Dual antiplatelet therapy (DAPT) with aspirin and an oral P2Y₁₂ receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is the cornerstone of treatment for patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI).¹ Prasugrel and ticagrelor are characterized by more prompt and potent antiplatelet effects compared to clopidogrel, which translates into a reduction in ischemic outcomes in patients with ACS.^2,3 However, this benefit is hampered by an increase in major bleeding events, underscoring the need for strategies to reduce bleeding risk without a trade-off in ischemic protection. Multiple strategies to reduce bleeding after PCI have been established through the conduct of several clinical trials. These strategies include reducing DAPT intensity (e.g., de-escalation) or shortening DAPT duration (e.g., shorten clopidogrel treatment, shorten duration of aspirin, no aspirin) (Table 1).⁴ In this expert analysis we will focus on providing the available evidence as well as practical recommendations on de-escalation.

Table 1: Clinical Trials Assessing Strategies to Reduce Bleeding After PCI

De-escalation of DAPT	Shortening of DAPT duration
	Shorten Clopidogrel	Shorten Aspirin	No Aspirin
TOPIC	RESET	GLOBAL LEADERS	WOEST*
POPULAR AGE	OPTIMIZE	GLASSY	PIONEER-AF
TROPICAL ACS#	REDUCE ACS	STOPDAPT-2	PCI*
POPULAR GENETICS #	ISAR TRIPLE*	SMART-CHOICE	RE-DUAL PCI*
	MASTER DAPT*†	TWILIGHT	AUGUSTUS*
		TICO	ENTRUST-AF PCI*
		MASTER DAPT*†
		STOPDAPT-2 ACS

De-escalation is defined as switching from prasugrel or ticagrelor to clopidogrel as a strategy to reduce long-term bleeding events without reduction in ischemic protection and has been tested in several clinical trials (Table 2).⁵ This approach is based on the concept that, while antithrombotic benefit of P2Y₁₂  inhibitors is greater during the early phase after ACS/PCI, the increase in bleeding risk associated with more potent P2Y₁₂ inhibitors seems to accrue mainly in the chronic phase. A de-escalation strategy was first tested in the TOPIC trial, which showed that de-escalation at 30 days post-ACS was associated with a 52% reduction in a composite of bleeding and ischemic events, mainly driven by a reduction in major bleeding events, as compared with prolonged treatment with potent P2Y₁₂ inhibitors.⁶ However, registry data have shown that unguided de-escalation was associated with increased risk of ischemic events.⁷ Therefore, due to conflicting results, a routine de-escalation approach may not be the optimal strategy, but de-escalation should be reserved for patients at higher bleeding risk. Although this latter approach seems intuitive, the only de-escalation trial specifically designed for high bleeding risk patients was the POPULAR AGE trial.⁸ This trial was performed in elderly (≥70 years old) patients with non-ST elevation-acute coronary syndrome (NSTE-ACS) and showed that clopidogrel was associated with a significant 6% absolute reduction in bleeding events compared to standard treatment with ticagrelor or prasugrel and was non-inferior for ischemic events.

