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Corresponding author at: Cardiology Department, Heart Institute, Sorbonne University, 47-83 Bld de l'hôpital, Pitié-Salpétrière Hospital, Paris F-75013, France.
Heart Institute, ACTION Study Group-CHU Pitié-Salpétrière, 47-83 Boulevard de l'Hôpital, Paris, FranceCollège National des Cardiologues Français (CNCF), Paris, France
The standard dual antiplatelet therapy duration of 6 months in stable patients undergoing percutaneous coronary interventions (PCI) and of 12 months in acute coronary syndromes (ACS) has been established in clinical trials presenting several differences compared with the modern clinical setting.
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High thrombotic risk is responsible for the increased ischemic risk in the early phase after ACS or PCI and can be mitigated by an intense antiplatelet therapy. After the early phase (1–3 months), the ischemic risk is related to other risk factors, the aggressive control of which plays a key role in reducing ischemic events.
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A “de-escalation” of antiplatelet therapy may be achieved by different strategies, requiring or not the use of tools such as platelet function or genetic testing for a guided selection of P2Y12 inhibitors, and aims at reducing bleeding without any trade-off in ischemic events.
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Current evidence support a larger use of de-escalation strategies of antiplatelet therapy in clinical practice and of an individualized approach to determine the best antithrombotic strategy in each patient.
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Further research are warranted to determine which de-escalation strategy is associated with the most favorable clinical outcomes, optimizing sources utilizations and taking into account of practical, real-world, considerations.
Abstract
Dual antiplatelet therapy (DAPT) is the gold standard after acute coronary syndromes (ACS) or chronic coronary syndromes (CCS) undergoing percutaneous coronary intervention (PCI).
Because local and systemic ischemic complications can occur particularly in the early phase (i.e. 1–3 months) after ACS or PCI, the synergistic platelet inhibition of aspirin and a P2Y12 inhibitor is of the utmost importance in this early phase. Moreover, the use of the more potent P2Y12 inhibitors prasugrel and ticagrelor have shown to further reduce the incidence of ischemic events compared to clopidogrel after an ACS. On the other hand, prolonged and potent antiplatelet therapy are inevitably associated with increased bleeding, which unlike thrombotic risk, tends to be stable over time and may outweigh the benefit of reducing ischemic events in these patients.
The duration and composition of antiplatelet therapy remains a topic of debate in cardiology due to competing ischemic and bleeding risks, with guidelines and recommendations considerably evolving in the past years. An emerging strategy, called “de-escalation”, consisting in the administration of a less intense antithrombotic therapy after a short course of standard DAPT, has shown to reduce bleeding without any trade-off in ischemic events. De-escalation may be achieved with different antithrombotic strategies and can be either unguided or guided by platelet function or genetic testing. The aim of this review is to summarize the evidence and provide practical recommendations on the use of different de-escalation strategies in patients with ACS and CCS.
Since more than two decades, dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is considered the gold standard for patients with acute coronary syndrome (ACS) as well as for those with chronic coronary syndrome (CCS) undergoing percutaneous coronary intervention (PCI) [
]. The more potent P2Y12 inhibitors prasugrel and ticagrelor have shown to reduce ischemic events at the cost of increased bleeding compared with clopidogrel [
Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient outcomes (PLATO) trial.
]. Therefore, a 12-month DAPT with potent P2Y12 inhibitors represents the standard-of-care after ACS and may be considered after PCI in CCS patients in specific high ischemic risk situations [
2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).
]. However, the efficacy and safety of a 12-month DAPT duration have been established in randomized controlled trials (RCTs) presenting several differences compared with the modern clinical setting, such as the low use of concomitant optimal medical therapy (i.e. statins) and the use of PCI without stenting or with old generation stent platforms, occurring late after the diagnosis of ACS and often performed by operators with little experience [
]. Moreover, fragile and high bleeding risk patients were typically excluded from an invasive strategy in early RCTs, while PCI is now currently extended to patients previously considered at prohibitive risk.
The increasing understating that bleeding events carry important clinical implications and that the response to antiplatelet agents vary widely according to the ischemic and bleeding risks as well as to the individual pharmacodynamic response to antiplatelets, suggests that a one-size-fits-all approach may represent a suboptimal approach in several subgroup of patients [
]. Recent guidelines have proposed a personalization of therapy according to patient's bleeding and ischemic risks, with dedicated scores designed to predict such risks [
2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).
