel as part of triple therapy with aspirin and an OAC is not recommended in the current western guidelines^5,7 because it is reported to increase the risk of bleeding compared with clopidogrel.^11,12

In Japan, low-dose prasugrel (3.75 mg/day) was approved for use as the P2Y12 receptor inhibitor in DAPT after PCI based on a dose-finding study in Japanese patients,^13,14 and its safety and efficacy in Japanese patients in cases of acute coronary syndrome (ACS)¹⁵ and elective PCI¹⁶ have been certified. However, to date the safety and efficacy of low-dose prasugrel as part of triple therapy in AF patients undergoing PCI have not been reported.

Methods

We identified 816 consecutive patients from 8 medical centers in Japan who had a history of AF or newly diagnosed AF and underwent PCI between January 1, 2011 and June 30, 2016. They were retrospectively registered in the Tokyo Women’s Medical University-Atrial Fibrillation Percutaneous Coronary Intervention registry (TWMU-AF PCI registry).⁴ We excluded 308 patients who were prescribed non-triple therapy following PCI, and so a total of 508 patients who received triple therapy (62.3% of the identified population) following PCI were enrolled. We compared the clinical outcomes of 57 patients prescribed low-dose prasugrel and 451 patients prescribed clopidogrel as part of their triple therapy. The study flow chart is shown in Figure 1. The antithrombotic therapies and their duration were chosen at the discretion of the attending physicians after assessment of each individual’s thrombotic and bleeding risk. Anticoagulation therapy with oral warfarin was adjusted to the therapeutic range of the prothrombin time-international normalized ratio (PT-INR) recommended in the Japanese guidelines.¹⁷ Time in therapeutic range (TTR) was calculated by the Rosendaal method.¹⁸ Baseline demographic parameters of the patients were collected from the initial hospital admission records and using these the CHADS₂, CHA₂DS₂-VASc, and HAS-BLED scores were calculated. The labile INR factor was omitted from the HAS-BLED score.

Figure 1.

Study flow chart. AF, atrial filtration; DAPT, dual antiplatelet therapy; OAC, oral anticoagulation; PCI, percutaneous coronary intervention; SAPT, single antiplatelet therapy.

Clinical Endpoints

The safety endpoint was defined as the cumulative incidence of bleeding complications defined as a composite of Thrombolysis in Myocardial Infarction (TIMI) major and minor bleeding¹⁹ at 1 year. The criteria for the diagnosis of TIMI major bleeding included hemorrhagic stroke (confirmed by computed tomography or magnetic resonance imaging of the head) or clinically overt signs of hemorrhage associated with a ≥5 g/dL decrease in hemoglobin level; TIMI minor bleeding was considered to be observed blood loss and a decrease in hemoglobin level of 3–5 g/dL or a decrease in hemoglobin level ≥4 g/dL if no bleeding site was identifiable.¹⁹

The efficacy endpoint was defined as the cumulative incidence of major adverse cardiac and cerebrovascular events (MACCE), a composite of all-cause death, nonfatal myocardial infarction (MI), ST, unplanned revascularization (PCI or coronary artery bypass grafting), and stroke at 1 year. MI was defined according to the definition of the European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Heart Federation Task Force for the Universal Definition of Myocardial Infarction.²⁰ ST was defined according to the Academic Research Consortium definition.²¹ Stroke was defined as a focal neurologic deficit lasting more than 24 h, that was presumably derived from vascular events, required hospitalization or resulted in death.

Patients’ clinical information during the observation period was obtained from outpatient clinic visits or medical records review.

Statistical Analysis

Categorical variables were compared using the χ² test. Continuous variables are expressed as mean value±standard deviation and were compared using Student’s t-test or the Mann-Whitney U-test based on the distributions. Two-sided P-values <0.05 were considered statistically significant. The cumulative incidence rate was analyzed based on the time to the first adverse event, estimated using the Kaplan-Meier method with the log-rank test. Statistical analyses were performed using statistical software (JMPPro 13, SAS Institute Inc., Cary, NC, USA) by an independent physician.

