The PIONEER AF-PCI study: its implications for everyday practice in the UK

Br J Cardiol 2018;25(suppl 1):S12–S15doi:10.5837/bjc.2018.s03 Leave a comment
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Sponsorship Statement:

Bayer plc. commissioned and funded this supplement. The company has reviewed the data to ensure factual accuracy in relation to Bayer products and compliance with industry guidelines. Rivaroxaban prescribing information current at the time of publication is available here.

Job code: UKXAR04170195a, Date of preparation: July 2018

For notes on dosing recommendations from Xarelto® ▼ (rivaroxaban) SmPC (Summary of Product Characteristics) please see the box at the foot of this page

Our ageing population is resulting in increasing rates of coronary artery disease and atrial fibrillation (AF), which require intervention. Anticoagulation in patients with non-valvular AF undergoing percutaneous coronary intervention (PCI) is a growing challenge. As a consequence, we are now in an era of investigating optimal regimens to minimise bleeding risk, while not compromising the efficacy of stroke prevention or coronary secondary prevention in patients with these comorbidities. This paper looks at current treatment guidelines and developments with the PIONEER AF-PCI study, and their implications for UK practice.

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Introduction

We are in a challenging era of increasing use of coronary stenting for coronary artery disease (CAD) in the UK,1 in conjunction with a growing population of patients with atrial fibrillation (AF) predominantly driven by age, hypertension, obesity and diabetes.2

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Inevitably, these two common diseases, with similar risk factors, occur simultaneously in a significant proportion (5 to 8%) of patients undergoing revascularisation.3-5 This equates to an estimated 4,500 to 7,200 patients in the UK population, based upon British Cardiovascular Intervention Society (BCIS) data in 2014.1

Atrial phase thrombus has a stasis and fibrin drive, whereas arterial phase thrombus is driven by endothelial plaque rupture and platelet aggregation. These two substrates, therefore, have different treatment regimens, but there is an overlap given that thrombus formation is both fibrin and platelet dependent. Antiplatelet agents (although not recommended by the National Institute for Health and Care Excellence [NICE]) have an evidenced-based secondary prevention role in stroke reduction in AF,6 and anticoagulants have a similar role in coronary secondary prevention.7,8

Unfortunately, but inevitably, the more aggressive the anticoagulant, antiplatelet or combined treatment regimen, the higher the risk of bleeding.9 As a consequence, we are now in an era of investigating optimal regimens to minimise this bleeding risk, while not compromising the efficacy of stroke prevention or coronary secondary prevention in patients with coronary disease and AF.

With an increasing number of antiplatelet and anticoagulant agents vying for our therapeutic attention, the permutations of possible combinations of drugs are rapidly approaching the point where we may never get a clear answer about optimal therapy. In the present crowded market there are many potential combinations of anticoagulant and antiplatelet agents that could be meaningfully investigated in these higher-risk patients, and this is before dose, patient comorbidities, length of treatment, stent type and many other factors are taken into account. Where to start?

PIONEER AF-PCI

The PIONEER AF-PCI (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 who Undergo Percutaneous Coronary Intervention) study is one of the first attempts to try and help answer this question in the non-vitamin K antagonist oral anticoagulant (NOAC) era. The study, covered in the previous commentary, has a complex three-way design, partly necessitated by the publication of the WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting) study during the design period of PIONEER AF-PCI.  WOEST10 supported the early use of a dual rather than triple strategy with concurrent treated CAD and a need for anticoagulation. WOEST has no doubt changed practice and guidelines, but remains a small-scale trial, which created as many questions as it answered. Has PIONEER AF-PCI addressed these questions or, like WOEST, simply added more data pieces to an already difficult data jigsaw?

Current guidelines

The current European Society of Cardiology (ESC) guidelines11 for anticoagulant and antiplatelet therapy in stenting and AF are both somewhat complex and admit to a degree of uncertainty with an, at best, class IIa/B level of evidence/recommendation.

