Platelet inhibition represents the cornerstone of cardiovascular therapy, owing to the central role of platelets in the genesis of acute ischaemic events. Dual antiplatelet therapy (DAPT) addresses two main pathways of platelet activation: inhibition of cyclo-oxygenase-mediated thromboxane A2 formation by aspirin; and inhibition of the ADP-activated surface receptor P2Y12 by means of a family of drugs including cangrelor, clopidogrel, prasugrel, ticagrelor and ticlopidine (fig. 1).
Figure 1: Pathways of platelet activation and their pharmacological targets.
Even though much is known about the efficacy and safety of DAPT, as reflected by the most recent international guidelines [1–3], some specific issues are a matter of ongoing discussion. The aim of this review is to give a concise overview of current knowledge on this topic and to discuss some open issues, such as preloading in patients with an acute coronary syndrome (ACS), which aims to prepare the lesion in view of the imminent percutaneous treatment, the optimal duration of DAPT after stent implantation, defined at the shortest period necessary to protect the stent against the risk of early and late stent thrombosis, and, finally, the long-term treatment (more than 12 months) recently considered as a potential alternative in patients at very high ischaemic risk (fig. 2). A final glimpse of new concepts, upcoming studies and applications of DAPT after valve and structural interventions, as well as in combination with oral anticoagulation, will also be provided.
Figure 2: Current open issues in dual antiplatelet therapy.
Historical background
The hypothesis of an auxiliary effect of clopidogrel on top of aspirin in reducing cardiovascular ischaemic events rose from the well-established knowledge that platelet adhesion and activation occur through many different molecular mechanisms [4, 5]. After the introduction of bare metal stents (BMSs) in the early 1990s, aspirin was combined with an additional antithrombotic drug, initially ticlopidine, later clopidogrel, to prevent stent thrombosis during the first 4 weeks after stent implantation [6].
The first data in the BMS era, showing a clinical advantage of extended (>1 month) combination therapy with clopidogrel and aspirin in non ST-segment elevation ACS, came in 2001 from the CURE trial (Clopidogrel in Unstable Angina to prevent Recurrent Events), where the prolonged combined treatment led to an absolute reduction of 2.1% in risk for the composite endpoint, with a benefit maintained over time, particularly in the subgroup of patients undergoing percutaneous revascularisation [7, 8]. A similar trend was observed in 2003 in the CREDO trial, which showed an absolute 3% and a relative 27% risk reduction in the cumulative endpoint when comparing 1 month with 12 months of DAPT [9].
A few years later (2005–2006), safety issues with first-generation drug eluting stents (DESs), concerning the occurrence of late and very late stent thrombosis related to the use of antiproliferative drugs inhibiting complete re-endothelialisation for a prolonged time, prompted concerns about the optimal length of DAPT [10–13].
The CHARISMA trial (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) was the first to hypothesise that DAPT lasting more than 12 months could provide greater protection against recurrent events than aspirin alone [14].
More recently, two large ground-breaking trials, TRITON-TIMI 38 and PLATO, tested two new P2Y12 inhibitors, prasugrel and ticagrelor, and reassessed the antithrombotic approach in patients presenting with ACS [15, 16].
Available drugs
A summary of currently used P2Y12 inhibitors is available in table 1.
Table 1: Details of available P2Y12 inhibitors.
Oral administration
Intravenous administration
Clopidogrel
Prasugre!
Ticagrelor
Cangrelor
Drug class — antiplatelet mechanism
Thienopyridine P2Y12 inhibitor
Thienopyridine P2Y12 inhibitor
Cyclopentyltriazolopyrimidine P2Y12 inhibitor
ATP analogue — ADP P2Y12 inhibitor
Loading/maintenance dose
300–600 mg / 75 mg once daily
60 mg / 10 mg once daily
180 mg / 90 mg twice daily
30 pg/kg bolus / 4 pg/kg/min infusion
Reversibility
Irreversible
Irreversible
Reversible
Reversible
Bio-activation
prodrug, variable cytochrome P450 metabolism
prodrug, predictable cytochrome P450 metabolism
Active drug
Active drug
Onset of action
2–6 hours
30 min.
30 min.
2 min.
