New 2018 Canadian Cardiovascular Society (CCS)/Canadian … · 2020. 3. 10. · The new england journal of medicine thrombosis, and ischemia-driven target-lesion revascularization

2018 Canadian Cardiovascular Society (CCS)/Canadian Association of Interventional Cardiology (CAIC)

Focused Update of the Guidelines for the use of Antiplatelet Therapy

Simon Robinson (on behalf of CCS Guideline Group)

Interventional Cardiologist, Royal Jubilee Hospital Victoria BCClinical Associate Professor, UBC

Co-Director, Victoria Heart Institute Foundation

Disclosures

• Simon Robinson

– Consulting Fees / Honoraria: AstraZeneca, Bayer

– Clinical Trials: AstraZeneca, Bayer, Novartis, Sanofi, Esperion, Medinol

2018 APT Guideline Authors

Primary Panel MembersShamir R. Mehta (co-chair), Kevin R. Bainey, Warren J. Cantor, Marie Lordkipanidzé, Guillaume Marquis-Gravel, Simon D. Robinson, Matthew Sibbald, Derek So, Graham C. Wong, Joseph G. Abunassar, Margaret L. Ackman, Alan D. Bell, Raymond Cartier, James D. Douketis, Patrick R. Lawler, Michael S. McMurtry, Jacob A. Udell, Sean van Diepen, Subodh

Verma, G.B. John Mancini, John A. Cairns, and Jean-François Tanguay MD (co-chair)

Secondary Panel MembersPaul Armstrong, Akshay Bagai, Claudia Bucci, Jean-Pierre Déry, Jean Diodati, Jocelyn Dupuis, David Fitchett, Michael P. Love, Robert Welsh

2018 Anti-Platelet Therapy UpdateOverview Of Presentation

• Optimal duration of dual antiplatelet therapy (DAPT) following PCI• stable coronary disease and elective PCI

• acute coronary syndromes and high risk elective PCI

• Management of DAPT in patients requiring surgery• Coronary Artery Bypass Grafting and Non-Cardiac Surgery

• Switching between antiplatelet agents

• Antiplatelet therapy in PCI patients who also require oral anticoagulation (OAC)• AF, valvular disease, LV thrombus, venous thromboembolism

2011 CCS Antiplatelet Therapy Guideline Topics

Antiplatelet Therapy (APT) • Post MI• Post PCI (aspirin and clopidogrel dose)• Beyond 1yr post MI/PCI• Following CABG• Symptomatic cerebrovascular disease• Primary prevention CV events• Patients with diabetes mellitus• Patients with heart failure• Patients with CKD• Women who are pregnant• APT management during surgery• APT management following bleeding• APT in combination with warfarin• APT and proton pump inhibitors• APT in combination with NSAIDs

clopidogrel to 4.7% with ticagrelor (HR, 0.49; 95% CI,0.32-0.77), cardiovascular death from 7.9% to 4.1% (HR,0.52; 95% CI, 0.32-0.85), and noncardiovascular deathfrom 2.0% to 0.7%.38 There was no significant difference inCABG-related major bleeding between the treatment arms.Of note, 70% of ticagrelor recipients stopped therapy 3-7days before surgery, suggesting that the protocol recom-mendation to stop ticagrelor 1-3 days before surgery wasupheld in only a minority of patients. Approximately 2/3 ofpatients restarted antiplatelet therapy after CABG, of whichapproximately half restarted within the first 14 days afterCABG. In the 422 patients who required CABG afterrandomization in TRITON-TIMI 38, prasugrel signifi-cantly reduced all-cause mortality (2.31% vs 8.67% withclopidogrel; adjusted odds ratio, 0.26; P ¼ 0.025) andincreased 12-hour chest tube blood loss (655 " 580 mL vs503 " 378 mL; P ¼ 0.050) without significantly increasingred blood cell transfusion.39

Because of the greater potency of these newer antiplatelettherapies, cardiac surgeons must balance bleeding and efficacyin determining the timing of CABG after ACS. In stablepatients with non-life-threatening coronary anatomy, therapyshould ideally be withheld for 5 days for clopidogrel or tica-grelor and 7 days for prasugrel. In unstable and emergentpatients, surgeons must weigh the potential risk of excessbleeding. Although there is no clear recommendation in theliterature, bridging with a glycoprotein IIb/IIIa inhibitor inthe 5-7 days before surgery or transfusing platelets at the timeof surgery might be considered.35 Considering data suggestingthat the rate of stent thrombosis could be as high as 20% inpatients undergoing CABG shortly after PCI,40 patientsrequiring CABG after PCI should continue taking DAPT asrecommended in the post-PCI guidelines, particularly if thestented vessel is not bypassed during surgery.

The following are changed recommendations for anti-platelet therapy (Fig. 4).

Figure 1. Recommendations for non-STeelevation acute coronary syndrome (NSTEACS) 1. ASA, acetylsalicylic acid; CABG, coronary artery bypassgrafting; CAD, coronary artery disease; MI, myocardial infarction; PCI, percutaneous coronary intervention; PLATO, Platelet Inhibition and PatientOutcomes. * Moderate to high-risk NSTEACS as defined in PLATO16: # 2 of: (1) ischemic ST changes on electrocardiogram; (2) positive biomarkers;and (3) 1 of the following: 60 years of age or greater, previous MI or CABG, CAD > 50% stenosis in 2 vessels, previous ischemic stroke, diabetes,peripheral arterial disease, or chronic renal dysfunction.

Tanguay et al. 13392012 Update of the CCS Antiplatelet Guidelines

New Since Last CCS Antiplatelet Therapy Guidelines

Trends in Percutaneous Coronary Intervention (PCI) and Contemporary

Antiplatelet Therapies• Ongoing evolution in PCI use

• PCI more commonly used in ACS including STEMI

• PCI used in more complex patients and lesions e.g. CABG ineligible pts

• Drug eluting stents (DES) predominantly used now – DES vs BMS ≊ 1:1 in 2011– DES vs BMS ≊ 9:1 in 2017

Baseline and procedural characteristics. The mean age ofthe PCI patients increased over the year cohorts, from amean age of 60.1!9.9 years in the cohort 1990 to 1995, to67.1!11.2 years in the cohort 2009 to 2010 (Table 1). Theproportion of patients ages !75 years increased from 5.8%to 28.4%. The indication for PCI changed over time, witha majority of patients treated for stable coronary arterydisease (66.4%) in 1990 to 1995, and a majority treated forunstable coronary artery disease (47.7%) or STEMI (32.5%)in 2009 to 2010 (Fig. 2). The proportion of smokers wasbetween 19.7% and 21.8% in the different year cohorts.Diabetes and hypertension increased while hyperlipidemiadecreased, and a lower proportion of patients had a historyof myocardial infarction over time. Three-vessel diseaseincreased from 3.8% in the cohort 1990 to 1995, to 17.3%to 19.0% in the cohorts from 2003 to 2010 (Table 2). Inaddition, stent use increased from nearly no stent usage(0.8%) to approximately 93% from the cohort 2003 to 2004and later. Among the patients treated with a stent, theproportion receiving DES varied between 17.2% and 48.0%after its introduction in 2002.Mortality. Figure 3A shows the mortality for the differentyear cohorts, with a median follow-up of 2,082 days(interquartile range: 1,105 to 3,335 days), and up to 21 yearsof total follow-up. The mortality rate was higher in the lateryear cohorts compared to the earlier year cohorts. Mortalityat 1 year after PCI increased from 2.2% in 1990 to 1995, to5.9% in 2009 to 2010 (Table 3). After adjustment for age

and indication, a modest decrease in the mortality risk wasseen over time (Fig. 3B). That was mainly due to a decreasein the risk of mortality in the subgroup of STEMI patients,with an age-adjusted HR up to approximately 2 in theearlier year cohorts, compared to the reference cohort 2009to 2010 (Table 3, Fig. 4). Furthermore, the unadjustedmortality rate was lower in males compared to females in thelong term after PCI (HR: 0.82 [95% CI: 0.80 to 0.84]).However, after adjustment for age, indication, and yearcohort, no sex difference was seen at 1 year after PCI (HR:1.00 [95% CI: 0.95 to 1.06]), whereas males had a slightlyhigher risk of mortality in the long term (HR: 1.12 [95%CI: 1.09 to 1.15]). When we performed the analyses in allPCI procedures, including repeated PCI procedures, theresults were consistent.

