Introduction

While the necessity of dual antiplatelet therapy (DAPT) following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) with coronary stenting is undisputed, the optimal duration of DAPT remains a major topic of discussion. Research data supports both prolonged and shortened duration of DAPT in certain situations. The present paper aims to summarize current evidence and give an overview of contemporary treatment options for patients in need of dual antiplatelet therapy.

Key words: dual antiplatelet therapy, acute coronary syndrome

Overview of current guidelines

The duration of DAPT is an individual decision based on the ischemic and haemorrhagic patients’ risk profile. A balance between preventing ischemic cardiovascular (CV) events and bleeding hazards caused by continued antithrombotic treatment has to be made. The European (ESC/EACTS) and North American (ACC/AHA) Guidelines are providing clinical recommendations for the optimal duration of DAPT in patients with stable coronary artery disease (sCAD) and ACS, respectively. (figure 1) (1, 2)

After PCI with stent placement DAPT (aspirin plus clopidogrel) is usually recommended for duration of 6 months in the setting of sCAD. For patients following ACS DAPT, preferably including aspirin plus a potent P2Y12-inhibitor (ticagrelor or prasugrel), is usually recommended for 12 months. According to the patients’ risk profile both a shortened 1-3 months for sCAD and 6 months for ACS and an extended, up to 3 years, duration of DAPT may be appropriate to prevent ischemic CV and haemorrhagic events. (1, 2)

Risk stratification

Risk stratification tools have been established to help guiding the decision making of the treating physician.

The PRECISE-DAPT Score serves as a clinical tool to predict the risk of bleeding in patients treated with DAPT. (table 1) The calculation is based on the levels of haemoglobin, creatinine clearance, white blood cells, age and prior bleeding events. A value of ≥25 is associated with a significantly increased risk of haemorrhagic events and should, therefore warrant caution and may support the decision of a shortened DAPT regime. (3)

The DAPT Score is another clinical tool for the ischemic risk assessment of patients treated with DAPT for 12 months without having any major bleeding or ischemic events during the course of treatment. (table 2) Patient characteristics and procedural characteristics are included in the calculation. A score of ≥2 is associated with a favourable benefit/risk ratio of prolonged DAPT. The utility of the DAPT score is limited by its lack of data for ticagrelor and its modest discrimination power. Accordingly, additional studies investigating its predictive value are necessary and ongoing. (4)

Rationale for prolonged DAPT

The risk of future ischemic CV events in patients with a history of myocardial infarction (MI) remains high beyond 1 year following the initial event according to the Swedish national registry study. 5 Even patients without a major CV event during the first year had a risk of 20% for a composite endpoint in the following 36 months. Thus, indicating a need for extensive surveillance and sufficient antithrombotic treatment in patients at high ischemic risk. (5)

The DAPT study (performed in the US) was a prospective, randomized trial testing the efficacy and safety of prolonged DAPT after coronary stenting in patients with sCAD and ACS. (6) It was the first of its kind powered to detect differences in ischemic events between an extended DAPT regime and standard duration of DAPT. Patients, who tolerated DAPT well for 12 months without any adverse ischemic or bleeding events were randomized to an additional 18 months of DAPT (aspirin plus clopidogrel or prasugrel) or placebo, leading to a total treatment duration of 30 months. The authors found a significant reduction of stent thrombosis and the composite of death, MI or stroke under prolonged DAPT. The expected increase of major bleedings was limited to non-fatal events. Surprisingly, prolonged DAPT also caused an increase of all-cause mortality, which was, however, not driven by the excess of bleeding events, but rather by non-cardiovascular causes. (6) Based on preliminary data, an increase of solid cancers has been associated with the long-term use of thienopyridines. (7) Recent post hoc investigations of the TRILOGY trial (8), meta-analyses (9-11), and cancer registries (12), however, do not confirm scientific rationale for such relationship.

The PEGASUS-TIMI 54 trial prospectively evaluated the effect of prolonged DAPT on clinical outcomes in patients with prior MI. (13) After one year of physician-directed DAPT, patients were randomized to ticagrelor 90 mg BID, ticagrelor 60 mg BID, or placebo for additional 18 months. Low dose aspirin (75-150 mg OD) was prescribed to all patients. Both ticagrelor dosages were effective in reducing the primary efficacy endpoint, which was largely attributed to a substantial reduction of MI. Extended DAPT also led to an expected increase of major bleeding events, without affecting the incidence of intracranial or fatal haemorrhages. Differences in mortality were not observed. Based on the findings of this study low dose ticagrelor (60 mg BID) was approved for prolonged DAPT by the European Medicines Agency (EMA). (13)

Several meta-analyses have been performed to confirm the efficacy and safety of an extended DAPT regime in both, sCAD and ACS patients. (14-16) A decrease of stent thrombosis and MI with a concomitant increase of non-fatal bleeding events under prolonged DAPT was a consistent finding. The association of prolonged DAPT and mortality, however, remains still a subject of debate primarily in patients presenting with sCAD, based on conflicting results. (14-16)

Prolongation of DAPT for up to 30 months (preferably with ticagrelor 60 mg BID) should be offered to patients at high ischemic but normal bleeding risk following ACS. Similarly, a continuation of DAPT beyond the recommended duration of 6 months in patients with sCAD, who tolerated DAPT well and are at an increased risk of thrombogenic events, may be considered.