Duration of action
3–10 days
7–10 days
3–5 days
1–2 hours
Withdrawal before surgery
5 days
7 days
5 days
1 hour
Cost
740 CHF/year
1135 CHF/year
1354 CHF/year
Hospital administration only
Clopidogrel
Clopidogrel (300–600 mg loading dose and 75 mg/day maintenance dose) is an oral thienopyridine derivative. Its active metabolite blocks platelet P2Y12 receptors irreversibly, thereby preventing the binding of adenosine diphosphate (ADP) and thus counteracting ADP-dependent activation of GpIIb-IIIa, the major platelet receptor for fibrinogen. As an inactive prodrug, clopidogrel requires a two-step oxidation by the hepatic cytochrome P450 system (specifically by CYP2C19) to generate an active metabolite. This two-step conversion results in a slower onset of action than those of prasugrel and ticagrelor. Furthermore, substantial interindividual variability in the antiplatelet response to this drug has been documented: several different alleles of CYP2C19 have been related to reduced or increased enzymatic activity of the cytochrome and variable clinical efficacy of clopidogrel.
Prasugrel
Prasugrel (60 mg loading dose and 10 mg/day maintenance dose) is an orally inactive prodrug, also derived from thienopyridine, which irreversibly binds and thus inhibits P2Y12 receptors on platelets. Prasugrel requires conversion to an active metabolite through a one-step cytochrome P450-dependant reaction, ensuring a faster onset of action and a more predictable clinical effect than with clopidogrel. According to the TRITON-TIMI 38 post-hoc analysis data, prasugrel is contraindicated in patients with prior stroke (or transient ischaemic attack), or in patients older than 75 years or with low body weight (<60 kg) [2, 3, 14]. The role of a reduced 5-mg dose of prasugrel in these subsets of patients is currently under investigation.
Ticagrelor
Ticagrelor (180 mg loading dose and 90 mg twice a day maintenance dose) is an oral P2Y12 receptor antagonist belonging to the chemical class of cyclopentyltriazolopyrimidines [16]. It acts through a double antiplatelet mechanism, inhibiting both P2Y12 receptors and adenosine reuptake via the equilabrative nucleoside transporter 1 (ENT1). Unlike clopidogrel and prasugrel, ticagrelor binds reversibly to the P2Y12 receptor, leading to a faster offset of action with more rapid recovery of platelet function (5 days). Furthermore, ticagrelor is an orally active drug requiring no metabolic activation, which provides a much faster onset of action and more reliable inhibition than clopidogrel. Adverse effects, potentially linked to its inhibition of ENT1, include dose-related episodes of dyspnoea and bradycardia. To date, the only head-to-head comparison data between ticagrelor and prasugrel come from the recent, but greatly underpowered, Prague 18 trial, which did not show any difference between the two potent antithrombotic drugs in term of predefined endpoints at 7 and 30 days in 1250 “real world” patients with ST-segment elevation myocardial infaction (STEMI) treated with primary PCI [17].
Cangrelor
Cangrelor (30 mg/kg bolus and 4 mg/kg/min infusion) is an intravenous adenosine triphosphate analogue that binds directly and reversibly to the P2Y12 receptor, without requiring metabolic activation. It produces reversible and highly effective platelet inhibition, with an almost immediate onset after administration of the intravenous bolus. It has a short plasma half-life (3–6 min), thus allowing restoration of platelet function within 1–2 hours after infusion discontinuation. The CHAMPION-PHOENIX trial, comparing cangrelor with clopidogrel in an all-comers population with stable coronary heart disease and acute coronary syndromes [18], failed to demonstrate any convincing and cost effective advantages of the parenteral drug. Thus, current use of cangrelor is limited to a bridge to surgery in patients with a high bleeding risk, or as an alternative for preloading in ACS patients experiencing nausea and vomiting or reduced oral drug absorption due to impaired peripheral perfusion.
Current role of dual antiplatelet therapy
In the following section we will focus on open issues about DAPT: the role of preloading in acute coronary syndromes, the optimal length of treatment after PCI in stable coronary artery disease and ACS, and the role of extended DAPT after 12 months in selected patients.
Preloading in acute coronary syndromes
The rationale for P2Y12 receptor blocker administration before PCI in ACS arises from the observation that the risk of early thrombotic complications, such as re-infarction or acute stent thrombosis, is directly related to the level of platelet reactivity (fig. 3).
Figure 3: The course of the level of platelet inhibition over time in patients with P2Y 12 pretreatment (green curve) and in patients without pretreatment (red curve). The opportunity to benefit from pretreatment effect exists within the area with slanted grey lines, the area between the red and green curves. The risk of stent thrombosis (black curve) is highest during and in the early period after percutaneous coronary intervention, with a subsequent decline in risk thereafter. Following a loading dose with P2Y 12 inhibitors, the maximum level of platelet inhibition is usually seen within hours and up to the day after percutaneous coronary intervention, with a minor decline in inhibition during maintenance therapy before reaching a steady-state level. From: Sibbing D, Kastrati A, Berger PB. Pre-treatment with P2Y 12 inhibitors in ACS patients: who, when, why, and which agent? Eur Heart J. 2016;37(16):1284–95. Reprinted with permission.
