Balancing Act　― Prasugrel’s Efficacy and Safety in Japanese Patients Undergoing Percutaneous Coronary Intervention ―

DAPT With Prasugrel After PCI in Japanese Patients

Prasugrel is a potent P2Y₁₂ receptor inhibitor and a first-line choice for acute coronary syndrome (ACS) in Western countries.¹ Unlike clopidogrel, prasugrel is not affected by CYP2C19 metabolism, which, theoretically, makes it promising for Japanese patients who often possess CYP2C19 polymorphisms. However, the potent nature of prasugrel raises concerns about bleeding risks, particularly in the Japanese population, which is generally at higher risk for bleeding complications.² Based on Phase II trial results, prasugrel has been carefully adjusted and approved at a low dose in Japan, and is now widely used.³ The Table summarizes the evidence from low-dose prasugrel trials reported in Japan. The trials can be categorized into those evaluating dual antiplatelet therapy (DAPT) with prasugrel and those assessing prasugrel monotherapy. The only randomized controlled trials (RCTs) comparing DAPT with low-dose prasugrel to DAPT with clopidogrel are the PRASFIT-ACS and PRASFIT-Elective trials,^4,5 which were conducted for market approval. In those trials, the event rate of ischemic events, a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke within 24 weeks, was numerically lower in patients treated with low-dose prasugrel than in those treated with clopidogrel, in both ACS (9.4% vs. 11.8%) and elective percutaneous coronary intervention (PCI) populations (4.1% vs. 6.7%), without an increase in clinically serious bleeding events when used with aspirin. On the other hand, real-world observational studies consistently show comparable efficacy of low-dose prasugrel to clopidogrel. In this issue of the Journal, a study by Kuno et al. from the JCD-KiCS registry also demonstrate comparable efficacy and safety of DAPT with low-dose prasugrel to DAPT with clopidogrel after PCI in a 2-year follow-up (adjusted hazard ratio (HR) for ACS: 0.58, 95% confidence interval (CI): 0.29–1.16, adjusted HR for bleeding: 0.62, 95% CI: 0.29–1.32).⁶ Their previous study of short-term outcomes reported a hazardous effect of DAPT with prasugrel for bleeding risk (odds ratio for bleeding complications within 72 h after PCI: 2.91 95% CI: 1.63–6.18),⁷ whereas the present study did not show such an unfavorable effect (in-hospital all types of bleeding, 2.0% vs. 1.8%; 2-year bleeding requiring readmission, 1.4% vs. 2.3%).⁶ These inconsistent results from the same registry might be attributed to patient selection (ACS vs. ACS/CCS, major teaching hospital vs. non-selected hospital, short-term vs. long-term follow-up, etc.). Therefore, its definitive superiority remains uncertain at this point. The recent Japanese guideline does not prioritize prasugrel over clopidogrel or vice versa for both ACS and CCS patients undergoing PCI.⁸ The inconsistent findings of bleeding events would necessitate further investigation of optimizing antiplatelet strategy depending on the individual patient’s background and time course after PCI.

Table.

