Complexity of Antiplatelet Therapy in Coronary Artery Disease Patients

Pierre Sabouret; Michael P. Savage; David Fischman; Francesco Costa

Disclosures

Am J Cardiovasc Drugs. 2021;21(1):21-34. 

In This Article

Abstract and Introduction

Abstract

Patients with coronary artery disease (CAD) presenting with acute coronary syndrome or undergoing coronary stenting are indicated to treatment with dual antiplatelet therapy (DAPT) combining aspirin with a P2Y12 receptor inhibitor. The management of patients with CAD who present with a complex clinical profile due to multiple comorbidities, and/or undergoing complex interventional procedures, remains challenging as a high risk for both ischemic and bleeding events is often present; hence, the risk–benefit balance on the optimal DAPT duration is difficult to evaluate. The complexity of antiplatelet therapy in CAD patients is due to the fact that this complexity embraces several aspects: the coronary anatomy, the number of vascular districts at risk for atherothrombosis, and patient comorbidities, including global frailty. Recent randomized and epidemiological studies have highlighted subgroups that could benefit from prolonged antithrombotic treatment, as well as frail patients, who may be better suited to a shorter course of therapy. We provide an overview of the current knowledge regarding treatment with DAPT, along with suggestions on its management.

Introduction

Recent clinical guidelines offer a wide range of options for antiplatelet agents and duration of treatment across several categories of patients.[1–5] Aspirin, in combination with an oral P2Y12 receptor inhibitor (i.e. clopidogrel, prasugrel, or ticagrelor), remains the cornerstone of treatment for patients with coronary artery disease (CAD). This dual antiplatelet therapy (DAPT) is still indicated for secondary coronary prevention after either an acute coronary syndrome (ACS) or a planned percutaneous coronary intervention (PCI).[6] These antiplatelet agents have various mechanisms of action (Table 1 and Figure 1). Clopidogrel, which was the first-in-class, was evaluated in randomized clinical trials (RCT) more than 25 years ago and remains recommended in patients undergoing elective PCI for chronic CAD, whereas in ACS, more potent P2Y12 inhibitors, such as ticagrelor and prasugrel, are preferred, unless specific contraindications exist. Indeed, two large RCTs have reported that ticagrelor and prasugrel are both more effective than clopidogrel in reducing major ischemic events in patients with ACS undergoing PCI.[7,8] However, ticagrelor has a wider spectrum of indications than prasugrel due to the inclusion criteria of the PLATO study, including ACS patients who were medically managed and those who were pretreated with clopidogrel.[1,2]

Figure 1.

Mechanism of action of antithrombotic agents. 5HT 5-hydroxytryptamine, ADP adenosine diphosphate, ATP adenosine triphosphate, GP glycoprotein, GPVI glycoprotein VI, PAR protease-activated receptor, TP thromboxane, TRA thrombin antagonist receptor

The use of P2Y12 inhibitors is supported by high-level evidence, but the optimal duration of DAPT is still debated.[1,2,4,9,10] A DAPT duration of 12 months is generally recommended in patients with ACS, while 6 months is the current recommended duration after elective PCI. The optimal duration is changing due to recent data that support a shorter duration of DAPT, from 12 months to 6 or 3 months, or even 1 month, after PCI, especially in frail patients with a high bleeding risk, in case of persistent nuisance bleedings or if a major bleed occurs, or when a surgical procedure is urgently required.[11–17]

Other data support prolonged DAPT beyond 1 year in several RCTs to reduce recurrent ischemic events in CAD patients, with the challenge of evaluation of the net clinical benefit, defined as the rate of major ischemic events (myocardial infarction [MI], ischemic stroke, cardiovascular death) prevented by antithrombotic agent(s) minus major bleeding attributable to an antithrombotic strategy.[18,19]

More recently, the TWILIGHT study is advocating for a DAPT duration of 3 months, followed by monotherapy with a potent P2Y12 inhibitor. Clinicians now have multiple options that promote a personalized approach to DAPT duration.[20–24] This review discusses the latest evidence evaluating the risk–benefit balance of a long versus short DAPT regimen, and the potential benefits of a personalized strategy in patients with complex clinical conditions, focusing on specific patient subgroups. We also report on ongoing trials focusing on interventional strategies to optimize the long-term management of coronary patients.