Discussion

We evaluated the clinical characteristics of all consecutivepatients undergoing a first PCI procedure in Sweden in thelast 2 decades. The mean age of the PCI treated populationincreased, and patients were more often treated for unstablecoronary artery disease or STEMI over time. As a conse-quence of the older population, the proportion of patientswith comorbidities increased. Mortality after PCI wasinfluenced by the increasing age and the changing indica-tion for PCI.

Figure 2 Indication for PCI Procedure

Proportion of patients undergoing percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD) (blue bars),unstable CAD (green bars), ST-segment elevation myocardial infarction (STEMI) (red bars), and other (lavender bars) in the different year cohorts.

1225JACC Vol. 61, No. 12, 2013 Fokkema et al.March 26, 2013:1222–30 Population Trends in Percutaneous Intervention

20-Year Results From theSCAAR (Swedish Coronary Angiography and Angioplasty Registry), JACC 2013, Fokkema et al

Superior Safety and Efficacy of Modern DES vs 1st Generation DES

n engl j med 373;18 nejm.org October 29, 20151716

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

thrombosis, and ischemia-driven target-lesion revascularization with everolimus-eluting stents than with paclitaxel-eluting stents among patients without diabetes. However, among 1869 patients with diabetes, there was no significant differ-ence with regard to any efficacy or safety out-come.6 In contrast, in a meta-analysis of 42 ran-domized studies that compared various stents and included 22,844 patient-years of follow-up of

patients with diabetes, everolimus-eluting stents, as compared with other drug-eluting stents and bare metal stents, were found to be the most efficacious and safe stents, and they had a high probability of being associated with the lowest rate of restenosis, myocardial infarction, and stent thrombosis.7 The discordance in the results between these meta-analyses is possibly a result of differences among the studies that were in-

Figure 2. Clinical Outcomes.

Time-to-event curves are shown for patients in the intention-to-treat population who were randomly assigned to receive a paclitaxel-eluting stent or an everolimus-eluting stent. The event rates were calculated with the use of Kaplan–Meier methods and compared with the use of the log-rank test; they differ slightly from the rates in the text and Table 2, which were calculated as categorical variables and compared with use of chi-square test. In each panel, the inset shows the same data on an enlarged y axis. CI denotes confidence inter-val, and F–M Farrington–Manning.

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A Target-Vessel Failure

Hazard ratio, 0.18 (95% CI, 1.09–2.47)P=0.02 by log-rank testP=0.38 for noninferiority by F–M test

No. at RiskPaclitaxel-eluting

stentEverolimus-eluting

stent

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Hazard ratio, 2.18 (95% CI, 1.20–3.95)P=0.009 by log-rank test



stent

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C Cardiac Death or Target-Vessel Myocardial Infarction

Hazard ratio, 1.69 (95% CI, 1.04–2.75)P=0.03 by log-rank testP=0.38 for noninferiority by F–M test



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Hazard ratio, 5.08 (95% CI, 1.74–14.87)P<0.001 by log-rank test



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The New England Journal of Medicine Downloaded from nejm.org on July 16, 2017. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.

Paclitaxel-Eluting versus Everolimus-Eluting Coronary Stents in Diabetes. TUXEDO-India Investigators;; NEJM 2015

Mortality in a propensity matched cohort of unselected patients undergoing PCI in BC from 2008 t0 2014. Iqbal et al, Am J Cardiol 2015

population, which would otherwise be associated withadverse outcomes. There are a number of possible mecha-nisms that may explain the late survival benefit observed withR-ZES. First, it is likely that reduced TVR may explain, atleast in part, the mortality benefit with R-ZES. Although wedid not have specific outcome data, TVR may reflect theincidence of myocardial infarction and stent thrombosis, asthese events often result in repeat revascularization.Furthermore, restenosis and repeat revascularization havebeen shown to be an important contributor to long-termmortality.8 In keeping with this, in our data set, we foundthat TVR in the first year, itself, was an independent predictorfor mortality at 2 years. Second, although our study wasconducted in the contemporary era, the E-ZES and R-ZEScohorts represent 2 periods, and it is possible that improve-ments in PCI techniques, antithrombotic and antiplatelettherapy may have contributed to the reduction in mortalitywith R-ZES. However, when we included the enrollment

year as a forced-in variable into the multivariate model, wedid not find an association with enrollment year and mor-tality, and the association with R-ZES use and mortality wasunchanged. Finally, as increased polymer biocompatibility isassociated with reduced inflammation and thromboge-nicity,10,16 one may hypothesize that the biocompatiblepolymer of R-ZES may potentially reduce thrombotic fatalcomplications.

Examining the KaplaneMeier curves for both un-matched and propensity-matched cohorts, TVR curves startto diverge beyond 100 days, largely due to increase in TVRwith E-ZES. The curves continue to diverge and becomeparallel beyond 250 to 300 days. A similar divergencepattern in KaplaneMeier curves for target lesion revascu-larization pattern has previously been reported for E-ZESand R-ZES, where the curves diverge after 4 months andbecome almost parallel beyond 8 months.13 Our data wouldsuggest that the key period where the increased repeat

Figure 3. KaplaneMeier curves for (A) unmatched (n ¼ 17,643) and (B) propensity-matched (n ¼ 8,344) cohorts.

Coronary Artery Disease/Polymer Coatings in Zotarolimus-Eluting Stents 5

Antiplatelet Strategies Following PCI

• Prior 1 year recommendation for DAPT post MI and PCI based on CURE and PCI-CURE trials

• More complex and extensive CAD now treated with PCI with higher risk of recurrent ischemic (thrombotic) events

• 5 x increase patients aged >75yrs treated by PCI since 1990– higher risk of bleeding, higher prevalence of AF requiring OAC– multiple co-morbidities, greater risk of recurrent MI

• Major bleeding higher on DAPT than aspirin monotherapy– Hazard ratio for (non-fatal) bleeding 1.5[CHARISMA] - 2.7[PEAGUSUS]

• Stent thrombosis rate ≈0.6% with modern generation DES

• 6 RCTs including 11,473 pts – Second generation DES

• 59% patients stable CAD

• 3 or 6 months or 1 year Clopidogrel based DAPTc

• 1 year DAPTc gave lower MI/stent thrombosis in ACS patients

• Shorter DAPTc similar risk reduction in stable CAD

• Bleeding events lower with shorter DAPT in all patients

Optimal Duration of DAPT‘Shorter vs Longer’ After PCI with DES

Palmerini et al. EHJ 2017

Extended DAPT vs Aspirin Beyond 1 year in Patients with Prior Myocardial Infarction

• Meta-analysis of 6 RCTs post MI involving 33,000 pts

• Extended DAPT (mean 31 months) compared to 1 year DAPT followed by aspirin alone

different between extended DAPT-treated patients and aspirinalone. Treatment with extended DAPT had no significant effecton non-CV death [RR 1.03 (95% CI 0.86–1.23); P ¼ 0.76; see Sup-plementary material online, Figure S7]. The net effect wasa non-significant RR of 0.92 (95% CI 0.83–1.03; P ¼ 0.13; seeSupplementary material online, Figure S8) for all-cause mortality.

