Is It Time to Shift the Monotherapy After Percutaneous Coronary Intervention From Aspirin to P2Y₁₂ Inhibitors?　― New Normal in the New-Generation Era ―

Aspirin has been the gold standard of the single antiplatelet therapy (SAPT) after percutaneous coronary intervention (PCI). However, aspirin is associated with a higher risk of gastrointestinal bleeding than P2Y₁₂ inhibitors because it acts by inhibiting cyclooxygenase.¹ Furthermore, P2Y₁₂ inhibitor monotherapy is associated with a reduced risk of myocardial infarction compared with aspirin monotherapy in the setting of secondary prevention.² Considering the balance between ischemic and bleeding risks after PCI, P2Y₁₂ inhibitor monotherapy is increasingly becoming the strategy for SAPT after a short duration of dual antiplatelet therapy (DAPT; Table). Clopidogrel monotherapy was reported to be associated with a lower risk of bleeding without an increase in ischemic events in the ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-2 Study (STOPDAPT-2) trial.³ Ticagrelor monotherapy has also been reported to reduce bleeding events with equivalent ischemic risk as the long duration DAPT, even in patients with a high thrombotic risk, such as those with acute coronary syndrome (ACS) or complex PCI.^4,5 However, the data for P2Y₁₂ inhibitor monotherapy are largely limited to ticagrelor and the clinical evidence for prasugrel monotherapy is not sufficient (Table). Because DAPT with prasugrel was associated with a lower incidence of bleeding events and a similar incidence of ischemic events to DAPT with ticagrelor in the Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome (ISAR-REACT 5), prasugrel could be an appropriate candidate for monotherapy.⁶ In The PrasugrEl moNotherapy after DrUg eLUting stent deployMent as a Management Of patients who are uNsuitable for lOng-term dual antiplatelet therapy (PENDULUM mono) study, Nakamura et al demonstrated the feasibility and applicability of SAPT with prasugrel in Japanese patients with high bleeding risk (HBR) undergoing PCI.⁷ Because most HBR patients also have high thrombotic risks, the benefits of short DAPT following P2Y₁₂ inhibitor monotherapy could be seen in HBR patients.^8,9 Considering the higher prevalence of HBR in the Japanese PCI population,¹⁰ an aspirin-off strategy would have a strong effect on daily clinical practice in Japan. However, the results of the PENDULUM mono study have not been verified in a comparative study with a long duration of DAPT.

Table. Clinical Studies Evaluating P2Y₁₂ Receptor Inhibitor Monotherapy vs. DAPT After PCI

Trial	No. patients	Target patients	DAPT duration (months)	P2Y12i	Primary endpoint	Trial design	Result
GLOBAL LEADERS14	15,968	PCI	1 vs. 12	Ticagrelor	Death/MI	Superiority	Not confirmed
STOPDAPT-23	3,045	PCI	1 vs. 12	Clopidogrel	NACE	Non-inferiority	Confirmed
SMART-CHOICE15	2,993	PCI	3 vs. 12	Clopidogrel	NACE	Non-inferiority	Confirmed
TWILIGHT4	9,006	HTR/HBR	3 vs. 12	Ticagrelor	Bleeding	Superiority	Confirmed
TICO5	3,056	ACS	3 vs. 12	Ticagrelor	NACE	Superiority	Confirmed
STOPDAPT-2 ACS	4,100	ACS	1 vs. 12	Clopidogrel	NACE	Non-inferiority	Ongoing
NEOMINDSET	3,400	ACS	0 vs. 12	Prasugrel	Bleeding/MACE	Superiority/ non-inferiority	Ongoing
STOPDAPT-3	3,110	HBR/ACS	0 vs. 1	Prasugrel	Bleeding/MACE	Superiority/ non-inferiority	Ongoing

ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; GLOBAL LEADERS, GLOBAL LEADERS: A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation; HBR, high bleeding risk; HTR, high thrombotic risk; MACE, major adverse cardiac event; MI, myocardial infarction; NACE, net adverse clinical event; NEOMINDSET, PercutaNEOus Coronary Intervention Followed by Monotherapy INstead of Dual Antiplatelet Therapy in the SETting of Acute Coronary Syndromes; PCI, percutaneous coronary intervention; P2Y₁₂i, P2Y₁₂ receptor inhibitor; SMART-CHOICE, Comparison Between P2Y₁₂ Antagonist Monotherapy and Dual Antiplatelet Therapy After DES; STOPDAT, ShorT and OPtimal Duration of Dual AntiPlatelet Therapy; TICO, Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus Stent for Acute Coronary Syndrome; TWILIGHT, Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention.