Trials of Low-Dose Prasugrel in Japan

Cohort name	Year	Trial design	Patient type	Other background	Patients (n)	Exposure/ intervention	Comparison	Ischemic endpoint	Event rate	Risk (95% CI)	P value	Bleeding endpoint	Event rate	Risk (95% CI)	P value	Reference
Studies evaluating DAPT with prasugrel
JCD-KiCS	2024	Prospective multicenter cohort	ACS & CCS		5,392	DAPT with P	DAPT with C	ACS requiring readmission at 2y	1.5% vs. 3.2%	adjHR: 0.58 (0.29–1.16)	0.12	Bleeding requiring readmission at 2y	1.4% vs. 2.3%	adjHR: 0.62 (0.29–1.32)	0.22	Kuno et al. Circ J 2024; 88: 1745–1753
Omori Medical Center	2023	Single-center, prospective, randomized pilot trial	ACS		80	DAPT with P	DAPT with C	Cardiac death, MI, heart failure hospitalization, TVR at 1y	8.1% vs. 20.5%	NA	0.124	TIMI major, minor at 1y	5.4% vs. 5.1%	NA	0.956	Yabe et al. Int J Angiol 2023; 32: 56–65
Tokai University	2023	Retrospective multicenter cohort	ACS		1,261	DAPT with P	DAPT with C	Death, MI, ischemic stroke at 3m	7.9% vs. 9.4%	adjHR: 0.66 (0.44–0.99)	0.04	BARC 3, 5 at 3m	5.2% vs. 7.5%	adjHR: 0.47 (0.30–0.74)	<0.01	Fujii et al. Int J Cardiol 2023; 375: 1–6
K-ACTIVE	2022	Prospective multicenter cohort	AMI		3,676	DAPT with P	DAPT with C	CV death, MI, stroke at 1y	2.5% vs. 4.5%	adjHR: 0.79 (0.51–1.23)	0.297	BARC 3, 5 at 1y	0.9% vs. 1.6%	adjHR: 0.76 (0.52–1.12)	0.163	Mori et al. J Clin Med 2022; 11: 2016
JAMIR	2021	Prospective multicenter cohort	AMI		2,604	DAPT with P & de-escalation (P to C) at discharge	Continuation of DAPT with P	CV death, MI, stroke at 1y	1.8% vs. 2.8%	NA	0.55	BARC 3, 5 at 1y	1.8% vs. 1.7%	NA	0.94	Honda et al. J Cardiol 2021; 78: 99–106
JMDC	2021	Retrospective multicenter cohort	ACS	Age <75y	2,731	DAPT with P	DAPT with C	ACS requiring PCI at 24m	NA	adjHR: 0.76 (0.27–2.10)	0.595	Any bleeding at 24m	NA	adjHR: 1.14 (0.67–1.93)	0.641	Hagiwara et al. J Cardiol 2021; 77: 285–291
JMDC	2021	Retrospective multicenter cohort	CCS	Age <75y	4,041	DAPT with P	DAPT with C	ACS requiring PCI at 24m	NA	adjHR: 0.42 (0.13–1.33)	0.140	Any bleeding at 24m	NA	adjHR: 1.12 (0.75–1.67)	0.593	Hagiwara et al. J Cardiol 2021; 77: 285–291
Shiga University	2020	Retrospective single-center cohort	ACS & CCS	CYP2C19 genotype available (IM or PM, 67%)	410	DAPT with C	DAPT with P	CV death, MI, definite ST, ischemic stroke at 1y	6.2% vs. 1.8%	adjHR: 3.15 (0.97–10.2)	0.06	BARC 2, 3, 5 at 1y	4.1% vs. 4.6%	adjHR: 0.88 (0.34–2.33)	0.80	Sawayama et al. Circ J 2020; 84: 1575–1581
PRASFIT- Practice II	2020	Post-marketing observational study	ACS & CCS		4,155	DAPT with P	NA	CV death, MI, ischemic stroke, ST at 360d	1.6%	NA	NA	TIMI major at 360d	1.0%	NA	NA	Nakamura et al. Circ J 2020; 84: 101–108
JCD-KiCS	2020	Retrospective multicenter cohort	ACS		2,559	DAPT with P	DAPT with C	Death, recurrent MI, ischemic stroke during hospitalization	5.1% vs. 3.7%	adjOR: 1.42 (0.90–2.23)	0.14	Bleeding complications within 72 h after PCI	5.0% vs. 1.8%	adjOR: 2.91 (1.63–5.18)	<0.001	Shoji et al. JAMA Netw Open 2020; 3: e202004
PRASFIT- Practice II	2019	Post-marketing observational study	ACS & CCS		4,157	DAPT with P	NA	CV death, MI, ischemic stroke; ST at 250d	1.4%	NA	NA	TIMI major at 150d	0.6%	NA	NA	Nakamura et al. Circ J 2019; 83: 637–646
Multicenter in Chiba	2019	Retrospective multicenter cohort	ACS		1,031	DAPT with P	DAPT with C	CV death, MI, ischemic stroke (mean P: 139d; C: 238d)	6.5% vs. 4.0%	HR: 1.41 (0.78–2.55)	0.25	BARC 3, 5 (mean P: 139d; C: 238d)	8.0% vs. 5.0%	HR: 1.39 (0.84–2.33)	0.25	Tokimasa et al. Heart Vessels 2019; 34: 1581–1588
