Dual antiplatelet therapy for the general cardiologist: recent evidence, balancing ischaemic and bleeding risk

Keywords

aspirin, bleeding, dual antiplatelet therapy, P2Y₁₂ inhibitor, thrombosis

Take-home messages

• The net benefit of dual antiplatelet therapy depends on the balance between the individual risks of thrombosis and bleeding
• Current European guidelines recommend for most patients undergoing PCI with DES implantation a period of DAPT of six months with aspirin and clopidogrel if the index clinical presentation is a chronic coronary syndrome and 12 months with aspirin and ticagrelor or prasugrel if an acute coronary syndrome (ACS)
• Advances in DES technology and PCI optimisation have substantially reduced the risk of target lesion failure and several recent randomised trials have shown that 1-3 months of DAPT can be sufficient
• In the setting of ACS, DAPT de-escalation is a viable alternative to short DAPT duration
• There is still uncertainty about the preferred antithrombotic monotherapy after DAPT, with recent data indicating a possible advantage of using a P2Y₁₂ inhibitor over the traditional therapy with aspirin
• Patients with high thrombotic risk may benefit from prolonged DAPT and potent P2Y₁₂ inhibitors

Dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stents

Dual antiplatelet therapy (DAPT), consisting of the combination of aspirin and an oral inhibitor of the platelet P2Y₁₂ receptor for adenosine 5’-diphosphate (ADP), is the mainstay treatment following percutaneous coronary intervention (PCI) with drug-eluting stents (DES) to prevent thrombotic events, particularly those that may occur at the site of the target lesion [1,2]. Over the past three decades, several investigations have tested new antithrombotic strategies that have progressively shaped and prompted revisions in clinical practice [1-5].

In the period following the introduction of DAPT following PCI, the limited amount of evidence along with the concerns arising from the experience with early-generation DES draw attention to the feared complication of stent thrombosis. As the field progressed with the development of highly biocompatible DES and the employment of intravascular imaging guidance and stenting optimisation techniques, a growing recognition emerged regarding the prognostic significance of bleeding events during DAPT [1-8]. Major or life-threatening bleeding events were detrimental to patient outcomes, underscoring the crucial interplay between ischaemic and haemorrhagic risks in determining the net effect of DAPT [1-8]. In recent years, an equipoise between the pursuit of more potent antithrombotic protection and a more favourable safety profile has been reached [1-8].

Against this background, novel antithrombotic strategies have been developed, aiming to achieve a balance between the individual risks of thrombosis and bleeding through the modulation of DAPT duration (short or prolonged treatment) and composition (clopidogrel or a potent P2Y₁₂ inhibitor) [1-8]. Associated therapeutic options involve the type of antiplatelet monotherapy following DAPT discontinuation (aspirin or a P2Y₁₂ inhibitor) and dual pathway inhibition (antiplatelet agents combined with low-dose oral anticoagulation) [1-8].

Ischaemic risk

The clinical presentation is a critical factor to consider in the assessment of the individual ischaemic risk profile. In addition to the pattern of coronary artery disease and the complexity of percutaneous coronary intervention, acute coronary syndrome (ACS) inherently has a higher ischaemic risk compared to chronic coronary syndrome [1].

Over the past four decades, endovascular devices and interventional techniques have undergone an extraordinary evolution, enabling the treatment of increasingly complex patterns of coronary artery disease as well as challenging patient populations [9]. Clinical and angiographic characteristics associated with a higher risk of thrombotic events need to be considered when evaluating the type and duration of antiplatelet therapy [9]. These considerations refer not only to DAPT following PCI but also to chronic maintenance antiplatelet therapy in the long-term period [9]. The thrombotic risk stratification aids in identifying patients who would benefit from intensified antithrombotic treatment following standard DAPT duration (Table 1).

Table 1. Higher thrombotic risk conditions.