Sensitivity analysesThere was no meaningful heterogeneity in results across trials foreither the primary or the secondary endpoints. No evidence of pub-lication bias was suggested by visual inspection of the funnel plots forMACE (see Supplementary material online, Figure S9) or secondaryendpoints. Results for the primary endpoint analysis remained

significant after removal of any one trial from the pooled result(see Supplementary material online, Table S5). More so, after simul-taneous removal of both the PEGASUS-TIMI 54 and DAPT results,the primary endpoint remained significant among the remaining fourtrials [RR 0.82 (95% CI 0.70–0.97); P ¼ 0.02; ARD ¼ 1.11% (95% CI0.09–2.13)]. The addition of 1-year landmark results from two trialstesting other strategies of more intensive antiplatelet therapy forsecondary prevention among stabilized patients .1 year from anMI,30,31 also did not materially change the results [RR 0.79 (95%CI 0.72–0.87); P , 0.00001; see Supplementary material online, Ap-pendix Figure S10]. Finally, results did not significantly differ amongany subgroup for MACE or major bleeding (all P-interactions ≥0.09;see Supplementary material online, Tables S6 and S7).

Figure 1 Risk of major adverse cardiovascular events comparing extended dual antiplatelet therapy vs. aspirin alone. Square data markers re-present risk ratios and horizontal lines the 95% confidence intervals with marker size reflecting the statistical weight of the study using inversevariance random effects meta-analysis. A diamond data marker represents the overall risk ratios and 95% confidence intervals for major adversecardiovascular events. There was no significant between-trial heterogeneity (Q statistic ¼ 8.36, d.f. ¼ 5; P ¼ 0.14; I2 ¼ 40%).

Figure 2 Risk of individual cardiovascular and bleeding endpoints comparing extended dual antiplatelet therapy vs. aspirin alone. Square datamarkers represent risk ratios and horizontal lines the 95% confidence intervals using inverse variance random effects meta-analysis.

Long-term dual antiplatelet therapy for secondary prevention 395

Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/4/390/2398390by gueston 23 November 2017

Udell et al. EHJ 2016

22% ↓ MACE

50% ↓ ST

15% ↓ CV death

70% ↑ major bleeding

Patients aged ≥50 years with a history of spontaneous MI 1–3 years prior to enrolment AND at least one additional atherothrombosis risk factor*

(N=21,162)

Ticagrelor 60 mg bid+ ASA 75–150 mg/day

Minimum of 12 months’ follow up:Every 4 months in Year 1,

then semi-annually

Primary efficacy endpoint: CV death, MI or strokePrimary safety endpoint: TIMI-defined major bleeding

Placebo+ ASA 75–150 mg/day

Ticagrelor 90 mg bid+ ASA 75–150 mg/day

*Age ≥65 years, diabetes mellitus, second prior MI, multivessel CAD or chronic non-end stage renal diseaseBonaca MP et al. Am Heart J 2014;;167:437–444Bonaca MP et al. N Engl J Med 2015;;372:1791–1800

PEGASUS-TIMI 54 Extended DAPT in Patients with Prior MI

Bansilal et al, JACC 2018

Enhanced Efficacy of Extended Ticagrelor In Patients With Multivessel Disease

versus no MVD (3-year Kaplan-Meier [KM] rate 9.37%vs. 8.57%; adjusted HR [HRadj]: 1.24; 95% CI: 1.03 to1.50; p ¼ 0.026). Likewise, the risk of coronary eventswas higher in patients with MVD (7.67% vs. 5.34%;HRadj: 1.49; 95% CI: 1.19 to 1.87; p ¼ 0.0005) (Figure 1).The incidence of TIMI major bleeding was similar inpatients with (1.08%) and without (1.03%) MVD(Figure 1).

TICAGRELOR EFFICACY. There was consistent rela-tive risk reduction with ticagrelor for MACE in pa-tients with MVD (pooled ticagrelor vs. placebo, HR:0.82; 95% CI: 0.72 to 0.94) (Figure 2) and in thosewithout MVD (pooled ticagrelor vs. placebo, HR: 0.87;95% CI: 0.74 to 1.03; pinteraction ¼ 0.61) (Figure 2).Given the higher absolute risk of MACE in patientswith MVD, the magnitude of the absolute risk reduc-tion with ticagrelor (1.43%; number needed to treatfor 3 years [NNT3yr] ¼ 70) tended to be greater than inpatients without MVD (0.97%; NNT3yr ¼ 103).

In terms of coronary events, the HR with ticagrelorwas 0.76 (95% CI: 0.66 to 0.88) in patients with MVDand 0.95 (95% CI: 0.77 to 1.16) in patients withoutMVD (pinteraction ¼ 0.09). Again, given the higher ab-solute risk of coronary events in patients with MVD,the magnitude of the absolute risk reduction tendedto be greater in those with MVD (1.65%; NNT3yr ¼ 60pooled ticagrelor) than in those without (0.17%,NNT3yr ¼ 588 pooled ticagrelor) (Figures 2 and 3). In

patients with MVD, there were large reductions in theindividual components, including a 36% reduction incoronary death (HR: 0.64; 95% CI: 0.48 to 0.85), a21% reduction in MI (HR: 0.79; 95% CI: 0.67 to 0.93),a 41% reduction in definite stent thrombosis(HR: 0.59; 95% CI: 0.37 to 0.94), and a 54% reductionwith the 90-mg dose (HR: 0.46; 95% CI: 0.25 to 0.84)(Figure 2). The number of stent thrombosis eventswere very low for the non-MVD group resulting inextremely wide CIs for the ticagrelor versus placebocomparison. Ticagrelor tended to have a beneficialeffect on the rate of coronary revascularization (PCIor CABG) in patients with MVD (HR: 0.88; 95% CI:0.78 to 1.01; as compared with HR: 1.03; 95% CI: 0.82to 1.29 in patients without MVD, pinteraction ¼ 0.25).

The efficacy signal was generally consistent acrossboth doses of ticagrelor (Figures 2 and 3).

SAFETY RESULTS. Ticagrelor increased TIMI majorbleeding to a similar degree (both relative and abso-lute risk) in those with (3-year KM rate 2.52% vs.1.08%; HR: 2.67; 95% CI: 1.81 to 3.93) and without MVD(3-year KM rate 2.36% vs. 1.03%; HR: 2.27; 95% CI: 1.44to 3.58; pinteraction ¼ 0.58) (Figure 3). Ticagrelor did notsignificantly increase the rate of ICH or fatal bleedingeither in patients with MVD (3-year KM rate 0.67% vs.0.63%; HRadj: 1.21; 95% CI: 0.69 to 2.12) or withoutMVD (3-year KM rate 0.67% vs. 0.56%; HRadj: 1.20; 95%CI: 0.61 to 2.38; pinteraction ¼ 0.98) (Figure 3).

FIGURE 1 Events by MVD Status in the Placebo Arm

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CHD Death MI Def. ST TIMI Major Bleeding

HRadj 1.24(95% CI 1.03-1.50)

HRadj 1.97(95% CI 1.3-2.99)

HRadj 1.39(95% CI 1.08-1.79)

Coronary Events HRadj 1.49(95% CI 1.19-1.87)

HRadj 2.14(95% CI 0.86-5.30)

HRadj 0.97(95% CI 0.54-1.75)

MVD No MVD

Illustration of event rates for patients with multivessel disease (MVD) in the placebo arm of the PEGASUS-TIMI 54 trial. The figure shows thatmajor adverse cardiovascular events and coronary events (including its components of coronary death, MI, and definite stent thrombosis) arehigher in patients with MVD. TIMI major bleeding rates are comparable between patients with and without MVD. CI ¼ confidence interval;CV ¼ cardiovascular; DEF ST¼ definite stent thrombosis; HR ¼ hazard ratio; KM ¼ Kaplan-Meier; MI ¼ myocardial infarction;TIMI ¼ Thrombolysis In Myocardial Infarction.

Bansilal et al. J A C C V O L . 7 1 , N O . 5 , 2 0 1 8

Ticagrelor for Multivessel Coronary Artery Disease F E B R U A R Y 6 , 2 0 1 8 : 4 8 9 – 9 6

492

Event rates for patients in the placebo arm of the PEGASUS-TIMI 54 trial according to the severity of coronary artery disease

DISCUSSION

In this pre-specified analysis from the PEGASUS-TIMI 54trial, we report multiple clinically relevant findings:1) In patients with prior MI, the presence of MVD isassociated with a higher risk of MACE and coronaryischemic events; and 2) this atherothromboticrisk is reduced significantly by ticagrelor, with arobust impact on coronary heart disease-relateddeath, MI, and stent thrombosis (CentralIllustration). Only 60 patients with MVD needed tobe treated with ticagrelor for 3 years to prevent 1coronary event.