]. Nevertheless, in the real world setting, a prolonged and intense antiplatelet therapy is often difficult to maintain due to the patient's clinical characteristics and comorbidities, and the use of scores is limited by a several challenges such as the large overlap between factors associated with increased ischemic and bleeding events. Therefore, a number of antithrombotic strategies have been tested in the last years with the aim of optimizing the balance between bleeding and ischemic risks [
]. Because the ischemic risk is highest in the early phase after ACS/PCI while bleeding risk remains relatively stable over time, there has been a great interest towards the use of a more intense antithrombotic regimen early after ACS or PCI, followed by a less intense regimen thereafter, in the attempt to reduce bleeding without any trade-off in ischemic events (the so called “de-escalation” strategy). In this review we discuss the rationale and provide an appraisal of the evidence in support of such a strategy.
2. Rationale for a de-escalation of antiplatelet therapy
Early after the introduction of PCI, the main focus of antithrombotic therapy was not only the reduction of ischemic recurrences, such as spontaneous myocardial infarction (MI), but also the prevention of local ischemic events such as stent thrombosis (ST) [
]. Later, with the introduction of first generation drug eluting stents (DES) which were burdened by an increased risk of ST, including those occurring late after PCI, a more prolonged and intense antithrombotic therapy has been implemented in the attempt of preventing ST [
Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials.
]. Such intensified antithrombotic regimens led to an increased risk of bleeding, which have been recently recognized to have important clinical implications, leading to increased mortality through direct and indirect mechanisms [
]. Indeed, bleeding can cause direct damages such as haemorrhagic stroke but can also lead to many indirect consequences associated with poor outcomes [
]. For example, a bleeding event results in the interruption of antiplatelet therapy which leads to a higher risk of thrombotic complications. Furthermore, anemia results in decreased oxygen supply and increased oxygen consumption due to neuroendocrine activation and requires blood transfusions which lead to depletion of 2,3-diphosphoglyceric acid and nitric oxide, resulting in low tissue oxygen and vasoconstriction which enhance platelets aggregation [
]. Compelling evidence supports the fact that, in both ACS or CCS patients undergoing PCI, the very early period after ACS or PCI is characterized by the greatest ischemic risk [
]. Indeed, MI and ST tend to be more common in the first 1–3 month following ACS or PCI, while the risk of bleeding represents a major threat continuously over time (Fig. 1) [
]. This is particularly evident among ACS patients in which the first months are characterized by enhanced inflammatory markers and thrombophilic status [
]. Based on the observation that ischemic risk tends to decrease while bleeding risk remains stable over time, there has been increasing interest in the developed of a strategy called “de-escalation”, aimed at using an intense antiplatelet therapy early after ACS or PCI, in order to reduce ischemic complications, followed by a less intense antiplatelet therapy thereafter, aimed at reducing bleeding events [
]. Another important issue to be considered when using antiplatelet therapy after PCI is that the superior clinical efficacy at the cost of increased bleeding of the potent P2Y12 inhibitors prasugrel and ticagrelor, as opposed to clopidogrel, is mainly related to the fact 20–40% of patients treated with clopidogrel are non-responders, while this rate is trivial in patients treated with prasugrel or ticagrelor [
Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention.
Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: the TAILOR-PCI randomized clinical trial.
]. Indeed, the wide interindividual variability in the gene responsible for the transcription of the hepatic cytochrome P450 (CYP) 2C19 system, which is responsible for the activation of clopidogrel, is associated with diminished levels of clopidogrel active metabolite [
Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.
]. Patients treated with clopidogrel, but not those treated with prasugrel or ticagrelor, who are carriers of one (intermediate metabolizer) or two (poor metabolizer) loss-of-function (LoF) alleles (CYP2C19×2 and CYP2C19×3) are associated with diminished CYP2C19 enzyme activity and diminished levels of clopidogrel active metabolite, leading to high platelet reactivity (HPR) and increased thrombotic risk [
Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention.
]. Moreover, the potent P2Y12 inhibition provided by prasugrel and ticagrelor has been associated with low platelet reactivity (LPR) and increased rates of bleeding without any benefit in ischemic events compared with patients responding to clopidogrel [
Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention[CE: duplicate reference with 16].
