SUN 03 ACC R Welsh 2018 R Welsh 201… · Alexander et al., N Engl J Med 2011;365:699-708 Patients (n=7392) with recent STEMI or NSTEACS (80% on dual antiplatelet therapy) and ≥2

Robert C. Welsh, MD, FRCPCProfessor of Medicine, University of Alberta

Zone Clinical Department Head, Cardiac Sciences

Re-‐Setting our COMPASS for Secondary Prevention in Atherosclerotic Vascular Disease

Inspiring Innovation and KnowledgeLeaders in Patient Care

Robert C. Welsh, MD, FRCPC

Faculty Disclosure (12 months):• Research and Clinical Trials: Abbott Vascular, Astra Zeneca, Bayer, BMS,

Boehringer Ingelheim, CIHR, CSL Behring LLC, Edwards Lifesciences, Eli Lilly, Jansen, Johnson and Johnson, Pfizer, Population Health Research Institute, University of Alberta Hospital Foundation

• Consulting Fees/Honoraria: Amgen, Astra Zeneca, Bayer, Bristol Myers-‐Squibb/Pfizer, Canadian Cardiovascular Society

• Other: University of Alberta (employee), Alberta Health Services (Clinical privileges) and President, The Canadian Centre for Clinicians and Scientists

Overview

1. Review the Dual Pathway approach to secondary prevention in atherosclerotic patients

2. Discuss the COMPASS data 1. Overall trial and the PAD and CAD cohorts

3. Initiate a ‘discussion’ regarding applying the dual pathway approach to patients in clinical practice

Traditional Secondary Prevention Inhibition of Pathways For Thrombus FormationTwo pathways connecting tissue injury, coagulation, and platelet response.

Collagen

TissueFactor

Thrombin

Plateletactivation

Prothrombin

ADP

TXA2

PlasmaClottingcascade

THROMBUS

Fibrinogen Fibrin

Plateletaggregation

Platelet Pathway

Coagulation Pathway


Anti-‐Platelet Therapy ASA

Dual Anti-‐Platelet Therapy ASA + Clopidogrel/Prasugrel or

Ticagrelor

Clopidogrel DAPT and all cause mortality in Secondary Prevention

Sammy Elmariah , Laura Mauri et al;; The Lancet, 2014

Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis

Experimental treatment of ACSPathways For Thrombus Formation

Two pathways connecting tissue injury, coagulation, and platelet response.

Collagen

TissueFactor

Thrombin

Plateletactivation

Prothrombin

ADP

TXA2


THROMBUS

Fibrinogen Fibrin

Plateletaggregation

Platelet Pathway Dual Anti-‐Platelet Therapy ASA + Clopidogrel/Prasugrel or

Ticagrelor

Coagulation Pathway


Oral Antithrombotic

Alexander et al., N Engl J Med 2011;365:699-708

Patients (n=7392) with recent STEMI or NSTEACS (80% on dual antiplatelet therapy) and ≥2 additional risk factors (Age ≥65 yrs, DM, prior MI ≤5 yrs, CVD, PVD, HF or LVEF <40%, CrCl <60 mL/min, no revascularization for index event) → DMC

recommended trial stop due to excess of clinically important bleeding without counterbalancing reduction in ischemic events

0.1 1 10Apixaban

BetterPlacebo Better

TIMI Major

TIMI Major or Minor

ISTH Major

ISTH Major or Clinically Relevant Non-‐Major

GUSTO Severe

Intracranial

1.3

2.2

2.7

3.2

1.0

0.3

0.5

0.8

1.1

1.2

0.3

0.1

vs.

vs.

vs.

vs.

vs.

vs.

Bleeding

Fatal bleeding: Apixaban = 5

vs. Placebo = 0

CV Death/MI/Stroke

0

2

4

6

8

0

%

3 6 159 12

HR 0.95 (0.80-1.11)p=0.51

7.57.9

PlaceboApixaban 5 (2.5*) mg BID

* CrCl <40 mL/min

Apix: 3705Plac: 3687

Months

2799

2751

20252030

12771248

561571

154164

Median 8 months

Median time from index ACS to randomization: 6 (4, 7) days

Atrial Fibrillation Dose Apixaban in ACS

ATLAS ACS 2-‐TIMI 51: A randomised, double-‐blind, event-‐driven Phase III trial in patients hospitalised with ACS

*184 patients were excluded from the efficacy analyses prior to unblinding because of trial misconduct at three sites.ACS=Acute coronary syndrome; ASA=Acetylsalicylic acid; bid=Twice daily; od=Once daily; TIMI=Thrombolysis In Myocardial Infarction.