Patients with MVD, not only represent an advancedstate of atherosclerosis quantitatively in the coronaryand other vascular beds, but also show qualitativelygreater endothelial dysfunction, higher grades ofplatelet reactivity, higher fibrinogen levels, andincreased thrombin activation (2–6,10,11). These fac-tors may cumulatively lead to worse clinical out-comes manifested as increased rates of in-hospitaland long-term mortality, recurrent MIs, and repeatrevascularization (12,13).

It has become clear that background medical ther-apy plays a critical role with regard to risk reductionin high-risk patients (14). We have previouslyshown larger absolute benefits for ticagrelor therapyin high-risk subjects such as those with type 2 dia-betes or PAD (15,16). An analysis from a pooled data-set of 6 randomized trials (N ¼ 9,577) evaluating theefficacy and safety of long-term dual antiplatelettherapy (DAPT) with aspirin and clopidogrel (>1 year)versus short-term DAPT (3 to 6 months) in patientsundergoing complex PCI (>50% subjects with MVD),showed that long-term DAPT provided significantreduction in major ischemic events (7).

Along with duration of therapy, potency of theantiplatelet therapy is also critically important. In amodest-sized trial of 3,000 patients, Lee et al. (17)showed that adding cilostazol to aspirin and clopi-dogrel for patients undergoing multivessel stentingmay be an efficacious strategy. In a secondary analysisfrom the CHARISMA (Clopidogrel for High Athero-thrombotic Risk and Ischemic Stabilization, Manage-ment, and Avoidance) trial (N ¼ 9,478), DAPT withclopidogrel and aspirin versus monotherapy with

CENTRAL ILLUSTRATION Ticagrelor in MVD: Coronary Events

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60 mg90 mg

Placebo

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4107 4043

Ticagrelor 60 mgHR 0.77, 95% CI (0.65-0.92)

Ticagrelor 90 mgHR 0.75, 95% CI (0.63-0.89)

3875 3474 2512 1145

Bansilal, S. et al. J Am Coll Cardiol. 2018;71(5):489–96.

The figure shows the Kaplan-Meier curves for the 2 ticagrelor doses tested versus placebo for the outcome of coronary events (coronary death,myocardial infarction, and definite stent thrombosis). CI ¼ confidence interval; HR ¼ hazard ratio; MVD ¼ multivessel coronary disease.

Bansilal et al. J A C C V O L . 7 1 , N O . 5 , 2 0 1 8

Ticagrelor for Multivessel Coronary Artery Disease F E B R U A R Y 6 , 2 0 1 8 : 4 8 9 – 9 6

494

KM curves for death/MI/definite stent thrombosis in patients with multivesseldisease in the PEGASUS-TIMI 54 trial.

93% of patients with MVD had undergone prior PCI69% of patients without MVD had undergone prior PCI

Temporal Differences For Efficacy and Bleeding Events During Extended DAPT

Consistent Efficacy Reduction Across Treatment Period

Bonaca MP et al. J Am Coll Cardiol. 2017

Early Bleeding Hazard

2018 Guideline Update on DAPT DurationPCI for a non-ACS indication

Recommendations• We recommend 6 months (and up to 1 year) of DAPT with ASA

and clopidogrel (Strong Recommendation, Moderate Quality Evidence).

• We suggest that in patients who have additional high-risk clinical or angiographic features for thrombotic cardiovascular events and who are at low risk of bleeding, it is reasonable to extend the duration of DAPT to greater than 1 year (Weak Recommendation, Moderate Quality Evidence for up to 3 years of treatment).

• We suggest that in patients who are at high risk of bleeding, the duration of DAPT be shortened to a minimum of 1 month (if a BMS was used) or 3 months (if a DES was used);; (Weak Recommendation, Low Quality Evidence).

Elective PCI

Not at high risk of bleeding1 High risk of bleeding1

DAPT for 6 monthsASA + clopidogrel

YES

1 Factors associated with increased bleeding risk include: need for OAC in addition to DAPT, advanced age (> 75 years), frailty, anemia with hemoglobin < 110 g/dL, chronic renal failure (creatinine clearance < 40 mL/min), low body weight (< 60 kg), hospitalization for bleeding within last year, prior stroke/intracranical bleed, regular need for NSAIDS or prednisone

2 Clinical and angiographic features associated with increased risk of thrombotic events include: age > 65, diabetes mellitus, prior myocardial infarction, chronic renal dysfunction (creatinine clearance < 60 mL/min), multi-vessel disease, multiple stents implanted, complex bifurcation lesion, total stent length > 60 mm, chronic total occlusion intervention or bioabsorbable vascular scaffold (BVS) implantation.

DAPT=dual antiplatelet therapy SAPT=single antiplatelet therapy BMS=bare metal stent DES=drug eluting stent

High-risk clinical or angiographic featuresfor thrombotic cardiovascular events2,

and not at high risk of bleeding?1

DAPT for 1 month if BMS, or 3 months if DES

NO

Extend DAPTup to 3 years

ASA 81 mg daily +

Clopidogrel75 mg daily

SAPT

ASA 81 mg daily or

Clopidogrel75 mg daily

Strong recommendation

Weak recommendation

SAPTASA 81 mg

daily orClopidogrel75 mg daily

Clinical AngiographicPrior myocardial infarction or troponin positive acute coronary syndrome

Multiple stents (≥ 3 stents implanted, ≥ 3 lesions stented)

Diabetes Mellitus treated with oral hypoglycemics or insulin

Long lesion length (> 60 mm total stent length)

Chronic kidney disease (creatinine clearance ≤ 60 ml/min)

Complex lesions (bifurcation treated with 2 stents, stenting of chronic occlusion)

Prior stent thrombosis Left main or proximal LAD stenting

Multivessel PCI

2018 CCS Guideline UpdateVariables Predicting Increased Risk For Thrombotic Events

2018 Guideline Update on DAPT DurationPCI For ACS (STEMI or NSTEACS)

Values and Preferences: These recommendations place greater emphasis on reduction of major cardiovascular events and stent thrombosis versus an increase in bleeding complications.

Recommendations1) We recommend dual antiplatelet therapy (DAPT) with ASA 81 mg daily plus

either ticagrelor 90 mg twice daily or prasugrel 10 mg once daily over clopidogrel 75 mg once daily for 1 year (Strong Recommendation, High Quality Evidence).

2) We recommend that in patients who tolerate 1 year of DAPT without a major bleeding event and who are not at high risk of bleeding, DAPT should be extended beyond 1 year (Strong Recommendation, High Quality Evidence for up to 3 years of treatment). After 1 year, we recommend a DAPT regimen of ASA 81 mg daily plus either ticagrelor 60 mg twice daily or clopidogrel 75 mg once daily (Strong Recommendation, High Quality Evidence) or prasugrel 10 mg once daily (Weak Recommendation, Moderate Quality Evidence).

