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Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology 2023
(CaracanJoaralot Carey, 20244201, Vesna 4, ue 2, Pages YE, Capyan © 2023 Caran Cadotarle Secy
Abstract
Aatiplatelet therapy (APT) isthe foundation of treatment and prevention of atherothrombotic events in patients with atherosclerotic cardiovascular disease. $
recommendations onthe following topis: (1 use of acetylsalicylic acid in primary prevention of atherosclerotic eardiovaseular disease; (2) dual APT (DAPT)
evasculariztion; (5) pretreatment with DAPT (P2Y 1 inhibitor) before elective or onelective coronary angiography; (6) perioperative and longer-te
{evelopment ofthese guidelines, provided inthe Sugpemeniay Matera ansact)
Résumé
Letraitement antplaquetiace est a base du traitement et de a prévention des manifestations athérothrombetiques cher ls patients atteints d'une maladie ee
«du Canada/Association canadienne de cardologie intervention pour Puiisation du traitement antiplaguettaire formule des recommandations surlessujets
antiplaquettair puissant (inbibiteur de P2Y y») chez les patients qui présentent un syndrome coronarienaigu et les strategies 6ventuelles de désescalade de
‘urgente ou urgente; 6 la prise en charge par un traitement antiplaquetaire périop ong terme chez ls patients qui ont besoin d'un pontage astoe
publications et les méta-analyses menées dans le but de formuler ces lignes directrices, fournies dans le masérasupekimontai apnsact}
‘Scope of the 2023 Antiplatelet Therapy Guideline Update
‘Toplace into conte, the Canadian Cardiovascular Society (CCS) rlessd the orginal practice guidelines onthe use of antiplatelet therapy (APT) inthe outpa
‘We provide updated recommendations on the basis of rcent evidence to inform clinical practice. The 2028 CCS/Canadian Assocation of Interventional Cardi
1. Use of actysaligc aid (ASA) in primary prevention of ASCYD;
2. Dual APT (DAPI) treatment duration after percutaneous coronary intervention (PC) in patients at high bleeding rs (BR;
43. Potent DAPT (P2Y 2 inhibitor) choie inpatients who presenting with an acute coronary syndrome (ACS) and possble DAPT de-scalation strategies afte
4. Choice and duration of DAPTin ACS patients who are medically treated without revasculaiztion;
5, Pretreatment with DAPT (P2Y sx iahibitor) before elective or noneectve coronary angiography;
6, Perioperative and longer-term APT management inpatients who require coronary artery bypass grafting (CABG) surgery, and
7..Use of APT in patients with atrial fibrillation (AF) who require oral
coagulation (OAC) after PCI or medically managed ACS.
Guideline Development
‘The guideline development process is described in detail in the Suslomental Aogondx 81 iapasec). The CCS Guidelines Committee approved the co-chairs of
analysis ofthe literature for each clinical question addressed. The topics were selected by the co-chairs and approved by the CCS Guidelines Committee. Each
(759) agreement forall recommendations, A summary of the systematic reviews and meta-analyses conducted for this guideline document are available onlin
Use of ASA in Primary Prevention of ASCVD
Although ASA has historically ben the cornerstone of secondary prevention of ASCVD, its ole inpatients without established ASCVD is less clear. Since the
‘aio [RR], 0.90; 95% confidence interval (CT, 0.86054), mainly driven by «reduction in nonfatal myocardial infarction (MI; no significant reduction in all-e
2-6 fewer) MACE.events, and 5 more (95% CT, 3-8 more) extracranial major Dleding events per 1000 patients treated with ASA over S yeas, None ofthe pres
‘who might choose ASA for prim
y prevention, weighing the individual risks and benefits, We provide a vival tsk representation of absolute risk eduction a
RECOMMENDATION 1. We recommend against the poutine use of ASA fr primary prevention of ASCVD regardless of sex, age or diabetes in patients without ASCVD (Strot
[BEST PRACTICE STATEMENT
1. The use of ASA for primary prevention of ASCVD might be appropriate in certain individuals deemed tobe at high ASCVD risk but with low bleeding r
‘Values and preferences: Inthe absence of a mortality benefit with ASA in primary prevention, we valued nonfatal ischemic and major bleeding events € Piguet
‘Share decor making regarding aspirin fr primary prevention o
osdrote cardiovascular dase, Cone of pat prelerencas er nina eutzomes i essen
Practical tips:
hence the lack of endorsement
+ Prescription of ASA on the besis of CV risk stratification tols has not been prospectively vali
+ Clinician shovld emphasize optimization of CV rsk factors before initiation of ASA treatment in primary prevention.