• Clinical characteristics: elder age, diabetes mellitus, current smoking, moderate-to-severe chronic kidney disease, previous myocardial infarction or stent thrombosis, multivascular atherosclerotic disease, etc.
• Procedural characteristics: implantation of three or more stents, treatment of three or more lesions, multivessel coronary artery disease, stenting of the last remaining patent coronary artery, treatment of the left main coronary artery, treatment of bifurcation disease with two stents, treatment of chronic total occlusion, stented length >60 mm, and mainly suboptimal results of PCI (stent malapposition, stent underexpansion, residual dissection, etc.).

Bleeding risk

The considerable drawback of DAPT, in terms of bleeding, is particularly influential in high-bleeding risk (HBR) patients, as this subset of patients not only encounters a higher frequency of bleeding events but also exhibits a notable prevalence of complex coronary artery disease [10,11].

A number of risk models have been developed to identify the patients with a higher likelihood of experiencing thrombotic and bleeding events at long-term follow-up. The PRECISE-DAPT score is a 5-item (age, creatinine clearance, haemoglobin, white-blood-cell count, and previous spontaneous bleeding) bleeding risk prediction, developed to predict the risk of out-of-hospital bleeding within one year following PCI [11]. In contrast, the DAPT score predicts the risk-benefit ratio of extending DAPT beyond 12 months after PCI in patients without indications for oral anticoagulation and prior major bleeding on DAPT [12]. Although employment of these tools is considered by guidelines, the class of recommendation is low [1,9].

The current standpoint emphasises that customisation of DAPT following PCI relies on the comprehensive assessment of patients with a weighing of those conditions that increase the risk of ischaemic and bleeding events [1,9,10]. Recently, the Academic Research Consortium for High Bleeding Risk (ARC-HBR) introduced standardised definitions for HBR in patients undergoing PCI, based on clinical consensus and a review of the existing literature [10]. According to this semi-quantitative scoring system, HBR is defined as a BARC 3 or 5 bleeding risk of at least 4% at one year or an intracranial haemorrhage risk of at least 1% at one year [10]. The ARC-HBR includes 20 clinical criteria (14 major, 6 minor) that incorporate the risk factors for HBR based on various risk prediction models [10]. Accordingly, patients are considered at HBR if they meet at least one major or two minor criteria (Table 2) [10].

Table 2. Major and minor criteria of HBR.

PCI: percutaneous coronary intervention

Potent P2Y₁₂ inhibiting therapy

Regardless of the performance of revascularisation (PCI or coronary artery bypass grafting), the primary strategy to reduce the occurrence of ischaemic events among patients with ACS is to use DAPT with potent P2Y₁₂ inhibitors (ticagrelor or prasugrel) rather than clopidogrel [1]. To this extent, prasugrel and ticagrelor are superior to clopidogrel in patients with ACS [1].

Ticagrelor, an oral cyclopentyl triazolopyrimidine, is a reversibly binding oral P2Y₁₂ receptor antagonist [13]. Ticagrelor is an active drug that produces a potent and predictable platelet inhibition over clopidogrel [13]. The PLATO trial enrolled 18,624 patients with ACS with or without ST-segment elevation to either ticagrelor or clopidogrel [13]. At 12 months, ticagrelor significantly reduced the incidence of a composite of cardiovascular death, myocardial infarction, or stroke compared with clopidogrel (9.8% vs. 11.7; hazard ratio [HR] 0.84, 95% confidence interval [CI]: 0.77-0.92; p<0.001) but was associated with a higher rate of major bleeding unrelated to coronary artery bypass grafting (4.5% vs. 3.8%; HR 1.19, 95% CI: 1.02-1.38; p=0.03) [13].

