Dual Antiplatelet Therapy after PCI: When Could We Go Shorter?

The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) remains an important clinical question in interventional cardiology. Several clinical and angiographic variables are associated with an increased risk for thrombotic events, and prolonged DAPT duration may improve long term clinical outcome. However, some patients also present high bleeding risk (HBR) characteristics and may require a shorter DAPT duration. The guidelines recommendations consider the data from randomized clinical trials, however numerous exclusion criteria may create gaps in the evidence leading to uncertain-ties, the need for expert opinion and patient level decision making. Furthermore, the stent platforms have evolved in such way that opportunities now exist to shorten duration of DAPT. This chapter will review the variables associated with ischemic and bleeding risks as well as different stent platforms to help clinicians optimize DAPT duration in patients undergoing PCI.


Introduction
The optimal antiplatelet therapy after percutaneous coronary intervention (PCI) remains an unanswered clinical question. The last 25 years of clinical investigations has mainly been focused on the choice of P2Y12 agents and on treatment duration. Initially, the observation that bare metal stents (BMS) implantation could be associated with thrombosis, and, subsequently, the observation that first-generation drug eluting stents (DES) were associated with very-late thrombosis risk led to studies evaluating prolonged duration regimens of DAPT after PCI, but also to innovations in stent technology. However, the newer, more potent drugs (prasugrel and ticagrelor) and the advent and evolution of modern second-and third-generation DES dramatically dwindled the incidence of late and very late thrombotic complications. Thus, interest has shifted in trying to find the optimal, shortened DAPT treatment to prevent the early thrombotic complications while avoiding the late hemorrhagic events, the latter being associated with a similar risk of all-cause mortality than post-PCI recurrent myocardial infarctions [1].
Numerous trials attempted to answer these important questions, sometimes leading to discrepant results. This chapter will focus on the current evidence listed on the guidelines of main scientific societies for three groups of patients: elective PCI,

Evaluation of bleeding and thrombotic risk
In order to tailor optimal DAPT duration, many variables must be taken into account to ensure adequate thrombotic protection while avoiding hemorrhagic complications. To that extent, different risk scores have been derived and validated.
The PARIS risk score was one of the first tools intended to predict risks for out-of-hospital events directly modified by prolonging DAPT beyond one year (i.e. coronary thrombosis and bleeding) [10]. The aim of the DAPT score is to identify patients expected to derive benefit or harm from continuing P2Y 12 beyond 1 year. To that extent, data was gathered among patients that had not experienced any major ischemic or bleeding event 12 months after the index procedure [11]. Similarly, the CALIBER score includes patients surviving 12 months after a MI, including those not treated with PCI [12]. Hence, these three risk scores help establishing the security of long term DAPT duration.
In contrast, the PRECISE-DAPT score [13] assesses the benefit of a short (3-6 month) versus a long (12-24 month) DAPT duration. Furthermore, it allows clinicians to select DAPT duration upfront instead of at another point in time during follow-up. Of note, patients with the need of OAC were excluded from the derivation cohort. Patients undergoing elective, urgent and emergent PCI were all included in the analysis. At the time of the index PCI, an additive score is calculated by means of the presence of five clinical and biochemical variables (age, creatinine clearance, hemoglobin, white blood cell count and prior spontaneous bleeding), ranging 0 to 100 points. Patients ≥25 points were considered high bleeding risk (HBR), while <25 points were defined as non-HBR. Among HBR patients based on this score, prolonged DAPT contributed to no significant ischemic benefit, while, on the other hand, led to an increased risk of bleeding (number to harm (NNH) = 38). In parallel, non-HBR patients benefited of a longer DAPT regimen in the form of a significant reduction in the composite endpoint of myocardial infarction (MI), definite stent thrombosis, stroke and target vessel revascularization (NNT for benefit of 68), with no significant increase in bleeding risk [13]. Results were consistent across the full spectrum of indications for PCI.
Some works have compared the accuracy of these scores head-to-head, in general showing little to no difference in their ability to predict bleeding [14][15][16].
More recently, the new ARC-HBR criteria have been validated at identifying patients at high bleeding risk, being more sensitive than the PRECISE-DAPT and PARIS risk scores (at the expense of specificity) [17]. Trials where these criteria are used to compare different antiplatelet durations are awaited.
It is worth noting, however, that no prediction model has been prospectively tested in the setting of a RCT.
On the other side of the coin, clinicians should be aware of certain clinical and angiographic features associated with a higher thrombotic risk in some patients, thus making it unadvisable to shorten their antiplatelet regimens. These characteristics are summarized in Table 2.

