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

*Marcel Santaló-Corcoy, Guillaume Marquis-Gravel and Jean-François Tanguay*

## **Abstract**

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 uncertainties, 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.

**Keywords:** percutaneous coronary intervention, stents, acute coronary syndrome, high bleeding risk, duration of antiplatelet therapy

#### **1. 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,

PCI in the setting of acute coronary syndromes (ACS), and PCI for patients with a coexisting indication of oral anticoagulation (OAC). For each of them we will highlight the standard recommendations for DAPT duration, as well as the main clinical, angiographic and stent-derived variables that should be used in the decision-making process to tailor a shortened DAPT therapy reflecting each patient need.

### **2. Latest guidelines on the topic**

This document will include the latest recommendations of Canadian, American and European guidelines. Canadian scientific societies published two documents in 2018 addressing antithrombotic treatment: The Canadian Cardiovascular Society (CCS)/Canadian Association of Interventional Cardiology focused update for the use of antiplatelet therapy [2] and the CCS focused update for the management of atrial fibrillation [3]. The American College of Cardiology/American Heart Association (ACC/AHA) published a focused update on the duration of DAPT in patients with coronary artery disease (CAD) in 2016, [4] while a recent AHA/ ACC/Heart Rhythm Society (HRS) focused update in the management of patients with atrial fibrillation was published in 2019 [5]. Lastly, the European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) published a focused update on DAPT in 2017 [6]. However, the most recent 2020 ESC guidelines for management of ACS in patients presenting without persistent ST-segment elevation [7] and 2020 ESC/EACTS guidelines for the management of atrial fibrillation [8] will also be reviewed. A dedicated, critical comparison of the available guidelines on DAPT was published previously this year [9].

#### **3. 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 P2Y12 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

*Dual Antiplatelet Therapy after PCI: When Could We Go Shorter? DOI: http://dx.doi.org/10.5772/intechopen.96328*

(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 [14–16].

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**.

## **4. 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, [18–22] 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**) [24–26].

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,


**Table 1.**

*Standard and shortened DAPT duration according to different guidelines. Adapted and updated from [9].*

**6**


#### **Table 2.**

*High risk features associated with thrombotic events. Adapted from [3].*

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].