They are best summarised as recommending the minimum number of drugs for the shortest time possible. This is achieved by minimum procedural interruption of anticoagulation with a well-controlled vitamin K antagonist (VKA) (international normalised ratio [INR] 2.0–2.5) or lower-dose NOAC, in conjunction with a shortest possible dual antiplatelet therapy (DAPT) period depending upon coronary stability. Single antiplatelet therapy should be adopted as soon as possible, depending upon bleeding risk and coronary status (acute coronary syndrome [ACS] or stable CAD). Treatment algorithms can be found in the 2016 ESC guidelines11 and the 2017 update from the ESC/European Association for Cardio-Thoracic Surgery (EACTS).12 Antiplatelet therapy should, ideally, not extend beyond a 12-month period, with the use of prasugrel or ticagrelor not recommended on current evidence.

The American College of Cardiology (ACC)/American Heart Association (AHA) focused update guidelines on patients with CAD13 are broadly similar to the ESC guidelines. The most important differences are ongoing support of warfarin in preference to a NOAC (with the caveat that important trials are pending in this area) and a minimum DAPT period of three months for stable CAD and a maximum of six months for ACS with third-generation stents. Ultimately (and sensibly) the authors recommend an individualised approach to therapy balancing stroke risk, stent thrombosis risk and bleeding risk.14

PIONEER

Does PIONEER AF-PCI change UK practice?

Rivaroxaban has no doubt stolen a march on its NOAC rivals in the CAD arena. The ATLAS 2 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome) trial8 supports the efficacy and safety profile of 2.5 mg rivaroxaban twice daily when used in ACS alongside DAPT, and more recently the PIONEER AF-PCI trial has indicated lower bleeding risk with a rivaroxaban/antiplatelet regimen versus a warfarin/antiplatelet regimen.15

The recent results of the dabigatran-centred REDUAL-PCI (Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting),16 study also shows a lower risk of bleeding with dabigatran and a P2Y12 inhibitor versus triple therapy with warfarin plus DAPT. Results from the apixaban-centred AUGUSTUS (A Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis Due to Having Had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart) trial17 and the edoxaban-centred ENTRUST-AF PCI (Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial18 are not yet reported so the evidence base currently sits with rivaroxaban and dabigatran. As this supplement focuses on PIONEER AF-PCI, we need to consider whether it takes us any further forward or whether it (and subsequent studies) simply muddy the multiple permutation waters even more?

Two important areas in PIONEER AF-PCI are worth highlighting. First, this is not a head-to-head study. The two rivaroxaban arms represent either a less aggressive anticoagulant or antiplatelet regimen than the warfarin arm. A lower bleeding rate in these two groups should, therefore, be expected. In the absence of a head-to-head study (15 mg dose rivaroxaban combined with DAPT vs. warfarin and DAPT), it is impossible to say whether the reduced bleeding rate is simply related to the less aggressive regimens in these two arms rather than any special pharmacological property of rivaroxaban, such as a steadier state anticoagulant effect.

Second, the study is based upon a primary bleeding end point (i.e. essentially a number needed to harm) rather than a cardiovascular event end point. Examining primary end points related to harm, without adequate power to detect meaningful major adverse cardiovascular events (MACE) increases in the less aggressive arms, is always going to be suboptimal. This is particularly important in PIONEER AF-PCI because both rivaroxaban arms represent a substantial reduction in either anticoagulation or antiplatelet treatment. The investigators have calculated that a sample size of over 40,000 would be required to look at efficacy end points in conjunction with bleeding risk, and such a trial is not pragmatic.

Efficacy signals

Nonetheless, despite the issue of power, the secondary MACE efficacy analysis in PIONEER AF-PCI showed minimal worrying signals, other than one strata in which rivaroxaban 2.5 mg twice daily with six months DAPT was inferior for stroke prevention compared with warfarin combined with DAPT.15 Should this worry us? Maybe not, but perhaps these data, and the fact that very-low-dose therapy for any anticoagulant does not enter current AF guidelines, means that very low-dose rivaroxaban will fall by the wayside in the setting of atrial fibrillation and PCI.