Why is the Optimal Antiplatelet Therapy so Complex to Define?

Despite life expectancy increasing in recent decades, cardiovascular diseases remain, with cancers being the leading cause of death and adverse events.[25] Advances in primary cardiovascular prevention have delayed the occurrence of the first cardiovascular event, and progress in secondary prevention has improved survival in cases of recurrent events. Therefore, cardiovascular events tend to occur in older and frail patients with multiple comorbidities, and careful evaluation of the risk–benefit balance becomes crucial to optimize the benefit of antithrombotic treatments in this more complex population. An antithrombotic treatment strategy is mainly based on the clinical setting (e.g. ACS or stable CAD),[26] number of vascular districts at risk of atherothrombosis,[27] coronary anatomy and PCI complexity,[28–30] clinical evolution under DAPT (e.g. major or nuisance bleeding or recurrent ischemic events), and evaluation of global frailty (comorbidities such as severe chronic kidney disease [CKD], history of major bleeding, age, anemia).[1,2] All these cited factors are key to personalizing the DAPT duration.

Evidence in Support of Extended Dual Antiplatelet Therapy in Coronary Patients

The CHARISMA trial was the first to explore the effect of prolonged DAPT in patients in secondary or primary prevention with multiple cardiovascular risk factors (Table 2).[31] Overall, 15,603 patients were randomized to receive either clopidogrel plus low-dose aspirin, or placebo plus low-dose aspirin, for a median follow-up of 28 months. No benefit of DAPT was observed for either the primary composite endpoint [MI, stroke of any cause, or death from any cause, including hemorrhage—6.8% in the clopidogrel and aspirin arm vs. 7.3% in the placebo plus aspirin arm; relative risk (RR) 0.93, 95% confidence interval (CI) 0.83–1.05; p = 0.22] or the main secondary efficacy endpoint (Figure 2a). The rates for the safety endpoint of severe bleeding were 1.7% and 1.3%, respectively (RR 1.25, 95% CI 0.97–1.61; p = 0.09). In the subgroup of patients with atherosclerotic cardiovascular disease (ASCVD), clopidogrel was associated with a reduction in major adverse cardiac events (MACEs; RR 0.88, 95% CI 0.77–0.998; p = 0.046), but was only a generated hypothesis of potential benefit with prolonged DAPT in secondary prevention.

Figure 2.

Randomized clinical trials with prolonged antiplatelet therapy in coronary patients. a CHARISMA trial [82]: cardiovascular death, myocardial infarction, or stroke in patients with previous myocardial infarction; b DAPT trial [32]: MACCE in patients with previous stenting; c TRILOGY ACS trial [68]: cardiovascular death, myocardial infarction, or stroke in patients < 75 years of age; and d TRA 2P-TIMI 50 [83]: cardiovascular death, myocardial infarction or stroke. CI confidence interval, HR hazard ratio, MACCE major adverse cardiac and cerebrovascular event

The DAPT study[32] was another major RCT that tested the potential ischemic benefits of prolonged treatment with P2Y12 inhibitors for 30 versus 12 months in combination with aspirin in coronary patients treated with PCI. In that study, the ischemic benefits (reduction of stent thrombosis and MI) (Figure 2b) were unfortunately counterbalanced by an excess of major bleedings and an increase in non-cardiovascular mortality, which were the subject of many controversial debates, without definitive explanation. Most of the ischemic benefits were observed for patients with an MI at inclusion, suggesting that prolonged DAPT was mainly beneficial for very high-risk ischemic patients with a history of atherothrombotic events.

In the other major RCT, the PEGASUS-TIMI 54 trial,[33] 21,162 patients with a previous MI 1–3 years before inclusion, as well as associated risk factors (i.e. diabetic patients, peripheral artery disease, or diffuse CAD), were randomly assigned to either ticagrelor 90 or 60 mg twice daily, or placebo in addition to an aspirin regimen. After a median treatment duration of 33 months, prolonged DAPT with ticagrelor provided a significant reduction in the composite ischemic endpoint compared with placebo, but a significant increase in TIMI major bleeding, with no life-threatening bleeding. There was no heterogeneity among the prespecified subgroups. The absolute risk reduction (ARR) in ischemic events was almost similar to the absolute increase of major bleeding, which makes the application difficult in daily practice. Ticagrelor causes symptoms of shortness of breath and some chest discomfort, which are usually not a major problem but may add complexity for physicians.