Several issues have to be addressed when considering preloading. First, the drug should be administered in a timely manner, early enough to allow complete inhibition at the time of PCI. Secondly, the delay between drug administration and its pharmacological action is related not only to the pharmacokinetics of the molecule, but also to some patient-specific clinical conditions (e.g., STEMI vs NSTEMI, low cardiac output syndromes, etc.) that may further delay absorption. Thirdly, the addition of a second antiplatelet agent on top of aspirin obviously increases the haemorrhagic risk, particularly in the subgroup of patients (5–10%) who might benefit from accelerated surgical revascularisation.
Given these premises, preloading with a P2Y12 inhibitor has been considered a rationally appealing approach, particularly in an era where clopidogrel, with its slow onset of action, was the first and the only available P2Y12 inhibitor.
ST-segment elevation ACS
ST-segment elevation myocardial infarction (STEMI) is characterised by strong platelet hyper-reactivity and the need to achieve vessel reperfusion within 90 minutes from symptom onset, clearly requiring fast and adequate platelet inhibition. In this context, the synergic action of heparin, aspirin and ADP receptor antagonists aims to reduce thrombotic activity at the site of plaque rupture and to minimise the thrombogenic impact of the percutaneous intervention.
The indications in guidelines have changed considerably over time, because of the introduction of newer drugs and of contrasting evidence on pretreatment in STEMI patients. Initial experience and, consequently, guidelines were strongly in favour of preloading [19, 20], but newer data challenged this concept [21, 22].
In particular, the recent ATLANTIC trial, the only available randomised study comparing out-of-hospital preloading with administration at the time of PCI in STEMI, failed to show any benefit of the upstream pretreatment in terms of coronary reperfusion and outcome at 30 days, nevertheless with a small but significant reduction of definite stent thrombosis up to 30 days [21]. Even though the 2014 European society of Cardiology (ESC) guidelines on coronary revascularisation still recommend preloading in STEMI [2], recent evidence derived from the ATLANTIC trial weakened the concept of preloading in STEMI and will probably lead to future modifications of recommendations.
Non-ST-segment elevation-ACS
In contrast to STEMI, the therapeutic goal of antithrombotic treatment in the setting of non-ST-segment elevation-ACS (NSTEMI) is to stabilise the coronary plaque in view of mechanical revascularisation, which should take place within 24 to 48 hours [3]. Whereas previous guidelines warmly recommended preloading with a P2Y12 inhibitor upstream [20], the only trial testing this hypothesis failed to demonstrate any advantage. In fact, the ACCOAST trial, published in 2013, which compared pretreatment with 30 mg of prasugrel (and a further 30 mg dose at the time of PCI) with prasugrel 60 mg given after diagnostic angiography, did not show any benefit in terms of cardiovascular death, recurrent myocardial infarction, stroke, urgent revascularisation and bailout use of GPIIb/IIIa inhibitors at 7 and 30 days. Instead, a significant increase in major bleedings in the pretreated group was observed [22].
Uncertainties about preloading are mirrored in the 2015 edition of the ESC NSTEMI guidelines, which clearly discourage pretreatment with prasugrel, and give no recommendation favouring or discouraging the use of clopidogrel or ticagrelor, clearly highlighting the lack of evidence to support either strategy [3].
A summary of the current recommendation is given in table 2.
Table 2: Current recommendations on pretreatment in STEMI and NSTEMI patients. Modified from: Sibbing D, Kastrati A, Berger PB. Pre-treatment with P2Y12 inhibitors in ACS patients: who, when, why, and which agent? Eur Heart J. 2016;37(16):1284–95. Reprinted with permission.
STEMI
Routine pre-hospital pretreatment cannot be recommended for patients with STEMI over the in-lab administration of the drug since the two strategies had similar outcomes.
It can be advisable to administer potent and rapidly acting antiplatelet agents (prasugrel or ticagrelor) in the emergency department (i.e., ambulance) once the diagnosis of STEMI is confirmed and the patient proceeds to primary PCI.
NSTEMI
It is advisable to administer a potent and rapidly acting antiplatelet agent (prasugrel or ticagrelor) once the coronary anatomy is known (and the patient proceeds to immediate PCI).
If prasugrel or ticagrelor are contraindicated, pretreatment with clopidogrel before coronary angiography may be advisable for patients with low bleeding risk and a high likelihood for immediate PCI, especially if radial access is planned.
Optimal length of DAPT after stent implantation
Current guidelines recommend routine use of DAPT for 6 months after DES implantation in stable patients and for 1 year after an ACS [2].