JAMIR	2019	Prospective multicenter cohort	AMI		3,069	DAPT with P	DAPT with C	CV death, MI, stroke at 1y	6.8% vs. 10.0%	adjHR: 1.07 (0.67–1.72)	0.78	BARC type3, 5 at 1y	3.8% vs. 7.8%	adjHR: 0.62 (0.39–0.99)	0.046	Yasuda et al. Circ J 2019; 83: 1633–1643
Dokkyo Medical University	2019	Single-center, retrospective	ACS & CCS		500	DAPT with P	DAPT with C	CV death, MI, stroke at 1y	1.6% vs. 3.2%	NA	0.243	PCI-related bleeding during acute phase after PCI	22.4% vs. 13.2%	NA	0.007	Koyabu et al. Intern Med 2019; 58: 2315–2322
PRASFIT- Practice I	2018	Post-marketing observational study	ACS		732	DAPT with P	NA	CV death, MI, ischemic stroke (mean 64.9d)	3.10%	NA	NA	Bleeding AE (mean 64.9d)	6.4%	NA	NA	Nakamura et al. Cardiovasc Interv Ther 2018; 33: 135–145
PRASFIT- ACS	2016	Post hoc analysis of double-blind RCT	ACS	CYP2C19 genotype available; IM or PM 62.7%	773	DAPT with P	DAPT with C	CV death, MI, ischemic stroke at 24w	10.3% vs. 12.3%	adjHR: 0.84 (0.55–1.28)	NA	TIMI major (follow-up 24–48w)	1.3% vs. 1.3%	adjHR: 0.96 (0.28–3.33)	NA	Ogawa et al. J Cardiol 2016; 68: 29–36
PRASFIT- Elective	2014	Double-blind RCT	CCS		742	DAPT with P	DAPT with C	CV death, MI, ischemic stroke at 24w	4.1% vs. 6.7%	NA	NA	TIMI major (follow-up 24–48w)	0% vs. 2.2%	NA	NA	Isshiki et al. Circ J 2014; 78: 2926–2934
PRASFIT- ACS	2014	Double-blind RCT	ACS		1,385	DAPT with P	DAPT with C	CV death, MI, ischemic stroke at 24w	9.4% vs. 11.8%	HR: 0.77 (0.56–1.07)	NA	TIMI major (follow-up 24–48w)	1.9% vs. 2.2%	HR: 0.82 (0.39–1.73)	NA	Saito et al. Circ J 2014; 78: 1684–1692
Studies evaluating prasugrel monotherapy
REIWA	2024	Prospective multicenter cohort	ACS & CCS	Resolute	1,202	1m DAPT followed by P2Y12i monotherapy (P 69.6%)	NA	CV death, MI, definite ST, stroke at 1y	2.25%	NA	NA	TIMI major, minor at 1y	1.08%	NA	NA	Ishida et al. Circ J 2024; 88: 876–884
ASET- JAPAN	2023	Prospective multicenter cohort	CCS	SYNERGY	206	Loading DAPT & P monotherapy	NA	Cardiac death, target-vessel MI >48 h after index PCI, definite ST ≤3m	0%	NA	NA	BARC 3, 5 at 3m	0%	NA	NA	Muramatsu et al. Circ J 2023; 87: 857–865
STOP DAPT-3	2023	Open-label RCT	ACS or CCS with HBR	XIENCE	6,002	P monotherapy	DAPT with P	CV death, MI, definite ST, ischemic stroke at 1m	4.12% vs. 3.69%	HR: 1.12 (0.87–1.45)	0.01 (non- inferiority)	BARC 3, 5 at 1m	4.47% vs. 4.71%	HR: 0.95 (0.75–1.20)	0.66	Natsuaki et al. Circulation 2024; 149: 585–600
STOP DAPT-3	2023	Prespecified subgroup analysis of RCT	ACS or CCS with HBR	XIENCE, complex PCI	1,230	P monotherapy	DAPT with P	CV death, MI, definite ST, ischemic stroke at 1m	5.78% vs. 5.93%	HR: 0.98 (0.62–1.55)	0.92	BARC 3, 5 at 1m	5.30% vs. 3.70%	HR: 1.44 (0.84–2.47)	0.18	Yamamoto et al. JACC Cardiovasc Interv 2024; 17: 1119–1130
PENDULUM mono/ PENDULUM	2022	Prospective multicenter cohort	ACS & CCS	HBR	3,380	Short DAPT & P monotherapy	DAPT with P	Death, MI, stroke, ST at 24m	8.0% vs. 9.5%	adjHR: 0.77 (0.59–1.01)	0.061	BARC 2, 3, 5 at 24m	5.8% vs. 7.2%	adjHR: 0.77 (0.57–1.04)	0.086	Nakagawa et al. Circ J 2022; 86: 1352–1361
PENDULUM mono/ PENDULUM	2021	Prospective multicenter cohort	ACS & CCS	HBR	3,708	Short DAPT & P monotherapy	DAPT with P	Death, MI, stroke, ST from 1 to 12m	3.8% vs. 4.3%	adjHR: 0.93 (0.63–1.37)	0.696	BARC 2, 3, 5 from 1 to 12m	2.8% vs. 4.1%	adjHR: 0.69 (0.45–1.06)	0.09	Nakamura et al. Circ J 2021; 85: 785–793
PENDULUM mono	2020	Prospective multicenter cohort	ACS & CCS	HBR	1,173	Short DAPT & P monotherapy	NA	Death, MI, stroke, ST from 1 to 12m	3.8%	NA	NA	BARC 2, 3, 5 from 1 to 12m	3.20%	NA	NA	Nakamura et al. Circ J 2020; 85: 27–36

