P2Y12 inhibitor monotherapy after complex percutaneous coronary intervention: a systematic review and meta-analysis of randomized clinical trials

概要

Title

P2Y12 inhibitor monotherapy after complex
percutaneous coronary intervention: a systematic
review and meta-analysis of randomized clinical
trials

Author(s)

Sotomi, Yohei; Matsuoka, Yuki; Hikoso, Shungo et
al.

Citation

Scientific Reports. 2023, 13(1), p. 12608

Version Type VoR
URL
rights

https://hdl.handle.net/11094/94602
This article is licensed under a Creative
Commons Attribution 4.0 International License.

Note

Osaka University Knowledge Archive : OUKA
https://ir.library.osaka-u.ac.jp/
Osaka University

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OPEN

P2Y12 inhibitor monotherapy
after complex percutaneous
coronary intervention: a systematic
review and meta‑analysis
of randomized clinical trials
Yohei Sotomi 1,4, Yuki Matsuoka 1,4, Shungo Hikoso 1*, Daisaku Nakatani 1, Katsuki Okada 1,2,
Tomoharu Dohi 1, Hirota Kida 1, Bolrathanak Oeun 1, Akihiro Sunaga 1, Taiki Sato 1,
Tetsuhisa Kitamura 3 & Yasushi Sakata 1
It remains unknown whether the recent trend of short dual antiplatelet therapy (DAPT) followed by
P2Y12 inhibitor monotherapy can simply be applied to patients undergoing complex percutaneous
coronary intervention (PCI). We performed a systematic review and meta-analysis to evaluate P2Y12
inhibitor monotherapy vs. conventional DAPT in patients undergoing complex PCI and non-complex
PCI (PROSPERO: CRD42022335723). Primary endpoint was the 1-year Net Adverse Clinical Event
(NACE). Among 5,323 screened studies, six randomized trials fulfilled the eligibility criteria. A total of
10,588 complex PCI patients (5,269 vs. 5,319 patients) and 25,618 non-complex PCI patients (12,820
vs 12,798 patients) were randomly assigned to P2Y12 inhibitor monotherapy vs. conventional DAPT.
In complex PCI patients, P2Y12 inhibitor monotherapy was associated with a lower risk of NACE than
conventional DAPT [Odds ratio (OR) 0.76, 95% confidence interval (CI) 0.63–0.91, P = 0.003], whereas
in non-complex PCI patients, P2Y12 inhibitor monotherapy was associated with a trend toward
lowering the risk of NACE (OR 0.86, 95% CI 0.72–1.02, P = 0.09). This meta-analysis across randomized
trials demonstrated that a strategy of short DAPT followed by P2Y12 inhibitor monotherapy reduces
the risk of 1-year NACE in patients undergoing complex PCI.
The Academic Research Consortium (ARC) proposed the new practical definition of patients at high bleeding
risk (HBR)1. These ARC-HBR criteria have been validated ­worldwide2–6. Although bleeding risk is now under
intensive discussion in the interventional field, a thrombotic event remains an important concern for interventional cardiologists. In particular, complex PCI is considered to be an important thrombotic risk factor, and
many interventional cardiologists believe that patients undergoing complex PCI should be prescribed relatively
long dual antiplatelet therapy (DAPT) to prevent stent thrombosis. This was true in the era of DAPT followed by
aspirin ­monotherapy7. In 2016, for example, Giustino et al. conducted a large-scale patient-level meta-analysis
involving 6 randomized controlled ­trials7, and reported that compared with short-term DAPT, long-term DAPT
yielded significant reductions in major adverse cardiovascular events (MACE) in the complex PCI group vs. the
non-complex PCI group. However, the current mainstream of antithrombotic therapy is a short DAPT followed
by P2Y12 inhibitor monotherapy. Bianco et al. performed a meta-analysis of recent trials comparing long DAPT
vs. short DAPT followed by P2Y12 inhibitor m
­ onotherapy8. The study showed that short DAPT followed by
P2Y12 inhibitor monotherapy was associated with a lower incidence of clinically relevant bleeding compared to
12-month DAPT with no significant differences in terms of cardiovascular events at 1-year follow-up. Nevertheless, it remains unknown whether this can simply be applied to patients undergoing complex PCI.

1

Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2‑2 Yamadaoka,
Suita, Osaka  565‑0871, Japan. 2Department of Medical Informatics, Osaka University Graduate School of
Medicine, Osaka, Japan. 3Division of Environmental Medicine and Population Sciences, Department of Social
and Environmental Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan. 4These authors
contributed equally: Yohei Sotomi and Yuki Matsuoka. *email: hikoso@cardiology.med.osaka-u.ac.jp
Scientific Reports |

(2023) 13:12608

| https://doi.org/10.1038/s41598-023-39213-3

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www.nature.com/scientificreports/
Several sub-analyses focusing on P2Y12 inhibitor monotherapy in patients with complex PCI have recently
been ­reported9–14. Here, we performed a systematic review and meta-analysis to investigate the impact of short
DAPT followed by P2Y12 inhibitor monotherapy on clinical outcomes in patients undergoing complex PCI.