Prasugrel is an oral thienopyridine, like clopidogrel, but its biotransformation into the active metabolite is substantially more efficient [14]. Therefore, prasugrel produces a more potent and predictable degree of platelet inhibition than clopidogrel [14]. The TRITON–TIMI 38 trial enrolled 13,608 patients with moderate- or high-risk ACS undergoing treatment with PCI randomly assigned to prasugrel or clopidogrel [14]. Prasugrel significantly reduced the incidence of cardiovascular death, myocardial infarction, or stroke compared to clopidogrel (9.9% vs 12.1%; HR 0.81, 95% CI: 0.73 0.90; p<0.001) but was associated with a significant increase in the bleeding events (2.4% vs 1.8%; HR 1.32, 95% CI: 1.03-1.68; p=0.03) [14].

In patients taking an oral anticoagulant, the use of clopidogrel seems to be preferred over ticagrelor or prasugrel, especially in the presence of HBR conditions, for the increased occurrence of bleeding associated with a potent P2Y₁₂-based triple antithrombotic therapy [1].

In the context of a paucity of head-to-head comparisons between potent P2Y₁₂ inhibitors, the ISAR-REACT 5 trial has recently indicated that, in the absence of major contraindications, prasugrel should be preferred over ticagrelor due to a significant reduction in major adverse cardiovascular events (6.9% vs 9.3%; HR 0.74, 95% CI: 0.59-0.91; p=0.006) without an increase in major bleeding (4.8% vs 5.4%; HR 0.89, 95% CI: 0.66-1.20; p=0.46) [15].

Studies have compared clopidogrel against potent P2Y₁₂ inhibitors but failed to demonstrate a clear net clinical benefit mainly due to an increase in bleeding complications [1,9]. For this reason, clopidogrel remains the preferred P2Y₁₂ inhibitor in combination with aspirin for elective PCI with a suggested DAPT duration of six months [1,9]. However, non-complex PCI associated with a reasonable ischaemic risk profile and the absence of substantial residual coronary artery disease can safely be handled with shorter DAPT durations. Similarly, in the presence of HBR conditions, shorter DAPT duration may be considered [1,9].

Dual antiplatelet therapy duration

Current European guidelines recommend for most patients undergoing PCI with DES implantation ‒ in the absence of high bleeding risk (HBR), indications for oral anticoagulation, or ischaemic risk exceeding the individual propensity to bleed ‒ a period of DAPT of six months with aspirin and clopidogrel if the index clinical presentation is a chronic coronary syndrome and 12 months with aspirin and a potent P2Y₁₂ inhibitor (i.e., ticagrelor or prasugrel) if an acute coronary syndrome (ACS) [1,9].

The rationale for a short DAPT duration derives from the consideration that the highest risk of stent thrombosis manifests within the initial 30 days following PCI, while the bleeding risk associated with DAPT remains relatively constant throughout the duration of the treatment [1,3]. The development of highly biocompatible DES, along with the employment of stenting optimisation techniques and intravascular imaging because of a deeper understanding of the major mechanisms leading to target lesion failure, have provided the conditions for shortening DAPT [1,9]. Multiple recent trials comparing different DAPT duration have generally not shown an excess of ischaemic events with shorter DAPT (Table 3) [3-5]. In all the trials with non-inferiority design, the primary endpoint was met except for the STOPDAPT-2 ACS, and in almost all the available trials, the individual key ischaemic outcomes were not significantly different between DAPT durations [3-5,16]. In some trials, prolonged DAPT was associated with a higher occurrence of clinically relevant non-major or major bleeding. Notably, the TWILIGHT trial showed in 7,119 patients the superiority of three months of DAPT compared with 15 months of DAPT in terms of clinically relevant non-major or major bleeding [17].

Table 3. Studies investigating short DAPT durations.

BARC: Bleeding Academic Research Consortium; DAPT: dual antiplatelet therapy; TIMI: Thrombolysis in Myocardial Infarction

*1161 patients from the STOPDAPT-2 trial.