1. Gibson CM, et al. Am Heart J. 2011;161:815–21.e6; 2. Mega JL, et al. N Engl J Med. 2012;366:9–19; 3. European Medicines Agency. Rivaroxaban Assessment Report 2013. EMA/CHMP/794349/2012.

ASA dose: 75–100 mg1Event-driven study – 983 events2

Physician's decision whether or not to add thienopyridine1

N=15,526*2

Rivaroxaban

2.5 mg bid

(n=349)3

Stratum 1: ASA alone (7%)2

Stratum 2: ASA + thienopyridine (93%)2

Placebo

(n=355)3

Rivaroxaban

5 mg bid

(n=349)3

Rivaroxaban

2.5 mg bid

(n=4825)3

Rivaroxaban

5 mg bid

(n=4827)3

Placebo

(n=4821)3

YESNO


ATLAS ACS 2-‐TIMI 51: Efficacy endpoints rivaroxaban 2.5 mg bid

The primary efficacy endpoint reduction was driven by reduced mortality

Both strata. CV=Cardiovascular; HR=Hazard ratio; ITT=Intention to treat; MI=Myocardial infarction; mITT=Modified intention to treat; NNT=Number needed to treat.

1. Mega JL, et al. N Engl J Med. 2012;366:9–19; 2. Gibson CM et al. LBCT.01. Presented at American Heart Association (AHA) Scientific Sessions 2011; 12-‐16 November, Orlando, Florida, USA.

CV death1,2 All-cause death2CV death/MI/stroke (primary efficacy endpoint)1,2

513

0

Months

NNT=71

0 24

4.1%

2.7%

Placebo

Rivaroxaban2.5 mg bid

HR=0.66mITT p=0.002ITT p=0.005

181260

5

Months

4.5%

2.9%

240

Placebo


HR=0.68mITT p=0.002ITT p=0.004

18126

NNT=63

Months

Cum

ulative incidence (%) HR=0.84

mITT p=0.02ITT p=0.007

10.7%

9.1%


Placebo

0240 18126

NNT=63


ATLAS ACS 2-‐TIMI 51: Safety endpoints rivaroxaban 2.5 mg bid

* p<0.001 vs placebo; † p=0.04 vs placebo.CABG=Coronary artery bypass graft; ICH=Intracranial haemorrhage; NS=Not significant.

1. Mega JL, et al. N Engl J Med. 2012;366:9–19; 2. Gibson CM et al. LBCT.01. Presented at American Heart Association (AHA) Scientific Sessions 2011; 12-‐16 November, Orlando, Florida, USA.

Rivaroxaban vs placebop=NS

Rivaroxaban vs placebop=NS

2-year Kaplan–Meier

estim

ate (%)

*

†

(principal safety outcome)

1

1 1 2


Experimental Secondary PreventionInhibition of Pathways For Thrombus Formation



Collagen

TissueFactor

Thrombin

Plateletactivation

Prothrombin

ADP

TXA2


THROMBUS

Fibrinogen Fibrin

Plateletaggregation

Platelet Pathway Safe/Effective Predictable

Anti-‐platelet

Safe/Effective Predictable

Anti-‐coagulantCoagulation Pathway

A Dual Pathway Approach Targeting Chronic Patients with CAD or PAD was Investigated in COMPASS

Objective: To determine the efficacy and safety of vascular dose rivaroxaban plus aspirin compared with aspirin alone for the prevention of MI, stroke and cardiovascular death in chronic CAD or PAD

Antithrombotic investigations‡ were stopped 1 year ahead of expectations in February 2017 due to overwhelming efficacy in the rivaroxaban 2.5 mg bid + aspirin arm2

Rivaroxaban 5.0 mg bid

Aspirin 100 mg od

Rivaroxaban 2.5 mg bid + aspirin 100 mg od

30-daywashout period

30-day run-in*aspirin 100 mg

Final follow-up visit

R

Final washout period visit

1:1:1

N=27,395Population:

Chronic CAD (91%)PAD (27%)

