European Heart Journal Supplements (2020) 22 (Supplement M), M26–M34 The Heart of the Matter doi:10.1093/eurheartj/suaa165 Prevention of stroke in patients with chronic coronary Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_M/M26/6024774 by guest on 31 October 2023 syndromes or peripheral arterial disease William A. E. Parker 1, Diana A. Gorog2,3, Tobias Geisler4, Gemma Vilahur5,6, Dirk Sibbing7,8,9, Bianca Rocca10, and Robert F. Storey1* 1 Cardiovascular Research Unit, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK 2 Department of Medicine, National Heart & Lung Institute, Imperial College, London, UK 3 Postgraduate Medical School, University of Hertfordshire, Hatfield, UK 4 Department of Cardiology and Angiology, University of Tübingen, Tübingen, Germany 5 Cardiovascular ICCC Program, Research Institute-Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain 6 Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain 7 Privatklinik Lauterbacher Mühle am Ostersee, Iffeldorf, München, Germany 8 Ludwig-Maximilians-Universität, München, Germany 9 Medizinische Klinik und Poliklinik I, Campus Großhadern, München, Germany and 10 Department of Pharmacology, Catholic University School of Medicine, Rome, Italy KEYWORDS Stroke is a common and devastating condition caused by atherothrombosis, thrombo- Stroke; embolism, or haemorrhage. Patients with chronic coronary syndromes (CCS) or Myocardial infarction; peripheral artery disease (PAD) are at increased risk of stroke because of shared Coronary artery disease; pathophysiological mechanisms and risk-factor profiles. A range of pharmacological Peripheral arterial disease; and non-pharmacological strategies can help to reduce stroke risk in these groups. Antiplatelet drugs; Antithrombotic therapy reduces the risk of major adverse cardiovascular events, in- Anticoagulant drugs; cluding ischaemic stroke, but increases the incidence of haemorrhagic stroke. Aspirin; Clopidogrel; Nevertheless, the net clinical benefits mean antithrombotic therapy is recommended Ticagrelor; in those with CCS or symptomatic PAD. Whilst single antiplatelet therapy is recom- rivaroxaban mended as chronic treatment, dual antiplatelet therapy should be considered for those with CCS with prior myocardial infarction at high ischaemic but low bleeding risk. Similarly, dual antithrombotic therapy with aspirin and very-low-dose rivaroxa- ban is an alternative in CCS, as well as in symptomatic PAD. Full-dose anticoagulation should always be considered in those with CCS/PAD and atrial fibrillation. Unless ischaemic risk is particularly high, antiplatelet therapy should not generally be added to full-dose anticoagulation. Optimization of blood pressure, low-density lipo- protein levels, glycaemic control, and lifestyle characteristics may also reduce stroke risk. Overall, a multifaceted approach is essential to best prevent stroke in patients with CCS/PAD. Introduction encompassing symptomatic or asymptomatic coronary ar- tery disease (CAD) with or without a history of acute coro- Significant mortality and morbidity arise from complica- nary syndrome (ACS),1 or peripheral artery disease (PAD), tions of either chronic coronary syndromes (CCS), including lower extremity arterial disease (LEAD), and ca- rotid artery stenosis.2 Those with CCS/PAD are at increased *Corresponding author. Email: r.f.storey@sheffield.ac.uk risk of acute atherothrombotic events, including ACS, Published on behalf of the European Society of Cardiology. V C The Author(s) 2020. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creati- vecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Prevention of stroke in patients M27 Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_M/M26/6024774 by guest on 31 October 2023 Figure 1 Mechanisms of stroke in patients with CCS/PAD. Stroke is caused by the interruption of blood supply to the brain. Ischaemic stroke may be due to atherothrombosis within a cerebral artery (thrombotic stroke) or from embolism of a thrombus formed at a distant site (embolic stroke), for example the left atrium, aortic arch or carotid arteries. Haemorrhagic stroke results from rupture of a cerebral artery aneurysm. Platelet activation and fibrin clot formation are the central processes in ischaemic stroke, whereas in haemorrhagic stroke these processes may limit its severity. PFO, patent foramen ovale. [myocardial infarction (MI) or unstable angina (UA)], acute use of antiplatelet therapy (APT) in these groups. Similarly, limb ischaemia (ALI), and acute stroke.1,2 those treated by coronary or peripheral artery stenting are There are three main mechanisms of stroke (Figure 1). at risk of platelet-mediated stent thrombosis.2 Patients with CCS/PAD may be at particular risk of stroke because of shared underlying disease processes and risk- Use of single antiplatelet therapy factor profiles (Figure 2). Pathological mechanisms of athe- Numerous randomized controlled trials (RCTs) have estab- rothrombotic stroke are shared with most ACS and ALI, in- lished the benefits of APT in patients with CCS/PAD. Single volving atheromatous plaque formation, rupture, and/or antiplatelet therapy (SAPT) with aspirin, which inhibits erosion, triggering thrombosis via activation of platelets platelet cyclooxygenase-1-mediated TXA2 synthesis,5 has and the coagulation cascade.3 The processes and risk fac- proven efficacy in the prevention of major adverse cardio- tors leading to cardioembolic stroke, on the other hand, vascular events (MACE, defined as cardiovascular (CV) have less in common with CCS and PAD. Compared to athe- death, non-fatal MI, or non-fatal stroke) in high-risk rothrombotic stroke in which platelets and adhesive mole- patients. A meta-analysis by the Antithrombotic Trialists’ cules are central, activation of the coagulation cascade Collaboration, including individual data from 135 000 primarily drives cardiac thromboembolism in a setting of patients with pre-existing CV disease, showed clear bene- stasis and inflammation, most notably from the left atrial fit, mainly with aspirin alone, in reducing MACE by around appendage in patients with atrial fibrillation (AF), although 25% [relative risk reduction (RRR): those with prior- there are other possible sources (Figure 1).4 MI ¼ 21%, P < 0.0001; other-CAD ¼ 37%, P < 0.0001; PAD In this review, we present pharmacological strategies to 23%, P ¼ 0.004].6 This included a significant reduction in prevent stroke in patients with CCS/PAD. Similarities in non-fatal ischaemic stroke (3.5% to 2.6%, RRR ¼ 25%). pathogenetic mechanisms can provide insights into thera- Increases in haemorrhagic stroke risk were offset by a non- pies, and we explore clinical data supporting or refuting significant reduction in total stroke risk of 21%. Similarly, a these. Whilst focusing on ischaemic stroke, preventing hae- more recent meta-analysis has provided further insight, morrhagic stroke is also important, particularly since some suggesting that aspirin significantly reduces the risk of treatments of CCS, PAD, and acute stroke may increase its large-artery atherothrombotic stroke [odds ratio ¼ 0.87, incidence. 95% confidence interval (CI) 0.76–1.00; P ¼ 0.046], but not small vessel occlusion or cardioembolism.7 Antithrombotic therapy Platelet P2Y12 receptor inhibitors have also been tested in CCS/PAD (Tables 1 and 2, Figure 3).16 P2Y12, its natural li- Antiplatelet therapy gand being adenosine diphosphate, plays a central role in As platelet activation is the central process in acute com- the amplification of platelet activation. Three orally-ac- plications of CCS and PAD, there is a clear rationale for the tive P2Y12 inhibitors have been marketed. The M28 W.A.E. Parker et al. Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_M/M26/6024774 by guest on 31 October 2023 Figure 2 Modifiable risk factors for stroke in patients with CCS/PAD and evidence-based therapies to address these. CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; DATT, dual antithrombotic therapy; GLP-1, glucagon-like peptide 1; HbA1c, glycated haemoglobin A1c; LDL-C, low-density li- poprotein cholesterol; LEAD, lower-extremity arterial disease; NOAC, non-vitamin K antagonist OAC; OAC, oral anticoagulant; PCSK9, proprotein conver- tase subtilisin/kexin type 9; RASi, renin-angiotensin-system inhibitor; SAPT, single antiplatelet therapy; T2DM, type 2 diabetes mellitus; VKA, vitamin K antagonist. thienopyridines clopidogrel and prasugrel are pro-drugs It has been hypothesized that more potent and consis- whose active metabolites irreversibly inhibit P2Y12.3 Both tent P2Y12 inhibitors than clopidogrel might offer better require metabolic activation, which is predictably consis- protection against MACE. The Examining Use of tiCagreLor tent and effective for prasugrel whereas, for clopidogrel, In peripheral artery Disease (EUCLID) trial randomized there is significant inter-individual variability and around patients with symptomatic PAD to ticagrelor or clopidogrel one-third of the population are poor responders.3 The (Table 2).14 Over a median follow-up of 30 months, there cyclopentyl-triazolopyrimidine ticagrelor is a directly-act- was no significant difference in MACE, although there was ing, reversibly-binding P2Y12 inhibitor and inverse agonist. a significant reduction in the secondary endpoint of ischae- Ticagrelor and prasugrel are more potent than clopidogrel mic stroke with ticagrelor, meaning that, for stroke preven- with less inter-individual variability.3,17 tion in PAD, ticagrelor may offer some benefit over In the Clopidogrel vs. Aspirin in Patients at Risk of clopidogrel, although ticagrelor monotherapy is not ap- Ischaemic Events (CAPRIE) study, P2Y12 inhibitor SAPT with proved in PAD.6 clopidogrel 75 milligrams (mg) once daily was compared In The Acute Stroke or Transient Ischaemic Attack with aspirin 325 mg once daily in patients with CCS and PAD Treated with Aspirin or Ticagrelor and Patient Outcomes (Tables 1 and 2).8 There was a modest RRR in MACE but a (SOCRATES) trial, ticagrelor monotherapy was not superior suggestion of greater efficacy in PAD patients, leading to to aspirin monotherapy in 13 199 patients with non-severe recommendations that, if SAPT is indicated in symptomatic ischaemic stroke or high-risk transient ischaemic attack, PAD, clopidogrel may be preferred to aspirin.2 There was with similar bleeding profile.18 Around 12% of the trial pop- no difference in rates between the two treatments for ulation had CAD or previous MI and similarly in these stroke, including in those with PAD. Current ESC guidelines patients there was no superiority of ticagrelor vs. aspirin recommend either aspirin or clopidogrel for patients with (P ¼ 0.89). symptomatic PAD and/or those who have required revascu- larization.2 In patients with asymptomatic LEAD, there is Use of dual antiplatelet therapy no clear evidence that SAPT with aspirin prevents vascular In ACS, aspirin plus a P2Y12 inhibitor [dual antiplatelet ther- events, including stroke, although studies have been small apy (DAPT)] has proven benefits over aspirin alone in pre- and underpowered (Supplementary material online).2 venting MACE.19 When used in DAPT, ticagrelor, in all ACS, Table 1. Primary and stroke outcomes of total study groups from key RCTs comparing regimens of P2Y12 inhibitors or rivaroxaban with aspirin monotherapy in patients with CCS/PAD in si- nus rhythm. Short name Population Experimental group(s) Comparator Primary endpoint Key safety Ischaemic Haemorrhagic Total stroke (year published) endpoint stroke stroke CAPRIE (1996)8 19 185 patients with Clopidogrel 75 mg once Aspirin 325 mg MI, ischaemic stroke, or CV Severe bleeding: NR NR 438 events vs. 432 atherosclerotic CV daily once daily death: 5.32% vs. 5.83%, 1.38% vs. Prevention of stroke in patients disease (including RRR 8.7% (0.3–16.5), 1.55% (P  6302 with prior MI, P ¼ 0.043. Subgroup 0.05) 6452 with PAD) analysis: only significant difference