The study protocol was based on the regulations of the ethics committee at each collaborating hospital. All participating patients provided written informed consent. Patient enrollment was conducted according to the principles of the Declaration of Helsinki.

Results

The baseline clinical characteristics of the prasugrel and clopidogrel groups are summarized in Table 1. Mean age was 73 years, approximately 80% were male, and over 70% were at high risk for stroke (CHADS₂ score ≥2). Most of the parameters were not significantly different except for the frequency of current smokers and the type of OAC. Direct oral anticoagulant (DOAC) use was higher in the prasugrel group than in the clopidogrel group (35% vs. 21%, respectively, P=0.02). Among 394 patients who were prescribed warfarin, TTR data were available for 335 (85.0%). The overall average TTR was 52.8% and it was not significantly different between the prasugrel and clopidogrel groups (P=0.15). The mean duration of triple therapy was 230±132 days in the prasugrel group and 252±128 days in the clopidogrel group, which was not significantly different (P=0.25).

Table 1. Patients Characteristics

Variable	Prasugrel (n=57)	Clopidogrel (n=451)	P value
Age, years	72±9	73±8	0.39
Male	48 (84)	364 (81)	0.60
Body mass index, kg/m2	23.8±5.8	23.5±3.7	0.60
Paroxysmal AF	33 (59)	223 (50)	0.21
Hypertension	42 (75)	352 (79)	0.53
Diabetes	29 (52)	185 (41)	0.14
Insulin treatment	4 (7)	47 (10)	0.44
Dyslipidemia	39 (68)	256 (57)	0.12
Current smoker	5 (9)	99 (22)	0.01
CKD (eGFR <60 mL/min/1.73 m2)	24 (42)	202 (45)	0.64
Hemodialysis	9 (16)	44 (10)	0.20
Heart failure	13 (24)	137 (30)	0.30
Peripheral artery disease	8 (14)	59 (13)	0.85
Prior MI	10 (18)	84 (19)	0.80
Prior PCI	18 (32)	140 (31)	0.89
Prior CABG	4 (7)	29 (6)	0.79
Prior stroke	9 (16)	95 (21)	0.37
Prior major bleeding	1 (2)	17 (4)	0.43
Risk stratification parameter
CHADS2 score ≥2	42 (74)	348 (78)	0.50
CHADS2 score	2.2±1.3	2.4±1.3	0.21
CHA2DS2-VASc score	4.2±1.5	4.5±1.5	0.12
HAS-BLED score	2.2±0.7	2.3±0.7	0.24
Medications at discharge
ACEI/ARB	35 (61)	320 (72)	0.11
β-blocker	36 (64)	296 (66)	0.81
Statin	32 (57)	266 (60)	0.68
Proton pump inhibitor	42 (75)	311 (70)	0.49
Aspirin	57 (100)	451 (100)	1.00
Warfarin	37 (65)	357 (79)	0.02
DOAC	20 (35)	94 (21)	0.02
Lesion and procedural characteristics
ACS	22 (39)	140 (31)	0.24
Multivessel disease	17 (30)	161 (36)	0.36
Femoral approach	31 (54)	195 (43)	0.11
DES implantation	48 (81)	325 (73)	0.18

Data are mean±SD or n (%). ACEI, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; CABG, coronary artery bypass grafting; CKD, chronic kidney disease; DES, drug eluting stent; DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; PCI, percutaneous coronary intervention.