Average follow-up: 23 months at early termination of study2

Factorial design ± pantoprazole#

PADCAD

*The CAD analysis includes 1448 patients who entered COMPASS immediately post-CABG (with no run-in)3; #Patients who were not receiving a proton pump inhibitor (PPI) were randomized to pantoprazole or placebo (partial factorial design); ‡1. Bosch J et al, Can J Cardiol 2017;33:1027–1035; 2. Eikelboom JW et al, N Engl J Med 2017;377:1319-1330;3. Connolly SJ et al, Lancet 2017; doi:10.1016/S0140-6736(17)32816-7

Inclusion and Exclusion Criteria Ensured That Patients Had Chronic CAD and Moderate Cardiovascular Risk

Key inclusion criteria*

u CAD (prior MI, multivessel coronary disease or multivessel revascularization)

u Plus ≥1 of:• Age ≥65 years• Age <65 years plus atherosclerosis in

≥2 vascular beds or ≥2 additional risk factors – Current smoker – Diabetes mellitus – Renal dysfunction (eGFR<60 ml/min)– Heart failure – Non-‐lacunar ischaemic stroke

≥1 month ago

Key exclusion criteria#

u Stroke within the past month or any haemorrhagic or lacunar stroke

u Severe HF with known ejection fraction <30% or NYHA class III or IV symptoms

u Need for dual antiplatelet therapy, other non-‐aspirin antiplatelet therapy or oral anticoagulant therapy

u eGFR <15 ml/min

#Including but not limited to; #Any other exclusion criteria in conjunction with the local Product Information and any other contraindication listed in the local labelling for rivaroxaban or the comparator have to be consideredBosch J et al, Can J Cardiol 2017;33:1027–1035

Patients had multiple risk factors

Patients with acute CAD or deemed to be at very high cardiovascular riskwere excluded because of need for DAPT

Baseline characteristicsRivaroxaban + aspirin N=9,152

RivaroxabanN=9,117

AspirinN=9,126

Age, yr, mean 68 68 68Female 22% 22% 22%SBP/DBP, mmHg, mean 136/77 136/78 136/78Cholesterol (total), mmol/L, mean 4.2 4.2 4.2

CAD 91% 90% 90%PAD 27% 27% 27%Stroke 3.8% 3.8% 3.7%Diabetes 38% 38% 38%Lipid-‐lowering 90% 90% 89%ACE-‐I/ARB 71% 72% 71%

Primary Outcome CV death, stroke, MI

OutcomeR + A

N=9,152Riva

N=9,117AspirinN=9,126

Riva + aspirin vs. aspirin

Rivaroxaban vs. aspirin

N (%) N (%) N (%) HR (95% CI) p HR (95% CI) p

CV death, stroke, MI

379(4.1)

448(4.9)

496(5.4)

0.76(0.66-‐0.86) <0.0001 0.90

(0.79-‐1.03) 0.11

Components of primary outcomeR + A



N(%)

N(%)

HR(95% CI) p

CV death 160(1.7)

203(2.2)

0.78(0.64-‐0.96) 0.02

Stroke 83(0.9)

142(1.6)

0.58(0.44-‐0.76) <0.001

MI 178(1.9)

205(2.2)

0.86(0.70-‐1.05) 0.14

Major bleeding components

Outcome Riva + aspirin N=9,152

AspirinN=9,126

Rivaroxaban + aspirin vs. aspirin

N % N % HR 95% CI P

Major bleeding 288 3.1 170 1.9 1.70 1.40-‐2.05 <0.0001

Fatal 15 0.2 10 0.1 1.49 0.67-‐3.33 0.32

Non fatal ICH* 21 0.2 19 0.2 1.10 0.59-‐2.04 0.77

Non-‐fatal other critical site* 42 0.5 29 0.3 1.43 0.89-‐2.29 0.14

Other 210 2.3 112 1.2 1.88 1.49-‐2.36 <0.0001

* symptomatic

Primary efficacy and major bleeding Landmark analyses

Rivaroxaban + aspirin vs aspirin Net benefit


AspirinN=9,126


N % N % HR 95% CI P

Primary outcome + severe bleeds 426 4.7 529 5.8 0.80 0.70-‐0.91 0.0005

Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-‐blind, placebo-‐controlled trial

Anand et al, Lancet, 391, 10117, January 2018, Pages 219-229

Primary Endpoint – CV Death, MI and Stroke MALE and Amputations

COMPASS Enrolled over 24,000 Patients with Advanced, Chronic CAD

CAD definition Number of patients (% of CAD population)1

All patients with CAD 24,824

Prior MI 17,028 (69%)

<1 year 1238 (5%)

1–<2 years 2341 (9%)

2–<5 years 4893 (20%)