in those with PAD CHARISMA 15 603 patients with Clopidogrel 75 mg once Aspirin 75–162 CV death, MI, or stroke: GUSTO severe 1.7% vs. NR 1.9% vs. 2.4%, (2006)9 clinically evident CV daily þ aspirin 75– mg once daily 6.8% vs. 7.3%, HR ¼ 0.93 bleeding: 1.7% 2.1%, HR ¼ 0.79 [0.64– disease or multiple 162 mg once daily [0.83–1.05], P ¼ 0.22 vs. 1.3%, HR ¼ 0.81 0.98], P ¼ 0.03 risk factors (48% with HR ¼ 1.25 [0.64– CCS, 23% with symp- [0.97–1.61], 1.02], tomatic PAD) P ¼ 0.09 P ¼ 0.07 PEGASUS TIMI 54 21 162 patients aged Ticagrelor 60-mg or 90- Aspirin 75–150- CV death, MI or stroke: TIMI major 1.28% vs. 0.19% vs. 0.19%, 1.47% vs. 1.94% (2015)10 50 years with a his- mg twice daily a plus mg once daily 7.77% vs. 9.04%, bleeding: 1.65%, HR ¼ 0.97 HR ¼ 0.75 [0.57- tory of spontaneous aspirin 75–150-mg HR ¼ 0.84 [0.74–0.95], HR ¼ 2.32 HR ¼ 0.76 [0.37 to 2.51], 0.98], P ¼ 0.03 MI 1–3 years prior to once daily P ¼ 0.008 [1.68–3.21], [0.56– P ¼ 0.94 enrolment AND at P < 0.001 1.02], least one additional P ¼ 0.06 atherothrombosis risk factorb 11 DAPT (2014) 9961 patients 12 Aspirin 75–162 mg once Aspirin 75–162 Stent thrombosis: 0.4% vs. GUSTO Moderate 0.5% vs. 0.3% vs. 0.2%, 0.8% vs. 0.9%, months post-PCI (26% daily þ continued mg once daily 1.4%, HR 0.29 [0.17– or severe 0.7%, HR ¼ 1.20 HR ¼ 0.80 [0.51– for MI) followed up thienopyridine (65% 0.48], P < 0.001; CV bleeding: 2.5% HR ¼ 0.68 [0.50 to 2.91], 1.25], P ¼ 0.32 for a further 18 clopidogrel 75 mg death, MI, or stroke: vs. 1.6%, [0.40– P ¼ 0.68 months once daily, 35% pra- 4.3% vs. 5.9%, HR ¼ 0.71 HR ¼ 1.61 1.17], sugrel 5 or 10 mg [0.59–0.85], P < 0.001 [1.21 to 2.16], P ¼ 0.16 once daily adjusted P ¼ 0.001 to weight) THEMIS (2019)12 19 220 patients with Aspirin 75–150 mg once Aspirin 75–150 CV death, MI, or stroke: TIMI major 1.6% vs. NR 1.9% vs. 2.3%, T2DM and CCS but no daily þ ticagrelor mg once daily 7.7% vs. 8.5%, HR ¼ 0.90 bleeding: 2.2% 2.0%, HR ¼ 0.82 [0.67– history of MI 60 mg twice daily [0.81–0.99], P ¼ 0.04 vs. 1.0%, HR ¼ 0.80 0.99] (reduced from 90 mg HR ¼ 2.32 [0.64–0.99] early in the trial) [1.82–2.94], P ¼ 0.005 (continued) M29 Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_M/M26/6024774 by guest on 31 October 2023 M30 Table 1. Continued Short name Population Experimental group(s) Comparator Primary endpoint Key safety Ischaemic Haemorrhagic Total stroke (year published) endpoint stroke stroke COMPASS 27 395 with CCS (91%) Aspirin 100 mg once Aspirin 100 mg CV death, MI, or stroke: Modified ISTH 0.7% vs. 0.2% vs. 0.1%, 0.9% vs. 1.6%, (2017)13 þ additional risk fac- daily þ rivaroxaban once daily 4.1% vs. 5.4%, HR ¼ 0.76 major bleed- 1.4%, HR ¼ 1.49 HR ¼ 0.58 [0.44– tors if <65 years 2.5 mg twice daily; [0.66–0.86], P < 0.001; ing: 3.1% vs. HR ¼ 0.51 [0.67–3.31], 0.76], P < 0.001 oldc) or symptomatic or, 1.9%, [0.38– P ¼ 0.33 PAD (27%) HR ¼ 1.70 0.68], [1.40–2.05], P < 0.001; P < 0.001; Rivaroxaban 5-mg 4.9% vs. 5.4%, HR ¼ 0.90 2.8% vs. 1.9%, 1.0% vs. 0.3% vs. 0.1%, 1.3% vs. 1.6%, twice daily [0.79–1.03], P ¼ 0.12 HR ¼ 1.51 1.4%, HR ¼ 2.70 HR ¼ 0.82 [0.65– [1.25–1.84], HR ¼ 0.69 [1.31–5.58], 1.05], P ¼ 0.12 P < 0.001 [0.53– P ¼ 0.005 0.90], P ¼ 0.006 a Data shown are for ticagrelor 60-mg twice daily vs. placebo: P-value of <0.026 denotes statistical significance. b Age 65 years, diabetes mellitus, second prior MI, multivessel CAD or chronic non-endstage renal disease. c Documentation of atherosclerosis involving at least two vascular beds or to have at least two additional risk factors (current smoking, diabetes mellitus, an estimated glomerular filtration rate [GFR] <60 mL/min, heart failure, or non-lacunar ischaemic stroke 1 month earlier). Values in square brackets represent 95% confidence intervals. CCS, chronic coronary syndromes; CV, cardiovascular; GUSTO, Global Strategies for Opening Occluded Coronary Arteries; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; MI, myo- cardial infarction; NR, not reported; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; RRR, relative risk reduction; T2DM, type 2 diabetes mellitus, TIMI, thrombolysis in myocardial infarction. W.A.E. Parker et al. Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_M/M26/6024774 by guest on 31 October 2023 Table 2. Primary and stroke outcomes of key RCTs or subgroup analyses comparing regimens of antithrombotic therapy in patients with PAD in sinus rhythm Short name (year published) Population/ Experimental Comparator Primary endpoint Key safety endpoint Ischaemic stroke Total stroke subgroup group(s) CAPRIE (1996)8 Subgroup of 6452 Clopidogrel 75-mg Aspirin 325-mg once MI, ischaemic stroke NR NR 81 events vs. 82 Prevention of stroke in patients with PAD once daily daily or CV death: events 3.71% vs. 4.86% per year, RRR ¼ 23.8% [8.9- 36.2), P ¼ 0.028 CHARISMA (2006)9 Subgroup of 3096 Clopidogrel 75-mg Aspirin 75 to 162-mg CV death, MI or GUSTO severe 2.3% vs. 2.4%, 2.6% vs. 2.9%, with PAD once daily þ aspi- once daily stroke: 8.2% vs. bleeding: 1.7% vs. HR ¼ 0.97 [0.75– HR ¼ 0.94 [0.74– rin 75 to 162-mg 6.8%, HR ¼ 1.25 1.7%, HR ¼ 0.97 1.25], P ¼ 0.782 1.20], P ¼ 0.635 once daily [1.08–1.44], [0.56–1.66], P ¼ 0.002 P ¼ 0.901 EUCLID (2017)14 13 885 patients with Ticagrelor 90-mg Clopidogrel 75-mg CV death, MI or TIMI major bleed- 1.9% vs 2.4%, NR symptomatic PAD twice daily for 36 once daily for 36 ischaemic stroke: ing: 1.6% vs. HR ¼ 0.78 [0.62– months months 10.8% vs. 10.6%, 1.6%, HR ¼ 1.10 0.98]. P ¼ 0.03 HR ¼ 1.02, [0.92– [0.84–1.43], 1.13], P ¼ 0.65 P ¼ 0.49 COMPASS (2017)13 Subgroup of 7470 Aspirin 100-mg once Aspirin 100-mg once CV death, MI or Modified ISTH major NR 1% vs. 2%, HR ¼ 0.54 patients with PAD daily þ rivaroxa- daily stroke: 5% vs. 7%, bleeding: 3% vs. [0.33–0.87] ban 2.5-mg twice HR ¼ 0.72 [0.57– 2%, HR ¼ 1.61 daily; or, 0.90], P ¼ 0.0047 [1.12–2.31], P < 0.0089 Rivaroxaban 5-mg 6% vs. 7%, HR ¼ 0.86 3% vs. 2%, HR ¼ 1.68 NR 2% vs. 2%, HR ¼ 0.93 twice daily [0.69–1.08], [1.17–2.40], [0.61–1.40] P ¼ 0.19 P < 0.0043 VOYAGER PAD (2020)15 6564 patients with Aspirin 100-mg once Aspirin 100-mg once ALI, major amputa- TIMI major bleed- 2.7% vs. 3.0%a, NR PAD treated by daily þ rivaroxa- daily tion, MI, ischae- ing: 2.65% vs HR ¼ 0.87 (0.63– revascularization ban 2.5-mg twice mic stroke, CV 1.87%a, HR ¼ 1.43 1.19) daily death: 17.3% [0.97–2.10], vs.19.9%a, P ¼ 0.07) HR ¼ 0.85 [0.76– 0.96], P ¼ 0.009 CV, cardiovascular; GUSTO, Global Strategies for Opening Occluded Coronary Arteries; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction; NR, not reported; PAD, peripheral artery disease; RRR, relative risk reduction; TIMI, Thrombolysis In Myocardial Infarction. a 3-year Kaplan–Meier estimation. M31 Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_M/M26/6024774 by guest on 31 October 2023 M32 W.A.E. Parker et al. Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_M/M26/6024774 by guest on 31 October 2023 Figure 3 Forest plots showing HR 6 95% CI for ischaemic stroke, total stroke and the key safety endpoint in RCTs of antithrombotic regimens vs. aspirin monotherapy in patients with CCS/PAD (see Table 1 for trial details). GUSTO, Global Strategies for Opening Occluded Coronary Arteries; ISTH, International Society on Thrombosis and Haemostasis; TIMI, Thrombolysis In Myocardial Infarction. and prasugrel, in those treated with percutaneous coronary factor benefit from long-term aspirin and reduced-dose intervention (PCI), are superior to clopidogrel.6 A recent ticagrelor (60-mg twice daily) vs. aspirin alone, although open-label RCT, Intracoronary Stenting and Antithrombotic underlying bleeding risk should be carefully evaluated. The Regimen: Rapid Early Action for Coronary Treatment (ISAR- Prevention of Cardiovascular Events in Patients with Prior REACT) 5, demonstrated lower MACE rates with aspirin and Heart Attack Using Ticagrelor Compared to Placebo on a prasugrel vs. aspirin and ticagrelor in those with ACS sched- Background of Aspirin–TIMI 54 (PEGASUS-TIMI 54) study uled for invasive evaluation.3 Similarly, in patients with showed MACE reduction in those receiving DAPT vs. SAPT CCS undergoing PCI, DAPT with aspirin, and clopidogrel for (Table 1).10 There was also a reduction in the risk of stroke. 