** 3 months in patients with indications for oral anticoagulation.

Despite this substantial body of evidence, several factors continue to influence current guidelines. Firstly, there is a lack of randomised trials with sufficient statistical power to evaluate the rare individual endpoints of stent thrombosis and major bleeding [4-6]. Secondly, a reduction in major bleeding associated with short DAPT was inconsistently observed across trials and, in the trials indicating a significant reduction in major bleeding, there was no improvement in survival [4-6]. Thirdly, a few trials (SMART-DATE and STOPDAPT-2 ACS) have shown an excess of myocardial infarction in patients assigned to short DAPT [16,18]. Although the explanation remains unclear, these results raised concerns. Fourthly, significant heterogeneity exists in the antithrombotic strategies employed in terms of DAPT duration and composition as well as in the type of antiplatelet monotherapy following DAPT discontinuation [3-5]. Finally, the available evidence is dispersed among various target populations and based on outcomes assessed according to different definitions [3-5].

Based on studies that validated the ARC-HBR bleeding risk criteria, significant proportions of patients undergoing PCI present with HBR [19]. This group of patients gains a lower net benefit from prolonged DAPT durations as indicated in the recent MASTER-DAPT trial, in which HBR patients were randomly assigned, one month after PCI, to a biodegradable-polymer sirolimus-eluting stent, to DAPT discontinuation (i.e., one month of DAPT) or DAPT continuation for two to five additional months, depending on the need for oral anticoagulation [20]. At one year, the three ranked hypotheses were all met since abbreviated DAPT was non-inferior to standard DAPT with respect to a net composite endpoint (7.5% vs 7.7%; HR 0.97, 95% CI: 0.78-1.20; p_{noninferiority}<0.001) as well as a composite endpoint of major adverse cardiac or cerebral events (6.1% vs 5.9%; HR 1.02, 95% CI: 0.80-1.30; p_{noninferiority}<0.001), and superior with respect to clinically relevant non-major or major bleeding (6.4% vs 9.2%; HR 0.68, 95% CI: 0.55-0.85; p<0.001) [20].

In contrast to the patients with predominant HBR, patients with chronic high ischaemic risk conditions (e.g., diabetes, chronic kidney disease, etc.), recurrent myocardial infarction, repeat myocardial revascularisation (e.g., multiple PCI following coronary artery bypass graft failure), and evidence of significant extracardiac vascular disease (e.g., cerebrovascular accident, carotid artery disease requiring intervention, peripheral artery disease requiring intervention, aortic disease, etc.) may benefit from extended DAPT, especially those without significant HBR and good tolerance to DAPT during treatment (Table 4) [1,6,9]. The DAPT trial was the first study designed to specially assess the safety and efficacy of prolonged DAPT [21]. A total of 9,961 patients were enrolled after PCI with DES and randomised to placebo (DAPT discontinuation) or DAPT prolongation after completion without events of 12 months of DAPT [21]. Prolonging DAPT, compared with placebo, reduced the rates of stent thrombosis (0.4% vs 1.4%; HR 0.29, 95% CI: 0.17-0.48; p<0.001) and major adverse cardiovascular events (4.3% vs 5.9%; HR 0.71, 95% CI: 0.59-0.85; p<0.001), but GUSTO moderate or severe bleeding was increased (2.5% vs 1.6%; p=0.001) [21]. However, except for the DAPT trial, smaller available trials testing prolonged DAPT after PCI did not show consistent improvements [3,5].

Table 4. Selected studies focused on minimizing the risk of thrombosis.

ACS: acute coronary syndrome; CI: confidence interval; DAPT: dual antiplatelet therapy; HR: hazard ratio; PCI: percutaneous coronary intervention

Some alternative long-term strategies have been tested with favourable results [22]. In the PEGASUS-TIMI 54 trial, 21,162 patients with prior myocardial infarction who completed 12 months of DAPT were randomised to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo on a background of aspirin for a median of 33 months [22]. Prolonging DAPT with ticagrelor, compared to placebo, significantly reduced the incidence of the primary endpoint (ticagrelor 90 mg vs placebo, HR 0.85, 95% CI: 0.75-0.96; p=0.008 and ticagrelor 60 mg vs placebo, HR 0.84, 95% CI: 0.74 to 0.95; p=0.004) [22]. The rates of major bleeding were higher with ticagrelor than with placebo (90 mg, 2.60%; 60 mg, 2.30%; placebo, 1.06%; p<0.001 for each dose vs placebo) [22].

