P2Y₁₂-inhibitor monotherapy after coronary stenting: are all P2Y₁₂-inhibitors equal?

Figures & data

Figure 1. Platelet activation mechanisms and targets of antiplatelet therapy.

ADP denotes adenosine diphosphate, COX cyclo-oxygenase, GP glycoprotein, NO nitric oxide, PAR proteinase-activated receptor, PGI2 prostacyclin receptor, P2Y purinoceptor, TPα TxA2 receptor isoform α, TxA2 thromboxane A2, and vWF von Willebrand factor. Adapted with permission from Springer Nature: Macmillan Publishers Ltd., Nature Reviews Cardiology, Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention, Capodanno et al. Copyright © 2018 [16].

Table 1. Pharmacological characteristics of P2Y₁₂-inhibitors used after PCI.

	Clopidogrel	Prasugrel	Ticagrelor
Drug class	Thienopyridine	Thienopyridine	Cyclopentyl-triazolopyrimidine
Reversibility	Irreversible	Irreversible	Reversible
Bioactivation	Yes, CYP450 dependent	Yes, CYP450 dependent*	No
Loading dose	600 mg	60 mg	180 mg
Maintenance dose	75 mg once daily	10 mg once daily^†	90 mg twice daily
Onset of effect	2 to 6 hours	30 min to 4 hours	30 min to 2 hours
Offset of effect	3 to 10 days	5 to 10 days	3 to 4 days

* Bioactivation of prasugrel is CYPP450 dependent, but genetic variance in CYP450 activity has little effect on the degree of platelet inhibition.

† Prasugrel 5 mg once daily is recommended in patients with a body weight <60 kg or age ≥75 years.

CYP450 denotes cytochrome P450 and PCI percutaneous coronary intervention.

Table adapted from 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation [3].

Figure 2. P2Y₁₂-inhibitor of choice in the experimental arms of RCTs evaluating P2Y₁₂-inhibitor monotherapy after PCI.

PCI denotes percutaneous coronary intervention and RCT randomized controlled trial.

Table 2. Bleeding and ischemic events in RCTs evaluating P2Y₁₂-inhibitor monotherapy after PCI.

Trial	N (ACS %)*	Experimental arm	Control arm	Bleeding endpoint^†HR (95%-CI)	Ischemic endpoint^‡HR (95%-CI)
GLOBALLEADERS [11]	15,968 (47%)	Ticagrelor alone (23 mo.) after DAPT (1 mo.)	Ticagrelor alone (12 mo.) after DAPT (12 mo.)	0.87 (0.75–1.01) P = 0.07	0.97 (0.78–1.20) P = 0.77
SMART-CHOICE [12]	2,993 (58%)	P2Y12-inhibitor alone (9 mo.) after DAPT (3 mo.)	DAPT (12 mo.)	0.58 (0.36–0.92) P = 0.02	1.19 (0.76–1.85) PNI<0.01
STOPDAPT-2 [13]	3,009 (38%)	Clopidogrel alone (11 mo.) after DAPT (1 mo.)	DAPT (12 mo.)	0.26 (0.11–0.64) P < 0.01	0.79 (0.49–1.29) PNI<0.01
STOPDAPT-2 ACS [14]	4,136 (100%)^§	Clopidogrel alone (10–11 mo.) after DAPT (1–2 mo.)	DAPT (12 mo.)	0.46 (0.23–0.94) P = NA	1.50 (0.99–2.26) P = NA
TICO [15]	3,056 (100%)	Ticagrelor alone (9 mo.) after DAPT (3 mo.)	DAPT (12 mo.)	0.64 (0.45–0.90) P = 0.01	0.69 (0.45–1.06) P = 0.09
TWILIGHT [16]	7,119 (65%)	Ticagrelor alone (12 mo.) after DAPT (3 mo.)	DAPT (15 mo.)	0.56 (0.45–0.68) P < 0.01	0.99 (0.78–1.25) PNI<0.01

* Number of patients included in intention-to-treat analysis.

† The bleeding endpoint was BARC type 3 or 5 bleeding in the GLOBALLEADERS trial, TIMI major or minor bleeding in the SMART-CHOICE, STOPDAPT-2, STOPDAPT-2 ACS, and TICO trial and BARC type 2, 3 or 5 bleeding in TWILIGHT trial, respectively.

‡ The ischemic endpoint was all-cause mortality or new Q-wave MI in the GLOBALLEADERS trial, all-cause mortality, MI, or stroke in the SMART-CHOICE and TWILIGHT trial, cardiovascular mortality, MI, definite stent thrombosis, or stroke in the STOPDAPT-2 and STOPDAPT-2 ACS trial and all-cause mortality, MI, stent thrombosis, stroke, or target-vessel revascularization in the TICO trial, respectively.

§ In the STOPDAPT-2 ACS trial, 1,161 patients came from the ACS subgroup of the STOPDAPT-2 trial.

