If atrial fibrillation (AF) and acute coronary syndrome (ACS) coexist, they should be treated with combined antithrombotic therapy. To reduce the risk of bleeding while maintaining the desired antithrombotic effect, choices should be made for each patient according to the balance between the bleeding and the thrombotic risk. There are many ways to select the type and dose of the oral anticoagulant (OAC) and P2Y12 inhibitors. As a rule of thumb, aspirin and P2Y12 inhibitors should be recommended to all patients. The duration of this combination therapy is a matter of debate; available data promote an initial period of one to four weeks of triple antithrombotic association with aspirin and P2Y12 inhibitors (clopidogrel in the absence of high ischaemic risk) and preferable direct oral anticoagulants (DOACs). On discontinuing aspirin, double therapy with P2Y12 inhibitors and a DOAC provides similar efficacy and superior safety for many patients on ACS medical or interventional treatment, especially if the risk of bleeding is high and that of thrombosis is low. Further studies are needed to clarify the concerns for a slight augmentation in the number of ischaemic cases (myocardial infarction and stent thrombosis) with double antithrombotic regimen in patients at high ischaemic risk.
The need for antithrombotic medications in double (single antiplatelet plus OAC;
alsoknown as “double therapy” [DAT]) or triple combination (dual antiplatelet
[DAPT] and OAC; also known as “triple therapy” [TAT]) is well recognized in
cases where atrial fibrillation (AF) coexists with an acute coronary syndrome
(ACS), with or without percutaneous coronary intervention (PCI) [1-5]. This is
the case for approximately 10% to 16% of ACS patients requiring stenting along
with concomitant AF. Moreover, due to the coexistence of ischaemic heart disease
(IHD) in AF patients, an increasing number—up to 20–30%—of them will have
urgent coronary revascularization for an ACS or during an elective procedure
[6-12]. These patients have more comorbidities, are older and have worse clinical
outcomes . Many AF patients need OAC to prevent and reduce the risk of
cardioembolic stroke because of the low shear stress that characterises the left
atrium. The thrombi thus appear frequently due to non-removal of thrombin and
fibrin monomer [13-15]. Risk of stroke in AF is not only related to the left
atrium stasis as described but also age (risk increasesamong those aged
Table 1 presents the principal pharmacological characteristics of commonly used oral antiplatelet agents in DAPT re-gimens.
Aspirin is a non-selective antiplatelet drug that suppresses the production of prostaglandins and thromboxane A2 with an irreversible acetylation process of serine residue on the cyclooxygenase enzymes. ISIS-2 trial (International Study of Infarct Survival) was the first to report that oral aspirin reduced short-term mortality in patients with suspected MI by 23% . In 1990, the newly released guidelines for patients with acute MI recommended first-time aspirin therapy for all patients, i.e., during the initial presentation which should then be continued for at least 1 month . The efficacy of aspirin in reducing nonfatal acute MI and cardiovascular death among patients with new or prior ACS was also demonstrated in the well-known meta-analysis (287 studies including 212,000 patients) by the Trialists’ Collaboration .
Clopidogrel is an oral antagonist of thienopyridine P2Y12 receptors that produces irreversible and competitive inhibition of platelets. Supplementary therapy with clopidogrel in ACS patients already treated with aspirin reduces MACE by 20% in the first 30 days and also results in similar reductions in the first year of treatment [23,51,52]. Thus, clopidogrel became the primary adjunctive to aspirin in DAPT regimens, following elective PCI, or in ACS patients medically or interventional treated with PCI [27,28].
Prasugrel is another oral antagonist of thienopyridine P2Y12 receptors that
produces irreversible and competitive inhibition of platelets. It is faster and
more consistent compared to clopidogrel. The TRITON-TIMI 38 study showed that
adding prasugrel to aspirin led to a 19% risk reduction of the primary composite
end point (MACE, cardiovascular death, stroke) when compared to DAPT with aspirin
and clopidogrel. This trial did not include medically managed ACS and proved a
lack of clinical benefit and higher rate of major bleeding among older patients
Ticagrelor is the oral, direct acting exponent of another chemical class.