Several trials evaluated the hypothesis that a shorter duration of DAPT would guarantee good efficacy and safety after newer-generation stent implantation [23-27], and tested various regimens of DAPT differing in terms of drugs used or length of treatment. Pooled data from these trials, including more than 30 000 patients, concluded that a short course of antithrombotic treatment lasting 3–6 months provides a similar safety profile to longer treatment (12 months) (table 3) [28].
Table 3: Adverse events according to the length of treatment.
DAPT 3–6 months
DAPT 12 months
RR
ST* rate (%)
0.5
0.4
0.1
Pooled MI+ (%)
1.7
1.5
0.2
Major bleeding (%)
0.4
0.8
0.4
Death rate (%)
1.7
1.9
0.2
*ST: stent thrombosis; +MI: Myocardial infarction; Pooled data derived from ISAR SAFE, ITALIC, SECURITY, OPTIMIZE, PRODIGY, RESET and EXCELLENT trials. Modified from G. Montalescot et al. J Am Coll Cardiol. 2015;66:832–47
Regardless of different therapeutic options and guideline recommendations, the current trend is to shorten DAPT to the minimum period required according to patient and stent characteristics. So far, this approach has been evaluated in the RESET [25] and OPTIMIZE (26) trials, which compared 3 and 12 months DAPT after implantation of a zotarolimus-eluting stent in patients with stable coronary artery disease. Both studies demonstrated noninferiority of the shorter treatment for the composite endpoint of all-cause death, myocardial infarction, stroke or major bleeding [26], as well as stent thrombosis and target vessel revascularisation [25].
In patients at high bleeding risk, the predefined DAPT period can be further shortened to 4 weeks when polymer-free drug-eluting stents are used. This is supported by evidence derived from the recent LEADERS FREE trial, which showed similar safety and superior efficacy with these stents as compared with conventional BMSs [29].
Factors that need to be considered in estimating bleeding (favouring shorter DAPT) and ischaemic risk (favouring longer DAPT) are listed in table 4.
Table 4: Characteristics related to increased ischaemic/bleeding risk.
Increased ischaemic risk or risk of stent thrombosis (may favour longer-duration DAPT)
*Modified from Levine GL et al ACC/AHAGuidelines Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease
DAPT beyond 12 months
Several studies [14, 24, 30–34] hypothesised that prolonged platelet inhibition might result in a better protection against recurrent cardiovascular events.
The first study evaluating this strategy, the CHARISMA trial (with more than 15 000 patients at risk of, or with established, cardiovascular diseases randomised to either aspirin alone or a combination of aspirin plus clopidogrel for a median of 28 months) failed to demonstrate any advantage of prolonged DAPT but raised some safety concerns in terms of bleeding [14]. A few years later, the DES-LATE study also failed to show any benefit associated with clopidogrel plus aspirin vs of aspirin alone in reducing the incidence of myocardial infarction or death from cardiac causes at 12 months [32].
More recently, the large Dual Antiplatelet Therapy (DAPT) study, compared the extension of DAPT up to 30 months after PCI vs the conventional approach in almost 10 000 event-free patients (30). Prolonged treatment after PCI significantly reduced the rates of stent thrombosis, myocardial infarction and major adverse cardiovascular events. Notably, the reduction in myocardial infarction was significant in both target and non-target lesions, suggesting a secondary prevention effect of long-term DAPT. However, in line with previous studies, a safety concern was raised owing to the increase in moderate to severe bleeding, all-cause mortality and deaths for non-cardiovascular causes in the treatment group.
Finally, the recent PEGASUS-TIMI 54 study, evaluating two different doses of ticagrelor (90 or 60 mg twice daily) plus aspirin vs aspirin alone in more than 21 000 stable high-risk patients (myocardial infarction 1–3 years earlier) with a median follow-up to 33 months, was reported [33]. Consistently with the previous observations, the study demonstrated a significant reduction in terms of the primary efficacy endpoint (combined death, reinfarction, stroke after 3 years). However, an increased risk of major bleeding for the two ticagrelor doses was also observed (2.6% for ticagrelor 90 mg vs 2.3% for ticagrelor 60 mg vs 1.0% for aspirin alone).
A summary of current evidence is available from an elegant meta-analysis, published in 2015 [35], which clearly showed that DAPT maintained well beyond 12 months (up to 24–30 months) reduces the incidence of thrombotic complications, in particular stent thrombosis and myocardial infarction, at the price of an increase in major bleeding and possibly in all-cause mortality. In other words, the dichotomy between efficacy and safety still represents the Achille’s heel of this appealing, but challenging approach.