ACS, acute coronary syndrome; adj, adjusted; AE, adverse events; AMI, acute myocardial infarction; BARC, Bleeding Academic Research Consortium; C, clopidogrel; CCS, chronic coronary syndrome; CI, confidence interval; CV death, cardiovascular death; d, day; DAPT, dual antiplatelet therapy; HBR, high bleeding risk; HR, hazard ratio; IM or PM, intermediate or poor metabolizer; m, month; MI, myocardial infarction; NA, not available; OR, odds ratio; P, prasugrel; P2Y12i, P2Y₁₂ receptor inhibitor; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; ST, stent thrombosis; TIMI, Thrombolysis in Myocardial Infarction; TVR, target vascular revascularization; w, week; y, year.

Article p 1745

Prasugrel Monotherapy After PCI in Japanese Patients

The Figure summarizes the trials investigating various short DAPT regimens. Short DAPT followed by P2Y₁₂ receptor inhibitor monotherapy has become the mainstream of antithrombotic therapy after PCI. The superiority of the short DAPT strategy was consistently observed, even in complex PCI patients who are considered to be at high thrombotic risk.⁹ In both ACS and CCS patients, P2Y₁₂ receptor inhibitor monotherapy after 1–3-month DAPT is recommended for patients with both high ischemic and high bleeding risk, as a Class IIa recommendation in the Japanese guidelines.⁸ The PENDULUM mono study¹⁰ and REIWA registry¹¹ both investigated the safety of the short DAPT followed by prasugrel monotherapy and showed that the incidence rates of both ischemic and bleeding events were acceptably low (ischemic event: 3.8% and 2.25%, bleeding event: 3.20% and 1.08% at 1 year, respectively). The combined PENDULUM mono and PENDULUM registry further showed a trend of lower bleeding events without an increase in ischemic events with short DAPT (≤6 months) followed by prasugrel monotherapy compared with prolonged DAPT with prasugrel (12 months) in Japanese patients with high bleeding risk undergoing PCI, using an inverse probability of treatment weighting method (adjusted HR for ischemic events: 0.92, 95% CI: 0.63–1.37 and for bleeding events: 0.69, 95% CI: 0.45–1.06).¹² However, the STOPDAPT-3 randomized trial comparing prasugrel monotherapy with DAPT with prasugrel within 1 month after PCI signaled a small caution of an increase in ischemic events with no DAPT strategy.¹³ There is still room for research on the optimal utilization of prasugrel monotherapy, including further evidence of the optimal DAPT duration and comparison with clopidogrel. We anticipate that low-dose prasugrel’s “balancing act” will play a crucial role in optimizing patient outcomes in Japan, offering hope for the fine-tuning of antiplatelet therapy and enhancing the efficacy and safety for Japanese patients.

Figure.

Trials evaluating short DAPT strategy. Optimizing the antiplatelet strategy can be classified into 3 categories: drug discontinuation, switch, and dose reduction. The trial names are categorized into chronic and acute coronary syndromes. ASA, acetylsalicylic acid; C, clopidogrel; DAPT, dual antiplatelet therapy; P, prasugrel; P2Y12i, P2Y₁₂ receptor inhibitor; PCI, percutaneous coronary intervention; T, ticagrelor.

Disclosures

Y. Sakata received speaker honoraria from AstraZeneca, Bayer, Daiichi-Sankyo and grants from Bayer. Y. Sakata is a member of the Circulation Journal’s Editorial Team. The other authors have nothing to disclose.

Acknowledgment

During the preparation of this manuscript, the authors used the assistance of ChatGPT, a language model developed by OpenAI, for English language editing and proofreading to enhance the clarity and precision of the text.