Methods

Study search and eligibility criteria.  We performed a systematic review and meta-analysis to evalu-

ate P2Y12 inhibitor monotherapy vs. conventional DAPT in patients undergoing complex PCI and non-complex PCI (PROSPERO: CRD42022335723). P2Y12 inhibitor monotherapy was defined as a short DAPT (up to
3 months) followed by P2Y12 inhibitor monotherapy. Conventional DAPT was defined as a standard course of
DAPT of 6–12 months followed by either aspirin or P2Y12 inhibitor monotherapy. Inclusion criteria were as follows: (1) randomized design comparing short DAPT (up to 3 months) followed by P2Y12 inhibitor monotherapy against standard DAPT, (2) use of contemporary drug-eluting stents, (3) follow-up duration ≥ 12 months,
and (4) stratified analysis according to complex PCI. PubMed and Web of Science were searched from the inception of each database up to June 8th, 2022, with no restriction on language or publication status. Two investigators (YS and YM) independently assessed publications for eligibility at the title and/or abstract level, with
divergences resolved by a third investigator (SH). We performed the systematic search using the following code:
((complex PCI) OR (high ischemic risk)) AND ((antiplatelet therapy) OR (monotherapy)). Because the present
meta-analysis was based on data extracted from previously published research, the data and study materials are
available to other researchers for purposes of reproducing the results or replicating the procedure. The analytic
methods are outlined as follows.

Data extraction and quality assessment.  The following data were extracted independently by two
reviewers using a standardized data abstraction form: the study year of publication, study design, inclusion
and exclusion criteria, sample size, patients’ baseline characteristics, P2Y12 inhibitor used, endpoint definitions,
complex PCI definitions, clinical outcomes, and follow-up duration. Quality assessment of RCTs was based
on the Cochrane risk of bias tool for randomized controlled trials considering the following criteria: random
sequence generation, allocation concealment, selective reporting, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and other sources of bias. We classified bias of the trials
as low, high, or unclear.
Study endpoints.  Primary endpoint was the Net Adverse Clinical Event (NACE), which is a composite
of major bleeding and major adverse cardiac and cerebrovascular events (MACCE) (Table 1) at 1-year followup. Secondary endpoints were bleeding endpoint (major bleeding) and all individual components of MACCE
(all-cause death, myocardial infarction, stent thrombosis, and stroke) at 1-year follow-up. Since definitions of
clinical endpoints were as prespecified in the individual trials, several discrepancies in definitions were present.
Specifically, repeat revascularization was included in NACE in the GLOBAL LEADERS and TICO trials but not
in the other trials. Stroke reported by TWILIGHT did not include hemorrhagic stroke but only ischemic stroke.
Stent thrombosis was reported according to the Academic Research Consortium (ARC) definite or probable
definition, except for data from GLOBAL LEADERS in which it was reported as ARC definite. Bleeding events
were according to the Bleeding Academic Research Consortium (BARC) or Thrombolysis in Myocardial Infarction (TIMI) definitions. Event rates reported by TWILIGHT were at 15 months rather than 12 months. Due to
limited access to the outcome data, we used these reported data as summarized in Table 1.
Complex PCI.  The original definitions used in each trial are summarized in Table  2. Complex PCI was
previously defined as including at least one of the following criteria: (1) chronic total occlusion, (2) stent
length > 60 mm, (3) bifurcation with 2 stents, (4) ≥ 3 lesions treated, (5) ≥ 3 stents implanted, and (6) ≥ 3 vessels
­treated7. All trials used similar definitions, with slight differences. For the current analysis, we used the original
definition in each trial. In the sub-analysis of the TICO trial only, patients were divided into high-ischemic vs.

Study name

death

MI

Stroke

Revascularization

Stent thrombosis

Bleeding

GLOBAL LEADERS

All cause

Any

Ischemic or haemorrhagic

Any revascularization

–

BARC Type 3 or 5

MASTER DAPT

All cause

Any

Ischemic or haemorrhagic

–

–

BARC Type 3 or 5

SMART CHOICE

All cause

Any

Ischemic or haemorrhagic

–

–

BARC Type 2 or
3 or 5

STOP-DAPT2

Cardiovascular

Any

Ischemic or haemorrhagic

–

Definite

TIMI major or minor

Definite or probable

TIMI major

–

BARC Type 3 or 5

TICO

All cause

Any

Ischemic or haemorrhagic

Target vessel revascularization

TWILIGHT*

Cardiovascular

Any

Ischemic

–

Table 1.  Components of the net clinical adverse event (primary endpoint). *The report from the TWILIGHT
did not provide the composite endpoint. We calculated the event numbers using the data of ischemic and
bleeding events, but this calculation is non-hierarchical. Furthermore, event rates reported by TWILIGHT
were at 15 months but not at 12 months. ...

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