≥5 years 8520 (34%)

Multivessel coronary disease* 15,469 (62%)

Prior PCI 14,862 (60%)

Prior CABG 7845 (32%)

Patients randomized immediately post-‐CABG 1448 (6%)

CAD

*Refers to stenosis of ≥50% in 2 or more coronary arteries, confirmed using invasive coronary angiography, or non-invasive imaging or stress studies suggestive of significant ischaemia in ≥2 coronary territories; or in 1 coronary territory if at least 1 other territory has been revascularized2

1. Connolly SJ et al, Lancet 2017; doi:10.1016/S0140-6736(17)32816-7;2. Bosch J et al, Can J Cardiol 2017;33:1027–1035

Half of all previous MIs occurred ≥5 years prior to enrolment in COMPASS1

Dual Pathway Inhibition with Rivaroxaban 2.5 mg bid + Aspirin Significantly Reduced MACE by 26% Versus

Aspirin

Connolly SJ et al, Lancet 2017; doi:10.1016/S0140-6736(17)32816-7

Stroke/MI/Cardiovascular death

Cum

ulative incidence risk (%)

0

2

4

6

8

10

0 1 2 3

Rivaroxaban + AspirinRivaroxaban

Aspirin

Year

Riva 2.5 mg bid + aspirin vs aspirin

Riva 5 mg bid vs aspirin

HR=0.74 (95% CI 0.65–0.86) p<0.0001

HR=0.90 (95% CI 0.79–1.02) p=0.11

CAD

Outcome Rivaroxaban 2.5 mg bid + aspirinN=8313

AspirinN=8261

Rivaroxaban 2.5 mg bid + aspirin

vs aspirin

N (%) N (%) HR(95% CI)

p-‐value

MACE 347 (4) 460 (6) 0.74 (0.65–0.86) <0.0001

CV death 139 (2) 184 (2) 0.75(0.60–0.93) 0.010

Stroke 74 (1) 130 (2) 0.56(0.42–0.75) <0.0001

MI 169 (2) 195 (2) 0.86(0.71–1.05) 0.15

Bleeding Rates Increased but Low with Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin Versus Aspirin Alone

Outcome


N=8313

AspirinN=8261


vs aspirin

N (%) N (%) HR(95% CI) p-‐value

Major bleeding 263 (3) 158 (2) 1.66(1.37–2.03) <0.0001

Fatal 14 (<1) 9 (<1) 1.55(0.67–3.58) 0.30

ICH 19 (<1) 19 (<1) 0.99(0.52–1.87) 0.98

Critical organ 36 (<1) 25 (<1) 1.42(0.85–2.36) 0.18

Other 194 (2) 105 (1) 1.85(1.46–2.34) <0.0001


CAD

No significant increase in critical organ bleeding

including intracranial or fatal bleeding

22% Reduction in Risk of the Composite Net Clinical Benefit Outcome with Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin vs Aspirin

• For every 1000 patients with CAD treated with rivaroxaban plus aspirin, 13 MACE events would be prevented and 2 fatal or critical organ bleedswould be caused over a mean 23-month period

Rates at mean follow-‐up of 23 months

Rivaroxaban 2.5 mg bid + aspirinN=8313

AspirinN=8261


vs aspirin

N (%) N (%) HR(95% CI)

p-‐value

Net clinical benefit(CV death, stroke, MI, fatal or critical organ bleeding)

392 (5) 494 (6) 0.78 (0.69–0.90) 0.0003

All-‐cause mortality 262 (3) 339 (4) 0.77(0.65–0.90) 0.0012

CV death 139 (2) 184 (2) 0.75(0.60–0.93) 0.010

Non-‐CV death 123 (2) 155 (2) 0.79 (0.62–1.00) 0.048


CAD

Persistent Reduction in MACE with Dual Pathway Inhibition; Increased Bleeding only in the First Year


n/N (%)

Aspirin alonen/N (%) HR (95% CI) HR (95% CI)

MACE<1 year 176/8313 (2) 221/8261 (3) 0.79 (0.65–0.96)1–<2 years 113/7228 (2) 169/7125 (2) 0.66 (0.52–0.83)>2 years 58/3655 (2) 70/3621 (2) 0.82 (0.58–1.16)

Major bleeding<1 year 163/8313 (2) 70/8261 (1) 2.32 (1.75–3.07)1–<2 years 70/7189 (1) 59/7183 (1) 1.19 (0.84–1.68)>2 years 30/3626 (1) 30/3628 (1) 1.05 (0.63–1.75)