]. Patients not responding to clopidogrel may be identified by specific tools: platelet function tests (PFT), aiming at identifying the level of platelet inhibition, and genetic tests, aiming at identifying patients carriers of LoF allels of the CYP2C19 gene [
]. The implementation of these tools aims to perform a guided selection of P2Y12 inhibiting therapy, selectively administering clopidogrel to patients responding to this drug and prasugrel or ticagrelor to patients non-responding to clopidogrel, with the goal of decreasing bleeding without any trade-off in ischemic events.
Fig. 1Rationale for de-escalation strategy. In the early phase after ACS or PCI, the risk of thrombotic events is highest and an aggressive antiplatelet therapy is needed to reduce ischemic events. After 3 months since ACS or PCI, the risk of thrombotic events decreases significantly and other risk factors are responsible for the risk of ischemic events. The bleeding risk remains stable over time, resulting in a benefit/risk ratio in favor of an aggressive antiplatelet therapy only in the early (1–3 months) phase after ACS or PCI. Abbreviations: acute coronary syndrome (ACS); chronic coronary syndrome (CCS); percutaneous coronary intervention (PCI).
3. De-escalation among ACS patients undergoing PCI
De-escalation strategies among patients with ACS consist in the shortening of DAPT duration and in the use of reduced dose or reduced potency of P2Y12 inhibitors, which can be either guided by platelet function or genetic testing or unguided (Fig. 2) (Table 1).
Fig. 2De-escalation of antiplatelet therapy among ACS patients. De-escalation strategies among patients with ACS include: (1) shortening DAPT followed by aspirin, clopidogrel or ticagrelor monotherapy; (2) guided de-escalation; and (3) unguided de-escalation. Abbreviations: acute coronary syndrome (ACS); percutaneous coronary intervention (PCI); dual antiplatelet therapy (DAPT).
6-month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): a randomised, open-label, non-inferiority trial.
Final results of the randomised evaluation of short-term dual antiplatelet therapy in patients with acute coronary syndrome treated with a new-generation stent (REDUCE trial).
Comparison of clopidogrel monotherapy after 1 to 2 months of dual antiplatelet therapy with 12 months of dual antiplatelet therapy in patients with acute coronary syndrome: the STOPDAPT-2 ACS randomized clinical trial.
Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome: the TICO randomized clinical trial.
Ticagrelor alone vs. ticagrelor plus aspirin following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes: TWILIGHT-ACS.
Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial.
Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study.
A prospective, multicentre, randomised, open-label trial to compare the efficacy and safety of clopidogrel versus ticagrelor in stabilised patients with acute myocardial infarction after percutaneous coronary intervention: rationale and design of the TALOS-AMI trial.
Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial.
3.1 Current recommendations from international guidelines
The de-escalation strategies recommended by the European Society of Cardiology (ESC) guidelines consist in the shortening of DAPT followed by aspirin or by a P2Y12 inhibitor monotherapy, depending on the balance between the ischemic and bleeding risk [
2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).
]. In particular, the use of ticagrelor monotherapy after 3 months of standard DAPT is recommended in non-ST-elevation acute coronary syndromes (NSTE-ACS) with low bleeding risk, with class IIa, level of evidence (LoE) A. Among patients at HBR, current ESC guidelines recommend the use of clopidogrel as the P2Y12 inhibitor of choice and DAPT duration can be shortened to 6 months in ST-elevation acute coronary syndromes (STE-ACS) patients followed by aspirin alone, 1 month in NSTE-ACS patients followed by clopidogrel monotherapy or 3 months when DAPT discontinuation is followed by aspirin alone [
2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).
]. Moreover, in NSTE-ACS patients, ESC guidelines recommend a guided de-escalation by platelet function test or genetic testing or unguided de-escalation from potent P2Y12 inhibitors to clopidogrel with a class IIb, level of evidence B [
With regards to DAPT shortening with P2Y12 discontinuation in ACS, several trials have been carried out, comparing 6 versus 12-month DAPT and 3 versus 12-month DAPT durations [
] (Table 1). The DAPT-STEMI was a non-inferiority trial conducted in 2018, enrolling 1100 patients and comparing 6 versus 12 months DAPT in ACS patients. The primary endpoint was all-deaths, revascularization, stroke and major bleedings at 18 months [
The SMART-DATE trial was a non-inferiority trial comparing 6 versus 12 months DAPT in 2712 East Asian patients with ACS. The primary endpoint was the composite of all-cause death, MI or stroke [
6-month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): a randomised, open-label, non-inferiority trial.