References

• 1.   Byrne RA, Rossello X, Coughlan JJ, Barbato E, Berry C, Chieffo A, et al. 2023 ESC Guidelines for the management of acute coronary syndromes: Developed by the task force on the management of acute coronary syndromes of the European Society of Cardiology (ESC). Eur Heart J 2023; 44: 3720–3826, doi:10.1093/eurheartj/ehad191.
• 2.   Levine GN, Jeong YH, Goto S, Anderson JL, Huo Y, Mega JL, et al. Expert consensus document: World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol 2014; 11: 597–606, doi:10.1038/nrcardio.2014.104.
• 3.   Kimura T, Isshiki T, Ogawa H, Yokoi H, Yamaguchi T, Ikeda Y. Randomized, double-blind, dose-finding, Phase II study of prasugrel in Japanese patients undergoing elective percutaneous coronary intervention. J Atheroscler Thromb 2015; 22: 557–569, doi:10.5551/jat.26013.
• 4.   Isshiki T, Kimura T, Ogawa H, Yokoi H, Nanto S, Takayama M, et al. Prasugrel, a third-generation P2Y₁₂ receptor antagonist, in patients with coronary artery disease undergoing elective percutaneous coronary intervention. Circ J 2014; 78: 2926–2934, doi:10.1253/circj.cj-14-0266.
• 5.   Saito S, Isshiki T, Kimura T, Ogawa H, Yokoi H, Nanto S, et al. Efficacy and safety of adjusted-dose prasugrel compared with clopidogrel in Japanese patients with acute coronary syndrome: The PRASFIT-ACS study. Circ J 2014; 78: 1684–1692, doi:10.1253/circj.cj-13-1482.
• 6.   Kuno T, Miyamoto Y, Akita K, Shoji S, Numasawa Y, Ueda I, et al. Low-dose prasugrel vs. standard-dose clopidogrel for patients undergoing percutaneous coronary intervention. Circ J 2024; 88: 1745–1753, doi:10.1253/circj.CJ-24-0173.
• 7.   Shoji S, Sawano M, Sandhu AT, Heidenreich PA, Shiraishi Y, Ikemura N, et al. Ischemic and bleeding events among patients with acute coronary syndrome associated with low-dose prasugrel vs standard-dose clopidogrel treatment. JAMA Netw Open 2020; 3: e202004, doi:10.1001/jamanetworkopen.2020.2004.
• 8.   Nakamura M, Kimura K, Kimura T, Ishihara M, Otsuka F, Kozuma K, et al. JCS 2020 Guideline Focused Update on antithrombotic therapy in patients with coronary artery disease. Circ J 2020; 84: 831–865, doi:10.1253/circj.CJ-19-1109.
• 9.   Sotomi Y, Matsuoka Y, Hikoso S, Nakatani D, Okada K, Dohi T, et al. P2Y12 inhibitor monotherapy after complex percutaneous coronary intervention: A systematic review and meta-analysis of randomized clinical trials. Sci Rep 2023; 13: 12608, doi:10.1038/s41598-023-39213-3.
• 10.   Nakamura M, Morino Y, Kakuta T, Hata Y, Takamisawa I, Tanabe K, et al. Monotherapy with prasugrel after dual-antiplatelet therapy for Japanese percutaneous coronary intervention patients with high bleeding risk: A prospective cohort study (PENDULUM mono Study). Circ J 2021; 85: 27–36, doi:10.1253/circj.CJ-20-0786.
• 11.   Ishida M, Shimada R, Takahashi F, Niiyama M, Ishisone T, Matsumoto Y, et al. One-month dual antiplatelet therapy followed by P2Y₁₂ inhibitor monotherapy after biodegradable polymer drug-eluting stent implantation: The REIWA Region-Wide Registry. Circ J 2024; 88: 876–884, doi:10.1253/circj.CJ-24-0091.
• 12.   Nakamura M, Kadota K, Nakao K, Nakagawa Y, Shite J, Yokoi H, et al. Single antiplatelet therapy with prasugrel vs. dual antiplatelet therapy in Japanese percutaneous coronary intervention patients with high bleeding risk. Circ J 2021; 85: 785–793, doi:10.1253/circj.CJ-20-1058.
• 13.   Natsuaki M, Watanabe H, Morimoto T, Yamamoto K, Obayashi Y, Nishikawa R, et al. An aspirin-free versus dual antiplatelet strategy for coronary stenting: STOPDAPT-3 randomized trial. Circulation 2024; 149: 585–600, doi:10.1161/circulationaha.123.066720.