Clinical Outcomes

The Kaplan-Meier curve in Figure 2 shows the 1-year clinical outcomes after PCI. The cumulative incidence of TIMI major and minor bleeding was not significantly different between the 2 groups (event rate at 1 year, prasugrel vs. clopidogrel=5.6% vs. 8.1%; log-rank P=0.55; hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.17–1.94). The cumulative incidence of MACCE was also not significantly different (event rate at 1 year, 11.5% vs. 12.3; log-rank P=0.88; HR: 0.93, 95% CI: 0.36–2.01). The details of bleeding events and MACCE are shown in Table 2. The incidences of major and minor bleeding were also not significantly different between the groups. In terms of the components of MACCE at 1 year, all-cause death (3.8% vs. 5.2%), nonfatal MI (0% vs. 1.2%), ST (0% vs. 0.2%), unplanned revascularization (2.1% vs. 7.1%) and stroke (5.8% vs. 3.0%) were also not significantly different. Only 1 case of ST occurred on day 7 in the clopidogrel group. The sites of the bleeding events are shown in Table 3.

Figure 2.

Kaplan-Meier curves for adverse events (prasugrel vs. clopidogrel). (A) TIMI major+minor bleeding. (B) MACCE including all-cause death, nonfatal myocardial infarction, stent thrombosis, unplanned revascularization (PCI or coronary artery bypass grafting), and stroke. MACCE, major adverse cardiac and cerebrovascular event; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction.

Table 2. Adverse Events at 1 Year

Variable	Prasugrel (n=57)	Clopidogel (n=451)	Log-rank P value
Bleeding (TIMI major+minor)	5.6%	8.1%	0.55
TIMI major	1.9%	3.8%	0.49
TIMI minor	3.7%	4.2%	0.87
MACCE	11.5%	12.3%	0.88
All-cause death	3.8%	5.2%	0.65
Nonfatal myocardial infarction	0%	1.2%	0.43
Stent thrombosis	0%	0.2%	0.73
Unplanned revascularization	2.1%	7.1%	0.17
Stroke	5.8%	3.0%	0.26
Hemorrhagic	0%	1.4%	0.38
Ischemic	5.8%	2.1%	0.06

All data are event rates at 1 year estimated by Kaplan-Meier analysis.

Table 3. Sites of Bleeding

Variable	Prasugrel (n=57)	Clopidogrel (n=451)	P value
Intracranial	0 (0)	6 (1.3)	–
Gastrointestinal	0 (0)	11 (2.4)	–
Respiratory	0 (0)	1 (0.2)	–
Nose	1 (1.8)	1 (0.2)	0.08
Urogenital	0 (0)	3 (0.6)	–
Intramuscular	1 (1.8)	0 (0)	–
Access site	1 (1.8)	8 (1.8)	0.99

Data are n (%).

Discussion

The primary finding in the present study was that the incidences of bleeding and MACCE were not significantly different between Japanese patients with AF undergoing PCI who were prescribed prasugrel or clopidogrel as part of their triple therapy. To the best of our knowledge, this is the first report on the safety and efficacy of low-dose prasugrel as part of triple therapy compared with clopidogrel in patients with AF undergoing PCI.

In the current western guidelines, clopidogrel is the standard drug used in triple therapy with aspirin and an OAC.^5,7 Prasugrel is not recommended in the current guidelines because it carries an increased risk of bleeding compared with clopidogrel. Sarafoff et al reported that prasugrel increased the risk of bleeding compared with clopidogrel when prescribed as part of triple therapy.¹¹ However, their study had a relatively small number of patients (prasugrel n=21, clopidogrel n=356) and the dose of prasugrel was about 3-fold greater than the dose used in our study.

It has been reported that platelet inhibition by clopidogrel is attenuated in the patients who are poor metabolizers of CYP2C19,^22,23 and approximately 20% of Japanese patients are poor metabolizers of CYP2C19.²⁴ Also, there are still some concerns about resistance of clopidogrel, especially in Japanese patients. In contrast, the antiplatelet effect of prasugrel is not attenuated by the CYP2C19 pathway, so pharmacological interpatient variability is less than with clopidogrel. Based on the results of our study, low-dose prasugrel might be a good candidate for use as part of triple therapy.