]. Despite the primary endpoint of non-inferiority consisting in all-deaths, MI, or stroke was met, short DAPT was associated with a doubled risk of MI and with a 50% increased risk of ST, compared to standard DAPT [
6-month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): a randomised, open-label, non-inferiority trial.
]. The REDUCE trial compared 3 versus 12-month DAPT in 1496 patients. The primary endpoints were all-cause death, MI, ST, stroke, target vessel revascularization and Bleeding Academic Research Consortium (BARC) 2–5 bleedings at 12 months [
Final results of the randomised evaluation of short-term dual antiplatelet therapy in patients with acute coronary syndrome treated with a new-generation stent (REDUCE trial).
Final results of the randomised evaluation of short-term dual antiplatelet therapy in patients with acute coronary syndrome treated with a new-generation stent (REDUCE trial).
]. Red flags, raising some concern about the use of aspirin monotherapy after a short course of DAPT were the non-inferiority design of these three trials and, in the DAPT-STEMI and the REDUCE, the inclusion of both ischemic and bleeding outcomes as primary endpoint. Of note, an individual patient data meta-analysis has shown a higher rate of MI or ST with reduced DAPT duration followed by aspirin alone in ACS [
Three, six, or twelve months of dual antiplatelet therapy after DES implantation in patients with or without acute coronary syndromes: an individual patient data pairwise and network meta-analysis of six randomized trials and 11 473 patients.
]. RCTs in this setting have tested a strategy of aspirin discontinuation 1 or 3 months after ACS versus standard 12-month DAPT (Table 1). Despite RCTs including both ACS and CCS patients showed encouraging results with this strategy, the recent STOPDAPT-2 ACS non-inferiority trial including 4169 East Asian patients with ACS showed clopidogrel monotherapy after a 1 or 2-months DAPT not to be non-inferior to standard DAPT for the primary endpoint of CV death, MI, any stroke, definite ST or bleeding. Moreover, despite short DAPT followed by clopidogrel reduced by 54% the incidence of bleeding, it was associated with a 50% increase in the composite CV death MI, ST and stroke and a nearly doubled risk of MI, compared with standard DAPT [
Comparison of clopidogrel monotherapy after 1 to 2 months of dual antiplatelet therapy with 12 months of dual antiplatelet therapy in patients with acute coronary syndrome: the STOPDAPT-2 ACS randomized clinical trial.
]. Importantly, it must be highlighted that the evidence of clopidogrel monotherapy after a short course of DAPT comes from RCTs including only East-Asians, which are a population typically exposed to greater bleeding and lower ischemic risks compared to other ethnicities [
]. Furthermore, the non-inferiority design of STOPDAPT-2 ACS and the inclusion of both ischemic and bleeding outcomes as primary endpoint limit the statistical power with respect of ischemic outcomes, which requires further studies to be addressed [
Comparison of clopidogrel monotherapy after 1 to 2 months of dual antiplatelet therapy with 12 months of dual antiplatelet therapy in patients with acute coronary syndrome: the STOPDAPT-2 ACS randomized clinical trial.
If some concerns exists for a shortening of DAPT followed by clopidogrel monotherapy, a strategy of ticagrelor monotherapy after 1–3 month of DAPT has shown to reduce bleeding events without any trade-off in ischemic risk among ACS patients, in RCTs including both Eastern and Western countries [
Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome: the TICO randomized clinical trial.
O'Donoghue M.L., Murphy S.A., Sabatine M.S. The safety and efficacy of aspirin discontinuation on a background of a P2Y12 inhibitor in patients after percutaneous coronary intervention: a systematic review and meta-analysis. Circulation. 2020 Aug 11;142(6):538–45. doi: 10.1161/CIRCULATIONAHA.120.046251.
]. Specifically, TICO randomized 3056 South Korean ACS patients to either 3-month DAPT followed by ticagrelor monotherapy compared with standard 12-month DAPT with ticagrelor, showing a reduction of bleeding with no trade-off in ischemic events [
Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome: the TICO randomized clinical trial.