It cause reversible binding of cyclopentyltriazolopyrimidine P2Y12 receptor
antagonist. Because it does not require hepatic metabolization for activation, it
acts more rapidly and is more potent compared to thienopyridines. Ticagrelor was
superior to clopidogrel in the PLATO trial, reducing not only the composite end
point of cardiovascular mortality, MI, or stroke by 16% but also the total
mortality (4.5% versus 5.9%; p
|Variables||Pharmacologic class||Mechanism of action||Half-life, h||Length of action||Doses|
|Aspirin||NSAIDs||Irreversible inhibition of COX enzyme||Dose dependent||10 d||Loading 325 mg, then 75–325 mg QD|
|Clopidogrel||Thienopyridine, P2Y12 receptor antagonist||Irreversible and competitive P2Y12 receptor blockade||6 h||5–7 d||Loading 300–600 mg, then 75 mg QD|
|Prasugrel||Thienopyridine, P2Y12 receptor antagonist||Irreversible and competitive P2Y12 receptor blockade||7 h||7–10 d||Loading 60 mg, then 10 mg QD (wt |
|Ticagrelor||Triazolopyrimidine, P2Y12 receptor antagonist||Reversible and noncompetitive P2Y12 receptor blockade||8–12 h||3–5 d||Loading 180 mg, then 90 mg BID|
|Legend: NSAIDs, nonsteroidal anti-inflammatory drug (low-dose aspirin as in DAPT is not normally considered to be an NSAID); COX, cyclooxygenase; h, hours; d, days; QD, once daily; BID, twice daily; wt, weight; kg, kilograms.|
The principal pharmacological characteristics for the OAC commonly used in DAT or TAT regimens and doses in AF/ACS/PCI patients are presented in Table 2.
|Variables||Target and bioavailability (%)||Half-life, h||Time to peak effect and interactions||Renal elimination (Unchanged drug, %)||Doses in AF/ACS/PCI patients|
|Warfarine||VKORC1||40||4–5 d||-||usually started at a dose of 5 mg per day/QD then following INR|
|Dabigatran||Thrombin||14–17||1–3 h||80%||150 mg BID/110 mg BID: no criteria for dose reductions in phase|
|Rivaroxaban||Factor Xa||7–11||2–4 h||33%||15 mg QD: dose reduction to 10 mg QD if CrCl 30–49 mL/min|
|Apixaban||Factor Xa||8–14||1–2 h||27%||– 5 mg BID|
|(60%)||(3A4/P-gp)||– 2.5 mg BID if two out of three fulfilled: weight |
|Edoxaban||Factor Xa||5–11||1–2 h||50%||60 mg QD: 30 mg QD if weight |
|(62%)||(cyt3A4/P-gp)||or concomitant therapy with strong P-gp inhibitor|
|Legend: VKORC1, vitamin K epoxide reductase complex subunit 1; cyt3A4, cytochrome P450 3A4 enzyme; P-gp, P glycoprotein; CrCl, creatinine clearance; INR, international normalized ratio; h, hours; d, days; QD, once daily; BID, twice daily; %, percentages.|
Warfarin is the oldest VKA in clinical use. An early, well-known patient on this OAC was United States’ president Dwight D. Eisenhower after a myocardial infarction in 1955 . Warfarin acts on vitamin K’s metabolism and inhibits the epoxide reductase enzyme. The ischaemic and bleeding outcomes of DAT with warfarin and clopidogrel versus warfarin plus clopidogrel plus aspirin as TAT was compared in the WOEST study—a randomized trial of more than 550 patients (70% patients with AF, 25% with ACS) undergoing PCI. The patients under TAT were treated with aspirin and clopidogreldaily for at least 1 month after bare-metal stenting (BMS), and for at least 1 year after drug-eluting stenting (DES). Patients under DAT and BMS stenting were treated with clopidogreldaily for at least one month (up to 1 year for patients with ACS) and those with DES stenting were treated for at least one year. The WOEST trial investigated the new idea of discontinuing aspirin from the TAT combination in AF patients with coronary stenting. The results showed an impressive 64% relative risk reduction (RRR) in bleeding events at one year in patients treated with DAT as opposed to TAT. Moreover, the thrombotic risk did not increase by omitting aspirin, however, the trial was small and not powered for these events—Table 4[38,55]. The ISAR-TRIPLE trial randomly studied if a short TAT of aspirin plus warfarin plus clopidogrel for a duration of six weeks compared with a long TAT (for six months) was different in efficacy and safety after a DES placement in 614 patients. Many patients continued DAT (warfarin and aspirin) after the study ended; less than 30% had an ACS while around 83% in each group had AF. Patients from the short TAT group had lesser combined events 9.8% (death, acute MI, definite stent thrombosis, stroke, or major bleeding) compared to the 8.8% of patients from long TAT. This difference was not statistically significant; however, bleeding frequency was statistically different in the long TAT group (27.9% vs 20.5%, HR 0.68, p = 0.04). The combined ischaemic end point was similar for both groups,as presented in Table 3. This study reconfirms that warfarin as OAC worked better than the combination of aspirin plus clopidogrelin AF patients and showed that, despite a lesser frequency of bleeding events, there was similar ischaemic clinical benefit in a 6-week TAT versus a 6-month TAT [55,57].