“+ Most of the rcent tials wore cared outwith entriocoated ASA tablets, Whether newer formulations of ASA, suchas extended-release espsuls, pharma
‘The role of ASA in subeliniel ASCVD remains undefined and would encourage patient- 979% to the allocated trestment. #? We pooled these 2 trials (a = 3843)
«reasonable alternative inthe care of ACS patients, in whom ischemic and bleeding rsks continuously evolve (Fig 4).
Potent dual antiplatelet agent de-escalation by dose reduction
‘The Harmonizing O ptimal Strategy for T restment of Coronary Artery Diseases Trial - Comparison of Redue tion of Prasugre | Dose or Poly mer Tech no
the composite of all-cause death, nonfatal MI, stoke, and major bleeding. ** This strategy has yet tobe investigated in non-Asian countries. In this context,»
‘Because of the low-cerainy evidence from a single tral, no recommendation for de-escalation by dose reduction of a potent P2Y,2 inhibitor therapy as part ¢
5. We suggest, when potent DAPT is considered inpatients with ACS who receive PCI, either ticagrlor or prasuarel can be used, without preference fore
‘4. We suggest that the option of de-escalatng potent DAPT by switching to clopidogrel-based DAPT be considered in appropriate patients with ACS who
‘Values and preferences: Unguided potent P2Y x2 inhibitor dose de-escalaton strategies have mostly been studied in RCTs conducted in Kast Asia, Whe
Practical tips:
+ Potential side effets (eg, dyspnea with tcagretor), dosing frequency (once vs twice dais), drug interactions (eg, Cytochrome P50 34 [CYP8A4] inhibitor
+ Aclear follow-up strategy needs tobe established with the patent st discharge to ensure that DAPT de-escalation by switching (if eonsidered) is performec
+ Appropriate patients for DAPT deescalation by switching to clopidogret may include patients whose bleeding risk might be higher and the ischemic risk a)
+ Ifa DAPT de-esealation by switching strategy is chosen, current practioe emphasizes de-sealating to clopidogrel directly at 75 mg daily (first dose taken
+ Selecting petiens for DAPT de-escalation by switching canbe supported by an evaluation ofthe risk of bleeding (Eg.2 2} ) vs PCI complexity (Fa. $a
Choice and Duration of DAPT in Patients With ACS Treated Medically Without Revascularization
Choice of APT
Patients with ACS who aze medically managed without revasculatization tend to be heterogeneous in their presentation (ig, 5a6)). The Targeted Platelet
‘older or weighing < 60 kg) in addition to ASA, orto clopidogrel 75 mg,dailyn addition to ASA. Ata median follow-up of 17 months, rasugrel didnot signitic
(UR, 0,85; 95% CI, 0.72-1.00), © but benefits started appearing after the standard 12-month DAPT duration Although the rates of severe and ife-threate
insbitosin patents baer hay undergo coronary angicraphy. ASA aceasta cath exthelrizaton NSTEACS, non.ST.albvaion acu orone
NSTEACS patants no prtestment), °2 = I STEMI patent raceving Heino,
NSTEACS.
Among patients who undergo coronary angiography in the setting of NSTEACS, the benefits of P2Y x2 inhibitor pretreatment remain unclear. The largest stud
pdogrel 300 mg ostng doses te only ences.
pretreatment with prasugrel or prasugrel administered i the catheterization laboratory if PCI was indicated. At days, there was no difference in MACE (10.