]. Indeed, the primary composite endpoint of net adverse clinical event, defined as a composite of major bleeding, all-deaths, MI, ST, stroke, or target-vessel revascularization, was reduced by 44% in the de-escalation versus standard DAPT group. Further evidence on the safety and efficacy of this strategy - mainly including patients from Western Countries - were provided by the sub-analysis of GLOBAL LEADERS and TWILIGHT trials, showing a greater reduction of bleeding with a de-escalation strategy in the subgroup of ACS as compared with CCS [
Ticagrelor alone vs. ticagrelor plus aspirin following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes: TWILIGHT-ACS.
]. It should be acknowledged that these two subgroup analysis should only be considered hypothesis generating, also in light of the fact the GLOBAL LEADERS trial did not meet its primary endpoint and that the rate of ischemic events was lower than expected in high-risk PCI patients in the TWILIGHT trial [
Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial.
]. Although these studies are underpowered to assess ischemic outcomes, a study-level meta-analysis has suggested ticagrelor monotherapy after a short court of DAPT may represent a safe and effective strategy [
O'Donoghue M.L., Murphy S.A., Sabatine M.S. The safety and efficacy of aspirin discontinuation on a background of a P2Y12 inhibitor in patients after percutaneous coronary intervention: a systematic review and meta-analysis. Circulation. 2020 Aug 11;142(6):538–45. doi: 10.1161/CIRCULATIONAHA.120.046251.
]. Finally, possible practical concerns surrounding the use of ticagrelor monotherapy stems from the fact ticagrelor is associated with higher rates (20–25%) of discontinuation by the patients due to the incidence of side effects (i.e. dyspnea) when compared with other antiplatelet drugs and to the fact its action is reversible and short, potentially leading to a prompt increase in platelet reactivity in case of voluntary or involuntary discontinuation of the drug by the patient [
Long-term tolerability of ticagrelor for the secondary prevention of major adverse cardiovascular events: a secondary analysis of the PEGASUS-TIMI 54 Trial.
Among patients with ACS, a guided selection of P2Y12 inhibitors allows for a selective administration of clopidogrel to clopidogrel responders, limiting the use of prasugrel and ticagrelor to clopidogrel non-responders, with aim of reducing bleeding without any trade-off in ischemic events [
]. This strategy, resulting in a guided de-escalation of antiplatelet therapy early (<7 days) after ACS or PCI, may be achieved by the use of PFT or genetic testing (Table 1).
The first study comparing a PFT-guided de-escalation with standard therapy in elderly patients with ACS undergoing PCI was ANTARCTIC (n = 877). This study failed to show any difference in the primary endpoint of CV death, MI, stroke, ST, urgent revascularization, and BARC 2–5 bleeding with a guided de-escalation versus standard therapy [
Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial.
]. Nevertheless, low dose of prasugrel rather than clopidogrel was used in this study both in the guided and standard groups, potentially blunting the superior safety of a de-escalation strategy [
Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial.
]. TROPICAL-ACS is the largest RCT comparing a PFT-guided de-escalation with standard therapy among ACS patients (n = 2610). A guided de-escalation was non-inferior in the primary composite endpoint of CV death, MI, stroke or BARC bleeding 2–5 as compared to standard DAPT, with a trend towards reduced bleeding at 12 months compared to the standard group [
]. Furthermore, POPular genetics showed both the non-inferiority of the primary endpoint of all-deaths, MI, definite ST, stroke, or major bleeding and a significant 22% reduction of the co-primary endpoint of major and minor bleeding at 12 months, in 2488 STE-ACS patients randomized to either genotype-guided de-escalation or standard therapy (mainly ticagrelor) within 48 h after PCI [
Limitations of RCTs testing a guided de-escalation in ACS patients are the use of a primary composite endpoint including both ischemic and bleeding outcomes and the non-inferiority design, both leading to a relatively low statistical power with respect to hard ischemic events. Nevertheless, a recent comprehensive meta-analysis at least partially overcoming this limitation, showed that a strategy of guided de-escalation is associated with a 19% reduction of bleeding without any trade-off in ischemic events [
]. Furthermore, a network meta-analysis focusing on ACS has shown a guided selection of P2Y12 inhibitors is associated with the most favorable safety and efficacy profile compared to standard treatment with prasugrel or ticagrelor [
Comparative effects of guided vs. potent P2Y12 inhibitor therapy in acute coronary syndrome: a network meta-analysis of 61 898 patients from 15 randomized trials.