|WOEST 2013||AF-69%, ACS-27%||Group 1 DAT||VKA (INR = 2)||1. Any bleeding||1. any bleeding at 1 yr.: group 1 DAT - 19.4% vs group 2 TAT -|
|N = 573||Clopidogrel 75 mg QD: 1 to 12 m||44.4%, HR = 0.36, p |
|Open label,||Group 2 TAT||VKA (INR = 2)||2.Death, MI, stroke, TVR, ST||2. group 1 DAT - 11.1% vs group 2 TAT - 17.6%, HR = 0.6, p =|
|RCT-1 year||Aspirin 80–100 mg/QD||0.025|
|Clopidogrel 75 mg QD: 1 to 12 m|
|ISAR TRIPLE 2015||AF-80%, CCS-65%||Group 1 Short TAT||VKA (INR = 2 )||1. composite: MI, ST, stroke,||1. group 1 (short TAT-6 w) 9.8% vs group 2 (long TAT-6 m) 8.8%:|
|N = 614||Aspirin 70–200 mg/QD + Clopidogrel 75||TIMI major bleeding, death||no significant difference at 9 months|
|Open label,||mg QD: 6 w|
|N = 614||Group 2 Long TAT||VKA (INR = 2)|
|RCT-1 year||Aspirin 70–200 mg/QD Clopidogrel 75 mg QD: 6 m|
|PIONEER AF 2016||AF with PCI, 52% ACS||Group 1 DAT||Rivaroxaban 15 (10) mg QD||1. TIMI major + minor +||1. group 1 DAT (R15) - 16.8%; group 2 TAT (R 2.5) - 18%,|
|N = 2124||Clopidogrel 75 mg QD: 12 m (93%)||CNRM||group 3 TAT (AVK) - 26.7%, p |
|Open label||Group 2 TAT||Rivaroxaban 2.5 mg BID, Aspirin 75–100||2. composite: MI, stroke, CV||2. no difference|
|Clopidogrel 75 mg QD: 1, 6 or 12 m (93%)|
|Group 3 TAT||VKA (INR = 2–3)|
|Aspirin 75–100 mg/QD|
|Clopidogrel 75 mg QD: 1, 6 or 12 m (96%)|
|RE-DUAL PCI 2017||AF with PCI||Group 1 DAT||Dabigatran 110 mg BID||1. ISTH major + CRNMB||1. group 1 DAT (D110) - 15.4%; group 2 DAT (D150) - 20.2%,|
|N = 2725||50% ACS||Clopidogrel 75 mg QD (86%)||group 3 TAT (VKA) - 25.7%, p |
|Open label||Group 2 DAT||Dabigatran 150 mg BID||2. composite: MI, stroke, SE,||2. no difference|
|RCT-1 year||Clopidogrel 75 mg QD (87%)||death|
|Group 3 TAT||VKA (INR = 2–3)|
|Aspirin 75–100 mg/QD for 1 to 3 m|
|Clopidogrel 75 mg QD (90%)|
|ENTRUST AF 2019||AF with PCI, 52% ACS||Group 1 DAT||Edoxaban 60 (30) mg QD Clopidogrel 75||1. CRNMB and ISTH||1. annualized event rate group 1 DAT (E60) - 20.7% vs group 2|
|N = 1506||mg QD: 12 m (93%)||TAT (VKA) - 25.6 %, HR = 0.83, p = 0.001, noninferiority only|
|Open label,||Group 2 TAT||VKA (INR = 2)||2. composite: MI, SE, ST,||2. no difference|
|RCT-1 year||Aspirin 70–200 mg/QD: 1 to 12 m||stroke, CV death|
|Clopidogrel 75 mg QD (92%)|
|AUGUSTUS 2019||AF and PCI or ACS;||Group 1 & 2 DAT/TAT||Apixaban 5 mg BID open label||1. CRNMB and ISTH||1. group apixaban -10.5% vs group VKA -14.7%, HR = 0.69, p |
|1. group aspirin|
|N = 4614||Aspirin or placebo 81 mg double blind||- 9.0 % vs group placebo-16.1%, HR = 0.89, p |
|Double blinded||37% ACS and PCI||Clopidogrel 75 mg QD: 6 m (92%)|
|RCT - 6 months||24% ACS medical||Group 3&4 DAT/TAT||VKA (INR = 2–3) open label +||2. composite: MI, ST, stroke, urgent revascularization, death||2. group apixaban- 23.5% vs group VKA – 27.4%, HR = 0.83, p|
|Aspirin for all on the day of ACS or PCI and after for a median of 6 d||Aspirin or placebo 81 mg double blind +|
|Aspirin vs Placebo after randomization||Clopidogrel 75 mg QD: 6 m (92%)|
|Legend: AF, atrial fibrillation; ACS, acute coronary syndrome; BID, twice daily; CV, cardiovascular; CCS, chronic coronary syndrome; CNRM, clinically relevant non-major bleeding; DAT, double antithrombotic therapy; D110, dabigatran 110 mg; D150, dabigatran 150 mg; E60, edoxaban 60 mg; HR, hazard ratio; INR, international normalized ratio; ISTH, international society on thrombosis and hemostasis bleeding criteria; m, months; MI, myocardial infarction; N, number; PCI, percutaneous coronary intervention; QD, once daily; R15, rivaroxaban 15 mg; R 2.5, rivaroxaban 2.5 mg; RCT, randomized controlled trial; SE, systemic embolism; ST, stent thrombosis; TAT, triple antithrombotic therapy; TIMI, thrombolysis in myocardial infarction bleeding criteria; TVR, target vessel revascularization; w, weeks; VKA, vitamin K antagonist; WOEST, What is the Optimal Antiplatelet & Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting; ISAR TRIPLE, Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation; PIONEER AF, Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation; RE-DUAL PCI, Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Non-valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention; Entrust AF PCI, Edoxaban-Based Antithrombotic Regimen in Patients With Atrial Fibrillation; AUGUSTUS, Antithrombotic Therapy After Acute Coronary Syndrome or PCI in Atrial Fibrillation.|
|PIONEER AF 2016||Group 1||Rivaroxaban 15 (10) mg QD||Patients with AF and PCI and/or ACS treated with rivaroxaban (15 mg or 2.5 mg) and clopidogrel (DAT or TAT)|
|N = 2124||Clopidogrel 75 mg QD: 12 m (93%)||had statistically significative less bleeding compared with warfarin and DAPT (TAT). Ischemic events were similar|