Evidence for DAPT duration after PCI in non-ACS setting
Many trials have demonstrated the non-inferiority of 6-month versus longer treatment duration amid "all-comer" patients undergoing PCI for stable and ACS settings, [18][19][20][21][22] and so the recommendations for elective PCI are extrapolated for the aggregated results. The ACC and ESC guidelines give strong recommendations on a standard 6-month duration of DAPT in stable patients. As for the CCS, it places greater emphasis on reduction of major CV thrombotic events vs. an increase in bleeding complications, by recommending DAPT duration from 6 up to 12 months. ( Table 1) This is due to some metanalysis showing increased risk of ischemic outcomes with shorter DAPT durations in certain groups with high risk angiographic features ( Table 2) [24][25][26].
All three guidelines suggest considering a 3-month DAPT course in patients at HBR. This comes from the experience of two trials where a zotarolimus-eluting stent was tested [27,28]. However, due to the fact that this platform is no longer available, the recommendation stands at a weak level of evidence. The ESC guidelines also include the possibility of a 1-month period of DAPT in patients in whom 3-month DAPT poses safety concerns. This recommendation comes from two trials in which a zotarolimus-eluting Endeavor sprint stent or Biofreedom drug-coated stent reduced ischemic endpoints compared to bare-metal stent under similar DAPT duration [29,30].
Since their publication, some new evidence supports aspirin-free strategies early after PCI: the TWILIGHT trial included high risk patients who had not had an ischemic or bleeding event after a three-month course of aspirin plus ticagrelor and randomized them to aspirin or placebo for one year. Patients with ticagrelor monotherapy had a lower clinically relevant bleeding incidence while providing no higher death or ischemic endpoints [31]. The SMART-CHOICE randomized patients to receive aspirin plus a P2Y12 inhibitor for 3 months and thereafter a P2Y12 inhibitor alone or DAPT por 12 months. The monotherapy arm resulted in noninferior rates of major adverse cardiac events [32].
The GLOBAL LEADERS trial assessed the combination of ticagrelor and aspirin for one month followed by ticagrelor alone for 23 month versus 12 months of standard DAPT followed by 12 month of aspirin alone, with neutral results [33]. Later, its ancillary substudy (GLASSY) showed the non-inferiority, but not superiority, of shortened DAPT arm in a selected subpopulation of the 20 highest recruiting sites of the main trial [34]. On the other hand, the STOPDAPT-2 trial showed the benefit of 1 month of aspirin plus clopidogrel followed by clopidogrel monotherapy vs. 12 month of standard DAPT, meeting the criteria for both noninferiority and superiority [35].

Evidence for DAPT duration after PCI in ACS setting
The three sets of guidelines provide strong recommendation for a standard 12-month DAPT treatment after an ACS, based on the CURE trial and the PCI-CURE substudy published nearly two decades ago, in which DAPT with aspirin and clopidogrel was prescribed for 3 to 12 months after PCI [36,37]. More recently, the pivotal prasugrel and ticagrelor trials, conducted in patients with ACS, used a 12-month default DAPT duration, furthermore establishing this approach as the standard of practice (Table 1) [38,39].

Scenarios for shortened DAPT
Due to the time gap between the latest ESC guidelines on this topic and its American and Canadian counterparts, recommendations on minimal DAPT duration differ between the former and the latter ( Table 1). The scarce evidence available at the time of the last ACC/AHA and CCS guidelines led to only weak recommendation for a 6-month DAPT on the former, while the latter holds at a 12-month recommendation. This year's ESC guidelines on the management of ACS in patients presenting without persisting ST-segment elevation includes various guidance on short DAPT.
As discussed previously, the insight from the PRECISE-DAPT study led to consider a shortened 3-month DAPT duration in patients at HBR (PRECISE-DAPT score ≥ 25) (Recommendation IIa B) [13]. What is probably more interesting, however, is the evidence gathered recently on patients at low-to-intermediate ischemic risk and low bleeding risk. The previously described TWILIGHT and SMART-CHOICE trials included a high proportion of patients presenting with ACS (64.8% and 58.2%, respectively), with the benefits of antiplatelet monotherapy Clinical [23] Previous myocardial infarction

Diabetes mellitus
Chronic kidney disease (creatinine clearance <60 mL/min) Previous stent thrombosis Current smoker
High risk features associated with thrombotic events. Adapted from [3].
being consistent between subgroups. On the other hand, the SMART-DATE trial [40] specifically assessed 6 versus 12-month DAPT in patients with ACS. Although mortality, stroke and BARC type 2-5 bleeding did not differ between the two groups, the rate of myocardial infarction was higher in the short DAPT group. Combining the information of these three trials, the ESC guidelines suggest a 3 to 6-month DAPT therapy depending on the balance of ischemic and hemorrhagic risk in a Class IIa, level A recommendation. The recent TICO trial evaluated another aspirin-free strategy, specifically among patients undergoing PCI for an ACS [41]. Ticagrelor monotherapy after 3 months of DAPT resulted in a slight, significant reduction of the composite outcome of major bleeding and cardiovascular events at one year, compared with a ticagrelor-based 12-month DAPT.