Unguided de-escalation of P2Y12 inhibiting therapy may be implemented at least 1 month after ACS or PCI, when the risk of local ischemic events has declined significantly, and consists in the use of clopidogrel or reduced dose of prasugrel or ticagrelor after a short course (>1 month) of DAPT with full dose prasugrel or ticagrelor. TOPIC was a single center trial enrolling 646 ACS patients that compared an unguided de-escalation from potent P2Y12 inhibitor to clopidogrel after one month of DAPT versus 12-month standard DAPT [
Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study.
]. There was a 52% reduction of the primary endpoint of CV death, urgent revascularization, stroke and BARC 2–5 bleeding in the de-escalation compared to standard group, driven by a reduction of BARC 2–5 bleeding. Of note, this was a relatively small trial mainly including patients not undergoing complex-PCI [
Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study.
TALOS-MI trial was the largest RCT (n = 2697) comparing an unguided de-escalation from ticagrelor to clopidogrel 1 month after ACS versus standard 12-month DAPT with ticagrelor. There was a 45% reduction of the primary endpoint of CV death, MI, stroke and BARC 2–5 bleeding with a de-escalation as compared to standard therapy driven by a reduction of BARC 2–5 bleeding [
A prospective, multicentre, randomised, open-label trial to compare the efficacy and safety of clopidogrel versus ticagrelor in stabilised patients with acute myocardial infarction after percutaneous coronary intervention: rationale and design of the TALOS-AMI trial.
Finally, HOST-REDUCE-POLYTHEC-ACS was the first trial to compare a de-escalation strategy by reducing prasugrel from 10 to 5 mg 1 month after ACS versus standard 12-month DAPT with prasugrel in 3429 East Asian patients. The primary endpoint of all-cause death, MI, ST, repeat revascularization, stroke, and BARC bleeding 2–5 was reduced by 30% in the de-escalation versus standard group [
Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial.
Collectively, limitations of an unguided de-escalation of antiplatelet therapy are the fact they were underpowered to assess ischemic outcomes, the fact the vast majority of patients enrolled were East Asians undergoing non-complex PCI, and the fact that this strategy may not sufficiently consider the individual increased ischemic risk of patients not responding to clopidogrel.
4. De-escalation among CCS patients undergoing PCI
De-escalation strategies among patients with CCS consist in the shortening of DAPT duration followed by either aspirin or P2Y12 inhibitors monotherapy (Fig. 3) (Table 2).
Fig. 3De-escalation of antiplatelet therapy among CCS patients undergoing PCI with or without concomitant AF. De-escalation strategies among patients with CCS with or without concomitant AF include shortening DAPT followed by aspirin or clopidogrel monotherapy. Abbreviations: dual antiplatelet therapy (DAPT); oral anticoagulant (OAC); chronic coronary syndrome (CCS); atrial fibrillation (AF).
Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study.
A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation).
Six versus 12 months of dual antiplatelet therapy after implantation of biodegradable polymer sirolimus-eluting stent: randomized substudy of the I-LOVE-IT 2 Trial.
Safety of six-month dual antiplatelet therapy after second-generation drug-eluting stent implantation: OPTIMA-C Randomised Clinical Trial and OCT Substudy.
Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial.
Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial.
Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: the STOPDAPT-2 randomized clinical trial.
4.1 Current recommendations from international guidelines
In the clinical setting of CCS, according to current ESC guidelines, DAPT should be administered for six months, regardless of the stent used during PCI [
]. The only de-escalation strategy allowed by current recommendations consists in DAPT shortening, ranging from 3 months in patients at high bleeding risk, to 1 month in patients at extremely high bleeding risk [
A total of 10 RCTs including both ACS and CCS patients have compared a strategy of DAPT shortening to 1, 3 or 6 months versus a standard DAPT duration (Table 2) [
Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study.
A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation).
Six versus 12 months of dual antiplatelet therapy after implantation of biodegradable polymer sirolimus-eluting stent: randomized substudy of the I-LOVE-IT 2 Trial.
Safety of six-month dual antiplatelet therapy after second-generation drug-eluting stent implantation: OPTIMA-C Randomised Clinical Trial and OCT Substudy.