In conclusion, although 2014 ESC guidelines on myocardial revascularisation do not recommend routine extension of DAPT, on the other hand and in the light of the more recent results of the DAPT and Pegasus trials, treatment for more than 12 months can be considered in selected patients with a very high ischaemic burden (e.g., severe coronary artery disease in young patients with multiple risk factors, recurrent events) and at a very low bleeding risk
DAPT and oral anticoagulation
Almost 6–8% of patients undergoing PCI have an indication for chronic oral anticoagulation (OAC) with vitamin K antagonists (VKAs) or new oral anticoagulants (NOACs), as a result of various conditions such as atrial fibrillation, mechanical heart valves and recent or recurrent venous thromboembolism. However, adding antiplatelet agents to warfarin increases nonfatal and fatal bleeding risk more than 3-fold as compared with DAPT [36]. Therefore, clinical judgment and regular reassessment of the indication for OAC is essential.
Current guideline recommendations, derived from large registries [36], from rather small and underpowered randomised trials [37, 38] and from post-hoc analyses of the large randomised trials on atrial fibrillation, still recommend a pragmatic approach mainly based on a clear distinction between stable and acute coronary syndromes and on balancing the systemic bleeding risk by use of validated risk scores [3]. In patients with an acute coronary event and low bleeding risk (HAS-BLED score ≤2) extension of the triple therapy, consisting of aspirin, clopidogrel and either a vitamin K antagonist or NOAC, up to 6 months is recommended. In patients with stable coronary artery disease but at a high haemorrhagic risk (HAS-BLED score >2), a shortened triple therapy (1–3 months) and then a switch to a combination of one antiplatelet drug (either aspirin or clopidogrel) and one oral anticoagulant for up to 12 months is advised.
In accordance with a joint consensus document [39], and in line with the most recent European Guidelines on atrial fibrillation [40], discontinuation of any antiplatelet agent at 1 year is encouraged irrespective of stent type, whereas dual therapy with oral anticoagulation and one antiplatelet agent (aspirin or clopidogrel) may be considered in very selected patients at high risk of recurrent ischaemic events. Prasugrel or ticagrelor as part of triple therapy should be avoided, since these potent P2Y12 receptor inhibitors generate an unpredictable risk of fatal bleeding. In addition, when VKAs are used, the prothrombin time international normalised ratio (INR) should be carefully maintained within a target of 2.0–2.5. In patients treated with NOACs, the lowest tested dose for stroke prevention should be applied (e.g., rivaroxaban 15 mg once daily).
The appropriate role of NOACs was investigated in the hypothesis-generating PIONEER AF-PCI [42], which enrolled 2124 patients with non-valvular atrial fibrillation who had undergone PCI. Patients were randomly assigned to receive low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months, very-low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6 or 12 months, or standard therapy with a dose-adjusted VKA (once daily) plus DAPT for 1, 6 or 12 months. Despite its complexity, the study showed a clear benefit in terms of bleeding rates and similar safety for the two rivaroxaban groups as compared with the standard treatment. Even though the trial was not powered to evaluate efficacy, it definitely opens new perspectives in this increasingly important area of antithrombotic treatment.
Open questions and future perspectives
One of the future directions being currently investigated is the potential role of a single antiplatelet treatment with one of the novel potent antithrombotic drugs as an alternative to the conventional DAPT approach.
The ongoing Global LEADERS trial, with more than 16 000 patients included and a 2-year follow up, aims to evaluate whether, after an initial short (1-month) DAPT period, ticagrelor monotherapy will provide similar antithrombotic efficacy without increasing the long-term risk of bleeding [43]. If this trial succeeds in demonstrating this, it could have a revolutionary impact on the clinical management of patients with ischaemic heart disease.
Moreover, the currently ongoing, large-scale COMPASS trial, which includes more than 20 000 patients with documented atherosclerosis, is currently investigating the role of a low dose factor X inhibitor (rivaroxaban 2.5 mg twide daily + aspirin vs rivaroxaban 5 mg twice daily alone vs aspirin alone) in protecting against future cardiovascular events. Also in this case, if efficacy were proven, this would represent an important game-changer in the immediate future [44].
In other words, the antithrombotic perspective could considerably change in the coming years, according to the results of ongoing trials.
Platelet inhibition following structural interventions
The rationale behind platelet inhibition following structural interventions such as transcatheter aortic valve implantation (TAVI), transcatheter edge-to-edge mitral valve repair, left atrial appendage occlusion or patent foramen ovale / atrial septal defect occlusion is represented by both the need to prevent early thrombosis due to the loss of integrity of the endothelium at the time of the procedure and the need to prevent device thrombosis until complete endothelialisation is achieved.