6 months reduces stent thrombosis risk vs. aspirin alone.1 Although TIMI-major bleeding was significantly more fre- This regimen is also recommended for 1 month in patients quent with ticagrelor, intracranial haemorrhage, haemor- undergoing carotid artery stenting and, with weaker evi- rhagic stroke, or fatal bleeding were not. dence, in those undergoing percutaneous revascularization Evidence for thienopyridines comes from the DAPTstudy, for LEAD.2 which showed 30 vs. 12 months of thienopyridine, along- After a minor stroke or transient ischaemic attack (TIA), side aspirin, significantly reduced MACE in prior-MI patients a short period of DAPT offers superior protection from ma- (Table 1).22 Stroke was not significantly reduced, although jor ischaemic events when compared to aspirin alone, in- there was a signal of possible benefit in ischaemic stroke. cluding in patients with CCS or PAD, albeit at the expense Unlike MI, the stroke did not occur significantly more fre- of more bleeding.20,21 quently in those with a prior MI compared to those without Considering the longer-term use of DAPT vs. aspirin (e.g. total stroke ¼ 0.73% vs. 0.85%, P ¼ 0.51). Current rec- alone in patients with CCS/PAD, the Clopidogrel for High ommendations suggest long-term thienopyridine in prior- Atherothrombotic Risk and Ischaemic Stabilization, MI patients at moderate/high ischaemic risk.1 Prasugrel in Management, and Avoidance (CHARISMA) study provided combination with aspirin in any situation is contraindicated valuable initial data (Tables 1 and 2).9 There was a non- in those with prior stroke, and aspirin with ticagrelor is sim- significant reduction in the primary efficacy endpoint of ilarly not recommended for long-term use in this group. MACE, although there was slightly greater reduction in the In patients with CCS but without prior MI, there is lit- secondary efficacy endpoint (primary endpoint events/ tle evidence for long-term DAPT. THE effect of ticagrelor hospitalization for UA, TIA, or revascularization) [hazard on health outcomes in diabetes Mellitus patients ratio (HR) ¼ 0.92, 95% CI (0.86–1.00); P ¼ 0.04]. Most of the Intervention Study (THEMIS) randomized 19 220 aspirin- benefit appeared to be stroke-derived [e.g. non-fatal treated patients with T2DM and CCS, but no MI, to tica- stroke HR ¼ 0.79 (0.64–0.98); P ¼ 0.03], with no significant grelor (90-mg reduced to 60-mg twice daily during the effect on MI or CV death. course of the trial) or placebo, for a median of 40 months Subsequent RCTs have built an evidence base for long- (Table 1).12 Whilst there was lower MACE incidence in term DAPT post-ACS. For those at high ischaemic but low those receiving ticagrelor vs. placebo, there was a bleeding risk who have tolerated 1 year of DAPT, continu- greater increase in TIMI-major bleeding including intra- ation beyond 1 year after MI is a recommended option.1 For cranial haemorrhage. Ischaemic stroke occurred less fre- example, post-MI patients with at least one additional risk- quently when receiving DAPT, as did all stroke. Although Prevention of stroke in patients M33 meeting its primary endpoint, the net clinical benefit has CCS or symptomatic PAD, but without AF, is very-low-dose not supported adoption in practice. rivaroxaban in combination with low-dose aspirin. In the Cardiovascular OutcoMes for People using Anticoagulation Ticagrelor monotherapy StrategieS (COMPASS) study, treatment with aspirin 100-mg Ticagrelor monotherapy has been investigated as an alter- once daily plus rivaroxaban 2.5-mg twice daily [low-dose native to DAPT in CCS patients treated with PCI, though dual antithrombotic therapy (DATT)] led to a significant re- this is not yet endorsed in recommendations (Supplemen- duction in the primary endpoint of MACE after a