]. These studies have generally provided reassuring results on the efficacy and showed a consistent reduction of bleeding in favor of a short or very short DAPT as opposed to a standard DAPT duration [
]. However, none of these trials have focused only on CCS patients. It could be speculated that because ACS patients are at increased ischemic risk compared to CCS patients, the fact that the majority of RCTs on the topic included a variable percentage of ACS patients should provide a further reassurance on the efficacy and safety of a shortening of DAPT duration in these patients, despite the level of evidence remaining limited, especially for high ischemic risk patients.
4.3 Short DAPT followed by clopidogrel monotherapy
The STOPDAPT-2 and the SMART-CHOICE trials reported promising results on the possible discontinuation of aspirin 1–3 months after ACS or PCI followed by clopidogrel monotherapy in a mixed population of ACS and CCS [
Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: the STOPDAPT-2 randomized clinical trial.
Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial.
]. A sub-study of the STOPDAPT-2 trial suggested clopidogrel monotherapy after 1-month of DAPT was superior in major bleeding and non-inferior in the primary endpoint of CV death, MI, definite ST, any stroke or bleeding compared to 12 months DAPT, regardless ACS or CCS presentation [
Limitations of this strategy are represented by the fact these studies were underpowered for ischemic outcomes, the fact the populations from these two trials were from East-Asia and the fact that the use of unguided clopidogrel monotherapy does not take into account of the interindividual response to this antiplatelet agent.
4.4 Short DAPT followed by prasugrel monotherapy
Prasugrel monotherapy after a short course of DAPT has not been adequately tested in RCTs, and its use is limited to a pilot study enrolling 201 patients [
]. In this study, selected low-risk CCS patients treated with third-generation DES underwent aspirin discontinuation on the day of the index procedure and prasugrel monotherapy represented the only antiplatelet agent used. At 3 months, the rate of ischemic and bleeding events was extremely low in both treatment arms [
No RCTs using ticagrelor monotherapy after a short course of DAPT have focus on CCS patients (Table 1). Evidence in this setting comes from a pre-specified sub-analysis of the GLOBAL LEADERS trial according to clinical presentation (ACS versus CCS)[58]. In this study, while there was no difference in efficacy, defined as all-deaths and MI, between treatment strategies by subgroup, a strategy of ticagrelor monotherapy after 1 month of DAPT appeared to reduce bleeding risk in patients with ACS but not in patients with CCS, compared to standard DAPT with ticagrelor [
Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial.
]. This setting was the first in which a very early de-escalation strategy, consisting in clopidogrel monotherapy after a very short course of DAPT (about one week) on the background of OAC was adopted [
]. Guidelines suggest as gold standard in this setting a triple therapy (aspirin plus clopidogrel plus an oral anticoagulant) for 1 week after PCI, followed by aspirin discontinuation for 6 months in CCS and 12 months in ACS [
2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).
]. This recommendation stems from the results of 4 recent RCTs, each using a different novel OAC (NOAC, dabigatran, rivaroxaban, apixaban, or edoxaban) in combination with a P2Y12 inhibitor (mainly clopidogrel) versus a prolonged triple therapy [
]. However, because of several limitations of these studies and the fact they were not statistically powered to rule out any increase in ischemic events with a de-escalation strategy, whether the optimal duration of triple therapy for the majority of patients should be 1 week or 1 month remains debated [
]. Meta-analysis have played an important role in increasing statistical power for ischemic endpoints, but found inconsistent results with a possible increase of ST with the de-escalation strategy in the overall population and of MI in the ACS subgroup [
Safety and efficacy of antithrombotic strategies in patients with atrial fibrillation undergoing percutaneous coronary intervention: a network meta-analysis of randomized controlled trials.
Safety and efficacy outcomes of double vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials.
Intracranial haemorrhages vs. stent thromboses with direct oral anticoagulant plus single antiplatelet agent or triple antithrombotic therapy: a meta-analysis of randomized trials in atrial fibrillation and percutaneous coronary intervention/acute coronary syndrome patients.
]. Moreover, the use of ticagrelor was low (<10%) and that of prasugrel very low (<3%) in this trials, limiting the evidence in support of the use of P2Y12 inhibitors different from clopidogrel in this setting. Finally, the use of unguided clopidogrel monotherapy very early after ACS or PCI, which is the period considered at highest ischemic risk, may represent a source of concern especially in ACS and high ischemic risk patients, as it does not take into account of the interindividual response to this antiplatelet agent (Fig. 3).