Although there is a general consensus among cardiologists on the need for platelet inhibition, multiple empirical approaches are adopted in clinical practice. In the absence of clinical trials evaluating alternate antithrombotic regimens, especially after TAVI, no consensus on the optimal agent(s) or duration of therapy is yet available [45].
The recent WRITTEN survey highlighted that DAPT was the most common antithrombotic treatment prescribed at hospital discharge after TAVI. Nonetheless, significant differences were observed in terms of duration, this varying from 1 month in 14.3%, 3 months in 43.8%, 6 months in 35.5%, 12 months in 4.6% and indefinitely in 0.5% centres, while only a minority reported systematic use of single antiplatelet therapy with aspirin alone [46]. Even though some authors [47, 48] questioned the need for DAPT, we strongly support the current recommendation to consider DAPT for a minimum period of 1 to 3 months, as long as data from a large randomised trial are not available.
The concomitant presence of atrial fibrillation or alternative indications for oral anticoagulation clearly add complexity to complexity, and in fact it is not yet clear whether platelet inhibition is needed in the presence of oral anticoagulation.
The introduction of NOACs also opened new possibilities in patients undergoing TAVI. The currently running phase III GALILEO study, in which approximately 1 500 TAVI patients with no previous indication for OAC were randomly allocated to either rivaroxaban 10 mg plus aspirin once daily for 3 months followed by rivaroxaban 10 mg alone, or to standard DAPT with clopidogrel on top of aspirin for 3 months followed by aspirin alone, will most probably add new information and most probably impact on the current practice [49].
Concerning use and length of the dual antiplatelet therapy in the clinical context of structural interventions such as patent foramen ovale, atrial septal defect and left atrial appendage closure or after percutaneous mitral valve repair, the medical evidence is even more scanty and the current practice is still based on empirical recommendations which suggest combining aspirin with clopidogrel for up to 3 months followed by aspirin (or clopidogrel) alone for up to 6 months or as long as required by the clinical condition.
Conclusions
Dual antiplatelet treatment in the clinical context of coronary stent implantation is an evolving area with rapidly changing medical evidence and recommendations. On the basis of recent negative trials, preloading in ACS has been definitely called into question; concerning post-stent DAPT therapy, the current trend is to shorten treatment to the minimum required period and to stratify the approach according to patient and stent characteristics; finally, long term treatment for more than 12 months should only be considered in highly selected cases with a high ischaemic burden and a predicted low bleeding risk.
Ongoing large trials are currently investigating the role of single antiplatelet therapy with the new P2Y12 inhibitors and the potential use of new oral anticoagulants both in the setting of coronary artery disease and as an adjunctive therapy after structural interventions.
Disclosure statement
No financial support and no other potential conflict of interest relevant to this article was reported.
Correspondence
Correspondence: Giovanni Pedrazzini, MD Fondazione Cardiocentro Ticino Division of Cardiology. Via Tesserete 48 CH-6900 Lugano giovanni.pedrazzini[at]cardiocentro.org
References
1 Steg PG, James SK, Atar D, Badano LP, Blömstrom-Lundqvist C, Borger MA, et al., Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33(20):2569–619. doi:https://doi.org/10.1093/eurheartj/ehs215.
2 Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, et al., Authors/Task Force members. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35(37):2541–619. doi:https://doi.org/10.1093/eurheartj/ehu278.
3 Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(3):267–315. doi:https://doi.org/10.1093/eurheartj/ehv320.
4 Andrews RK, López JA, Berndt MC. Molecular mechanisms of platelet adhesion and activation. Int J Biochem Cell Biol. 1997;29(1):91–105. doi:https://doi.org/10.1016/S1357-2725(96)00122-7.
5 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348(9038):1329–39. doi:https://doi.org/10.1016/S0140-6736(96)09457-3.
6 Schömig A, Neumann FJ, Kastrati A, Schühlen H, Blasini R, Hadamitzky M, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996;334(17):1084–9. doi:https://doi.org/10.1056/NEJM199604253341702.
7 Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494–502. doi:https://doi.org/10.1056/NEJMoa010746.
8 Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, et al.; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358(9281):527–33. doi:https://doi.org/10.1016/S0140-6736(01)05701-4.
9 Steinhubl SR, Berger PB, Mann JT, 3rd, Fry ET, DeLago A, Wilmer C, et al.; CREDO Investigators. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411–20. doi:https://doi.org/10.1001/jama.288.19.2411.
10 Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, et al.; SIRIUS Investigators. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349(14):1315–23. doi:https://doi.org/10.1056/NEJMoa035071.