Hospitalisation

Clinicians, along with clinical commissioning groups (CCGs), in the UK have an active interest in minimising hospitalisation. Hospitalisation has, therefore, become popular as part of a combined study end point, particularly in chronic diseases, such as heart failure. In a post-hoc analysis of PIONEER AF-PCI19 using a combined end point of all-cause mortality and need for rehospitalisation, the authors found a statistically significant difference between the individual rivaroxaban arms versus warfarin (35% and 32% in the rivaroxaban groups vs. 42% in the warfarin group). A major drive to this difference, not unexpectedly, was reduced hospitalisation due to bleeding. This is a finding of interest, both for the surprisingly huge number of readmissions in all groups, and the potential cost savings from a 10% absolute reduction (25% relative risk reduction) in readmissions in this study.19

Convenience

When WARIS (Warfarin Re-Infarction Study) was published in 1992,7 cardiologists threw up their collective hands in horror that they might be forced to engage with the difficulties of warfarin management in the context of myocardial infarction. Luckily, things moved on rapidly with antiplatelet regimens, and warfarin was marginalised.

NOACs, hopefully, will provide a similar escape. It seems likely that with the increasing UK (but variable 21.8% to 84.8% across CCGs) uptake of NOAC therapy for NVAF stroke prevention,20 and support with data from trials, such as PIONEER AF-PCI, NOAC therapy will be adopted as the primary anticoagulant regimen in ACS complicating AF.

Summary

PIONEER AF-PCI has added new data to the complex and difficult management of patients with concurrent AF and unstable or intervention-requiring CAD. The study gives us no reason to ‘unadopt’ the current European guidelines but increases our confidence in the use of NOACs in this group of patients, and, for the time being, suggests rivaroxaban, with its label update, is currently the preferential NOAC in this arena.

Key messages

  • Bleeding is a major problem in atrial fibrillation (AF) patients with concurrent coronary artery disease (CAD) who require anticoagulation and antiplatelet therapy
  • Non-vitamin K antagonist oral anticoagulant (NOAC) therapy may be part of the solution to minimise bleeding while not increasing major adverse cardiovascular events (MACE), but more information is required in order to substantially change the current guidelines
  • A large trial powered for efficacy end points, as well as bleeding analysis, is unlikely to happen, and future guidelines are likely to be based upon similar trials to PIONEER AF-PCI combined with consensus expert opinion, with clinicians taking responsibility for individualising therapy based upon risk

Conflict of interest

JG has received speaker fees and advisory board fees from Bayer plc.

 

Articles in this supplement include:

Introduction
Anticoagulation in patients with non-valvular AF undergoing PCI: clinical evidence from PIONEER AF-PCI
The potential for NOACs in cardiac ablation in the UK
Use of NOAC drugs in DC cardioversion for patients with non-valvular AF

 

References

1. British Cardiovascular Intervention Society. BCIS audit returns adult interventional procedures. Jan 2014 to Dec 2014. Basingstoke: BCIS, October 2015. Available at: https://www.bcis.org.uk/wp-content/uploads/2017/01/BCIS-audit-2014.pdf

2. National Institute for Health and Care Excellence. Atrial fibrillation: management. CG180. London: NICE, June 2014. Available from: https://www.nice.org.uk/guidance/cg180

3. Rubbioli A, Colletta M, Herzfeld J, Sangiorgio P, Di Pasquale G. Periprocedural and medium-term antithrombotic strategies in patients with an indication for long-term anticoagulation undergoing coronary angiography and intervention. Coronary Artery Dis 2007;18:193–9. https://doi.org/10.1097/MCA.0b013e328012a964

4. Wang TY, Robinson LA, Ou F-S et al. Discharge antithrombotic strategies among patients with acute coronary syndrome previously on warfarin anticoagulation: physician practice in the CRUSADE registry. Am Heart J 2008;155:361–8. https://doi.org/10.1016/j.ahj.2007.09.003

5. Perez-Gomez F, Alegria E, Berjon J et al. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol 2004;44:1557–66. https://doi.org/10.1016/j.jacc.2004.05.084

6. The ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360:2066–78. https://doi.org/10.1056/NEJMoa0901301

7. Smith P. Long-term anticoagulant treatment after acute myocardial infarction. The Warfarin Re-Infarction Study. Ann Epidemiol 1992;2:549–52. https://doi.org/10.1016/1047-2797(92)90105-Y

8. Mega JL, Braunwald E, Wiviott SD et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9–19. https://doi.org/10.1056/NEJMoa1112277

