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Peripheral Artery Disease: causes and consequences

Coronary Artery Disease: causes and consequences

Patients with AF Undergoing PCI

This section provides an overview of the epidemiology of AF and concomitant coronary artery disease, and the issues faced when treating these patients.

20-40% of patients with atrial fibrillation (AF) are estimated to have concomitant coronary artery disease (CAD).1,2 These patients with AF and CAD have complex treatment needs, and approximately 20% of them will require revascularization by percutaneous coronary intervention (PCI).3
Furthermore, AF is particularly prevalent amongst the elderly.4 Populations worldwide are ageing, therefore the prevalence of AF is also set to increase.5,6 CAD is also highly prevalent in the elderly,6 and is frequently treated with PCI in this population7. Therefore, stenting in patients with AF is likely to be increasingly encountered in clinical practice.8

Up to 4 in 10 patients with AF have concomitant CAD

Up to 4 in 10 patients with AF have concomitant CAD1,2

There is clear guidance for the management of AF and PCI when they manifest individually. Oral anticoagulation (OAC) therapy can protect patients with AF from stroke,4 while dual antiplatelet therapy (DAPT) with aspirin and an oral P2Y12 receptor inhibitor after PCI, can prevent serious complications, such as myocardial infarction (MI) and stent thrombosis, and protect patients with CAD from cardiovascular (CV) death.7,9
However, when AF and PCI coincide, treatment decisions can become more difficult. Due to the significantly increased risk of thromboembolic events, triple therapy, a combination of DAPT and OAC therapy, has previously been recommended for use in patients with AF undergoing PCI.4 However, this is an extremely high dose of antithrombotic therapy which puts patients at a serious risk of bleeding, worsens clinical outcomes and increases the risk of death.8,10,11
Balancing the prevention of thromboembolic events with the risk of bleeding is a crucial issue that needs addressing to protect this susceptible population of patients.

 

Four randomized controlled trials have investigated the use of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with AF undergoing PCI. The results from these trials indicate that improved safety profiles are observed with NOAC treatment.12-15 Due to the differing designs, drug regimens and patient characteristics of each trial, it is not possible to make conclusions on the limitations and advantages of one NOAC over another. Furthermore, all trials were underpowered to assess ischaemic endpoints for individual NOAC regimens versus standard of care.12-15

Resumen del estudio PIONEER FA-ICP, que evaluó la seguridad y eficacia de rivaroxabán en pacientes con FA sometidos a ICP

YYMMDD Author/Uploaded by

Fibrilación auricular, intervención coronaria percutánea, FA e ICP, rivaroxabán, revascularización

PIONEER AF-PCI trial overview
Overview of the PIONEER AF-PCI trial, which assessed the safety and efficacy of rivaroxaban in patients with AF undergoing PCI
Approval number: PP-XAR-ALL-0042-1

PIONEER AF-PCI

PIONEER AF-PCI was the first prospective study of a NOAC in patients with AF undergoing PCI. The trial compared the safety of two rivaroxaban treatment strategies with VKA plus DAPT in patients with non-valvular AF (NVAF) after PCI with stent placement.12
Rivaroxaban 20 mg once daily (od) is indicated for stroke prevention in patients with AF. However, due to the increased risk of bleeding in patients receiving anticoagulation therapy and DAPT, a reduced dose of 15 mg rivaroxaban od was evaluated in PIONEER AF-PCI.12 Additionally, rivaroxaban 2.5 mg twice daily (bid) was investigated in line with the dose administered in the ATLAS ACS 2-TIMI 51 and COMPASS trials in patients with acute coronary syndrome and atherosclerotic disease, respectively.12,16,17

PIONEER AF-PCI trial design

PIONEER AF-PCI trial design12,18

At 12 months, both rivaroxaban strategies were associated with a significant reduction in the primary safety endpoint of clinically significant bleeding (defined as a composite of Thrombosis in Myocardial Infarction [TIMI] major bleeding, TIMI minor bleeding and bleeding requiring medical attention) versus the triple therapy strategy.12 The difference in bleeding was largely driven by the reduction of bleeding requiring medical attention.12 These results provide reassurance that rivaroxaban treatment has a good safety profile in this high-risk patient population.