11 Bavry AA, Kumbhani DJ, Helton TJ, Bhatt DL. What is the risk of stent thrombosis associated with the use of paclitaxel-eluting stents for percutaneous coronary intervention?: a meta-analysis. J Am Coll Cardiol. 2005;45(6):941–6. doi:https://doi.org/10.1016/j.jacc.2004.11.064.
12 Moreno R, Fernández C, Hernández R, Alfonso F, Angiolillo DJ, Sabaté M, et al. Drug-eluting stent thrombosis: results from a pooled analysis including 10 randomized studies. J Am Coll Cardiol. 2005;45(6):954–9. doi:https://doi.org/10.1016/j.jacc.2004.11.065.
13 Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Am J Med. 2006;119(12):1056–61. doi:https://doi.org/10.1016/j.amjmed.2006.01.023.
14 Berger PB, Bhatt DL, Fuster V, Steg PG, Fox KA, Shao M, et al.; CHARISMA Investigators. Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease: results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Circulation. 2010;121(23):2575–83. doi:https://doi.org/10.1161/CIRCULATIONAHA.109.895342.
15 Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al.; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001–15. doi:https://doi.org/10.1056/NEJMoa0706482.
16 Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al.; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57. doi:https://doi.org/10.1056/NEJMoa0904327.
17 Motovska Z, Hlinomaz O, Miklik R, Hromadka M, Varvarovsky I, Dusek J, et al., PRAGUE-18 Study Group. Prasugrel Versus Ticagrelor in Patients With Acute Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention: Multicenter Randomized PRAGUE-18 Study. Circulation. 2016;134(21):1603–12. doi:https://doi.org/10.1161/CIRCULATIONAHA.116.024823.
18 Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, et al.; CHAMPION PHOENIX Investigators. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368(14):1303–13. doi:https://doi.org/10.1056/NEJMoa1300815.
19 Van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist C, Crea F, Falk V, et al.; ESC Committee for Practice Guidelines (CPG). Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2008;29(23):2909–45. doi:https://doi.org/10.1093/eurheartj/ehn416.
20 Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernández-Avilés F, et al.; Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J. 2007;28(13):1598–660. doi:https://doi.org/10.1093/eurheartj/ehm161.
21 Montalescot G, van ’t Hof AW, Lapostolle F, Silvain J, Lassen JF, Bolognese L, et al.; ATLANTIC Investigators. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med. 2014;371(11):1016–27. doi:https://doi.org/10.1056/NEJMoa1407024.
22 Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay JF, et al.; ACCOAST Investigators. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013;369(11):999–1010. doi:https://doi.org/10.1056/NEJMoa1308075.
23 Gwon HC, Hahn JY, Park KW, Song YB, Chae IH, Lim DS, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation. 2012;125(3):505–13. doi:https://doi.org/10.1161/CIRCULATIONAHA.111.059022.
24 Valgimigli M, Campo G, Monti M, Vranckx P, Percoco G, Tumscitz C, et al.; Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation. 2012;125(16):2015–26. doi:https://doi.org/10.1161/CIRCULATIONAHA.111.071589.
25 Kim BK, Hong MK, Shin DH, Nam CM, Kim JS, Ko YG, et al.; RESET Investigators. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol. 2012;60(15):1340–8. doi:https://doi.org/10.1016/j.jacc.2012.06.043.
26 Feres F, Costa RA, Abizaid A, Leon MB, Marin-Neto JA, Botelho RV, et al.; OPTIMIZE Trial Investigators. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA. 2013;310(23):2510–22.
27 Colombo A, Chieffo A, Frasheri A, Garbo R, Masotti-Centol M, Salvatella N, et al. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol. 2014;64(20):2086–97. doi:https://doi.org/10.1016/j.jacc.2014.09.008.
28 Giustino G, Baber U, Sartori S, Mehran R, Mastoris I, Kini AS, et al. Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2015;65(13):1298–310. doi:https://doi.org/10.1016/j.jacc.2015.01.039.
29 Urban P, Meredith IT, Abizaid A, Pocock SJ, Carrié D, Naber C, et al.; LEADERS FREE Investigators. Polymer-free Drug-Coated Coronary Stents in Patients at High Bleeding Risk. N Engl J Med. 2015;373(21):2038–47. doi:https://doi.org/10.1056/NEJMoa1503943.
30 Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, et al.; DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014;371(23):2155–66. doi:https://doi.org/10.1056/NEJMoa1409312.
31 Collet JP, Silvain J, Barthélémy O, Rangé G, Cayla G, Van Belle E, et al.; ARCTIC investigators. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet. 2014;384(9954):1577–85. doi:https://doi.org/10.1016/S0140-6736(14)60612-7.