PCI for STEMI or NSTEACS

DAPT for 1 year

ASA 81 mg OD +Ticagrelor 90 mg BID or Prasugrel 10 mg OD

preferred overClopidogrel 75 mg OD

At 1 year, determine bleeding risk

Not at high risk of bleeding1

1 Factors associated with increased bleeding risk include: need for OAC in addition to DAPT, advanced age (> 75 years), frailty, anemia with hemoglobin < 110 g/dL, chronic renal failure (creatinine clearance < 40 mL/min), low body weight (< 60 kg), hospitalization for bleeding within last year, prior stroke/intracranical bleed, regular need for NSAIDS or prednisone

2 Instead of ticagrelor or clopidogrel, prasugrel 5-10 mg daily is also an option (weak recommendation)

DAPT=dual antiplatelet therapy SAPT=single antiplatelet therapy STEMI=ST segment elevation myocardial infarction NSTEMI=non-ST segment elevation myocardial infarction OD=once daily BID=twice daily

Strong recommendation

Weak recommendation

High risk of bleeding1

Continue DAPT for up to 3 yearsASA 81 mg OD +

Ticagrelor 60 mg BID (strong recommendation)

SAPTASA 81 mg OD

orClopidogrel 75 mg OD

or Clopidogrel 75 mg OD2 (weak recommendation)

Risk Scores Variables Predicted outcomesDAPT 1 Age, MI at presentation, prior MI

or PCI, diabetes, stent diameter <3 mm, smoking, paclitaxel-eluting stent, CHF/low EF, SVG PCI

Trade-off between ischemic/bleedingoutcomes >1 year afterPCI

PRECISE-DAPT 2 Age, previous bleeding, WBC, hemoglobin, creatinine clearance

Trade-off between ischemic/bleedingoutcomes with 3-6 versus 12-24 months of DAPT

CALIBER 3 Ischemic score: 20 variablesBleeding score: 18 variables

Ischemic and bleeding events 2-6 years post-MI, with or without DAPT

1. Yeh RW et al. JAMA. 2016. 2. Costa F et al. Lancet. 2017. 3. Pasea L et al. Eur Heart J. 2017.

Risk Scores may help clinicians decide who should, and who should not be treated with extended DAPT

DAPT Duration Following PCISome Of The Unresolved Issues in 2018

• No prospective validation of risk scores so residual uncertainty about how to best identify patients– At risk of bleeding events with prolonged DAPT– At risk of thrombotic events with shorter DAPT

• Scores combining bleeding and thrombotic risk assume equal clinical importance of each type of event

• Very low dose NOAC+ASA vs prolonged DAPT therapy?– Limited discussion of COMPASS trial as Rivaroxaban 2.5mg BID yet approved in Canada and outcome of PPI arm not yet known

• Abbreviating aspirin duration vs P2Y12 inhibitor duration? (GLOBAL Leaders)

Switching Anti-Platelet Therapies – When and How?

Examples of some common clinical scenarios for P2Y12 inhibitor switching

Intensification from clopidogrel to prasugrel or

ticagrelor

Switching between prasugrel and ticagrelor

De-escalation from prasugrelor ticagrelor to clopidogrel

In patients:

-‐‑ with ACS, who are initially treated with clopidogrel at presentation

-‐‑ admitted with thrombotic event (e.g., stent thrombosis or ACS), who have been treated with clopidogrel

-‐‑ who are known poor metabolizer of clopidogrel (e.g., CYP2C19 loss-of-function)

In patients:

-‐‑with intolerance or side effects, who have additional high-risk clinical or angiographic features for thrombotic events warranting completion of the prescribed course of DAPT

-‐‑admitted with thrombotic event (e.g., stent thrombosis or ACS), who have been treated with the initial P2Y12 receptor inhibitor agent

-‐‑Interactions between CYP3A inducers which affect pharmacodynamics of one specific agent

In patients with:

-‐‑major bleeding complication that has resolved, who have additional high-risk clinical or angiographic features for thrombotic events, warranting completion of the prescribed course of DAPT

-‐‑clinically relevant nuisance bleeding and patient unwilling to continue agent

-‐‑intolerance or side effects to prasugrel / ticagrelor in patients who do not have additional high-risk clinical or angiographic features for thrombotic events

-‐‑a new indication for requiring concurrent treatment with an oral anticoagulant

2018 CCS Recommended APT Regimenvs ‘Approved’ Public Drug Reimbursement

National Public Reimbursement StatusBRILINTA (ticagrelor)

1

BC AB SK MB ON QC NB NS PEI NL NIHB

CoverageStatus

Legend:

• Full ACS criteria

• STEMI w/PCI + high-risk NSTEMI/UA

• STEMI w/PCI + NSTEMI/UA w/PCI

• STEMI w/PCI + high-risk NSTEMI/UA w/PCI

FOR INTERNAL USE ONLY.

Note: Limited to 12 months on most plans

• No public plans cover ticagrelor60mg BID for extended duration as yet

• 84% of people with private insurance have access to ticagrelor 60mg BID though only ½ of these have unrestricted coverage

Data courtesy of Astra Zeneca

CCS 2018 Guideline Update Recommendations For Intensification strategies

Ticagrelor

Clopidogrel

Prasugrel

Loading dose: 180 mg Maintenance dose: 90 mg twice dailyTiming: regardless of the timing of the last clopidogrel dose

Loading dose: 60 mgMaintenance dose: 10 mg dailyTiming: regardless of the timing of the last clopidogrel dose

CCS 2018 Guideline UpdateDe-escalation strategies

Ticagrelor

Clopidogrel

Prasugrel

Loading dose: Optional loading 300-600 mg * Maintenance dose: 75 mg dailyTiming: At next scheduled ticagrelor dose †

Loading dose: NoneMaintenance dose: 75 mg dailyTiming: At next scheduled dose

* Short-term (48h) PD advantage, might be relevant in the early post-ACS/PCI period, if no bleeding risk† Extending to 24h post last ticagrelor dose may also be reasonable** Consider monotherapy with ASA if switch because of bleeding

ASA 80 mg daily**

Management of DAPT in Patients Undergoing CABG

Undergoing Non-cardiac Surgery

2018 CCS Update Recommendations CABG surgery after ACS

• Continuation of ASA in all patients with ACS who require CABG (Strong Recommendation, Moderate Quality Evidence).

• We suggest a minimum interruption of

ü ticagrelor for 48-72 hours prior to semi-urgent CABG and 5 days prior to elective CABG

ü clopidogrel for 48-72 hours prior to semi-urgent CABG and 5 days prior to elective CABG

ü prasugrel for 5 days prior to semi-urgent CABG and an ideal interruption period of 7 days prior to elective CABG

2018 CCS Update Recommendations Interrupting DAPT for non-cardiac surgery • In patients who require elective non-cardiac surgery we recommend

ü delaying surgery for at least 1 month after BMS implantationü delaying surgery for at least 3 months after DES implantation (Strong Recommendation, Moderate Quality Evidence)

ü Restarting when deemed safe to complete recommended period of DAPT (Weak Recommendation, Very Low Quality Evidence)

• If there is a need for semi-urgent non-cardiac surgery, we suggest delaying surgery for at least 1 month after PCI (Weak Recommendation, Low Quality Evidence)

• Following PCI with stenting, we suggest continuing ASA perioperatively if possible (Weak Recommendation, Low Quality Evidence)

Management of Antiplatelet Therapy in Patients Requiring OAC Following PCI• Atrial Fibrillation

– Approx 20% of patients with AF will require PCI at some timec

– Approx 21% of ACS patients will new or established AFd

– Dual antiplatelet therapy is less effective than warfarin in patients with AFa

– Aspirin and thienopyridine more effective than warfarin post stentingb

– >2 million permutations of OAC+APT in ACS patient with AF undergoing PCIe

aACTIVE-W Investigators, Lacent 2006;; bLeon et al, N Eng J Med 1998;; cKralev et al, PLoS One 2011;; dSchmitt et al, Eur Heart J 2009;; Gibson J Am Coll Cardiol 2016

Management of Antiplatelet Therapy in Patients Requiring OAC Following PCI

• Atrial Fibrillation– Approx 20% of patients with AF will require PCI at some timec

– Approx 20% of ACS patients will new or established AFd

– Dual antiplatelet therapy is less effective than warfarin in patients with AFa

– Aspirin and thienopyridine more effective than warfarin post stentingb

– >2 million permutations of OAC+APT in ACS patient with AF undergoing PCIe

• Prosthetic heart valves (PHV)– Vitamin K antagonists and/or antiplatelet therapy is indicated to prevent thrombotic complications of surgically implanted prosthetic heart valves (PHV).