6. Conclusions and future perspectives
Current evidence support a larger use of de-escalation strategies of antiplatelet therapy in clinical practice. An individualized approach remains more than ever mandatory to determine the best antithrombotic strategy, providing an optimal balance between bleeding and ischemic risks at the individual patient level. Because the primary scope of de-escalation strategies is to reduce bleeding, the benefit of this strategy is greater among patients at high bleeding risk. Thus, the identification of this cohort of patients is of the utmost importance in clinical practice and should be routinely performed. Furthermore, the increasing evidence supporting the clinical impact of the interindividual variability in response to clopidogrel support the implementation of tools aiming a guiding the use of P2Y12 inhibitor after ACS or PCI.
Since a number of de-escalation strategies have been proposed, a careful appraisal of the available evidence is key for the adoption of these strategies in clinical practice. Unfortunately, no comparison between different de-escalation strategies is currently available, as the only evidence in this regards is represented by a network meta-analysis in which effect estimates are mainly based on indirect comparisons and its results should be interpreted with caution [
]. Among ACS, a guided selection of antiplatelet therapy is of particular interest, allowing for a guided de-escalation from the potent P2Y12 inhibitor (prasugrel and ticagrelor) to clopidogrel selectively among patients responding to clopidogrel, reducing bleeding without any trade-off in ischemic events. To this extent, the availability of bedside point-of-care, rapid, relatively cheap and easy to use genetic testing may facilitate the adoption of this strategy in the future. Another very promising strategy in ACS is represented by the use of a potent P2Y12 inhibitor or of guided clopidogrel after 1 to 3 months of standard DAPT. Nevertheless, current evidence are only available on the use of ticagrelor monotherapy after 3 months of standard DAPT, a strategy already recommended by guidelines. In the light of the available evidence, a 12-month DAPT duration with potent P2Y12 inhibitors should only be applied to selected patients with high-ischemic risk and low bleeding risk.
On the other hand, among CCS with or without concomitant AF, the evidence in support of a de-escalation strategy is weaker and basically consists in the shortening of DAPT duration followed by aspirin in patients with sinus rhythm or clopidogrel in patients with concomitant AF. A de-escalation strategy in these patients is likely to be advantageous in high bleeding risk patients, but whether it should represent the standard of care remains uncertain. Moreover, whether the use of clopidogrel (either unguided or guided) may be advantageous as compared to aspirin after DAPT discontinuation requires further investigations. Furthermore, because prasugrel and ticagrelor are associated with increased bleeding risk compared to clopidogrel, whether the use of prasugrel or ticagrelor monotherapy could represent a valuable option for CCS patients is unlikely.
Finally, other fundamental issues to be considered when adopting de-escalation strategies are the control of risk factors and patient's compliance with guideline recommended treatments. Patients with intensive control of all cardiovascular risk factors, with a good compliance to therapy and receiving the best possible cardiovascular therapy (statins, ezetimibe +/- proprotein convertase subtilisin/kexin type 9 inhibitors, glucagon-like peptide 1-receptor agonists, sodium-glucose cotransporter-2 inhibitors, beta-blockers) are the best candidates to receive a de-escalated antiplatelet therapy.
Disclosures
P.S. reports consulting fees by Astra Zeneca, Amgen, BI, BMS, Lilly, Novartis, Sanofi, Servier, Vifor, outside the submitted work. M.B.: speakers bureau: Amgen, KRKA, Polpharma, Novartis, Sanofi-Aventis, Teva, and Zentiva; consultant to Amgen, Daiichi Sankyo, Esperion, Novartis, and Sanofi-Aventis; grants from Amgen, Sanofi, and Valeant, outside the submitted work. M.G. reports consulting fees by Terumo, outside the submitted work. L.S., D.F., W.U., M.G., J.P.C., S.D.R., M.S., report no disclosures. GBZ has consulted for Balmed, Cardionovum, Crannmedical, Eukon, Innovheart, Guidotti, Meditrial, Microport, Opsens Medical, Replycare, Teleflex, and Terumo outside the submitted work. No funding for this article.
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