mean tary material online). follow-up of 23 months, when compared to aspirin 100-mg once daily alone (Tables 1 and 2).13 When compared with Anticoagulant therapy aspirin monotherapy, low-dose DATT appeared to have the Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_M/M26/6024774 by guest on 31 October 2023 Oral anticoagulants (OACs) include vitamin K antagonists strongest effect on cardioembolic stroke [HR ¼ 0.40 (0.20– (VKAs), e.g., warfarin, and non-VKA oral anticoagulants 0.78), P ¼ 0.005] or embolic stroke of undetermined source (NOACs), e.g., the factor Xa (FXa) inhibitors (apixaban, [0.30 (0.12–0.74), P ¼ 0.006]. Benefits of low-dose DATT on edoxaban, and rivaroxaban) or the thrombin inhibitor stroke prevention appear present in subgroups with CAD or dabigatran.23 symptomatic PAD, including carotid disease. These data support use of low-dose DATTover aspirin alone in high-risk Anticoagulants in coronary syndromes or peripheral patients with CCS and/or symptomatic PAD, both in provid- artery disease patients with atrial fibrillation ing general anti-ischaemic protection but also specifically Atrial fibrillation increases the risk of cardioembolism from for stroke prevention. This is reflected in the current ESC the left atrium through disruption in flow and inflamma- CCS guidelines,1 whereas the current PAD recommenda- tion. Anticoagulation reduces stroke risk in AF by around tions were last updated before the COMPASS results were 60%.1 The CHA2DS2-VASc score is recommended for deter- known;2 however, regional bodies such as the European mining whether an OAC is warranted.1 An OAC is recom- Medicines Agency has approved low-dose DATT in symptom- mended with a score 2, and should be considered if 1 atic PAD as well as high-risk CCS. Recently, the Vascular (excluding females without other criteria).1,2 Outcomes Study of Aspirin Along with Rivaroxaban in Non-VKA oral anticoagulants offer superior stroke pro- Endovascular or Surgical Limb Revascularization for PAD tection vs. VKA, outside of situations such as moderate/se- (VOYAGER-PAD) study has shown similar findings in a PAD vere mitral stenosis, metallic valve prosthesis, very poor population treated by revascularization (Table 2).15 renal function, or non-compliance, groups in whom there In patients with PFO and CCS/PAD who have no prior his- are negative data or therapeutic drug monitoring is neces- tory of stroke, there is no clear evidence that stroke risk is sary. A meta-analysis including 71 683 participants of four reduced by intensifying antithrombotic therapy beyond phase 3 RCTs (15% with prior MI) showed significantly lower that already indicated for the underlying atherothrombotic rates of stroke or systemic embolism [HR ¼ 0.81 (0.73– disease.4 0.91), P < 0.0001] and haemorrhagic stroke [0.49, (0.38– 0.64), P < 0.0001] in those receiving a NOAC compared to VKA.23 There were numerically fewer ischaemic strokes in Other preventive therapies those receiving a NOAC [0.92 (0.83–1.02), P ¼ 0.10]. Beyond antithrombotic therapy, a wide range of therapies Different NOACs have never undergone head-to-head clini- and lifestyle interventions should be incorporated into the cal outcome-driven RCTs, although observational studies routine management of CCS and PAD patients for reducing have provided some insight (Supplementary material on- the risk of stroke (Figure 2 and Supplementary material line). The availability of selective antidotes to both FXa online). inhibitors (andaxenet alfa) and dabigatran (idarucizumab) has increased the safety of these drugs. There are limited data regarding long-term use of OAC- Conclusions APTcombinations in patients with CCS/PAD and AF, but cur- rent recommendations generally advise OAC alone during Patients with CCS/PAD are at increased risk of a range of long-term maintenance therapy.1 Recently, evidence from ischaemic events, including stroke, with a significant over- the Atrial Fibrillation and Ischaemic Events with lap of risk factors and