|Open label||Group 2||Rivaroxaban 2.5 mg bid, or 15 (10) mg QD||for all the groups, but the results are disputable due to wide confidence interval.|
|RCT-1 year||Aspirin 75–100 mg/QD|
|Not designed to assess ischemic efficacy||Clopidogrel 75 mg QD: 1, 6 or 12 m (93%)|
|Group 3||VKA (INR = 2–3)|
|Aspirin 75–100 mg/QD.|
|Clopidogrel 75 mg QD: 1, 6 or 12 m (96%)|
|RE-DUAL PCI 2017||Group 1||Dabigatran 110 mg BID||Patients with AF and PCI and/or ACS treated with dabigatran (110 or 150 mg) and clopidogrel (DAT) had sta-|
|N = 2725||Clopidogrel 75 mg QD (86%)||tistically significative less or major CNRM bleeding than TAT with warfarin. Incidence of a composite secondary|
|Open label,||Group 2||Dabigatran 150 mg BID||efficacy endpoint (thromboembolic events, death, or unplanned revascularization) was similar in the DAT group|
|RCT-1 year||Clopidogrel 75 mg QD (87%)||as compared with the TAT.|
|Not designed to assess ischemic efficacy||Group 3||VKA (INR = 2–3)|
|Aspirin 75–100 mg/QD: 1 to 3 m.|
|Clopidogrel 75 mg QD (90%)|
|ENTRUST AF 2019||Group 1||Edoxaban 60 (30) mg QD.||Patients with AF and PCI and/or ACS, treated with edoxaban and clopidogrel (DAT) had less bleeding compared|
|N = 1506||Clopidogrel 75 mg QD: 12 m (93%)||with the AVK group, but the difference was statistically significative only for the non-inferiority. Ischemic events|
|Open label,||Group 2||VKA (INR = 2)||were not statistically different.|
|RCT-1 year||Aspirin 70-200 mg/QD: 1 to 12 m.|
|Not designed to assess ischemic efficacy||Clopidogrel 75 mg QD (92%)|
|AUGUSTUS 2019||Group 1||Apixaban 5 mg bid open label.||Patients with AF and ACS |
|N = 4614||Aspirin or placebo 81 mg double blind||tically significant less bleeding and fewer hospitalizations. Ischemic events were not statistically increase compared|
|Double blinded||Clopidogrel 75 mg QD: 6 m (92%)||with a regimen of VKA and/or aspirin.|
|RCT - 6 months||Group 2||VKA (INR = 2–3) open label|
|Aspirin for all on the day of ACS or PCI||Aspirin or placebo 81 mg double blind|
|and after for a median of 6 days||Clopidogrel 75 mg QD: 6 m (92%)|
|Aspirin vs Placebo after randomization|
|Not designed to assess ischemic efficacy|
|Legend: AF, atrial fibrillation; ACS, acute coronary syndrome; BID, twice daily; DAT, double antithrombotic therapy; DAT, double antithrombotic therapy; DAPT, dual antiplatelet therapy; CNRM, clinically relevant non, major bleeding; INR, international normalized ratio; m, months; N, number; QD, once daily; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; TAT, triple antithrombotic therapy; VKA, vitamin K antagonist; PIONEER AF, Open, Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose, Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation; RE, DUAL PCI, Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Non, valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention; Entrust AF PCI, Edoxaban, Based Antithrombotic Regimen in Patients With Atrial Fibrillation; AUGUSTUS, Antithrombotic Therapy After Acute Coronary Syndrome or PCI in Atrial Fibrillation.|
Rivaroxaban is an oral selective direct-acting factor Xa inhibitor that leads to the inactivation of both free and prothrombinase-bound factor Xa. It was the first DOAC exploratory investigated in the PIONEER AF-PCI trial. It was completed in patients undergoing PCI and having DAPT and then compared to TAT with VKA and DAPT. The 2124 stented subjects with non-valvular AF were randomly assigned to one of three antithrombotic combinations in a 1:1:1 ratio—low dose rivaroxaban (15 mg daily) and a P2Y12 inhibitor for 12 months, very low-dose rivaroxaban (2.5 mg twice daily) and DAPT for one, six, or twelve months, or dose-adjusted VKA and DAPT for one, six, or twelve months. The ACS represented around 50% of the subjects. The principal P2Y12 inhibitor was clopidogrel- 93.1% of group 1, 93.7% of group 2, and 96.3% of group 3. Of the prescribed P2Y12 inhibitors, prasugrel-treated patients were limited to 2% and ticagrelor to 5%. The primary safety end point for bleeding events was less frequent in both groups receiving rivaroxaban, as presented in Table 3. This trial adds new data on the use of low dose rivaroxaban in ACS patients and offersthe first clear signal for less bleeding with both reduced antithrombotic regimens-DAT (Rivaroxaban 15 mg/day and P2Y12 inhibitor), TAT with very low dose OAC (Rivaroxaban 2.5 mg twice daily) and DAPT [55,58]. PIONEER AF-PCI trial was not calibrated for ischaemic and thrombotic efficacy and low doses of rivaroxaban were not demonstrated to reduce stroke in AF patients [39,59].