ACS denotes acute coronary syndrome, CI confidence interval, DAPT dual antiplatelet therapy, HR hazard ratio, MI myocardial infarction, NA not applicable, NI non-inferiority, PCI percutaneous coronary intervention, and RCT randomized controlled trial.

Table 3. Ongoing or future RCTs evaluating P2Y₁₂-inhibitor monotherapy after PCI.

Trial	N	Study population	Experimental arm	Control arm	Primary outcome(s)
A-CLOSE (NCT03947229)	3,200	Patients at high ischemic risk and event free at 12 mo. after PCI	Clopidogrel monotherapy (until 36 mo. after PCI)	DAPT (until 36 mo. after PCI)	NACE between 12 and 36 mo. post-PCI
BULK-STEMI (NCT04570345)	1,002	STEMI patients undergoing PCI	DAPT (3 mo.) followed by ticagrelor	DAPT (12 mo.)	NACE, MACCE, and BARC type 3 or 5 bleeding at 12 mo.
CAGEFREEII (NCT04971356)	1,908	ACS patients undergoing PCI using DCB	DAPT (1 mo.) followed by ticagrelor (5 mo.) and aspirin (6 mo.)	DAPT (12 mo.)	NACE at 12 mo.
C-MODE (NCT05320926)	3,744	Patients without MI undergoing PCI	DAPT (1–3 mo.) followed by clopidogrel (9–11 mo.)	DAPT (1–3 mo.) followed by aspirin (9–11 mo.)	NACE at 12 mo.
ELECTRA-SIRIO (NCT04718025)	4,500	ACS patients	DAPT (1 mo.) followed by DAPT with low-dose ticagrelor (11 mo.)*	DAPT (12 mo.)	MACCE and BARC type 2, 3 or 5 bleeding at 12 mo.
LEGACY (NCT05125276)	3,090	NSTE-ACS patients undergoing PCI	P2Y12-inhibitor monotherapy (12 mo.)	DAPT (12 mo.)	MACCE and BARC type 2, 3 or 5 bleeding at 12 mo.
NEOMINDSET (NCT04360720)	3,400	ACS patients undergoing PCI	Prasugrel or ticagrelor monotherapy (12 mo.)	DAPT (12 mo.)	MACCE and BARC type 2, 3 or 5 bleeding at 12 mo.
OPT-BIRISK (NCT03431142)	7,700	ACS patients at high ischemic and bleeding risk	DAPT (9–12 mo.) followed by clopidogrel (9 mo.)	DAPT (18–21 mo.)	BARC type 2–5 bleeding during 9 mo. follow-up
SMART-CHOICE 2 (NCT03119012)	1,520	Patients undergoing PCI with BRS and event free for 12 m	DAPT (12 mo.) followed by clopidogrel or low-dose ticagrelor (24 mo.)	DAPT (36 mo.)	MACCE between 12 and 36 mo. post-PCI
SMART-CHOICE 3 (NCT04418479)	5,000	Patients at high ischemic risk with prior PCI (≥12 mo.)	DAPT (12 mo.) followed by clopidogrel (12 mo.)	DAPT (12 mo.) followed by aspirin (12 mo.)	MACCE between 12 and 24 mo. post-PCI
STOPDAPT-2ACS (NCT03462498)	3,008	ACS patients undergoing PCI	DAPT (1 mo.) followed by clopidogrel (59 mo.)	DAPT (12 mo.) followed by aspirin (48 mo.)	NACE at 60 mo.
STOPDAPT-3 (NCT04609111)	3,110	ACS or HBR patients undergoing PCI	P2Y12-inhibitor monotherapy (12 mo.)	DAPT (1 mo.) followed by aspirin (11 mo.)	MACCE and BARC type 3 or 5 bleeding at 1 mo.
TARGET-FIRST (NCT04753749)	2,246	AMI patients undergoing complete revascularization	DAPT (1 mo.) followed by P2Y12-inhibitor monotherapy (11 mo.)	DAPT (12 mo.)	NACE and BARC type 2, 3 or 5 bleeding at 11 mo. follow-up
ULTIMATE-DAPT (NCT03971500)	3,486	ACS patients undergoing PCI	DAPT (1 mo.) followed by ticagrelor (11 mo.)	DAPT (12 mo.)	BARC type 2 to 5 bleeding or MACCE between 1 and 12 mo. post-PCI

* The ELECTRA-SIRIO trial includes an additional interventional arm in which patients will be treated with DAPT (1 mo.) followed by DAPT with low-dose ticagrelor (2 mo.) followed by low-dose ticagrelor monotherapy (9 mo.).

ACS denotes acute coronary syndrome, AMI acute myocardial infarction, BARC bleeding academic research consortium, BRS bioresorbable stent, DAPT dual antiplatelet therapy, DCB drug-coated balloon, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NACE net adverse clinical events, NSTE-ACS non-ST-segment elevation acute coronary syndrome, PCI percutaneous coronary intervention, RCT randomized controlled trial and STEMI ST-segment elevation myocardial infarction .

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