Rationale for shortened DAPT

While the necessity of DAPT after PCI with stent placement is undisputed, it may also lead to serious bleeding complications in patients at high haemorrhagic risk. Such high-risk patients should be carefully assessed for shorter durations of DAPT. The use of new generation drug-eluting stents (DES) with shorter re-endothelialization time, thinner struts, and the use of stents with biodegrable polymer or polymer-free stents thereby support the clinical use of shorter DAPT durations. (17) The advantage of certain new generation DES over the prior used bare metal stents in patients with increased bleeding risk has been presented in several trials including the LEADERS FREE, SENIOR and ZEUS trials, respectively. (18-20)

A well-designed individual patient data meta-analysis by Palmerini et al. investigated the clinical effects of shortened DAPT (3 or 6 months) compared to 1-year DAPT. (21) A total of 11,473 patients (58.5% presenting with sCAD, 41.5% with ACS) from six studies were included in the analysis. Shorter DAPT durations led to a significant reduction of bleeding events regardless of clinical presentation. In patients with sCAD, 1-year duration of DAPT had no advantages compared to 6 months of DAPT with respect to mortality, stent thrombosis or MI, respectively. These results remained persistent in sCAD patients with an only 3-month course of DAPT. Similar results were obtained for ACS patients followed by 6- vs. 12-months of DAPT. However, a significant increase in the rate of MI and stent thrombosis was demonstrated in patients randomized to only 3-months DAPT duration, while no differences in mortality were observed compared to 1-year DAPT. Unfortunately, the majority of patients presenting with ACS suffered from unstable angina (67%) thus leading to an underrepresentation of STEMIs and NSTEMIs. (21)

Shortened duration of DAPT should be considered in patients in whom bleeding risk prevails the ischemic risk as it reduces the number of bleeding hazards while providing comparable antithrombotic protection.

DAPT in the setting of oral anticoagulation

The presence of both, atrial fibrillation and PCI, requires a combination of oral anticoagulation (OAC) and antiplatelet treatment. The current ESC/EACTS Guidelines for DAPT recommend an individualized treatment strategy based on the ischemic and bleeding risk of each patient after PCI with coronary stenting. (figure 2) (1)

Triple therapy (TAT) consisting of aspirin, clopidogrel and an oral anticoagulant (NOAC or warfarin) should be offered for a duration of 1 up to 6 months (depending on the individual bleeding risk), followed by dual antithrombotic therapy (DAT; OAC plus aspirin or clopidogrel) for up to 12 months and finally by long-term OAC monotherapy. Recently, safety of DAT (consisting of a NOAC plus clopidogrel), started at or shortly after hospital dismission has been investigated and published in two randomized trials (PIONEER AF with rivaroxaban, RE-DUAL PCI with dabigatran). (22, 23) Both trials showed a significant reduction of bleeding events for DAT vs. triple therapy with at the same time neutral effect on ischemic events, while two further safety trials are still ongoing (AUGUSTUS with apixaban, ENTRUST with edoxaban). Unfortunately, all these trials investigating DAT for 12 months vs. different durations of triple therapy are not sufficiently powered to evaluate ischemic outcomes. Nevertheless, the recent ESC guidelines now recommend DAT for up to 12 months in patients at high haemorrhagic risk followed by long-term OAC monotherapy. (1)

Conclusion

Duration of DAPT is based on the specific ischemic and bleeding risk of the patient and has to be individualized. Prolongation of DAPT beyond 12 months is reasonable if ischemic risk prevails the bleeding risk and DAPT is well tolerated. Shortening of DAPT should be considered in patients at high risk of haemorrhagic events. As a majority of routine patients bear increased bleeding and ischemic risks at the same time, risk stratification tools may be useful to guide decision making in this important subset of patients.

Table 1. PRECISE-DAPT Score;(3)

Table 2. DAPT Score; (4)

LVEF = left ventricular ejection fraction, PCI= Percutaneous coronary intervention

Figure 1. Algorithm for DAPT after PCI adapted after the ESC Guidelines for DAPT;(1)

DAPT = dual antiplatelet therapy, PCI = Percutaneous coronary intervention, A = aspirin, C = clopidogrel, T = ticagrelor, P = prasugrel, cont. = continuation, mo. = month, 1 =first-line treatment ,2 = second-line treatment

Figure 2. Algorithm for Triple- and Dual therapy adapted after the ESC Guidelines for DAPT;(1)

OAC = oral anticoagulant (NOAC / warfarin), A = aspirin, C = Clopidogrel, PCI = percutaneous coronary intervention, mo. = month;

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Corresponding author:
Kurt Huber
3rd Department of Medicine, Cardiology and Intensive Care Medicine
Wilhelminenhospital,
Montleartstrasse 37,
A-1160 Vienna, Austria.
Phone: +43 1 49150 2301.
E-mail: kurt huber@medunwien.ac.at

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