Editorial

to prescribe more potent agents but may Heart: first published as 10.1136/heartjnl-2021-319830 on 12 August 2021. Downloaded from Adding to the evidence or to the have feared a higher bleeding risk with prasugrel or ticagrelor. confusion: dual antithrombotic therapy Interestingly, the authors report no difference in major bleeding between in chronic coronary syndrome and both cohorts (2.35% vs 2.95%, p=0.456) which again contrasts with atrial fibrillation the findings of HOST-­EXAM where clopidogrel was associated not only with Shinwan Kany ‍ ‍ , Renate Schnabel ‍ ‍ fewer thrombotic events (3.7% vs 5.5%, p=0.003) but also less bleeding (2.3% vs 3.3%, p=0.003).7 The pathophysio- Atrial fibrillation (AF) is the most common Patients in the dual antithrombotic logical background of aspirin-induced­ arrhythmia in the world with the lifetime arm were compared in regard to addi- gastric bleeding is nicely explained by risk estimated to be 1/3 in men and women tional APT (P2Y inhibitors n=297 vs 12 the inhibition of cyclo-­oxygenase which over the age of 50 years.1 Cardiovascular aspirin n=778) and a primary outcome of not only leads to the desired inhibition disease, like misfortune, does not come composite of stroke, systemic embolism, of platelet-­aggregator thromboxane A singly in most cases. Coronary artery myocardial infarction, unstable angina 2 but also the synthesis of prostaglandins disease (CAD) with the chronic coronary requiring urgent revascularisation or syndrome (CCS) or acute coronary death from any cause. No difference in the which are essential for gastric mucus syndrome (ACS) is a common comorbid primary outcome was observed in patients secretion (figure 1). condition. Management of patients with One of the strengths in the work by receiving P2Y12 inhibitors or aspirin AF with a comprehensive treatment of risk (6.76% vs 5.28%, p=0.178). However, Fukaya et al may be the utilisation of factors and concomitant diseases is the key proton pump inhibitors (PPIs) in both mortality was higher in the P2Y12 inhibi- to treat these patients. Yet, the devil is in tors group (4.44% vs 2.85% per patient-­ cohorts (64.3% in the P2Y12 group and the details as treatment becomes increas- year; p=0.041). 62% in the aspirin group). In the ‘Rivar- ingly complex. There is limited evidence in the compar- oxaban for the Prevention of Major Patients with AF and CAD require anti- Cardiovascular Events in Coronary or ison of aspirin with P2Y12 inhibitors in platelet therapy (APT) in addition to oral addition to OAC in patients with CCS. Peripheral Artery Disease (COMPASS)’ anticoagulation (OAC) after myocardial The AFIRE main trial showed that these trial where rivaroxaban 2.5 mg daily in infarction or percutaneous coronary inter- patients do not benefit from additional addition to aspirin in stable atheroscle- vention (PCI) for a limited time period. APT,5 but doubts remain, and dual anti- rotic disease was shown to reduce cardio- Depending on ischaemic risk, bleeding thrombotic therapy is still common in vascular mortality, an interesting substudy risk and unplanned PCI, different treat- 6 clinical practice. The benefit seen with was conducted. Patients who were not on ment regimens are available with dual http://heart.bmj.com/ clopidogrel compared with aspirin in PPI at baseline were randomised to PPI antithrombotic therapy with OAC and the monotherapy of patients undergoing or placebo resulting in two groups over APT up to 12 months.2 Looking at PCI, recently shown with the ‘Harmo- 8000 patients with a mean follow-up­ of each possible combination of drugs and nizing Optimal Strategy for Treatment of therapy length, the cardiologist is left with 3 years. Therapy with PPI was shown to Coronary Artery Stenosis-­EXtended Anti- 2.8 million possible combinations in the be very safe without increase in cardio- platelet Monotherapy (HOST-EX­ AM)’ first 12 months only.3 vascular events, cancer or pneumonia trial, is not evident in patients with AF in or dementia but a twofold increase of