(DUBIUS) trial was a smaller open-label ral that tested tiagrelor pretreatment vs on-table P2Y inhibitor immediately before PCI, and showed no ditferene
Jn the Canadian conten, patients commonly present to community hospitals where access to angiography might be delayed well beyond 24 hours. The C lopi¢
subgroup of 2658 patients with NSTRACS treated with PCI. Patients received the study drug fora median of 6 days before PCI. Those who received clopidogre
‘reduces ischemic vascular events as erly 36 24 hours after initiation and continuing out to 12 montha, 5°
‘We performed a meta-anslyss of 7 pretreatment RCTS in patients with NSTEACS and no difference was shown in 30-day mortality, MACE, or definite stent t
beyond 24 hours from diagnosis (orf iming is uncertain or unknown atthe time of presentation), as is the case fr many patients in Canada, we srongly bell
Stable ischemic heart disease
‘The A niplatelet Therapy for Reduction of My ocardial B amage during A ngioplasty (ARMYDA-5 PRELOAD) til evaluated the safety and efiacy of highs
Coronary A ngiogeaphy and A ngioplesty Registry (SCAAR) involving nearly
ference in bleeding or vascular complications. A study from the S wedi
{nclaboratory administration was associated with a reduction in in-hospital bleeding (1.9% vs 2.1%; adjust
sn major bleeding risk was observed (RR, 1.30; 95% CI 0.35-4.84; Supplemenlal Assen S7(annsec
OR, 0.70; 95% CI, 0.51-0,96), § We performed
As for choice of P2Y inhibitor for elective PCL inpatient with stable ischemic heart disease, the A ssessment of L oading With the P 2V22 Inhibitor Teagre
[Negative Angina (SASSICAIA} tral compared a 60 mg prasugrel loading dose with 600 mg of clopidogrel and showed no difference in MACK orbeding at 80
(Overall the totality of data do not support pretreatment with a P2Y x2 inhibitor asthe standard of car in patents who undergo elective coronary angiography
‘STEMI
7. We suggest routine pretreatment with 2 P2Y 2 inhibitor before the procedure inpatients who undergo primary PCI for STEMI (i ta8) ; Weak Rec
NSTEACS
8. We suggest against routine pretreatment with « P2Y js inhibitor before the procedure inpatients who undergo coronary angiography for NSTEACS,
9. We suggest routine pretreatment with @ P2¥ ;2 inhibitor before the proceduce inpatients who undergo coronary angiography for NSTEACS, ifthe pre
Stable Ischemic Heart Disease for Elective PCL
10. We suggest against rautine pretreatment with a P2Y ;zinhibitr before the procedure in patients who undergo elective coronary angiography for st
‘Values and preferences: We value nonfatal ischemic end major bleeding events equally inthis topic. In uch circumstances, consideration of patient pr
Practical tips: + Corrent practice emphasizes consideration for maintenance of chronic ASA therapy before elective coronary angiography. For elective coronary angiograp!
+ For planned elective PCI, current practice emphasizes consideration for pretreatment with DAPT at least 2 hours before PCI
+ Inpatients who undergo eletive PCI, clopidogrel (witha loading dose of 600 mg) isthe preferred P2Y : inhibitor.
+ In patients who undergo PCI for ACS (regardless of need for pretreatment), Ioading doses are required for P2Y ;piahibitors—tieagrelor 180 mg, * prasup
+ Clopidogrel isthe P2¥ 12 inhibitor that has been the most studied inpatients who have undergone elective PCL
+ Pretreatment with P2Y :2 inhibitor for NSTEACS depends on local practice and needs tobe individualized on the bass of access toa catheterization labor
+ Ifthe suspicion ofa coronary anatomy requting.CABG is high before coronary angiography inpatients with ACS, itis reasonable to not pretest with P2"
+ Routine preloading with lopidogre-based DAP (300 ma) atthe time of fibrinolysis (the only P2¥ 12 inhibitor of choice) and before coronary anlgraphy
Perioperative and Longer-term APT Management in Patients Who Require CABG Surgery
‘More than 10% of patients who present with ACS have anatomy that requires revascularization with CABG surgery. This poses a clinical dilemma if patient
analysis that compared more potent antiplatelet strategies with weaker strategies in patients who required CABG suggested an overall survival benefit among,
‘Timing of P2Y :»inhibitor discontinuation in patients with ACS befare CABG: clopidogrel
Pharmacodynamic data show complete offset of P2Y yp receptor inhibition by days after clopidogrel cessation. ® To date there has only been { small rand
{increase in intraoperative blood loss and need fo blood produts among patients who underwent surgery onthe day of clopidogrel discontinuation, there wen
evidence (Sugplmantal Append 58 (apnsac) the panel elected to issue a best pratice statement rather than a recommendation on this topic. We strongly bel
BEST PRACTICE STATEMENT
2, Recognizing the limited evidence, the time from clopidogrel discontinuation to CABG surgery should be onthe bass of factors such as coronary anstor Fowe?