• Established or suspected left ventricular thrombus– OAC recommended if confirmed LV thrombus to reduce systemic embolism– Currently Class IIb recommendation for patients with apical dyskinesis even in absence of clinical benefit of OACf,g

• Patients with venous thromboembolismaACTIVE-W Investigators, Lacent 2006;; bLeon et al, N Eng J Med 1998;; cKralev et al, PLoS One 2011;; dSchmitt et al, Eur Heart J 2009;; Gibson J Am Coll Cardiol 2016;; fUdell at al, PLoS One 2010;; gShavadia et al, JAHA 2017

Copyright © 2018 Canadian Cardiovascular Society™ All Rights Reserved

2018 CCS/CAIC Focused Update of the Guidelines for the Use of Antiplatelet Therapy

Differing OAC regimens in published randomized trials of patients with AF

undergoing PCI

Trials Studied regimens Primary endpoint Comments

WOEST (n=573) Lancet 2008

Warfarin (target INR 2.0) + clopidogrel 75 mg daily Versus Warfarin (target INR 2.0) + clopidogrel 75 mg daily + ASA 80-100 mg daily

Any bleeding episode at 12 months Warfarin + clopidogrel: 19.4% Warfarin + clopidogrel + ASA: 44.4% (p<0·0001)

Prevalence of AF/flutter: 69% Use of PPI: 40% Stents used 65% DES, 35% BMS

ISAR-TRIPLE (n=614) JACC 2015

ASA 75-200 mg daily + clopidogrel 75 mg daily + warfarin (lowest recommended target INR) for 6 weeks versus 6 months

Composite of death, MI, definite stent thrombosis, stroke, or major bleeding at 9 months •6 weeks triple therapy: 9.8% •6 months triple therapy: 8.8% (p=0.63)

Prevalence of AF: 84% Use of PPI: 37.2% Stents used 99% DES INR therapeutic range 64%

PIONEER-AF (n=2124) NEJM 2016

Rivaroxaban 15 mg daily + P2Y12 inhibitor (group 1) vs Rivaroxaban 2.5 mg twice daily + DAPT (group 2) vs Warfarin (INR 2.0-3.0) + DAPT (group 3)

Clinically significant bleeding at 12 months Group 1: 16.8% Group 2: 18.0% Group 3: 26.7% (p<0.001 versus both groups 1 and 2)

Prevalence of AF: 100% Clopidogrel used in 93% of patients Use of PPI: <40% Stents used 65% DES, 32% BMS INR therapeutic range 65%

RE-DUAL PCI (n=2725) NEJM 2017

Dabigatran 110 mg twice daily + P2Y12 inhibitor (clopidogrel 75 mg daily or ticagrelor 90 mg twice daily) vs Dabigatran 150 mg twice daily + P2Y12 inhibitor (clopidogrel 75 mg daily or ticagrelor 90 mg twice daily) vs Warfarin (INR 2.0-3.0) + P2Y12 inhibitor (clopidogrel 75 mg daily or ticagrelor 90 mg twice daily) + aspirin d100 mg daily

Time to first major or clinically relevant non-major bleeding event 15.4% in 110mg dual therapy vs 26.9% comparable triple therapy group (P<0.001 for noninferiority; P<0.001 for superiority) 20.2% in 150mg dual therapy vs 25.7% comparable triple therapy group (P<0.001 for noninferiority)

Prevalence of AF: 100% Clopidogrel used in 88% of patients Stents used 83% DES, 35% BMS Use of PPI: unknown INR therapeutic range 64%

Randomized Trials of OAC Following PCI

Clopidogrel 88%Ticagrelor 12%

Clopidogrel 94%Ticagrelor 5% Prasugrel 1%

Clopidogrel 100%

Clopidogrel 100%10% patients prosthetic heart valve

7% patients prosthetic heart valve

Patients With Atrial Fibrillation Undergoing Coronary Stent Placement: PIONEER AF-PCI

Rivaroxaban vs Warfarin Based OAC

• 1o endpoint: TIMI major + minor + bleeding requiring medical attention • 2o endpoint: CV death, MI, and stroke (Ischemic, Hemorrhagic, or Uncertain Origin)*Rivaroxaban dosed at 10 mg once daily in patients with CrCl of 30 to <50 mL/min.†Alternative P2Y12 inhibitors: 10 mg once-daily prasugrel or 90 mg twice-daily ticagrelor.‡Low-dose aspirin (75-100 mg/d). ∆ Open label VKAGibson CM et al, New Engl J Med 2016

u 2100 patients with NVAF

u Coronary stenting

u No prior stroke/TIA, GI bleeding, Hb<10, CrCl<30

RANDOMIZE

1,6, or 12 months

Rivaroxaban 15 mg qd*Clopidogrel 75 mg qd†

Rivaroxaban 15mg QDAspirin 75-100 mg qd

Rivaroxaban 2.5 mg bidClopidogrel 75 mg qd†Aspirin 75-100 mg qd‡

VKA∆(target INR 2.0-3.0)

Aspirin 75-100 mg qd

VKA∆ (target INR 2.0-3.0)Clopidogrel 75 mg qd†Aspirin 75-100 mg qd

≤72hours

AfterSheath removal

1,6, or 12 months

End oftreatment12 months

WOEST Like

ATLAS Like

TripleTherapy

Pre randomization MD Choice

Pre randomization MD Choice

16% OAC+DAPT 1 month;; 35% OAC+DAPT 6 months;; 49% OAC+DAPT 12 months

Both Rivaroxaban Strategies Were Associated With Significant Reductions in

the Primary Bleeding Endpoint

Gibson CM et al, New Engl J Med 2016;; doi: 10.1056/NEJMoa1611594]

TIMI major, TIMI minor or bleeding

requiring medical attention (%)

Time (days)

Rivaroxaban 15 mg OD plus single antiplatelet vs VKA plus DAPT: HR=0.59;; (95% CI 0.47–0.76);; p<0.001Rivaroxaban 2.5 mg BID plus DAPT vs VKA plus DAPT: HR=0.63 (95% CI 0.50–0.80);; p<0.001

30

25

20

15

10

5

00 30 60 90 180 270 360

26.7%

18.0%16.8%

Group 2 (Rivaroxaban 2.5 mg BID plus DAPT)Group 1 (Rivaroxaban 15 mg OD plus single antiplatelet)

Group 3 (VKA plus DAPT)

ARR8.7%

ARR9.9%

NNT=12

NNT=11

All subgroups analyzed were consistent with overall resultsNon-inferior, open label trial design

Approx 16% OAC+DAPT 1 month;; 35% OAC+DAPT 6 months;; 49% OAC+DAPT 12 months

Comparable Efficacy Between All Three Treatment Strategies*

Gibson CM et al, New Engl J Med 2016;; doi: 10.1056/NEJMoa1611594

CV death, MI or stroke (%)

Time (days)

8

6

4

2

00 30 60 90 180 270 360

Group 2 (Rivaroxaban 2.5 mg BID plus DAPT)Group 1 (Rivaroxaban 15 mg OD plus single antiplatelet)

Group 3 (VKA plus DAPT)

6.0%5.6%

6.5%

Rivaroxaban 15 mg OD plus single antiplatelet vs VKA plus DAPT: HR=1.08;; (95% CI 0.69–1.68);; p=0.750Rivaroxaban 2.5 mg BID plus DAPT vs VKA plus DAPT: HR=0.93 (95% CI 0.59–1.48);; p=0.765

*Trial not powered to detect moderate differences in MI, stroke or stent thrombosis

Dabigatran and Antiplatelet Therapy in Patients Undergoing PCI

Exclusion criteria included CVA within 1 month, CrCl <30mL/min

*Study drug should be administered 6 hours after sheath removal and no later than ≤120 hrs post-PCI (≤72 hrs is preferable). PROBE, prospective, randomized, open, blinded end-point; R, randomization; BMS, bare metal stent; DES, drug-eluting stent. ClinicalTrials.gov: NCT02164864; Cannon et al. Clin Cardiol 2016