Despite these limitations, these RCT have been integrated in the last American and European guidelines, to help clinicians in their decision making.[9,34,35]

Antiplatelet Therapy in Patients With Chronic Kidney Disease

Approximately 30–40% of ACS patients have renal dysfunction, which is a validated marker of worse prognosis.[36] The management of antiplatelet therapy in CKD patients is especially challenging due to the presence of uremic solutes in terminal CKD stage, which is associated with a higher thrombotic milieu, while longer drug elimination times and polypharmacotherapy increase the risk of major bleeding.

The risk–benefit balance of antiplatelet therapy in CKD patients is uncertain and was analyzed in specific subgroup analyses of the TRITON-TIMI 38[7] and PLATO[37] trials. TRITON-TIMI 38[7] compared prasugrel 10 mg with clopidogrel 75 mg in ACS patients who had undergone PCI; prasugrel was more potent and efficient than clopidogrel across various prespecified subgroups, including those with moderate renal dysfunction, with no significant interaction between patient characteristics and treatment group. Regarding the other potent P2Y12 inhibitor, ticagrelor reduced the rate of the primary endpoint (a composite of cardiovascular death, MI, or stroke at 12 months follow-up) versus clopidogrel (hazard ratio [HR] 0.84, 95% CI 0.5–0.94; p = 0.0025) in the PLATO trial.[37] These ischemic benefits remained consistent in the subgroup of 3237 patients with moderate CKD (i.e. creatinine clearance < 60 mL/min), with an HR reduction of 23% for the primary endpoint (HR 0.77, 95% CI 0.65–0.90; P interaction = 0.13). The rates of major bleeding were similar between patients with and without renal dysfunction, reassuring the use of ticagrelor in this setting.

The PEGASUS-TIMI 54 trial demonstrated a slight net clinical ischemic benefit of prolonged DAPT with ticagrelor, including those patients with CKD.[33,38] In this subgroup analysis, in which patients were stratified according to estimated glomerular filtration rate (eGFR), patients with versus those without eGFR < 60 mL/min/1.73 m2 had a higher risk of major ischemic events at 3 years (adjusted HR 1.54, 95% CI 1.27–1.85; p < 0.001). The RR reduction (RRR) with ticagrelor was similar in patients with or without renal dysfunction (Pinteraction = 0.44), but the ARR was higher in those with renal dysfunction (2.7% vs. 0.63%), which was expected as the risk was higher at inclusion. The absolute increase in TIMI major bleeding with ticagrelor was 1.19% in patients with normal eGFR versus 1.43% in patients with eGFR < 60 mL/min/1.73 m2, and also with an increase in minor bleeding (1.93% vs. 0.69%).[38] An exploratory analysis of 24 subgroups from the PEGASUS study reported that younger patients, women, and patients with diabetes or CKD were most likely to benefit from long-term secondary prevention with ticagrelor 90 mg,[39] but the risk–benefits balance seems narrow.

For ACS patients with renal insufficiency (i.e. CKD stage 4 or below, with eGFR ≥ 15 mL/min/1.73 m2),[2] dose adjustment of antiplatelet drugs is therefore not required. However, few data are available for P2Y12 inhibitors in patients with stage 5 CKD (i.e. eGFR < 15 mL/min/1.73 m2),[2] therefore future research is warranted.

Antiplatelet Therapy in Elderly Patients

Elderly patients deserve particular attention because they combine increased bleeding and ischemic risks due to the high prevalence of multiple comorbidities and frequent alterations in renal and/or hepatic metabolism. Furthermore, elderly patients are often underrepresented in clinical trials, which represents a major limit for optimal management in daily practice.