Preoperative ante! selaies in patents scheduled o undergo coronary bypass rating (CABG) suger. ACS, as coronary syndome: ASA, Bee Haley ae. =
“Troated by €ornary A ory B ypass 6 raf Surgery (RAPIO.CABO),
Timing of P2Y ;2inhibitor discontinuation in patients with ACS before CABG: ticagrelor
To date there has only boen 1 rendomized study to eveluate the ideal timing from cessation of icagrelor to CABG among patients with ACS who do not requir
vw delayed surgery (5-7 day after teagrelor cessation) in Canada, The early group had 46% rate of severe or massive perioperative bleeding compared with
Inadaition, several large cohort studies further suppor the safety of shortening the time fom tcagrelor cessation to CABG. tn a Swedish cohort of 1266 tcag
ticagrelor cessation compared with 4-14 days cessation, but discontinuation of ticagrelor within 2 days of CABG was associated with an increased risk of CABC
antiplatelet eet of teageelor.
‘We provide guidance for ticagrelor discontinuation in ACS before nonurgeat/emergent CABG surgery in Figure 77). Recommendations were solely on the b
RECOMMENDATION
11, We suggest holding iagrelor for 23 days rather than 5-7 days before CABG surgery (E77); Weak Recommendation; Low-Quality videnee).
DAPT vs SAPT after CABG
‘The use of ASA-based SAPT at a dose of 75-162 mg daily after CABG is supported by early evidence showing a reduction in bypass graft occlusion ** and is re
clopidogrel was associated with areduetin in saphenous vein graf failure compared with ASA-based SAPT (tcageelor: OR, 0.50; 95% CT, 0.31-0.79, number
0.40; 95% Cl, 0.21-0.74; clopidogrel: OR, 0.64; 95% CI, 0.42-0.8). ® In the meta-analysis by Sandner eta, including 4ticagrelor RCTS, DAPT was associat
‘or mortality outcomes compared with ASA-based SAPT,
‘We performed a study-lvel meta-analyses of 10 trials involving 3947 patients and a consistent reduction in graft occlusion per patient (RR, 0.73; 95% CT, 0.5
‘on-pump surgery, inferring a potentially groster benef of DAPT. In our meta-analysis, DAPT significantly reduced MACE after off-pump surgery (RR, 0.42; 5
12, We suggest the ute of DAPT over SAPT after CABG surgery with or without ACS (£g.8 (if); Weak Recommendation; Maderate-Quality Evidence), Fiues
Postoperative arpstcet statis in patents who have undergone coronary artery bypass eating (CABG) surgery. ACS, acute coronary syndame; ASA, scetysaeyie 2
Practical tips:
+ Im patients witha concomitant indication for OAC, either SAPT or no APT therapy could be used after CABG.
+ This generally advised to continue ASA until surgery (Eg. 7 a), to resume ASA early postoperatively (Fig 8 (ig) and to start the second antiplatelet + In patients at HBR, abbreviated DAPT might be preferred to SAPT after CABG for ACS, and SAPT could be considered for elective CABG.