Dabigatran is the only oral direct thrombin inhibitor available for clinical use until now. It has no ischaemic benefit and, depending on the dose, the clinically relevant major and minor bleeding had an approximatively four-fold increase in phase II of a dose-ranging randomized study in ACS patients . Dabigatran was tested in AF/ACS/PCI patients in the randomized open-label REDUAL PCI trial, which assigned 2725 patients to a TAT regimen with warfarin, a P2Y12 receptor inhibitor (clopidogrel or ticagrelor) and aspirin for one to three months, or to a DAT regimen with dabigatran (110 or 150 mg twice daily) and a P2Y12 inhibitor. Antithrombotic combinations have been administered for at least six months; after one year, administration of a P2Y12 inhibitor instead of aspirin was done at the investigator’s discretion. The principal P2Y12 inhibitor was clopidogrel, but ticagrelor was also chosen by the investigators in 12% to 13.5% of the patients, depending on the dabigatran regimen. The primary safety end point for bleeding events was less frequent in both groups receiving dabigatran. The combined ischaemic end point (thromboembolic events, death, or unplanned revascularization) was not that different in the DAT groups as compared with the TAT group, as shown in Table 3. However, the lower dose of dabigatran (110 mg) was associated with numerical more MI, stent thrombosis, stroke, and death events. In the United States, a lower dose of dabigatran, i.e., 110 mg, studied in the RE-LY (Dabigatran versus warfarin in patients with atrial fibrillation) is not approved in stroke prevention for AF patients [61,62]. The REDUAL trial only included patients undergoing PCI, about 50% of whom had ACS. Due to the study design, it is not clear whether the reduction in bleeding is dependent on the use of dabigatran or avoidance of aspirin [40,55]. Additionally, REDUAL PCI was not powered for efficacy in terms of ischaemic and antithrombotic events.
Edoxaban is another selective oral, direct-acting factor Xa inhibitor that leads
to the inactivation of both free and prothrombinase-bound factor. It was
investigated in the Entrust-AF PCI randomised open-label trial in patients who
recently underwent PCI and had edoxaban plus clopidogrel as DAT, then compared
with VKA plus DAPT as TAT. A number of 1506 patients were assigned to DAT with 60
mg edoxaban and 75 mg clopidogrel daily for one year versus a TAT regimen with
VKA, clopidogrel (75 mg daily for one year) and aspirin (100 mg daily, for 1–12
months). A lower dose of Edoxaban (30 mg daily) was used if the creatinine
clearance was 15–50 mL/min, weight
Apixaban is an oral selective, direct-acting FXa inhibitor of both free and
prothrombinase-bound factor Xa. It was investigated in the AUGUSTUS trial with
the scope of determining the optimal antithrombotic strategy among AF patients
and recent ACS, with or without PCI. The trial adopted a 2
A summary of findings from the four pivotal RCTs on DOACs in AF/ACS/PCI patients, especially encompassing the benefit of the regimens, is presented in Table 4.