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In this issue of the Journal, Nakamura et al compared clinical outcomes between a SAPT cohort with prasugrel from the PENDULUM mono study and a DAPT cohort with HBR from the PENDULUM registry as a historical control.¹¹ The PENDULUM registry is an all-comers PCI registry, but the PENDULUM mono study recruited PCI patients who were not considered appropriate for long-term DAPT because of their HBR status. The historical cohort in this analysis was extracted from patients who met the criteria for the PENDULUM mono study among those enrolled in the PENDULUM registry. The adjusted cumulative incidence of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding from 1–12 months after PCI (primary endpoint) was numerically lower in the PENDULUM mono study than in the historical control, without an increase in major adverse cardiac and cerebrovascular events (MACCE; Figure). The adjusted cumulative incidence of BARC 2, 3, or 5 bleeding 12 months after PCI was significantly lower in the PENDULUM mono study than in the historical control. These findings suggest that prasugrel SAPT may reduce bleeding events without increasing MACCE in Japanese patients who were not considered appropriate for long-term combination treatment with aspirin because of their HBR status.

Figure.

Major adverse cardiac and cerebrovascular events (MACCE) and bleeding events in patients enrolled in The PrasugrEl moNotherapy after DrUg eLUting stent deployMent as a Management Of patients who are uNsuitable for lOng-term dual antiplatelet therapy (PENDULUM mono) study and PENDULUM registry. DAPT, dual antiplatelet therapy; MI, myocardial infarction.

Attention should be paid to the design of the PENDULUM mono registry. Although this is a prospective registry enrolling HBR patients, the duration of DAPT was not previously determined.⁷ The median duration of DAPT was 108 days and prasugrel monotherapy was achieved in only 30.3%, 63.0%, and 79.7% of patients at 3, 6, and 12 months, respectively (Figure). Indeed, bleeding events diverged beyond 6 months after PCI when prasugrel monotherapy was mainly implemented. Nevertheless, it should be noted this is the first prospective registry evaluating prasugrel monotherapy without using aspirin after PCI in a Japanese HBR population. In the Japanese Circulation Society 2020 focused update guideline on antithrombotic therapy in patients with coronary artery disease (CAD), monotherapy with P2Y₁₂ inhibitors is recommended in patients with both high thrombotic and bleeding risks.¹² P2Y₁₂ inhibitor is also recommended after PCI for those treated with oral anticoagulation.¹² The results of the study of Nakamura et al¹¹ would support the recommendations in the 2020 updated guidelines.

An aspirin-free strategy is now emerging as a novel strategy for antiplatelet therapy after PCI. In the Acetyl Salicylic Elimination Trial (ASET) Pilot Study, aspirin-free prasugrel monotherapy following successful everolimus-eluting stent implantation was demonstrated to be feasible and safe, without any stent thrombosis, in selected low-risk patients with stable CAD.¹³ The PercutaNEOus Coronary Intervention Followed by Monotherapy INstead of Dual Antiplatelet Therapy in the SETting of Acute Coronary Syndromes (NEOMINDSET) trial (ClinicalTrials.gov ID NCT04360720), which is currently ongoing, has randomized 3,400 patients with ACS within 96 h of hospital admission to either to the P2Y₁₂ monotherapy or DAPT. The STOPDAPT-3 trial (ClinicalTrials.gov ID NCT04609111), which will randomize 3,110 patients with HBR and/or ACS before PCI to either an experimental arm (prasugrel monotherapy) or a control arm (DAPT), will also be launched in Japan (Table).^3–5,14,15

The use of P2Y₁₂ inhibitors had been limited to CAD patients using aspirin, and P2Y₁₂ inhibitor monotherapy had not been covered by insurance in Japan. However, the medical package insert of P2Y₁₂ inhibitors has recently been updated, and P2Y₁₂ monotherapy following the Japanese Circulation Society’s updated 2020 guidelines has now been accepted. Taken together, P2Y₁₂ inhibitor monotherapy could be the new normal in place of aspirin monotherapy in the new-generation drug-eluting stent and new-generation more-potent P2Y₁₂ inhibitor era.

Disclosures

K.N. is a member of Circulation Journal’s Editorial Team. M.N. has no conflicts of interest to disclose.

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