Study Design: Multicenter, randomized, open-label trial following a PROBE design

R

Randomization≤120 hourspost-PCI* 6-month minimum treatment duration with visits every 3 months for the first year, then visits

and telephone contact alternating every 3 months and a 1-month post-treatment visit

Patients with AF

undergoing PCI with stenting

Dabigatran 150 mg BID + P2Y12 inhibitor

Dabigatran 110 mg BID + P2Y12 inhibitor

Warfarin (INR 2.0–3.0) + P2Y12 inhibitor + ASA

Dabigatran (110 or 150 mg)

Warfarin

1 month of ASA (BMS)3 months of ASA (DES)

N=2725

Mean duration of follow-up:

~14 months

P2Y12 inhibitor

P2Y12 inhibitor

In comparison to PIONEER-AF patients receiving dabigatran did not receive aspirin therapy beyond randomization

Full analysis set presented. HRs and Wald CIs from Cox proportional-hazard model. For the dabigatran 110 mg vs warfarin comparison, the model is stratified by age, non-elderly vs elderly(<70 or ≥70 in Japan and <80 or ≥80 years old elsewhere). For the dabigatran 150 mg vs warfarin comparison, an unstratified model is used, elderly patients outside the USA are excluded. Non-inferiority P value is one sided (alpha=0.025). Wald two-sided P value from (stratified) Cox proportional-hazard model (alpha=0.05)

Dual Pathway Approach Associated with Lower Bleeding Than Warfarin Based Triple Therapy

Probabilityofevent(%)

00 90 180 540 630 720270 360

450

Time to first event (days)

40

35

30

25

20

15

10

5

Warfarin triple therapy

Dabigatran 110 mg dual therapy

HR: 0.52 (95% CI: 0.42–0.63)Non-inferiority P<0.0001

P<0.0001

0 90 180 540 630 720270 360450

Time to first event (days)

40

35

30

25

20

15

10

5

0

Dabigatran 150 mg dual therapy

Warfarin triple therapy

HR: 0.72 (95% CI: 0.58–0.88)Non-inferiority P<0.0001

P=0.002

Primary end-point: time to first ISTH major or clinically relevant bleeding event ISTH Major Bleed: Bleeding into critical organ, Hgb<2g/dL or transfusion >2units RBC or fatal bleeding.

Primary Endpoint: Time to First Bleeding Event

Results presented are times to event. Stent thrombosis is time to definite stent thrombosis

Secondary Thrombotic Endpoints Dabigatran vs Warfarin in AF Patients

Undergoing PCI

Warfarin triple therapy (n=981)n (%)

D110 DT vs warfarin TT

HR (95% CI)P value

Dabigatran 150 mg dual therapy (n=763)n (%)

Warfarin triple therapy (n=764)n (%)

D150 DT vs warfarin TT

HR (95% CI) P value

All-cause death 55 (5.6) 48 (4.9) 1.12 (0.76–1.65) 0.56 30 (3.9) 35 (4.6) 0.83 (0.51–1.34) 0.44

Stroke 17 (1.7) 13 (1.3) 1.30 (0.63–2.67) 0.48 9 (1.2) 8 (1.0) 1.09 (0.42–2.83) 0.85

Unplanned revascularization 76 (7.7) 69 (7.0) 1.09 (0.79–1.51) 0.61 51 (6.7) 52 (6.8) 0.96 (0.65–1.41) 0.83

MI 44 (4.5) 29 (3.0) 1.51 (0.94–2.41) 0.09 26 (3.4) 22 (2.9) 1.16 (0.66–2.04) 0.61

Stent thrombosis 15 (1.5) 8 (0.8) 1.86 (0.79–4.40) 0.15 7 (0.9) 7 (0.9) 0.99 (0.35–2.81) 0.98

Dabigatran 110mg dual

therapy 111 (n=981)112n (%)

110 mg BID dabigatran dose associated with trend to higher risk of death/thrombotic events (11% vs 8.5%, HR 1.30, 95% CI 0.98-1.73, P=0.07)

No signal for excess thrombotic events seen with 150 mg BID dose(7.9% vs 7.9%, HR 0.97, 95% CI 0.68-1.39, P=0.44).

Efficacy of NOACs in PCI Patients

• Modest numbers of high thrombotic risk patients enrolled in RCTs– Few STEMI patients included – Patients with recent CVA/TIA excluded from both PIONEER-AF and RE-DUAL PCI

• PIONEER-AF and Re-DUAL PCI not powered to assess efficacy of NOAC vs warfarin based strategies

• Use of NOAC will more easily facilitate initiation or restoration of therapeutic anticoagulation post PCI

• No trial data as yet with apixaban or edoxaban

• Analyses from the NOAC AF trials suggest a 30-60% increased bleeding risk in patients receiving a NOAC plus an antiplatelet agent so careful assessment of risk/benefit if consideration of longterm APT with NOAC

• Imbalance between clinical guidelines recommending NOAC use and provincial drug reimbursement criteria across Canada – special access if failed trial of warfarin, drug intolerance, inability to monitor INRs



AF and elective PCI without high-risk features1

Age < 65 and CHADS2 = 0 Age ≥ 65 or CHADS2 ≥ 1

ASA + Clopidogrel Duration: at least 1 month for BMS and at

least 3 months for DES (and up to 12 months)

OAC2 + Clopidogrel Duration: at least 1 month for BMS

and at least 3 months for DES (and up to 12 months)

1 A PCI is considered high-risk based on clinical and angiographic features such as: diabetes mellitus, prior ACS, chronic renal dysfunction (creatinine clearance < 60 mL/min), prior stent thrombosis, current smoker, multi-vessel disease, multiple stents implanted, complex bifurcation lesion, total stent length > 60 mm, chronic total occlusion intervention or bioabsorbable vascular scaffold (BVS) implantation.

2 OAC regimens evaluated in this context include rivaroxaban 15 mg daily (10 mg in patients with renal dysfunction), dabigatran 110 mg or 150 mg BID and warfarin. If warfarin is to be used, recommended INR target is 2.0-2.5. All patients should receive a loading dose of ASA 160 mg at the time of PCI (if previously ASA naïve). Thereafter, ASA can be discontinued as early as the day following PCI.

3 Extended treatment with a P2Y12 inhibitor can be added to ASA if high-risk clinical or angiographic features of ischemic events develop and low risk of bleeding.

4 The dose of OAC beyond the initial period of antithrombotic therapy (up to a year after PCI) should be standard stroke prevention doses as per the CCS Atrial Fibrillation Guidelines. Single antiplatelet therapy with either ASA or clopidogrel may be added to OAC if high-risk clinical or angiographic features of ischemic events develop and low risk of bleeding.

AF: atrial fibrillation; ASA: acetylsalicylic acid; BMS: bare-metal stent; DES: drug-eluting stent; OAC: oral anticoagulant; PCI: percutaneous coronary intervention; SAPT: single antiplatelet therapy

ASA +/- P2Y12 inhibitor3 OAC4 +/- SAPT



AF and PCI for ACS or high-risk1 elective PCI

Age < 65 and CHADS2 = 0 Age ≥ 65 or CHADS2 ≥ 1*

ASA + P2Y12 inhibitor2 (ticagrelor, prasugrel

preferred over clopidogrel for ACS) Duration after PCI: Up to 12 months

Reduced OAC3 + ASA + clopidogrel ASA: stop 1 day post PCI or any time up to

6 months4

Followed by: clopidogrel + OAC Duration after PCI: Up to 12 months

ASA +/- P2Y12 inhibitor5

*If CHADS2 =1 and Age< 65 another option for initial treatment (especially if high-risk for ischemic events) is DAPT alone using ASA+ticagrelor or ASA+prasugrel, similar to the recommendation for the CHADS2=0 patient 1. A PCI is considered high-risk based on clinical and angiographic features such as: diabetes, prior ACS, chronic renal dysfunction (creatinine clearance < 60 mL/min), prior stent thrombosis,

current smoker, multi-vessel coronary artery disease, multiple stents implanted, complex bifurcation lesion, total stent length > 60 mm, chronic total occlusion intervention or bioabsorbable vascular scaffold implantation.