Net clinical benefit<1 year 207/8313 (2) 237/8261 (3) 0.87 (0.72–1.04)1–<2 years 124/7201 (2) 182/7112 (3) 0.67 (0.53–0.84)>2 years 61/3637 (2) 75/3604 (2) 0.80 (0.57–1.12)

All death<1 year 117/8313 (1) 145/8261 (2) 0.80 (0.63–1.02)1–<2 years 93/7323 (1) 120/7242 (2) 0.77 (0.59–1.01)>2 years 52/3743 (1) 74/3762 (2) 0.70 (0.49–1.00)

Landmark analysis for key efficacy and safety outcomes


Favours rivaroxaban 2.5 mg bid + aspirin

Favours aspirin alone

CAD

Secondary Prevention in Atherosclerosis

COMPASS in contextLipid

lowering(1mmol/L)

BP Lowering(10mm Hg)

ACE(HOPE)

COMPASSRivaroxaban+ aspirin

MACE 21% 20% 22% 24%

Death 9% 13% 16% 18%

Stroke 15% 27% 32% 42%

MI 24% 17% 20% 14%

MALE -‐ -‐ 11% 46%

HOPE Investigators. N Engl J Med 2000;342:145-53. Ettehad D, et al. Lancet 2016;387:957-67.CTT Collaboration. Lancet 2015;385:1397-1405; Collins R, et al. Lancet 2016;388:2532-61.

Months from Randomization

Ticagrelor 60 mgHR 0.84 (95% CI 0.74 – 0.95)

P=0.004

CV Death, MI, or Stroke (%

)

3 6 9 120 15 18 21 24 27 30 33 36


P=0.008

Placebo (9.0%)

Ticagrelor 90 (7.8%)Ticagrelor 60 (7.8%)

6

5

4

3

10

9

8

7

2

1

0

N = 21,162Median follow-up 33 months

Bonaca MP et al., NEJM 2015

Residual Risk in ‘Stable CAD PatientsTicagrelor - Time to First Primary Efficacy Event:Composite of Cardiovascular Death, MI or Stroke

Figure 1

Canadian Journal of Cardiology 2018 34, 214-233DOI: (10.1016/j.cjca.2017.12.012) Copyright © 2018 Terms and Conditions

Anti-‐thrombotics Strategies for Secondary Prevention

PEGASUSTicagrelor 90+ aspirin

COMPASSRivaroxaban+ aspirin

PEGASUSTicagrelor 60+ aspirin

MACE 15% 24% 16%CV Death 0% 18% 11%Stroke 18% 42% 25%MI 19% 14% 16%

Major Bleeds -‐169% -‐70% -‐132%ICH -‐44% -‐16% -‐33%

*Non-fatal. †severe and moderate GUSTO, respectively

A B C

Amputations 70%

MALE 46%All Cause Mortality 18%

Dual Anti-‐thrombotic Therapy has the Same Bleeding Risk as DAPT with either Ticagrelor or Clopidogrel

*Hazard Ratio (95%CI)

Ohman et al, Lancet, March 18, 2017 (online)

Primary Endpoint: TIMI Non-CABG Clinically Significant Bleeding

Adverse events leading to drug discontinuation

1. Eikelboom JW, et al. N Engl J Med 2017;; DOI: 10.1056/NEJMoa1709118;; Bonaca MP et al. N Engl J Med 2015

“Drugs don't work in patients who don't take them” Former US Surgeon General, C. Everett Koop

Contemporary Secondary PreventionInhibition of Pathways For Thrombus Formation



Collagen

TissueFactor

Thrombin

Plateletactivation

Prothrombin

ADP

TXA2


THROMBUS

Fibrinogen Fibrin

Plateletaggregation

Platelet Pathway Safe/Effective Predictable

Anti-‐platelet

Safe/Effective Predictable

Anti-‐coagulantCoagulation Pathway

Summary

The ‘Vascular Protection’ dose of rivaroxaban 2.5 mg bid and low dose ASA offers a new standard of care in long term secondary prevention of patients with atherosclerotic disease

-‐ With larger reductions in MACE, Death and Stroke than previously adapted therapies (Statins, ACE-‐I, etc)