+ Because DAPT has been shown to reduce MACE after of- pump CABG surgery, but not after on-pump CABG surgery, this weak recommendation to use Dy
+ Inpractice, DAPT duration after CABG for ACS is generally of 1 yea, but tis dura
Specific type of P2Y ,.inhibitor as part of DAPT in ACS after CABG
{nthe PLATO and the Trial to Assess Improvement in Therapeutic O utcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis
(0.01), * Similarly inthe subgroup of patients who underwent CABG in the TRITON-TIMI 38 study, total mortality with prasugre-based DAPT was reduced
‘may be mortlated according individual patient ischemic and bleed
‘We pooled the results ofthese 2 subgroup analyses and a large reduction in mortality with potent P2Y 12 -inhibitor DAPT was shown compared with clopidogt
administration and most patients in TRITON-TIMI 38 had CABG more than 90 days after presentation. © + 72 In these studies, CABG decision was apostra
RECOMMENDATION
13. We suggest using DAPT with tcagreor/presugrel rather than clopidogrel-based DAPT in patients with a recent ACS who undergo CABG surgery (Fig
‘Values and preferences: This recommendation puts a high value on the mortality benefits with intensitied P2Y inhibitors observed in CABG substudi
Practical tip:
+ When sleting which potent P2Y inhibitor to use as part of DAPT after CABG in patients with ACS, eagrelor might be preferred over prasugel because
Use of APT in Patients With AF Requiring OAC After PCI or Medically Managed ACS
Upto 10% of patents who undergo PCI and 21% of patients who present with ACS require long-term anticoagulation OAC for A¥ or other indications, "» 7
{nhibitor) in this population, redefining the standard for antithrombotic therapy. 7 1n appropriate patients with AF and an indication for OAC who undergo
‘Since then, 2 major RCTs have been published: An Open-Label, 22 Factorial, Randomized Controlled, Clinieal Trial to Evaluate the Safety of Apixaban Vers
ptervention (ENTRUST-AF-PCI trials. "+ " AUGUSTUS was the only tral witha double-blind, randomized 2x 2 factorial design comparing ASA 81 mgé
(treated with or without PCD, and patents who underwent elective PCI, Major or clinically relevant nonmajor bleeding events were reduced in patients who r
antagonists (28.5% vs 27.4%; respectively; HR, 0.83; 95% CI, 0.74-0.98) whereas there vias no significant difference for ASA and placebo, The combination of
‘increased thersk of severe Bleeding before and after 30 days by 1.0% and 1.25%, respectively). In the ENTRUST-AF-PCI tsa, patients with AF treated
bleeding, without a significant increase in ischemic events.”
‘We performed an updated systematic review and meta-analysis, including 6 trials (21,256 patients) and showed a significant reduction in major bleeding wit
be associated with 28 fewer major bleeds (95% Cl, from 28 to 16 fewer), 4 more stent thrombosis events (95% CI, rom 0 to 8 more), and 8 more MACE (85%
as part ofa dual pathway strategy has not been elucidated. However, the allowed maximal interval between PCI (or ACS in the AUGUSTUS trial) and random
‘Recently, there have boon 2 RCTS to investigate the most appropriate antithrombotic therapy strategy inpatients with AF and concomitant stable CAD who re
terminated because of slow participant enrollment (696 participants in 38 months) The primary composite end point of all-cause death, MI, systemic emboli
Disease (AFIRE) trial rivaroxaban monotherapy was eveluated (10 mg or 15 mg once dally, according to the patients erestnine clearance) compared with rive
‘with the rvaroxaban monotherapy group (HR, 0.55; 95% CI, 0.$8-0.81, favouring rivaroxaban monotherapy). The primary efficacy end poin (a composite of|
(HR, 0.59; 95% CI, 0.99-0.89; P= 0.01 for supeririy).