In the CURE trial,[40] the results for DAPT with aspirin and clopidogrel were consistent in many prespecified groups. No statistical heterogeneity was observed for patients < 65 versus ≥ 65 years of age. For patients > 65 years (n = 6208), the primary endpoint was 15.3% with aspirin versus 13.3% with DAPT, confirming the benefits of dual therapy in the 'elderly'. Specific studies are warranted in elderly patients beyond 80 years of age.

The TRITON-TIMI 38 trial[7] demonstrated an increased risk of major bleeding (both fatal and intracranial bleeding) in patients over 75 years of age treated with prasugrel 10 mg. Therefore, the European Medicines Agency do not recommend prasugrel 10 mg in patients aged over 75 years. For elderly patients, a 5-mg daily dose should preferentially be used following a 60-mg starting dose.[41] The US FDA also states that prasugrel is generally not recommended for patients ≥ 75 years of age, except in high-risk patients (with diabetes or previous myocardial infarct), where its effect appears to be greater and its use 'may be considered'.[42] The academic ANTARCTIC trial assessed the effect of platelet function monitoring in elderly patients (≥ 75 years of age) treated with prasugrel 5 mg (n = 877). Adjustment of the antiplatelet regimen in the first arm was guided by the results of the VerifyNow assay, with an option to increase the prasugrel dose to 10 mg or decrease the antiplatelet effects by switching from prasugrel 5 mg to clopidogrel 75 mg, This trial did not show a clinical benefit for the monitoring approach. A prespecified analysis from the PLATO study investigating elderly patients (≥ 75 years of age) versus younger ACS patients was performed.[7] The clinical benefit of ticagrelor over clopidogrel was similar between patients ≥ 75 years (n = 2878) and those < 75 years of age (n = 15,744). Surprisingly, no increase in PLATO-defined overall major bleeding with ticagrelor versus clopidogrel was observed in elderly patients ≥ 75 years of age (HR 1.02, 95% CI 0.82–1.27). Dyspnea and ventricular pauses were more frequent in the ticagrelor arm but without evidence of an age-by-treatment interaction. The significant clinical benefit and overall safety of ticagrelor compared with clopidogrel in the PLATO study seems to not depend on age in this study; however, only 'healthy elderly' patients were included, therefore management of elderly and frail patients remains a major challenge in clinical practice.[43]

In the PEGASUS-TIMI 54 trial,[33] a narrow net clinical benefit was observed with prolonged use of ticagrelor plus aspirin in the prespecified elderly subgroup (≥ 75 years) with stable coronary disease, with a reduction in the primary ischemic endpoint counterbalanced by an excess of TIMI major bleeding. The benefits observed for the 'very elderly' (> 85 years) population remain uncertain because of the global frailty of these patients, with no specified published results.

With respect to the duration of treatment with DAPT, a treatment-by-age heterogeneity was observed in the ISARSAFE (Pint = 0.03) and IVUS-XPL (Pint = 0.05) trials, indicating a significant interaction between age and treatment duration (i.e. 6 vs. 12 months of DAPT) for each study primary endpoint. These studies suggest an unfavorable effect of longer treatment duration in elderly patients (i.e. 65 years).[29,33] A similar trend was shown in the PRODIGY trial, which reinforces the cautious approach in the elderly population and the powerful trend to a shorter DAPT duration.