4 on September 26, 2021 by guest. Protected copyright. the analysis by Fukaya et al. Clostridium difficile infections.8 The PRECISION MEDICINE BUT TOO MANY Interpretation of this data is to be seen COGENT trial showed that concomitant OPTIONS WITH LOW EVIDENCE? in the contexts of its many caveats. The therapy with PPI (in this case omeprazole) This subanalysis from the recently AFIRE trial was randomised, but the in patients with APT reduces gastrointes- published randomised controlled ‘Atrial comparison of P2Y inhibitors and aspirin 12 tinal bleeding without a rise in thrombotic Fibrillation and Ischemic Events With was not, as seen with significant base- events.9 However, the most recent Euro- Rivaroxaban in Patients With Stable Coro- line differences between the groups. The pean Society of Cardiology (ESC) guide- nary Artery Disease Study’ (AFIRE) by design was open label, which certainly 4 lines for management of ACS without Fukaya et al examines whether aspirin or can introduce bias. Also, the general- ST-segment­ elevation (NSTEMI) do not P2Y12 inhibitors (clopidogrel in 94.6%) in isability of the cohorts to European/ addition to rivaroxaban impacts outcomes Western patients is limited. In particular, recommend omeprazole due to concerns in patients with CCS. The main trial of inhibition of CYP2C19 and thus effi- anticoagulant dosing is different here and 2 showed that dual antithrombotic therapy significant numbers of patients received cacy of clopidogrel. is associated with increased mortality bare-metal­ stents (more than 30% in the The ESC guidelines on management of compared with OAC monotherapy in aspirin group) which is not standard of AF mention PPIs without giving a level patients with AF and CCS. care anymore in the guidelines. General of recommendation akin to the NSTEMI guidelines. With the abundance of data assumptions on P2Y12 inhibitors should supporting the use of PPI in patients Cardiology, University Heart and Vascular Centre be avoided, since almost 95% of patients with antiplatelet or dual antithrombotic Hamburg-Eppendorf­ , Hamburg, Germany with P2Y12 inhibitors received clopidogrel instead of more potent antiplatelet drugs therapy, they should be considered more Correspondence to Dr Shinwan Kany, Cardiology, University Medical Center Hamburg-­Eppendorf, like prasugrel or ticagrelor. Prescribing frequently and guidelines have to provide Hamburg 20246, Germany; s.​ ​kany@uke.​ ​de physicians in the AFIRE trial were free more powerful recommendation.

Kany S, Schnabel R. Heart Month 2021 Vol 0 No 0 1 Editorial

Non Commercial (CC BY-­NC 4.0) license, which permits Heart: first published as 10.1136/heartjnl-2021-319830 on 12 August 2021. Downloaded from others to distribute, remix, adapt, build upon this work non-­commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-­commercial. See: http://​ creativecommons.org/​ ​licenses/by-​ ​nc/4.​ ​0/. © Author(s) (or their employer(s)) 2021. Re-­use permitted under CC BY-­NC. No commercial re-­use. See rights and permissions. Published by BMJ.

To cite Kany S, Schnabel R. Heart Epub ahead of print: [please include Day Month Year]. doi:10.1136/ heartjnl-2021-319830