The THEMIS trial was a placebo-controlled, randomised trial evaluating the role of ticagrelor in preventing ischaemic events in patients with stable CAD and diabetes with or without previous PCI [23]. A total of 11,154 patients aged 50 years or older, with type 2 diabetes with stable CAD, and one of three other mutually non-exclusive criteria (history of previous PCI, history of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery) were randomised to ticagrelor plus aspirin or placebo plus aspirin [23]. At a median of 3.3 years, ticagrelor reduced the incidence of a composite of cardiovascular death, myocardial infarction, or stroke compared with placebo (7.3% vs. 8.6%; HR 0.85, 95% CI: 0.74-0.97; p=0.013) but increased the rate of major bleeding (2.0% vs. 1.1%; HR 2.03, 95% CI: 1.48-2.76; p< 0.0001) [23]. The benefit was present regardless of time from the most recent PCI [23].

Dual antiplatelet therapy followed by aspirin or P2Y₁₂ receptor inhibitor monotherapy

Aspirin has been used for decades as an antiplatelet monotherapy during chronic maintenance in patients who undergo coronary stenting [24]. However, the status quo has been challenged recently in the HOST-EXAM trial (Table 4), in which 5,530 patients receiving DAPT for 6-18 months after PCI with DES without clinical events were randomly assigned to aspirin or clopidogrel for an additional 24 months [24]. At 24 months, clopidogrel monotherapy reduced the incidence of death, myocardial infarction, stroke, readmission for ACS, and BARC 3-5 bleeding compared to aspirin monotherapy (5.7% vs 7.7%; HR 0.73, 95% CI: 0.59-0.90; p=0.0035) as a result of a reduction in both major adverse cardiovascular events (3.7% vs 5.5%; p=0.003) and BARC major bleeding (1.2% vs 2.0%; p=0.035) [24].

However, there is a paucity of evidence on the comparison between aspirin and P2Y₁₂ in the period following PCI [4]. In recent years, several trials compared one to three months of DAPT followed by a P2Y₁₂  inhibitor with 12-15 months of DAPT [4]. In a meta-analysis of these trials including 32,145 patients, major bleeding was significantly lower in the patients assigned to short DAPT followed by P2Y₁₂ inhibitor monotherapy compared with those assigned to 12-month DAPT, while no significant differences between groups were observed in terms of stent thrombosis, death, myocardial infarction, and stroke [4]. However, after adding the group of trials comparing ≤3 months of DAPT followed by aspirin monotherapy with 12 months of DAPT, for each endpoint, there was no treatment-by-subgroup interaction with the group of trials comparing ≤3 months of DAPT followed by P2Y₁₂ monotherapy with 12 months of DAPT [4].

Dual antiplatelet therapy switch

DAPT de-escalation involves switching from a more potent P2Y₁₂ inhibitor (i.e., ticagrelor or prasugrel) to a less potent P2Y₁₂ inhibitor (i.e., clopidogrel) to ensure more potent platelet inhibition in the initial period following PCI, when the thrombotic risk is higher and stents are not adequately endothelialised, and minimise the risk of bleeding in the subsequent months, when the need for potent platelet inhibition decreases [3]. Among the trials supporting DAPT de-escalation, TROPICAL-ACS demonstrated that DAPT de-escalation is non-inferior to prasugrel-based DAPT in terms of cardiovascular death, myocardial infarction, stroke, or BARC 2-5 (7% vs 9%; HR 0.81, 95% CI: 0.62-1.06; p_{noninferiority}=0.0004, p_superiority=0.12) [25].