The therapeutic goal in ACS is to prevent platelet adhesion and clot formation by interrupting platelet activation and the coagulation cascade. Two factors (factor Xa and thrombin – factor II a) are involved in the process of clot formation. The thrombin production persists beyond acute presentation, and, consequently, antithrombin therapy, in addition to platelet inhibition, has been proposed [65-67]. Warfarin plus aspirin reduce the risk of ischaemic events after ACS with or without stenting when compared to aspirin alone. However, oral VKA is prone to interaction with food and drugs, needs laboratory monitoring, and increase the bleeding events [68,69]. Thus, the long-term use of warfarin in such patients is not recommended . The DAPT regimen became the golden standard for the prevention of coronary stent thrombosis after the first trial with double antiplatelets regimens (aspirin plus ticlopidine), followed by other trials and meta-analyses [22,71,72]. Recent trials investigated the role of DOACs in ACS patients, but only very low-dose rivaroxaban (2.5 mg twice, daily) combined with DAPT (aspirin plus clopidogrel) reduced ischaemic events without a significant increase in fatal bleeding [58,60,73]. Thus, only the addition of this very low-dose rivaroxaban to aspirin and clopidogrel is recommended by the 2015 European Society of Cardiology guidelines (ESC) on selected ACS patients with low risk of bleeding [27,28].
We describe an illustrative scenario of a patient admitted to the intensive coronary care unit (ICCU) to better emphasize the challenges and unanswered questions concerning antithrombotic management in the setting of AF/ACS patients with or without PCI.
A 71-year-old male with a history of IHD [prior MI with stenting of right
coronary artery (RCA) 2 years ago] had recurrent chest pain. The
electrocardiogram (ECG) showed ST-segment depression in the V2–V6 leads and
paroxysmal AF. His blood pressure was 125/75 mmHg and CKD eGFR = 58
The case challenges the following questions.
The ACS prevalence in different trials ranges from 28% to 61% with a focus on reducing bleeding events . All these trials were underpowered to assess ischaemic efficacy, and the effects on ischaemic events and stent thrombosis were imprecise. There are signals that suggest a slight numerical increase of acute MI and stent thrombotic events, which came from a sub analyses of ACS subgroups or from meta-analyses, in the absence of studies dedicated only for ACS patients [40,43-47,63,64]. The duration and components of combination therapy for these high-risk patients are crucial, and further dedicated studies for ACS patients are needed to know the best ischaemic and thrombotic risk, and the management options.
The AUGUSTUS trial was the latest published study and the only one that
evaluated whether DOAC (apixaban) or VKA is preferable as part of DAT or TAT. It
is the only trial specially designed (2
Until now, there were no specific trials to determine the optimal duration of antithrombotic combinations on AF/ACS patients with or without PCI. The only trial that tried to investigate if a 6-week period of TAT works better than six months of TAT in terms of safety was ISAR – TRIPLE. Bleeding frequency was highest in the long TAT group (27.9% vs 20.5%, HR 0.68, p = 0.04) but the combined ischaemic end point was similar between the groups . Thus, the trial suggested that a short TAT period of six weeks is preferable over a longer one with six months. However, these results were applicable for a mixed population, with only 32% having an ACS. A longer TAT administration (three, six or twelve months), considering the balance between ischaemic and/or thrombotic and bleeding risk, was promoted by 2016 ESC guidelines for the management of atrial fibrillation . Due to the favourable results with DAT/DOACs regimens, the 2019 updated North American AF guidelines recommend it for patients with high-risk ACS (ST segment elevation or recurrent MI) as well to minimize duration of TAT to a period of four to six weeks . Recently, the 2020 ESC-AF guidelines as well as those for non-ST- elevation ACS recommend a short course of TAT for up to one week or until discharge in several AF patients (low risk of ischaemic and/or thrombotic complications) undergoing PCI [2,31]. These new recommendations highlight the concerns regarding early stent thrombotic events with DAT and argue an initial course of TAT in all AF/ACS patients having PCI [43-47]. An important issue is that in all these trials, aspirin was administered from two up to six days even in DAT regimens until randomization [39-42]. For ACS patients with medical management, the new recommendation is a DAT [DOACs and P2Y12 inhibitor (preferably clopidogrel)] regimen from the beginning . Interestingly, the post hoc results from the AUGUSTUS trial demonstrated that the ischaemic and antithrombotic efficacy of TAT was highest in the first month after the index event and lesser after this period . Moreover, the data from an SCA registry with almost 5000 patients who had MI and AF, showed that one in four patients were under TAT, which increased twice the frequency of intracranial haemorrhage but did not reduce recurrent ischaemic events . Therefore, while awaiting new data, an initial period of one week of TAT seems enough for low ischaemic and thrombotic risk in AF/ACS patients with uncomplicated PCI (GRACE score less than 140 in case of ACS, and high or non-correctable bleeding risk), while a longer period of up to four or six weeks of TAT is useful for patients at an increased ischaemic (recurrent events) or thrombotic risk (stents for left main or proximal descending coronary artery and bifurcation, longer or kissing stents, recurrent MI, stent thrombosis, scores over the mentioned values) and low bleeding risk [1,2,5,79]. After the removal of aspirin, DAT with a P2Y12 inhibitor (usually clopidogrel) is generally continued for 12 months in AF/ACS patients with or without PCI, but could be stopped at six months (as we did for our patient) considering the ischaemic and bleeding risk [1,2,5]. In our case scenario, the patient had both, a high ischaemic/thrombotic as well as bleeding risk. If he had TAT, in the first four to six weeks after the index event (as guidelines recommend in such patients), he would have likely escaped from the reported stent thrombosis. While the aspirin discontinuation was motivated by possible bleeding and the increased risk of bleeding, this approach exposed him to the increase in the ischaemic and thrombotic risk in the early period after stenting.