32 Lee CW, Ahn JM, Park DW, Kang SJ, Lee SW, Kim YH, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation. 2014;129(3):304–12. doi:https://doi.org/10.1161/CIRCULATIONAHA.113.003303.
33 Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al.; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372(19):1791–800. doi:https://doi.org/10.1056/NEJMoa1500857.
34 Valgimigli M, Campo G, Monti M, Vranckx P, Percoco G, Tumscitz C, et al.; Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation. 2012;125(16):2015–26. doi:https://doi.org/10.1161/CIRCULATIONAHA.111.071589.
35 Navarese EP, Andreotti F, Schulze V, Kołodziejczak M, Buffon A, Brouwer M, et al. Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials. BMJ. 2015;350(apr16 25):h1618. doi:https://doi.org/10.1136/bmj.h1618.
36 Hansen ML, Sørensen R, Clausen MT, Fog-Petersen ML, Raunsø J, Gadsbøll N, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010;170(16):1433–41. doi:https://doi.org/10.1001/archinternmed.2010.271.
37 Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP, et al.; WOEST study investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107–15. doi:https://doi.org/10.1016/S0140-6736(12)62177-1.
38 Fiedler KA, Maeng M, Mehilli J, Schulz-Schüpke S, Byrne RA, Sibbing D, et al. Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After Drug-Eluting Stent Implantation: The ISAR-TRIPLE Trial. J Am Coll Cardiol. 2015;65(16):1619–29. doi:https://doi.org/10.1016/j.jacc.2015.02.050.
39 Lip GY, Windecker S, Huber K, Kirchhof P, Marin F, Ten Berg JM, et al.; Document Reviewers. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J. 2014;35(45):3155–79. doi:https://doi.org/10.1093/eurheartj/ehu298.
40 Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893–962. doi:https://doi.org/10.1093/eurheartj/ehw210.
41 Sarafoff N, Martischnig A, Wealer J, Mayer K, Mehilli J, Sibbing D, et al. Triple therapy with aspirin, prasugrel, and vitamin K antagonists in patients with drug-eluting stent implantation and an indication for oral anticoagulation. J Am Coll Cardiol. 2013;61(20):2060–6. doi:https://doi.org/10.1016/j.jacc.2013.02.036.
42 Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016;375(25):2423–34. doi:https://doi.org/10.1056/NEJMoa1611594.
43 Vranckx P, Valgimigli M, Windecker S, Steg PG, Hamm C, Jüni P, et al. Long-term ticagrelor monotherapy versus standard dual antiplatelet therapy followed by aspirin monotherapy in patients undergoing biolimus-eluting stent implantation: rationale and design of the GLOBAL LEADERS trial. EuroIntervention. 2016;12(10):1239–45. doi:https://doi.org/10.4244/EIJY15M11_07.
45 Otto CM, Kumbhani DJ, Alexander KP, Calhoon JH, Desai MY, Kaul S, et al. 2017 ACC Expert Consensus Decision Pathway for Transcatheter Aortic Valve Replacement in the Management of Adults With Aortic Stenosis: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2017;69(10):1313–46. doi:https://doi.org/10.1016/j.jacc.2016.12.006.
46 Cerrato E, Nombela-Franco L, Nazif TM, Eltchaninoff H, Søndergaard L, Ribeiro HB, et al. Evaluation of current practices in transcatheter aortic valve implantation: The WRITTEN (WoRldwIde TAVI ExperieNce) survey. Int J Cardiol. 2017;228:640–7. doi:https://doi.org/10.1016/j.ijcard.2016.11.104.
47 Ussia GP, Scarabelli M, Mulè M, Barbanti M, Sarkar K, Cammalleri V, et al. Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Am J Cardiol. 2011;108(12):1772–6. doi:https://doi.org/10.1016/j.amjcard.2011.07.049.
48 Rodés-Cabau J, Masson JB, Welsh RC, Garcia Del Blanco B, Pelletier M, Webb JG, et al. Aspirin Versus Aspirin Plus Clopidogrel as Antithrombotic Treatment Following Transcatheter Aortic Valve Replacement With a Balloon-Expandable Valve: The ARTE (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation) Randomized Clinical Trial. JACC Cardiovasc Interv. 2017;10(13):1357–65. doi:https://doi.org/10.1016/j.jcin.2017.04.014.
49 Windecker S, Tijssen J, Giustino G, Guimarães AH, Mehran R, Valgimigli M, et al. Trial design: Rivaroxaban for the prevention of major cardiovascular events after transcatheter aortic valve replacement: Rationale and design of the GALILEO study. Am Heart J. 2017;184:81–7. doi:https://doi.org/10.1016/j.ahj.2016.10.017.