Table 2: Clinical Trials on De-Escalation of DAPT Therapy

Study	Design	N of patients	Treatment arms	Primary endpoint	Main findings
TOPIC6	Open-label, single-center, randomized trial, 30 days post-ACS	645	Switched DAPT (prasugrel or ticagrelor to clopidogrel) vs. continued DAPT with prasugrel or ticagrelor)	Composite of cardiovascular death, urgent revascularization, stroke, and bleeding as defined by BARC ≥2 at 1 year post ACS	Primary endpoint: 13.4% in the switched DAPT group vs. 26.3% in the unchanged DAPT (HR 0.48; 95% CI 0.48 (0.34-0.68); p<0.01)
POPULAR AGE8	Open-label, multi-center, randomized controlled trial in elderly patients (>70 years) with NSTE-ACS	1002	Ticagrelor or prasugrel vs.  clopidogrel in patients	Composite of all-cause death, myocardial infarction, stroke, PLATO major and minor bleeding	Primary endpoint: clopidogrel 27.7% vs. ticagrelor/prasugrel 32.1%; HR 0.82; 95% CI 0.66 to 1.03; p=0.030 for non-inferiority PLATO major and minor bleeding: clopidogrel 18% vs. ticagrelor/prasugrel 24%; HR 0.71; 95% CI 0.54 to 0.94; p=0.018 for superiority
TROPICAL ACS10	Multicenter, randomized clinical trial in biomarker-positive ACS patients after successful PCI	2610	PFT-Guided de-escalation to clopidogrel vs. continued prasugrel	Composite of cardiovascular death, myocardial infarction, stroke, and BARC bleeding ≥ grade 2	Primary endpoint: 7% in the guided de-escalation group vs. 9% in the control group; HR 0.81; 95% CI 0.62-1.06; (p =0.0004 for non-inferiority; p=0.12 for superiority)
POPULAR GENETICS14	Randomized, open-label, assessor-blinded trial in STEMI patients treated with primary PCI	2488	Genotype-guided therapy (ticagrelor or prasugrel in LoF alleles carriers and clopidogrel in noncarriers) vs. standard treatment with ticagrelor or prasugrel	Composite of death from any cause, myocardial infarction, definite stent thrombosis, stroke, or PLATO major bleeding	Primary endpoint: genotype-guided group 5.1% vs. standard treatment group 5.9%; HR 0.87; 95% CI 0.62-1.21; p<0.001 for noninferiority; p=0.40 for superiority) PLATO major and minor bleeding: genotype-guided group 9.8% vs. standard treatment group 12.5%; HR 0.78; 95% CI 0.61-0.98; p=0.04 for superiority

Several studies have shown that potent P2Y₁₂ inhibitors have enhanced ischemic benefit compared with clopidogrel particularly in patients with high platelet reactivity (HPR) or CYP2C19 loss-of-function (LoF) alleles. This has set the basis for using platelet function testing (PFT) and genetic testing in patients undergoing PCI to improve outcomes by tailoring antiplatelet treatment to the individual patient. Guided de-escalation with PFT or genetic testing has therefore become an emerging strategy that allows selecting clopidogrel poor responders, who can benefit the most from potent P2Y₁₂ inhibition. The selective use of prasugrel or ticagrelor among clopidogrel poor responders has the potential to reduce bleeding complications related to the broad use of potent P2Y₁₂ inhibitors while avoiding the increased ischemic risk associated with unselected use of clopidogrel. Guided de-escalation has been tested in several clinical trials.⁹

The TROPICAL-ACS trial evaluated a PFT-guided de-escalation strategy in patients with ACS undergoing PCI.¹⁰ The trial showed that PFT-guided de-escalation was non-inferior to unchanged prasugrel treatment on a composite end point including ischemic and bleeding events (7% in the guided de-escalation group vs. 9% in the control group; p non-inferiority=0.0004). BARC ≥2 bleeding was also numerically lower in the de-escalation group, without an increase in ischemic events. However, although PFT guided de-escalation has the advantage of defining the platelet phenotype that is more related to thrombosis (i.e., HPR), it also deals with inherent limitations, such as requiring patients to be on treatment to define responsiveness, variability in assays and results, and need for patients with HPR after de-escalation to escalate again to more potent P2Y₁₂ inhibitors, which could represent a challenge in real-world clinical practice.¹¹ Genetic testing for CYP2C19 LoF alleles can overcome these limitations given that the genetic profile of an individual remains unchanged and does not require a patient to be on treatment. Importantly, the commercial availability of rapid bedside genotyping assays has now made their implementation feasible in real-world practice.^12,13 The use of genotype-guided de-escalation is supported by the results of the POPular Genetics trial, showing that in patients with ST-segment elevation myocardial infarction undergoing primary PCI, guided de-escalation was noninferior to a standard approach with respect to net adverse events (5.1% vs. 5.9; p<0.001 for noninferiority), with a significant reduction in major or minor bleeding events (9.8% vs. 12.5%; p=0.04).¹⁴ A meta-analysis by Pereira et al. compared the clinical effects of potent P2Y₁₂ inhibitors (ticagrelor or prasugrel) versus clopidogrel taking into consideration the presence or absence of LoF alleles. Pooling together 15,949 patients, mostly ACS, from seven randomized controlled trials, the authors showed that the use of potent P2Y₁₂ inhibitors was beneficial only in patients with LoF alleles, whereas it did not provide any additional benefit in patients without LoF alleles, supporting the potential benefit of genotype-guided de-escalation.¹⁵ A recent comprehensive meta-analysis pooling data from more than 20,000 patients showed that a strategy of guided selection of antiplatelet therapy significantly reduced the risk of major adverse cardiovascular events compared with standard antiplatelet therapy.¹⁶ In particular, the study showed that guided de-escalation of DAPT was superior in reducing bleeding events without increase in ischemic events (Figure 1), supporting the role of a precision-medicine approach in selecting antiplatelet therapy.