DOACs are preferred over VKA in all eligible AF patients [2,5]. When starting and selecting a DOAC, a preliminary evaluation of kidney and liver function is required asrenal function affects selection and dosing because all medications are eliminated in different proportions via the kidneys, as presented in Table 2. Frailty and bleeding risk, by themselves (usually evaluated with the HAS - BLED score), should not be a reason to deny DOACs. Outside the bio-clinical profile as mentioned above, however, different local factors (approval or regulatory restrictions, cost of the therapy) may influence selection of DOACs. All four DOACs tested in the pivotal trials for AF/ACS/PCI patients seems to be safe in terms of bleeding risks and ischaemic protection, with some differences according to the published and approved dose reduction criteria [39-42]. Therefore, the lowest, effective dose that was tested in AF trials should be used and dose reduction below the approved dose is not recommended as it may increase the thromboembolism risk [59,61,80-82]. While some caveats exist for rivaroxaban and dabigatran, the doses for apixaban and edoxaban remain in antithrombotic combinations similar to those for general AF patients, as presented in Table 2. Low-dose rivaroxaban (15 mg/day; dose reduction to 10 mg QD if CrCl 30–49 mL/min),and not the accepted 20 mg/day for AF, was investigated in the PIONEER AF-PCI due to the dose-dependent higher risk of bleeding [39,59]. Both doses (110 mg and 150 mg twice a day) of are approved for stroke prevention, but the lower dose seems to be associated with more ischaemic and thrombotic events in REDUAL PCI, and, therefore, might be less appropriate for patients with high thrombotic risk [40,83]. In the United States, as previously mentioned, the lower dose of dabigatran 110 mg studied in the RE-LY trial is not approved in stroke prevention for AF patients [61,62]. As recommended, we treated our patient with rivaroxaban 15 mg early after PCI and switched him from TAT to DAT due to haemoglobin loss and high bleeding risk.
The rate of new AF onset during index hospitalisation in ACS patients is around
10% and depends on the ischaemic burden, being more frequent at the onset of an
ischaemic episode or in those patients with extensive ischaemia [3,75,76,84].
However, short- and long-term prognosis of AF episodes during the ACS remains
unclear, especially if they are paroxysmal [6,85,86]. Different retrospective
studies showed a lesser OAC utilisation in these patients due to the belief that
the paroxysmal AF episode has a low stroke risk because it is transient and
triggered by acute ischaemia [86-89]. Thus, a practical guide in 2018 manifested
special attention for new onset AF/ACS patients and recommend OAC use,
considering the individual risk of stroke asassessed by the
Another challenging approach is the effectiveness of early OAC administration in
ACS patients with a low CHA
Clopidogrel is the P2Y12 inhibitor usually recommended by guidelines in AF/ACS patients [1-5]. While ticagrelor and prasugrel had a stronger antiplatelet effect and were superior to clopidogrel, prasugrel performed better in a more recent ACS study with equal bleedings [24,25,53]. However, they are not recommended in TAT due to more bleeding events, especially with prasugrel; this risk is less with ticagrelor, but always superior to clopidogrel [39,40,95-97]. Ticagrelor and prasugrel had a low percentage—6.2% and 1.2%, respectively—use in the antithrombotic trials in the AUGUSTUS trial; 5% and 2%, respectively, in the PIONEER AF-PCI trial, and 12% to 13.5% of the patients, (depending on the regimen of dabigatran) in the REDUAL-PCI trial, despite the documented superiority over clopidogrel in ACS population. Although the aforementioned studies were not powered to assess the antithrombotic preventing efficacy, it is possible that both new potent P2Y12 inhibitors have more protective effects in antithrombotic regimens when compared with clopidogrel [39-42]. Clopidogrel does not assure a sufficient platelet inhibition for around 40% of the patients, which could be a particularly important point when aspirin is omitted, as the last guidelines suggest [1,5,98]. Measuring the antiplatelet response to clopidogrel may warrant the reintroduction of aspirin or a switch to another P2Y12 inhibitor. A recent trial found that a clopidogrel prescription after STEMI, using genotype-guided point of care, produced less bleeding and equal ischaemic events when compared with ticagrelor or prasugrel . Moreover, similar results were documented in AF patients with interventional treatment [100,101]. Thus, genetic testing could be the answer when the thrombotic risk is not high and using clopidogrel in a DAT regimen represents the best option to reduce bleeding complications. Moreover, DOACs had similar efficacy as VKA in preventing strokes in AF patients and was also associated with less bleeding . Therefore, for most patients, different DAT regimens (clopidogrel or ticagrelor with DOACs) are valuable alternatives to TAT to reduce bleeding events. However, future studies are needed until this strategy can be widely implemented and the choice of P2Y12 inhibitor used is better documented [1,5,38]. We choose clopidogrel instead of ticagrelor for the six months treatment in combination with rivaroxaban as part of a guidelines recommended strategy to avoid bleeding complications in high bleeding risk patients (HAS-BLED score = 3, drop in Hb, possible gastrointestinal bleeding in our patient) [2,28,29,98]. As mentioned above, recent trials suggest the use of genotype-guided point of care to identify clopidogrel non – responders (a potentially risk for our patient), but the current guidelines do not recommend the routine testing .