Evidence of shortened DAPT duration in patients after PCI requiring lifelong oral anticoagulation
The landscape of evidence for the treatment of patients requiring lifelong oral anticoagulation after PCI has expanded notably in the last years, the main landmarks being (1) the ISAR-TRIPLE trial, where no significant difference was found in the primary endpoint of "net clinical benefit" (which included ischemic and bleeding outcomes) between 6 weeks and six months of triple therapy; [42] (2) the WOEST trial, where a dual pathway strategy (warfarin and clopidogrel) versus standard triple therapy (warfarin, clopidogrel and ASA) reduced bleeding while not increasing thrombotic events; [43] and (3)   [dabigatran/RE-DUAL PCI [44]; rivaroxaban/PIONEER AF-PCI [45]; apixaban/ AUGUSTUS [46]; edoxaban/ENTRUST-AF PCI [47]. The new 2020 ESC ESC/ EACTS guidelines for the management of atrial fibrillation is the latest consensus document on the subject, and the only one after the publication of the four DOAC trials for AF patients undergoing PCI [8].
As a whole, these trials evaluated dual (DOAC + P2Y 12 ) vs. triple (VKA + P2Y 12 + aspirin) therapy. They included a notable proportion of ACS (37-52%), although the highest risk patients were underrepresented (i.e., culprit lesions in a previously stented segment). Moreover, they all used triple therapy during PCI until randomization (1-14 days post PCI) and the most commonly P2Y 12 inhibitor used was clopidogrel, as neither prasugrel or ticagrelor have evidence supporting their safety in combination with an OAC. As per outcomes, they reported a significant reduction of major/clinically significant bleeding, comparable rates of ischemic stroke, similar or non-significantly higher rates of myocardial infarction and stent thrombosis and a neutral effect on major adverse cardiac events and all-cause mortality [48]. Also, it is worth emphasizing that the AUGUSTUS trial is the only one that studied whether the advantages of dual pathway (vs. triple therapy) is independent of the type of OAC.
The ESC guidelines include four recommendations, according to the clinical presentation and the ischemic/bleeding risk balance ( Table 3). Due to the under-representation of high ischemic risk patients on the trials, the recommendations for this population have a weak level of evidence. The evaluation of the ischemic risk is based on the presence of variables known to pose higher risk in the general population (also previously described in Table 2). Regarding the bleeding risk, evaluation with the AF-specific HAS-BLED risk score is recommended. This bleeding risk score has proven to be more useful at predicting bleeding risk in AF patients [49].

Beyond guidelines: tailored shortened DAPT durations according to stent platforms
Current guidelines include DAPT length recommendations irrespective of the DES type, encompassing the evidence of the multiple platforms in various trials. It is worth mentioning, however, some recent trials in which specific platforms have been tested in two main scenarios: one stent tested at short vs. longer DAPT durations; and two different stents compared in a short DAPT duration for patients not deemed amenable for prolonged DAPT duration. While acknowledging the limited value of a single trial, they may still be useful for tailored antiplatelet regimens. Table 4 summarizes the current knowledge of some specific DES platforms in these two scenarios.

Conclusions
As new antiplatelet and anticoagulant drugs have entered the therapeutic arsenal, and as stent platforms continue to be refined through the years, established dogmas of the treatment of patients with ischemic heart disease should be reassessed. Most notably, current evidence strongly supports that for a considerable number of patients, shorter antithrombotic, aspirin-free treatment is associated not only with fewer bleeding complications, but with comparable rates of hard ischemic endpoints. Hence, a paradigm shift is underway, in which the concern should not be to find reasons to reduce the classical 12 months of DAPT. Rather, patients should be evaluated for causes not to receive an abbreviated aspirin-free antithrombotic  regimen. In order to provide the most accurate treatment regimens, a careful evaluation should be made by taking into account the clinical presentation, coexisting conditions that are prone to a higher ischemic or bleeding risk and awareness of the stent platform used.

Author details
Marcel Santaló-Corcoy, Guillaume Marquis-Gravel and Jean-François Tanguay* Montreal Heart Institute, Université de Montréal, Montréal, Canada *Address all correspondence to: jean-francois.tanguay@icm-mhi.org © 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.