In our study, the proportions of the types of OACs differed; the prasugrel group had a high DOAC prescription rate. However, the incidences of bleeding and MACCE were not significantly different even after evaluating the types of OACs separately (Supplementary Figures 1,2).

Recent randomized controlled studies have revealed that dual antithrombotic therapy consisting of a P2Y12 receptor inhibitor and anticoagulation therapy with a DOAC reduced the risk of bleeding vs. triple therapy without increasing thromboembolic events.^25,26 According to those studies, the number of cases of dual therapy is increasing, especially for patients with a high bleeding risk.⁵ However, the guidelines do not mention the use of prasugrel as a component of dual therapy because the studies were conducted with clopidogrel as the P2Y12 receptor inhibitor.

Based on the results of our study, low-dose prasugrel might qualify as part of not only triple therapy but also dual therapy consisting of prasugrel plus a DOAC.

In terms of the component adverse events, the incidence of ischemic stroke was slightly higher in the prasugrel group (Table 2). One case of ischemic stroke in the prasugrel group occurred with off-label underdosing of the DOAC. Although it was difficult to demonstrate the influence of off-label underdosing of DOACs in our study, Steinberg et al²⁷ reported that off-label dosing of DOAC was associated with increased risk for adverse events. Further studies are warranted to evaluate the optimal dose of DOACs when combined with antiplatelet drugs.

Study Limitations

There are several important limitations to this study. First, it was a retrospective analysis of an observational cohort, not a prospective randomized trial. Second, the number of patients was small, although we collected consecutive patients across 6 years from 8 medical centers. Third, this study included only Japanese patients. Fourth, there might have been changes in the antithrombotic regimens during the follow-up period, which we could not follow completely.

Conclusions

Our study suggested that low-dose prasugrel might be an alternative to clopidogrel as a part of triple therapy for patients with AF undergoing PCI. With regard to poor metabolizers of CYP2C19, further large-scale studies are warranted to determine the potential benefit of this treatment approach.

English Language Editing

We thank Editage (www.editage.jp) for English language editing.

Grant Support and Conflicts of Interest

Dr. Yamaguchi belongs to a division (Clinical Research Division for Cardiovascular Catheter Intervention) financially maintained by donations from Abbott Vascular, Boston Scientific, Terumo and Medtronic. All other authors report that they have no relationships relevant to the contents of this paper to disclose.

Acknowledgments

Collaborating Centers and Investigators

We would like to thank the following collaborating centers and investigators: Saiseikai-Kurihashi Hospital: Yusuke Inagaki, Hiromu Kadowaki, Arata Nomura, Tonre Ri, Yuta Morioka and Yoshimi Ota; Nishiarai Heart Center: Ahsung Kim, Kensuke Shimazaki and Katsumi Saito; Saiseikai-Kawaguchi General Hospital: Yusuke Tanigaito, Risako Nakao, Yutaka Terashima, Suguru Matsumoto, Atsushi Yamamoto and Atsushi Takagi; Tokyo Metropolitan Tama Medical Center Hospital: Masataka Ogiso, Masahiro Watanabe, Shouhei Kataoka, Ayano Yoshida and Hiroyuki Tanaka; Sendai Cardiovascular Center: Mayui Nakazawa Keigo Kambayashi, Naoki Iiduka and Shinya Fujii; Tokyo Women’s Medical University Yachiyo Medical Center: Kaoru Iwasa, Keiko Endo, Koichiro Miura, Takahiro Yamada and Atsushi Honda; National Hospital Organization Yokohama Medical Center: Kyoichiro Yazaki, Eiji Shibahashi and Fumiaki Mori; Tokyo Women’s Medical University: Takanori Kawamoto, Masafumi Yoshikawa, Suguru Ebihara, Kazuki Tanaka, Masashi Nakao, Kazuho Kamishma, Kentaro Jujo, Hiroyuki Arashi, Junichi Yamaguchi, and Nobuhisa Hagiwara.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-1113

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