► http://dx.​​ doi.​​ org/​​ 10.​​ 1136/​​ heartjnl-​ 2021-​ 319321​ Figure 1 Overview about antiplatelet and anticoagulation mechanisms on haemostasis ► to prevent thrombotic events while increasing bleeding risk. In patients with AF and CCS, Heart 2021;0:1–2. doi:10.1136/heartjnl-2021-319830 antithrombotic drugs can be either antiplatelet drugs or oral anticoagulation (OAC). Aspirin and P2Y12 lead to an inhibition of glycoprotein IIb/IIIa, a fibrinogen receptor that aids platelet ORCID iDs Shinwan Kany http://orcid.​ ​org/0000-​ ​0001-8113-​ ​733X activation. Aspirin blocks the formation of thromboxane A2 (TXA2) limiting platelet aggregation and also reduces gastric mucus secretion. OAC either inhibits factor Xa (FXa) or thrombin to reduce Renate Schnabel http://orcid.​ ​org/0000-​ ​0001-7170-​ ​ 9509 clotting formation. Both medications reduce thrombotic events such as ischaemic stroke (mainly OAC) and coronary ischaemic events (antiplatelets) but increase bleeding risk, that is, gastric bleeding. Potential protection may arise from proton pump inhibitors (PPIs) and histamine H2 REFERENCES 1 Magnussen C, Niiranen TJ, Ojeda FM, et al. Sex receptor (H2 blockers) may provide protection by reducing stomach acid production. Adapted from 2 differences and similarities in atrial fibrillation Collet et al. AF, atrial fibrillation; CCS, chronic coronary syndrome. epidemiology, risk factors, and mortality in community cohorts: results from the BiomarCaRE Consortium (biomarker for cardiovascular risk assessment in CONCLUSION The personalised treatment of patients Europe). Circulation 2017;136:1588–97. In conclusion, the authors shed some new with concomitant AF and CCS remains 2 Collet J-­P, Thiele H, Barbato E, et al. 2020 ESC light on the dual antithrombotic therapy complex and more evidence is required to guidelines for the management of acute coronary syndromes in patients presenting without persistent of patients with AF and concomitant CCS. make guideline recommendations.

ST-segment­ elevation. Eur Heart J 2021;42:1289–367. http://heart.bmj.com/ While not recommended without acute 3 Gibson CM. Going polymer free and dual antiplatelet Twitter Shinwan Kany @kany_md coronary events and certainly related to free earlier. J Am Coll Cardiol 2017;69:172–5. an increased risk of bleeding, it represents Contributors SK wrote the initial draft of the 4 Fukaya H, Ako J, Yasuda S, et al. Aspirin versus manuscript. SK and RS worked on the figure and the P2Y12 inhibitors with anticoagulation therapy the clinical reality in many cases. Whereas final manuscript. for atrial fibrillation. Heart 2021. doi:10.1136/ heartjnl-2021-319321. [Epub ahead of print: 14 Jul the current study suggests that aspirin or Funding The authors have not declared a specific 2021]. a P2Y inhibitor may be equivalent, not grant for this research from any funding agency in the 12 5 Yasuda S, Kaikita K, Akao M, et al. Antithrombotic much is known on a potential net clinical public, commercial or not-­for-­profit sectors.

therapy for atrial fibrillation with stable coronary on September 26, 2021 by guest. Protected copyright. benefit for the prevention of thrombotic Competing interests None declared. disease. N Engl J Med 2019;381:1103–13. events and which patients may benefit Patient and public involvement Patients and/or 6 Steinberg BA, Kim S, Piccini JP, et al. Use and associated risks of concomitant aspirin therapy with most. Randomised trials on the type of the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. oral anticoagulation in patients with atrial fibrillation. antithrombotic agent and optimal anti- Circulation 2013;128:721–8. Patient consent for publication Not required. platelet drug, their dosing and duration 7 Koo B-­K, Kang J, Park KW, et al. Aspirin versus clopidogrel for chronic maintenance monotherapy after of therapy are lacking. Utilisation of PPI Provenance and peer review Commissioned; internally peer reviewed. percutaneous coronary intervention (HOST-­EXAM): an therapy in patients receiving antithrom- investigator-­initiated, prospective, randomised, open-­ botic therapy may be another target for label, multicentre trial. The Lancet 2021;397:2487–96. 8 Moayyedi P, Eikelboom JW, Bosch J, et al. Safety of optimisation of clinical management, proton pump inhibitors based on a large, Multi-Y­ ear, especially since it further reduces bleeding randomized trial of patients receiving rivaroxaban or events. Therapy with PPI is safe, and the aspirin. Gastroenterology 2019;157:682–91. 9 Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with benefits outweigh the risk in patients Open access This is an open access article distributed or without omeprazole in coronary artery disease. New 8 where therapy is indicated. in accordance with the Creative Commons Attribution England Journal of Medicine 2010;363:1909–17.

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