Antiplatelet Therapy in Patients Undergoing Complex Coronary Intervention

For many years, complex coronary interventions have been considered an important factor for DAPT duration decision making. However, definition and ascertainment of PCI complexity has been inconsistent in prior reports. To overcome these issues, Giustino et al.[28] carried out a pooled analysis of data from six randomized trials involving 9577 patients undergoing PCI with drug-eluting stents (DES). The authors define PCI complexity based on six anatomical/procedural factors: at least one of the following features present: three vessels treated, three or more stents implanted, three or more lesions treated, bifurcation with two stents implanted, total stent length > 60 mm, or chronic total occlusion. Patients carrying these anatomical features were associated with an approximately doubled risk of MACE (adjusted HR 1.98, 95% CI 1.50–2.60; p < 0.0001). Importantly, individuals undergoing complex PCI derived a significant benefit from longer (12 months or more) versus shorter (3–6 months) DAPT, with significant interaction testing for DAPT duration and PCI complexity supporting an heterogeneity of treatment benefit based on these anatomical characteristics (Pinteraction = 0.01). In addition, the magnitude of the benefit of extended DAPT duration was proportional to the number of procedural complexities. This definition of complex PCI and its potential to drive the treatment decision has been widely accepted and is endorsed by international guidelines. Nevertheless, despite the ischemic benefit, complex PCI patients were equally associated with an increased bleeding hazard when exposed to longer treatment durations. A recent analysis of the PRECISE-DAPT study evaluated the ischemic versus bleeding risk among patients deemed at high ischemic risk (based on the aforementioned complex PCI criteria) and concurrent high bleeding risk (based on the PRECISE-DAPT score).[44] The authors ultimately found that irrespective of the baseline ischemic risk, individuals considered at high bleeding risk at baseline did not derive any benefit from longer treatment with DAPT, but were only exposed to an increased risk of bleeding. Hence, when concordant, bleeding, more than ischemic risk, should inform decision making on the duration of DAPT.[24]

Antiplatelet Therapy and Sex-based Differences

CAD presentation in women starts approximately 10 years later than in men,[45] at which point women are likely to present with more comorbidities.[46–49] Women also present with other complex clinical (e.g. lower body weight, renal dysfunction) and angiographic features (e.g. more multivessel disease, small vessel size).[50,51] Therefore, women are at higher risk of thrombotic and bleeding events,[52] and the risk–benefit balance of antiplatelet agents appears smaller than in age-matched men.[53]

In the TRITON-TIMI 38 trial,[7] the superiority of prasugrel over clopidogrel was consistent irrespective of sex. Nevertheless, as prasugrel 10 mg is not recommended for patients weighing < 60 kg[2] (most women frequently have a low body weight), clopidogrel is still the preferred P2Y12 inhibitor in this population.[54] Indeed, the effectiveness of the prasugrel 5 mg dose has not been prospectively investigated in the TRITON study. Therefore, no definitive conclusion can be made, even if the platelet reactivity with prasugrel 5 mg in low body weight patients with stable CAD is similar to that of prasugrel 10 mg in high body weight patients.[55] In addition, the risk of bleeding with the 5 mg dose was similar to that of clopidogrel 75 mg in the FEATHER trial.

The prespecified analysis, according to sex, from the PRODIGY trial on 2-year outcomes after PCI in 459 women and 1511 men randomized to between 6 and 24 months of DAPT (aspirin 80–160 mg/day indefinitely plus clopidogrel 75 mg/day) was performed.[56] Prolonged DAPT did not reduce the rate of the primary ischemic composite endpoint (death, MI, or cerebrovascular event). No sex-related effect either in ischemic events or on relevant bleeding was noted; similar results were reported in the pooled analysis of six RCTs using DES.[57] In summary, these data suggest that despite their different clinical presentations and characteristics, sex has no significant impact on ischemic or bleeding events. Therefore, it should not be considered a decision factor in relation to the duration of DAPT.

The 2017 European guidelines focusing on DAPT[4] take into account these data and promote sex equality, with a dose adjustment of antithrombotic drugs only in case of low body weight and high bleeding risk, irrespective of sex.[58]

Antiplatelet Therapy in Medically Managed Patients

Despite guidelines advocating early invasive management for ST-segment elevation myocardial infarction (STEMI) and high-risk NSTEMI patients,[1,2,59] some ACS patients still do not benefit from coronary revascularization. The prognosis of medically treated patients is worse compared with patients who undergo PCI or CABG.[60–62] Factors explaining this worse prognosis and the conservative strategy choice include advanced age, delays between onset of chest pain and treatment, and 'global frailty'. Women are less likely to undergo invasive management than men due to all these factors.[63] It is important to underline very elderly patients, despite an inherently frailty, benefit more from invasive coronary revascularizations than from a medical strategy.[64] Furthermore, these frailty patients are less likely to receive evidence-based secondary prevention therapies, including DAPT, due to frequent comorbidities.[65,66]

In a retrospective subgroup analysis of 11,080 NSTEACS patients from the PLATO trial, the reductions in the composite endpoint (cardiovascular death, MI or stroke, and total mortality), was decreased in the ticagrelor arm versus clopidogrel regardless of the strategy (coronary revascularization or conservative strategy).[67] Optimal medical treatment, including optimal DAPT, should be prescribed, even in this frailty subgroup.