The effect of DAPT administration for less than three months on ischaemic and
bleeding events and the use of only a potent P2Y12 inhibitor was studied in
recent ACS clinical trials [103-106]. In AF/ACS/PCI patients, the AUGUSTUS trial
and other sub analyses showed that the use of aspirin was important, mainly
during the initial treatment, and can be generally safely dropped at discharge
with the continuation of DAT alone (OAC plus P2Y12 inhibitor) for at least six
months [42-47,63,64]. The signals for such an approach began with the
exploratory WOEST study, followed by the DOACs trials, that showed that bleeding
events were less with DAT (OAC plus P2Y12 inhibitor) as compared to TAT [38-42].
However, these trials were not designed to explore the anti-ischaemic and
antithrombotic efficacy even though the cardiovascular deaths and stroke were
similar between DAT and TAT regimens. The data coming from the subgroups of
ACS/PCI patients demonstrated that there exist more numerical ischaemic (OR 1.43,
95% CI 1.02–2.00, p = 0.04 for MI), thromboembolic events, or stent
thrombosis in DAT groups with lower doses of DOACs (e.g., dabigatran 110 mg,
twice a day in REDUAL-PCI), or placebo versus aspirin, or early after index
events as in the AUGUSTUS trial (or 1.92, 95% CI 0.98–3.75, p = 0.06
for stent thrombotic events) [47,107]. High thrombotic (e.g., prior stent
thrombosis, stents at bifurcation, left main stent, or long/complex stented
lesions) or ischaemic risk patients (recurrent or multiple MI, GRACE score risk
Finally, an accurate balance of risks is crucial for both regiments, and
bleeding and ischaemic/thrombotic risk should be assessed on a case-by-case
basis. It determines the type and duration of the DAT or TAT regimens. In our
case scenario, all patients taking OAC are at an increased risk of bleeding
compared to those not taking OAC, and the risk is higher in the first weeks after
initiation of anticoagulation [36,108]. The same pattern applies for ischaemic
and thrombotic risk in cases when antithrombotic therapy is discontinued after a
bleeding event, i.e., in the early days and weeks after the ACS . There are
no specific risk scores estimating bleeding or thrombotic risk for AF/ACS
patients; however, scores such as the DAPT, PRECISE – DAPT, CHA
Among AF patients developing ACS with or without PCI, the DAPT loading should be
considered in all patients. In addition to an OAC, a DOAC (if there is no
metallic valvular prosthesis or moderate to severe mitral stenosis) is usually
needed to reduce cardioembolic stroke for those at increased risk based on their
A summary of the practical recommendations is given below:
• Ischaemic and bleeding risks need to be assessed using va-lidated risk score
predictors (e.g., CHA • TAT is to be kept as short as possible considering the ischaemic, thrombotic and
bleeding risk. • DAT (preferably DOACs and clopidogrel) may be considered early after TAT in
select patients. • Clopidogrel is the P2Y12 inhibitor of choice. • Low-dose ( • Target INR is 2.0–2.5 when warfarin is used. • Prophylactic proton pump inhibitors should be routinely used for patients taking
antithrombotic regimens, especially for those with a history or with increased
risk of gastrointestinal bleeding.
• Ischaemic and bleeding risks need to be assessed using va-lidated risk score
predictors (e.g., CHA
• TAT is to be kept as short as possible considering the ischaemic, thrombotic and bleeding risk.
• DAT (preferably DOACs and clopidogrel) may be considered early after TAT in select patients.
• Clopidogrel is the P2Y12 inhibitor of choice.
• Low-dose (
• Target INR is 2.0–2.5 when warfarin is used.
• Prophylactic proton pump inhibitors should be routinely used for patients taking antithrombotic regimens, especially for those with a history or with increased risk of gastrointestinal bleeding.
CP, DT, AP conceived, structured, and organized this review. CP and DT performed the literature research and reviewed the studies’ data. CP and AP wrote the original draft. DT organized the tables and references. CP, DT and AP updated and revised the original draft by analysing the latest published studies and reports. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
The authors would like to thank all the peer reviewers for their opinions and suggestions.
This research received no external funding.
The authors declare no conflict of interest.