In PIONEER AF-PCI, both rivaroxaban treatment strategies were associated with a significant reduction in incidence of clinically significant bleeding compared with the VKA plus DAPT strategy

In PIONEER AF-PCI, both rivaroxaban treatment strategies were associated with a significant reduction in incidence of clinically significant bleeding compared with the VKA plus DAPT strategy12

The rate of major CV events (major adverse cardiovascular events [MACE]; composite of CV death, MI or stroke) and stent thrombosis was similar between all three treatment arms. However, the PIONEER AF-PCI trial was not powered to demonstrate superiority or inferiority for efficacy for these endpoints.12 Based on the results of PIONEER AF-PCI, rivaroxaban 15 mg od has been approved for use in the European SmPC for patients with AF undergoing PCI.19

 

AFIRE

In addition to PIONEER AF-PCI, the prospective, open-label, parallel-group AFIRE trial assessed the non-inferiority of rivaroxaban monotherapy compared with treatment with rivaroxaban in combination with a P2Y12 inhibitor in Japanese patients with AF and stable CAD.11
In contrast to PIONEER AF-PCI, which looked at treatment within 72 hours of PCI,12 AFIRE provided clarity on the optimum treatment for patients at least one year after a PCI.11
Another key difference between PIONEER AF-PCI and AFIRE was the rationale behind the use of rivaroxaban 15 mg od, which was evaluated in both studies (with dose reduction to rivaroxaban 10 mg od based on renal function).11,12 In PIONEER AF-PCI, rivaroxaban 15 mg od represented a lower dose than the 20 mg od dose that is typically indicated for stroke prevention in patients with AF in Europe and the USA.19,20 However, in Japan rivaroxaban 15 mg od is the standard dose for stroke prevention and so the use of rivaroxaban 15 mg od in AFIRE did not represent a dose reduction.21

AFIRE trial design

AFIRE trial design11

Rivaroxaban monotherapy was demonstrated to be non-inferior to rivaroxaban plus antiplatelet with respect to the primary efficacy endpoint; a composite of stroke, systemic embolism, MI, unstable angina requiring revascularization and all-cause mortality. A clear mortality benefit was associated with rivaroxaban monotherapy compared with the control and this led to early termination of the AFIRE trial.11

 

Rivaroxaban monotherapy was superior to combination therapy for the primary safety endpoint of International Society on Thrombosis and Haemostasis (ISTH) major bleeding, with event rates of 1.62% and 2.76% per patient-year, respectively.11

The rivaroxaban monotherapy treatment strategy was associated with a significant reduction in incidence of bleeding compared with the rivaroxaban plus antiplatelet strategy in AFIRE.

The rivaroxaban monotherapy treatment strategy was associated with a significant reduction in incidence of bleeding compared with the rivaroxaban plus antiplatelet strategy in AFIRE.11

RE-DUAL PCI

RE-DUAL PCI aimed to assess the non-inferiority of two regimens of dabigatran plus single antiplatelet compared with triple therapy with warfarin in patients with AF after PCI with stenting.15

RE-DUAL PCI study design

RE-DUAL PCI study design15,20

Both dabigatran treatment arms showed a significant reduction in the primary endpoint (time to first ISTH major or clinically relevant non-major [CRNM] bleeding) compared with the triple therapy arm.15

Both dabigatran treatment strategies in RE-DUAL PCI were associated with a reduction in incidence of clinically significant bleeding compared with the triple therapy strategy

Both dabigatran treatment strategies in RE-DUAL PCI were associated with a reduction in incidence of clinically significant bleeding compared with the triple therapy strategy15

The rate of the secondary endpoint (a composite of death, MI, systemic embolism and stroke) was similar between the pooled dual dabigatran treatment strategies and the triple therapy strategy.15 However, it is not possible to draw any conclusions on the efficacy of each individual regimen. The European SmPC of dabigatran approves the use of dabigatran 110 mg bid for the prevention of stroke and systemic embolism in patients with AF; however, the label is yet to be updated to reflect the results of RE-DUAL PCI and does not provide dosing guidance for patients undergoing PCI.23

 

ENTRUST-AF PCI

ENTRUST-AF PCI was a non-inferiority, randomized phase IIIb trial that aimed to assess the safety and efficacy of an edoxaban-based regimen in comparison with a vitamin K antagonist (VKA)-based regimen in patients with AF who had undergone a recent PCI.14

ENTRUST-AF PCI trial design

ENTRUST-AF PCI trial design14

The edoxaban-based therapy was demonstrated to be non-inferior to the VKA-based therapy for the primary endpoint, a composite of ISTH major or CRNM bleeding within 12 months.14

In ENTRUST AF-PCI, edoxaban treatment resulted in a non-significant reduction in the rates of bleeding compared with the VKA treatment strategy