pathological mechanisms (Figures 1 Rivaroxaban in Patients with Stable Coronary Artery and 2). Interventions targeting these factors and mecha- Disease (AFIRE) trial has largely supported this recommen- nisms present common therapeutic targets and have been dation (Supplementary material online). exploited with good results. Overall, a holistic approach to aggressively manage risk factors (Figure 2), including Anticoagulation in patients with coronary syndromes addressing lifestyle aspects, is central to the management or peripheral artery disease in sinus rhythm of patients with CCS/PAD to prevent the devastating com- The WArfarin Re-Infarction Study (WARIS) provided the first plication of stroke. RCTevidence that an OAC, with or without concurrent aspi- rin, may offer protection against MACE, including stroke, in Supplementary material CCS/PAD patients without AF, but at the expense of exces- sive bleeding.24 In the NOAC-era, an evidence-based option Supplementary material is available at European Heart for secondary prevention of MACE in high-risk patients with Journal Supplements online. M34 W.A.E. Parker et al. Funding Working group on GUCH, ESC Working group on Thrombosis, WAE Parker is funded by British Heart Foundation Clinical European Haematological Society (EHA), European Underwater and Baromedical Society (EUBS). European position paper on the man- Research Training Fellowship no. FS/18/49/33752. This agement of patients with patent foramen ovale. General approach paper was published as part of a supplement financially and left circulation thromboembolism. Eur Heart J 2019;40: supported by the European Society of Cardiology (ESC), 3182–3195. Council on Stroke. 5. Patrono C, Morais J, Baigent C, Collet JP, Fitzgerald D, Halvorsen S, Rocca B, Siegbahn A, Storey RF, Vilahur G. Antiplatelet agents for the treatment and prevention of coronary atherothrombosis. J Am Conflict of interest: Disclosures William A. E. Parker has no rele- Coll Cardiol 2017;70:1760–1776. vant disclosures. Diana A. Gorog reports honoraria from Astra- 6. Parker WA, Storey RF. Long-term antiplatelet therapy following myo- Zeneca, and institutional grants from Bayer and Boehringer- cardial infarction: implications of PEGASUS-TIMI 54. Heart 2016;102: Ingelheim. Tobias Geisler reports personal fees from Astra Zeneca, 783–789. Downloaded from https://academic.oup.com/eurheartjsupp/article/22/Supplement_M/M26/6024774 by guest on 31 October 2023 personal fees from Boehringer Ingelheim, personal fees from 7. Rajkumar CA, Floyd CN, Ferro A. Antiplatelet therapy as a modulator Pfizer, grants and personal fees from Bayer Healthcare, grants and of stroke aetiology: a meta-analysis. Br J Clin Pharmacol 2015;80: personal fees from Bristol Myers Squibb, grants and personal fees 331–341. 8. CAPRIE Steering Committee. A randomised, blinded, trial of clopi- from Daiichi Sankyo, grants and personal fees from Eli Lilly and per- dogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). sonal fees from Ferrer. Gemma Vilahur reports grants from Lancet 1996;348:1329–1339. AstraZeneca, personal fees from AstraZeneca and personal fees 9. Bhatt DL, Fox KAA, Hacke W, Berger PB, Black HR, Boden WE, from Bayer. Dirk Sibbing reports grants and personal fees from Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Roche Diagnostics, grants and personal fees from Daiichi Sankyo, Hamm CW, Hankey GJ, Johnston SC, Mak K-H, Mas J-L, Montalescot personal fees from Bayer AG, personal fees from Eli Lilly, personal G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, fees from MSD, personal fees from Pfizer and personal fees from Fabry-Ribaudo L, Booth J, Topol EJ; CHARISMA Investigators. Astra Zeneca. Bianca Rocca reports grants from Bayer AG, personal Clopidogrel and aspirin versus aspirin alone for the prevention of fees from Novartis and personal fees from Medscape. Robert F. atherothrombotic events. N Engl J Med 2006;354:1706–1717. 10. 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