‘We performed a pooled analysis ofboth studies und no difference in MACE (RR 0.91; 95% CI, 0.58-1.41) with OAC monotherapy, but a significant reduction i
lqr 8 ap) provides a summary of our recommendations regarding the antithrombotic management of AF patients who undergo PCI, or with an ACS who de
ypestension, Age 2 75, Diabetes, and Prior Stroke/Transient Ischemic Attack [doubled] store of one or greater who underwent PCL without ACS or high-ris
14. We suggest dual pathway therapy (P2Y inhibitor with oral anticoagulant and omit ASA from 1-30 days rather than tiple therapy (DAP with oral
‘Values and preferences: We place greater emphasis onthe large reduction in bleeding complications vs the smal increas in stent thrombosis with a dt owe 8
-Anplatlt saosin pation wit concomvtant ati ilaton (AF) an percutaneous coronary itvanton (Pi) ano cus coronary synrome (ACS). ASA. acta @
vauatd in is context include apzaban 5g ic daly BI: 2.5 ma BID ipabens mea 2 or mae ofthe folowing dosage rducton ceri: oir than 80 years of ago, < 60 kg
Arsfincton, and wera, warfarin isto be uted, recommended nkematonal ornaized rat woes 22.5, Al patents should recevealoading dos of ASA 180/me atthe tr
RECOMMENDATION
15, We suggest OAC monotherapy rather than dual-pathway therapy (oral anticoagulant with APT) in patients with CAD and concomitant AF with an ine
‘Values and preferences: We place high emphasis on the internal vliity ofthe AFIRE RCT that evaluated tis strategy, and lower emphasis onthe
respectively
Practical tips:
+ When a P2Y :2inhiitor isto be combined with OAC, clopidogrel may be used rather than tcagrelor or prosugrel because ofits lower risk of Bleeding and t
+ For patients treated with a dual pathway strategy (OAC and SAPT), current practice emphasizes the use ofa east 1 dose of ASA atthe ime of PCT or tad
+ When considering the appropriate ASA duration for an individual patient, itis important to conser that ASA duration before switching to dul pthoeay's
+ When OAC is combined with aF2Y :inhbitr, current practice emphasizes consideration ofa dual OAC over a vitamin K antagonist because of the lower
+ Patients at igh ischemic risk and who underwent complex PC (ig 2.) were under-represnted inthe randomized trials that compared triple therap
+ For patients with «high schemie/thrombotic risk, history of stent thrombosis or a complex PCI (ig 3a), clinical judgement should be used in the
+ For patents with AF und PCT or ACS equiring medical management, bleding avoidance strategies shouldbe considered (Table 1 gu).
+ For al patients with AF, the indication for OAC and their dosing of OAC during and after completion of dual pathway treatment should follow the 2020 CC
Current Controversies With APT and Future Considerations
APT inthe treatment of ASCVD will unequivocally continue to evolve overtime. Although we are cognizant of potential sex and gender disparities, we could ne
© utco m es for People Using Anticoagulation Strategie s (COMPASS) trial and of new antithrombotie agents such as factor XIa inhibitors that are currents
with remote PCL, © One wonders about the role ofa'COMPASS strategy’ vs DAPI immediately after PCI (or even after ACS) and needs to be addressed in ar
Finally, pathways targoted on the basis of atherothrombotic disease state and pathophysiology might lead towards indvidualizod therapies tailored for patient
Ethies Statement
Allrescarch reported in the curren article adheres tothe relevant ethical guidelines.
Patient Consent
‘The authors confirm that patient consent is not applicable to this article because this isa guidelines document.
Acknowledgements
‘The authors thank:
+ Drs Dennis Ko and Brad Sarak, CCS Guidelines Committee members who provided support, guidance, and advice through the duration of development
+ Ms Carolyn Gall Casey for contributions and suppor othe co-chairs and document preparation proces.
Msi
oulard (Canadian VIGOUR Centre) for design contributions for wes + (Net), 2(Ne2), 3), and 5.5)
‘The authors acknowledge and recognize the ongoing the volunteer contributions of ll writing panel members, the OCS Guidelines Committee, CCS membe: Funding Sources
‘he CCS verifies that funding for systematic review services was provided from its general Guidelines Administration budget and that no external funding w
‘he CCS provided gran-in-aid support to Dr Emilie Beley-Cté (Emilie Belley-Cé4é Medicine Professional Corporation) and Dr Ricky D, Turgeon (Ube Uni
Editorial Disclaimer
‘Because of thet roleas associate editors, Stephen Fremes, Michelle Graham, and Guillaume Marquis-Gravel had no involvement in the peer review of this 2
Supplementary Material
‘The dtlosure information.
yauthors and reviewers is aval from the CCS on ther guidelines library at wes.ca np Uc.)
Thi statement was developed following thorough consideration of medial erature abd the bet evlable evidence and linia enerfence. It represents the consensus ofa
change at sient owed and technology advance and as practic patterns evolve. The slaemeat snot intended to bea substitute or ysis using their india] ue
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