2. Ticagrelor and prasugrel are recommended in ACS patients, whereas clopidogrel is recommended for elective PCI.

3. Regimens evaluated in the context of triple therapy include rivaroxaban 2.5 mg BID or warfarin. If warfarin is to be used, recommended INR target is 2.0-2.5. OAC options evaluated in the context of a dual pathway strategy include rivaroxaban 15 mg daily (plus clopidogrel) or dabigatran 110 mg/150 mg BID (plus clopidogrel).

4. DAPT will have been started as part of ACS management or prior to high risk elective PCI. ASA may be discontinued as early as the day following PCI or it can be continued longer term (eg. 1, 3 or maximum 6 months after PCI). The timing of when to discontinue ASA will vary, depending on the individual patient’s ischemic and bleeding risk.

5. A P2Y12 inhibitor can be added to ASA if high-risk clinical or angiographic features of ischemic events and low risk of bleeding.

6. The dose of OAC beyond 1 year after PCI should be standard stroke prevention doses as per the CCS Atrial Fibrillation Guidelines. Single antiplatelet therapy with either ASA or clopidogrel may be added to OAC if high-risk clinical or angiographic features of ischemic events and low risk of bleeding.

AF: atrial fibrillation; ACS: acute coronary syndrome; ASA: acetylsalicylic acid; OAC: oral anticoagulant; PCI: percutaneous coronary intervention; DAPT: dual antiplatelet therapy; SAPT: single antiplatelet therapy

OAC6 +/- SAPT

Practical Considerations Around Time of PCI in Patients Requiring OAC

• All patients should receive ASA 81 mg (or 160-300mg if ASA naïve) on the day of the PCI procedure. ASA may be discontinued from the day after PCI onwards up to 6 months post PCI

• Triple therapy regimens evaluated as part of RCTs– rivaroxaban 2.5 mg BID + ASA 81 mg daily + clopidogrel 75 mg daily – warfarin + ASA 81 mg daily + clopidogrel 75 mg daily

• Dual pathway regimens evaluated as part of RCTs– rivaroxaban 15 mg daily (10 mg CrCl 30-50) + clopidogrel 75 mg daily– dabigatran 110mg BID or 150mg BID + clopidogrel 75 mg daily

• Clopidogrel suggested over ticagrelor or prasugrel in patients requiring OAC given its lower risk of bleeding complications and the relative lack of data on ticagrelor or prasugrel in combination with OAC

Practical Considerations Around Time of PCI in Patients Requiring OAC

• Emphasis on bleeding reduction strategies in OAC pts having PCI– Wide variation in clinical practice regarding holding OAC prior to angio/PCI– transradial access, limit use of IIbIIIa inhibitors– Avoid routine peri-procedural bridging for anticoagulation– Routine gastroprotection using PPI along with triple therapy

• If warfarin used as part of triple therapy suggested INR is lower therapeutic range for specific indication e.g. AF 2-2.5

44Copyright © 2018 Canadian Cardiovascular Society™ All Rights Reserved


Following the initial period of antithrombotic therapy for patients with AF undergoing PCI for

ACS or elective PCI with high-risk features:

29. If age < 65 and CHADS2 = 0, we recommend long-term therapy with either ASA alone or, if high-risk clinical or angiographic features of ischemic events and low risk of bleeding, ASA + P2Y12 inhibitor (Strong Recommendation, High Quality Evidence); or

If age ≥ 65 or CHADS2 ≥ 1, we recommend long-term therapy with either OAC alone (Strong Recommendation, Moderate and High Quality Evidence) or, if high-risk clinical or angiographic features of ischemic events persist and low risk of bleeding, OAC plus single antiplatelet therapy with ASA or a P2Y12 inhibitor (Weak Recommendation, Low Quality Evidence).

Recommendation

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Other reasons for anticoagulation In patients with established left ventricular thrombus undergoing PCI for an ACS or non-ACS indication:

37. We suggest an initial regimen of triple therapy with ASA 81 mg daily plus clopidogrel 75 mg daily plus OAC. ASA may be discontinued as early as the day following PCI or it can be continued up to 6 months of treatment, depending on the risk of recurrent coronary ischemic events versus major bleeding. Following ASA discontinuation, we suggest treatment with OAC plus clopidogrel 75 mg daily for up to 1 year. If there is evidence of LV thrombus resolution ≥ 3 months after PCI, we suggest discontinuation of OAC and treatment with ASA 81 mg daily plus a P2Y12 inhibitor for up to 1 year after PCI (Weak Recommendation, Very Low Quality Evidence).

Practical tip: • Warfarin is the only anticoagulant evaluated for the treatment of established

left ventricular thrombus. While NOACS are generally safer than warfarin, they have not been evaluated specifically in this context.



Other reasons for anticoagulation

38. We recommend dual antiplatelet therapy (DAPT) with ASA 81 mg daily plus either ticagrelor 90 mg twice daily or prasugrel 10 mg once daily for up to 1 year (Strong Recommendation, Moderate Quality Evidence).

In patients undergoing PCI for an ACS indication who are high-risk of developing LV thrombus:

39. We suggest triple therapy should be avoided given the weak evidence for prevention of LV thrombus and higher risk of bleeding events (Weak Recommendation, Moderate Quality Evidence).




30. We recommend that patients who have concomitant symptomatic CAD and another condition requiring OAC receive a regimen of antithrombotic therapy that is based on a balanced assessment of their risk of (1) systemic embolism, (2) future coronary event(s) and (3) clinically significant bleeding associated with the use of antithrombotic agents (Strong Recommendation, High Quality Evidence).

Recommendation

In patients with a prior valve replacement who undergo PCI for an ACS or non-ACS indication:

31. For patients with a mechanical valve replacement, we suggest an initial regimen of ASA 81 mg daily plus clopidogrel 75 mg daily plus a vitamin K antagonist (VKA) (triple therapy). ASA may be discontinued as early as the day after PCI or it can be continued up to 6 months of treatment, depending on the risk of recurrent thrombotic events versus major bleeding (Weak Recommendation, Very Low Quality Evidence).




32. For patients with a mechanical valve replacement, we recommend against the use of a NOAC regardless of whether it is in combination with antiplatelet therapy or used alone (Strong Recommendation, Moderate Quality Evidence).

In patients with a prior valve replacement who undergo PCI for an ACS or non-ACS indication:

33. For patients with a surgical bioprosthetic valve replacement, (implanted < 6 months), we suggest DAPT with ASA 81 mg daily and clopidogrel 75 mg daily for at least 6 months (and up to 12 months) (Weak Recommendation, Very Low Quality Evidence).

34. For patients with a transcatheter aortic valve replacement (TAVR) (implanted < 6 months), we suggest DAPT with ASA 81 mg daily and clopidogrel 75 mg daily for 3-6 months (Weak Recommendation, Very Low Quality Evidence).

Closing Thoughts On2018 CCS Focused Update On APT

ü More potent P2Y12 inhibitors preferred following ACS with emphasis for reducing thrombotic events whilst acknowledging some excess in non-fatal bleeding events

ü For some patients ‘less may be better’ (or at least as good) than moreü shorter duration DAPT may be ok following elective PCI

ü not all post MI patients should have prolonged DAPT

o utilize risk scores for DAPT duration in everyday clinical practice

ü OAC+P2Y12 inhibitor as good or better than OAC+DAPT in AF patients undergoing PCI (but for how long)

ü Prophylaxis against LV thrombus formation with OAC discouraged in those already on DAPT e.g. post PCI for STEMI

ü NOACs generally preferred as OAC with antiplatelet therapy in those with CAD (unless severe renal impairment or metallic prosthetic valve)

ü Communication vital between hospital physicians and primary care given increasing numbers of potential treatment options

Contemporary Canadian Travel Advisory February 2018

Documents

New 2018 Canadian Cardiovascular Society (CCS)/Canadian … · 2020. 3. 10. · The new england journal of medicine thrombosis, and ischemia-driven target-lesion revascularization