Figure 1: Guided (Platelet Function/Genetic Testing) versus Standard Antiplatelet Therapy in Patients Undergoing PCI: A Systematic Review and Meta-analysis

De-escalation of P2Y₁₂ inhibitor therapy has recently been endorsed by guidelines as an alternative option in patients unsuitable for potent platelet inhibition.¹⁷ However, de-escalation is only one of the available strategies for bleeding reduction following PCI, and selecting the best option represents a clinical conundrum. When compared to shortening of aspirin duration, an emerging strategy tested in several recent clinical trials, both approaches show overall a reduction in bleeding without an increase in ischemic events (Figure 2). Therefore, the choice of the strategy should be based on the specific characteristics of the individual patient, including bleeding and thrombotic risk, affordability of potent P2Y₁₂ inhibitors, and presence of clinical factors, including genotype, favoring poor response to clopidogrel. In addition, despite the report that in the presence of potent P2Y₁₂ receptor blockade aspirin may provide little additional platelet inhibition, setting the basis for aspirin-free strategies,¹⁸ aspirin is known to have an important synergistic antithrombotic effect when used in combination with P2Y₁₂ inhibitors. De-escalation, by preserving the synergistic inhibition of multiple pathways, might indeed be beneficial over other strategies in terms of ischemic protection.¹⁹

Figure 2: Comparison Between Bleeding Reduction Strategies in ACS/PCI

In conclusion, although de-escalation of P2Y₁₂ inhibitors commonly occurs in clinical practice, routine de-escalation should not be recommended. This strategy should be considered in selected patients to reduce bleeding risk and based on the available evidence; an approached based PFT- or genotype-guided de-escalation should be preferred if possible (Figure 3). Because of the above-mentioned limitations of PFT and because genotype is only one of the factors involved in clopidogrel response variability, integrating genetic information with clinical and procedural variables have been shown to have greater accuracy than the individual components alone, and is likely to represent the most successful strategy for personalization of antiplatelet therapy in patients undergoing PCI.²⁰ Due to high thrombotic risk, early (<30 days) de-escalation should be avoided, especially if unguided, and clinicians should be aware of the correct switching approach to avoid the risk of drug-drug interactions, which could potentially expose the patient to enhanced thrombotic risk.⁵

Figure 3: Dual Antiplatelet Therapy Strategies After PCI

References

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Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Vascular Medicine, Interventions and ACS, Interventions and Vascular Medicine, Chronic Angina

Keywords: Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Prasugrel Hydrochloride, Clopidogrel, Ticagrelor, Purinergic P2Y Receptor Antagonists, Fibrinolytic Agents, Cytochrome P-450 CYP2C19, Percutaneous Coronary Intervention, Aspirin, ST Elevation Myocardial Infarction, Genotype, Precision Medicine, Genetic Profile, Alleles, Control Groups, Thrombosis, Registries, Phenotype, Genetic Testing, Reference Standards, Hemorrhage, Blood Platelets, Drug Interactions, Pharmaceutical Preparations

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