9. Sørensen R, Hansen ML, Abildstrom SZ et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009;374:1967–74. https://doi.org/10.1016/S0140-6736(09)61751-7

10. Dewilde WJ, Oirbans T, Verheugt FW et al. 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;381:1107–15. https://doi.org/10.1016/S0140-6736(12)62177-1

11. Kirchhof P, Benussi S, Kotecha D et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. https://doi.org/10.1093/eurheartj/ehw210

12. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease if the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoraric Surgery (EACTS). Eur Heart J 2018;39:213–54. https://doi.org/10.1093/eurheartj/ehx419

13. Levine GN, Bates ER, Bittl JA et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082–115. https://doi.org/10.1016/j.jacc.2016.03.513

14. American College of Cardiology. Eagle KA. Important updates to the recommendations on dual antiplatelet therapy. Available at: http://www.acc.org/latest-in-cardiology/features/dual-antiplatelet-therapy-dapt-focused-update-hub

15. Gibson CM, Mehran R, Bode C et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375:2423–34. https://doi.org/10.1056/NEJMoa1611594

16. Cannon CP, Bhatt DL, Oldgren J et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017;377:1513–24. https://doi.org/10.1056/NEJMoa1708454

17. Clinicaltrials.gov. A study of apixaban in patients with atrial fibrillation, not caused by a heart valve problem, who are at risk for thrombosis (blood clots) due to having had a recent coronary event, such as a heart attack or a procedure to open the vessels of the heart. April 2015. Available at: https://clinicaltrials.gov/ct2/show/NCT02415400

18. Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (ENTRUST-AF-PCI). https://clinicaltrials.gov/ct2/show/NCT02866175

19. Gibson CM, Pinto DS, Chi G et al. Recurrent hospitalization among patients with atrial fibrillation undergoing intracoronary stenting treated with 2 treatment strategies of rivaroxaban or a dose-adjusted oral vitamin K antagonist treatment strategy. Circulation 2017;135:323–33. https://doi.org/10.1161/CIRCULATIONAHA.116.025783

20. NHS Business Services Authority. Medicines Optimisation Dashboard https://apps.nhsbsa.nhs.uk/MOD/AtlasCCGMedsOp/atlas.html

 

Notes on dosing recommendations from Xarelto® ▼ (rivaroxaban) SmPC (Summary of Product Characteristics)

For the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (AF) with one or more risk factors, the recommended dose is 20 mg once daily (15 mg once daily in patients with moderate [creatine clearance {CrCl} 30-49 ml/min] or severe [CrCl 15-29 ml/min] renal impairment). To be used with caution in severe renal impairment and use is not recommended in patients with CrCl <15 ml/min.

The above doses were studied in the pivotal ROCKET AF study in patients with non-valvular AF.

In the PIONEER AF-PCI study, participants with non-valvular AF who had undergone percutaneous coronary intervention (PCI) with stenting were randomly assigned to receive either rivaroxaban 15 mg once daily (10 mg once daily, CrCl 30-50 ml/min) plus a P2Y12 inhibitor for 12 months, or rivaroxaban 2.5 mg twice daily plus dual antiplatelet therapy (DAPT) for one, six, or 12 months, or dose-adjusted vitamin K antagonist once daily plus DAPT for one, six, or 12 months.

The Xarelto® (rivaroxaban) SmPC has been updated under ‘Special populations’ in the section on ‘Posology and method of administration’ following completion of the PIONEER AF-PCI study; the rivaroxaban 15 mg once daily regimen, but not the 2.5 mg twice daily regimen, has been included.

In summary, the SmPC update states that for patients with non-valvular AF who require oral anticoagulation and undergo PCI with stent placement, there is limited experience of a reduced dose of rivaroxaban 15 mg once daily (10 mg once daily, CrCl 30-49 ml/min) in addition to a P2Y12 inhibitor for a maximum of 12 months.

Disclaimer: Medinews Cardiology Limited advises healthcare professionals to consult up-to-date Prescribing Information and the full Summary of Product Characteristics available from the manufacturers before prescribing any product. Medinews Cardiology Limited cannot accept responsibility for any errors in prescribing which may occur.
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