In ENTRUST AF-PCI, edoxaban treatment resulted in a non-significant reduction in the rates of bleeding compared with the VKA treatment strategy14

In addition, there was no significant difference between the rate of the main efficacy outcome of the study (a composite of CV death, stroke, MI, stent thrombosis and systemic embolism): 7% for the edoxaban-based treatment group and 6% for the VKA-based treatment group. The edoxaban 60 and 30 mg doses administered during ENTRUST-AF PCI are approved for use in patients with AF by the European SmPC; however, the label does not provide specific dosing guidance for patients undergoing PCI and has not yet been updated to reflect the results of ENTRUST.24

 

AUGUSTUS

In the AUGUSTUS trial, patients with AF with concomitant CAD or who had undergone PCI were randomized to receive an apixaban- or VKA-based triple therapy regimen for 6 months.13 The patients were further randomized to receive aspirin or placebo. This allows comparisons between apixaban and warfarin in addition to evaluation of the effect of removing aspirin from the treatment regimen.13

AUGUSTUS trial design

AUGUSTUS trial design13,25

The primary outcome of AUGUSTUS was ISTH major or CRNM bleeding, of which significantly lower rates were observed after treatment with apixaban compared with that with warfarin after 6 months. Moreover, a significantly higher rate of bleeding was observed in patients with aspirin compared with those with placebo.13

In AUGUSTUS, treatment with apixaban was associated with a reduction in incidence of bleeding compared with treatment with warfarin

In AUGUSTUS, treatment with apixaban was associated with a reduction in incidence of bleeding compared with treatment with warfarin13

The combined endpoint of death or hospitalization was significantly lower with apixaban compared with warfarin (23.5% compared with 27.4%; hazard ratio [HR]=0.83, 95% confidence interval [CI] 0.74–0.93, p=0.002), driven by a significant reduction in the number of new hospitalizations. The rate of this endpoint, however, was similar between aspirin and placebo. Additionally, the rate of ischaemic events was similar between the treatment arms.13 Apixaban 5 mg and 2.5 mg bid are approved for use in patients with AF in the European SmPC; however, specific dosing guidance for patients undergoing PCI are not stated because the label is yet to be updated to reflect the results of AUGUSTUS.26

 

For patients at high risk of bleeding events, the 2017 European Society of Cardiology (ESC) guidelines on dual antiplatelet therapy in CAD recommend the following upon hospital discharge of patients with an indication for OAC undergoing PCI9:

  • The use of dual therapy (OAC plus clopidogrel) for ≤12 months post PCI, followed by OAC monotherapy from 12 months

Or

  • The use of triple therapy (OAC plus clopidogrel plus aspirin) for 1 month followed by dual therapy (OAC plus clopidogrel or aspirin) up to 12 months, with OAC monotherapy from 12 months

When the patient’s ischaemic risk outweighs the risk of bleeding, the ESC guidelines recommend triple therapy for 1 month, continuing up to 6 months, followed by dual therapy (OAC plus clopidogrel or aspirin) up to 12 months after undergoing PCI, after which OAC monotherapy is recommended9.
While one NOAC is not recommended over another, the lowest approved dose for stroke prevention of each NOAC should be considered when administered in combination with clopidogrel or aspirin.9

2017 ESC guidelines for patients with an indication for OAC undergoing PCI

2017 ESC guidelines for patients with an indication for OAC undergoing PCI9

The 2019 American Heart Association (AHA), American College of Cardiology (ACC), and Heart Rhythm Society (HRS) (AHA/ACC/HRS) guidelines for the management of patients with AF has been written using data from PIONEER AF-PCI and RE-DUAL PCI.27 The guidelines recommend that patients with AF (CHA2DS2-VASc score ≥2) who have undergone PCI receive dual therapy with a P2Y12 receptor inhibitor and either rivaroxaban (15 mg od), dabigatran (150 mg bid) or dose-adjusted VKA. Alternatively, triple therapy with aspirin can be administered for 4–6 weeks when the risk of stent thrombosis is greatest. DAPT should be considered for patients with a CHA2DS2-VASc score ≤1; however, the patient’s indication for anticoagulation should be reviewed over time.27
This is supported by North American clinical practice guidelines which recommend that upon hospital discharge of patients with AF post-PCI, a dual therapy of a NOAC at the established stroke prevention dose plus P2Y12 inhibitor should be administered for most patients.28 Furthermore, the North American guidelines suggest that triple therapy may be considered for patients at high ischaemic risk for 1 month. These guidelines, however, do not support the use of one NOAC over another.28

References

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