Conversely, DAPT escalation can be defined as the switch from a less potent P2Y12 inhibitor (i.e., clopidogrel) to a more potent P2Y₁₂ inhibitor (i.e., ticagrelor or prasugrel). This therapeutic decision is generally based on the observation of a coronary thrombotic event during DAPT with clopidogrel or the detection of resistance to clopidogrel [3].

Different tools can guide the selection of patients in which an escalation or de-escalation can be of clinical benefit. In particular, the use of platelet function tests can detect patients with high on-treatment platelet reactivity and cytochrome P450 2C19 genotyping can identify those with loss-of-function alleles that carry an increased risk of ischaemic events when treated with clopidogrel. Several studies have assessed the role of guided escalation or de-escalation using platelet function tests or genotyping with mixed results [3]. A meta-analysis of randomised trials and observational studies suggested that guided escalation may be associated with a significant reduction in ischaemic events without any trade-off in safety [6].

Dual pathway inhibition

Dual pathway inhibition involves the simultaneous blockade of two pathways of thrombus formation to gain synergistic benefits, thus it differs from DAPT due to the combination of an anticoagulant, usually a direct factor Xa inhibitor, with a single antiplatelet agent (Table 4) [22,26].

In ACS patients, dual pathway inhibition was tested in the ATLAS ACS 2-TIMI 51 trial in which 15,526 patients were randomised to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo [26]. At a mean of 13 months, as compared with placebo, rivaroxaban significantly reduced a composite of cardiovascular death, myocardial infarction, or stroke (8.9% vs 10.7%; HR 0.84, 95% CI: 0.74-0.96; p=0.008), with significant improvement for both the twice-daily 2.5 mg dose (9.1% vs 10.7%; p=0.02) and the twice-daily 5 mg dose (8.8% vs 10.7%; p=0.03) [26]. However, rivaroxaban was associated with higher rates of major bleeding compared to placebo (2.1% vs 0.6%; p<0.001), including intracranial haemorrhage (0.6% vs 0.2%; p=0.009), without a significant increase in fatal bleeding [26]. The 2.5 mg twice-daily dose resulted in fewer fatal bleeding events than the 5 mg twice-daily dose (0.1% vs 0.4%; p=0.04) [26].

In stable coronary artery disease, dual pathway inhibition was tested in the COMPASS trial, in which a total of 27,395 patients were randomised to rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or placebo plus aspirin 100 mg once daily [22]. At a mean of 23 months, the incidence of a composite of cardiovascular death, myocardial infarction, or stroke was lower in the rivaroxaban plus-aspirin group than in the aspirin-alone group (4.1% vs 5.4%; HR 0.76, 95% CI: 0.66-0.86; p<0.001), but there were more major bleeding events in the rivaroxaban-plus-aspirin group (3.1% vs 1.9%; HR 1.70, 95% CI: 1.40-2.05; p<0.001) [22]. The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group [22].

Conclusions

DAPT and antithrombotic strategies are a crucial component in the management of patients with coronary artery disease undergoing PCI, as they help to prevent both local and systemic ischaemic thrombotic complications. Over the past three decades, several antithrombotic strategies involving aspirin and P2Y₁₂ inhibitors have been developed and implemented in clinical practice with different objectives and results. The current standpoint is that the highest benefit from available strategies is achieved after accounting for the individual trade-off between thrombotic prevention and bleeding occurrence. Tailoring the intensity and duration of aspirin and P2Y₁₂ inhibiting therapy to reduce the risk of ischaemic complications while minimising the risk of bleeding is crucial. Effective strategies to mitigate the risk of bleeding include shortening the duration of DAPT, with early aspirin or P2Y₁₂ inhibitor monotherapy, and DAPT de-escalation. In patients at increased ischaemic risk and without HBR, prolonging intensified antithrombotic therapy either by means of DAPT or dual pathway inhibition may be effective at the cost of a higher likelihood of bleeding events.