The PEGASUS-TIMI 54 trial,[33] reported similar results for patients medically managed (17%), with no statistical heterogeneity between patients with and without prior PCI (n = 3591). As the net clinical benefit was modest in this trial, prolonged DAPT in medically managed patients is usually not indicated, considering the global frailty.

The TRILOGY ACS trial included NSTEMI patients who were medically managed and who were randomly assigned to long-term (median of 17 months) treatment with prasugrel and aspirin or DAPT with clopidogrel and aspirin. Prasugrel did not reduce the rate of ischemic events (cardiovascular death, MI, or stroke) in either patients aged < 75 years or the total population (HR 0.96, 95% CI 0.86–1.05), with similar total mortality in both groups (HR 0.94, 95% CI 0.82–1.08)[68] (Figure 2c). Furthermore, an increase in major, severe, or life-threatening bleeding was observed, a reason why prasugrel is not indicated in medically managed CAD patients.

Antiplatelet Therapy in Patients with a History of Stroke

In the TRITON-TIMI 38 trial,[7] analyses suggested that in patients with a history of stroke or transient ischemic attack (TIA), prasugrel may be harmful, supporting the current contraindication in this subgroup,[42] whereas no increase of hemorrhagic stroke was observed In the PLATO study.[69]

Indeed, treatment effects of ticagrelor versus clopidogrel in patients with (n = 1152; 6.2%) and without a history of previous stroke or TIA have been specifically reported. Patients with a history of stroke/TIA have higher rates of MI (11.5% vs. 6.0%), death (10.5% vs. 4.9%), stroke (3.4% vs. 1.2%), and intracranial hemorrhage (ICH; 0.8% vs. 0.2%). Ticagrelor provided the same extent of ischemic benefits for the primary endpoint and total mortality among patients with a history of stroke/TIA as in the overall population.[8] The PLATO-defined bleeding rates were similar and intracranial bleeding occurred very rarely (n = 4 in both groups). The ticagrelor strategy provided a clinical benefit, even in this frail population.[69]

Antiplatelet Therapy and Oral Anticoagulation in Coronary Artery Disease Patients with Percutaneous Coronary Intervention and Atrial Fibrillation

The need for concomitant oral anticoagulation (OAC)[70] greatly increased the complexity of pharmacological treatment of patients prescribed DAPT. One of the most common indications for OAC use is thromboembolic prevention in high-risk atrial fibrillation (AF). AF has an estimated prevalence exceeding 3 million individuals in the US, with figures expected to at least double by the year 2050.[84] Twenty to 30% of AF patients have concomitant ischemic heart disease requiring PCI,[71,72] in which case DAPT is indicated to prevent recurrent coronary events and stent thrombosis. However, co-prescription of OAC and DAPT (i.e. triple antithrombotic therapy) also increases the risk of bleeding by three- to fourfold.[73–75] The optimal antithrombotic combinations that confer the greatest reduction in ischemic events and minimizes bleeding in AF patients have recently been well-evaluated.

Indeed, several studies have focused on whether dual antithrombotic therapy [i.e. single antiplatelet therapy (SAPT) with a P2Y12 inhibitor plus OAC] provides a better trade-off than triple therapy in terms of efficacy and safety. The first was the open-label WOEST study, including 573 patients on OAC undergoing PCI,[76] which found that clopidogrel alone versus clopidogrel plus aspirin was associated with a reduction in any bleeding events (19.4% vs. 44.4%; odds ratio 0.36, 95% CI 0.26–0.50; p < 0.0001), with no difference in the rates of thrombotic or thromboembolic events, and with a lack of statistical power to detect differences in embolic events, which has led to other RCTs.

More recently, three studies have explored the combined impact of dual therapy versus triple therapy in AF patients treated with direct oral anticoagulant (DOAC) therapies or vitamin K antagonists (VKAs). The PIONEER-AF PCI trial[77] assigned 2124 patients with AF undergoing PCI to three groups: rivaroxaban 15 mg once daily plus clopidogrel 75 mg/day for 12 months (dual therapy); rivaroxaban 2.5 mg twice daily plus DAPT (dose not approved for stroke prevention); or dose-adjusted VKA once daily plus DAPT (triple therapy). Dual therapy with rivaroxaban plus a P2Y12 inhibitor was associated with a lower rate of clinically significant bleeding events compared with triple antithrombotic therapy (HR 0.61, 95% CI 0.50–0.75; p < 0.001). The rates of ischemic events were similar for dual therapy versus triple therapy, albeit with broad CIs since the PIONEER-AF PCI was also not powered to detect differences in rare ischemic events (i.e. stroke, stent thrombosis, etc.). In a post hoc analysis from the PIONEER-AF PCI trial, rivaroxaban was associated with a reduced risk of all-cause mortality or recurrent hospitalization for adverse events versus VKA plus DAPT, with the limitations inherent to post hoc analysis.[78]

The RE-DUAL PCI trial randomized AF patients undergoing PCI to three study arms: dual therapy with dabigatran 110 mg twice daily; dabigatran 150 mg twice daily plus a P2Y12 inhibitor (i.e. clopidogrel or rarely ticagrelor); or triple therapy with warfarin plus DAPT. The study was designed to test superiority of dual therapy versus triple therapy for the primary composite endpoint of major or clinically relevant non-major bleeding. At a mean follow-up of 14 months, dual therapy with both dosages of dabigatran (i.e. 110 and 150 mg twice daily) provided a significant reduction in the primary major bleeding endpoint (RRR of 48% and 28%, respectively) compared with triple therapy. Results remained consistent for other secondary safety endpoints evaluating different bleeding definitions. Dual therapy with dabigatran was also associated with a reduction in ICH (dabigatran 110 mg twice daily: HR 0.30, 95% CI 0.08–1.07, p = 0.06; dabigatran 150 mg twice daily: HR 0.12, 95% CI 0.02–0.98, p = 0.047). Non-inferiority of the dual therapy versus triple therapy for ischemic endpoints (composite endpoint of thromboembolic events, death, or unplanned revascularization) was also demonstrated, even if the study was underpowered as per the previous RCT. The AUGUSTUS (NCT02415400) and ENTRUST-AF-PCI (NCT02866175) trials have also evaluated apixaban and edoxaban, respectively, and reported similar results in terms of safety (less major bleeding) and efficacy (similar thromboembolic events), advocating for a short duration of a triple antithrombotic strategy followed by an SAPT with a lower validated dose of DOAC in CAD patients with non-valvular AF. All these studies reported a negative signal regarding stent thrombosis in the SAPT + DOAC groups, but the absolute number of events was very low.

A recent meta-analysis including four RCTs supports these findings. In a total of 5317 patients randomized to dual therapy or triple therapy, a dual therapy strategy was associated with a 47% RRR of TIMI major or minor bleeding, with no difference in the rate of trial-defined major ischemic events. It has to be highlighted though that two of the four included studies were associated with the dual therapy with DOACs randomization scheme, whereas triple therapy was carried out with VKAs. Hence, with the current data, it is difficult to disentangle the real contribution to the bleeding risk reduction of dual therapy (by aspirin withdrawal) versus the proportion of bleeding risk reduction given by treatment with DOACs rather than with VKAs (which has already been demonstrated to be associated with a reduction in bleeding in all the DOAC registration studies).

In view of these results, the European Society of Cardiology (ESC) guidelines suggest gauging the expected ischemic versus bleeding risk before treatment decisions, targeting AF patients at higher ischemic risk with triple therapy for 1 month and up to 6 months, while those in which the bleeding risk is prevailing should be immediately targeted with dual therapy. The trend is for an as short as possible duration of triple therapy, i.e. in most cases, for 1 month. Guidelines also indicate that DOACs should be preferred over VKAs (to reduce the bleeding risk) and that clopidogrel is recommended in association with DOACs (also for its safety profile), while prasugrel and ticagrelor are contraindicated due to the excessive bleeding risk in this setting.

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