-‐ With reductions in amputations and MALE in PAD patients

Baseline characteristicsRivaroxaban + aspirin N=9,152

RivaroxabanN=9,117

AspirinN=9,126

Age, yr, mean 68 68 68Female 22% 22% 22%SBP/DBP, mmHg, mean 136/77 136/78 136/78Cholesterol (total), mmol/L, mean 4.2 4.2 4.2

CAD 91% 90% 90%PAD 27% 27% 27%Stroke 3.8% 3.8% 3.7%Diabetes 38% 38% 38%Lipid-‐lowering 90% 90% 89%ACE-‐I/ARB 71% 72% 71%

Primary Outcome CV death, stroke, MI

OutcomeR + A

N=9,152Riva




N (%) N (%) N (%) HR (95% CI) p HR (95% CI) p

CV death, stroke, MI

379(4.1)

448(4.9)

496(5.4)

0.76(0.66-‐0.86) <0.0001 0.90

(0.79-‐1.03) 0.11

Components of primary outcomeR + A



N(%)

N(%)

HR(95% CI) p

CV death 160(1.7)

203(2.2)

0.78(0.64-‐0.96) 0.02

Stroke 83(0.9)

142(1.6)

0.58(0.44-‐0.76) <0.0001

MI 178(1.9)

205(2.2)

0.86(0.70-‐1.05) 0.14

Myocardial infarction

Event

R + A N=9,152

AspirinN=9,126


N(%)

N(%)

HR(95% CI) p

MI or SCD 247(2.7%)

289(3.2%)

0.85(0.72-‐1.00) 0.06

MI, SCD, or cardiac arrest

273(3.0%)

333(3.6%)

0.81(0.69-‐0.95) 0.01

MI, SCD, resus. Cardiac arrest, or unstable angina

277(3.0%)

331(3.6%)

0.83(0.71-‐0.97) 0.02

Stroke severity

Rankin score at 7 days or discharge

R + A N=9,152

AspirinN=9,126


N(%)

N(%)

HR(95% CI) P

0 15(0.2)

30(0.3)

0.50(0.42-‐0.92) 0.02

1-‐2 36(0.4)

63(0.7)

0.57(0.38-‐0.85) 0.006

3 11(0.1)

17(0.2)

0.64(0.30-‐1.37) 0.25

4-‐5 9(<0.1)

26(0.3)

0.34(0.16-‐0.73) 0.004

6 12(<0.1)

13(0.1)

0.92(0.42-‐2.02) 0.84

PAD: limb outcomes

Outcome

R + AN=2,492

AN=2,504


N(%)

N(%)

HR(95% CI) P

MALE 30(1.2)

56(2.2)

0.54(0.35-‐0.84) <0.005

Major amputation

5(0.2)

17(0.7)

0.30(0.11-‐0.80) 0.01

MALE plus major amputation

32(1.3)

60(2.4)

0.54(0.35-‐0.82) 0.004

Secondary outcomes

Outcome

R + A N=9,152

Riva N=9,152

AspirinN=9,126



N(%)

N(%)

N(%)

HR(95% CI) p HR

(95% CI) P

CHD death, Isch. stroke, MI, ALI

329(3.6)

397(4.4)

450(4.9)

0.72(0.63-‐0.83) <0.0001 0.88

(0.77-‐1.01) 0.06

CV death,Isch. stroke, MI, ALI

389(4.3)

453(5.0)

516(5.7)

0.74(0.65-‐0.85) <0.0001 0.88

(0.77-‐0.99) 0.04

Death 313(3.4)

366(4.0)

378(4.1)

0.82(0.71-‐0.96) 0.01 0.97

(0.84-‐1.12) 0.66

Major bleeding components


AspirinN=9,126


N % N % HR 95% CI P

Major bleeding 288 3.1 170 1.9 1.70 1.40-‐2.05 <0.0001

Fatal 15 0.2 10 0.1 1.49 0.67-‐3.33 0.32

Non fatal ICH* 21 0.2 19 0.2 1.10 0.59-‐2.04 0.77

Non-‐fatal other critical site* 42 0.5 29 0.3 1.43 0.89-‐2.29 0.14

Other 210 2.3 112 1.2 1.88 1.49-‐2.36 <0.0001

* symptomatic

In patients with stable CAD or PADRivaroxaban 2.5mg bid + aspirin 100mg od vs. aspirin 100mg od:• Reduces MACE -‐ CV death, stroke, or MI • Improves CV death and all cause death • Increases major bleeding but does not increase fatal or intracranial bleeding

• Is associated with a net clinical benefit

Months from Randomization


P=0.004

CV Death, MI, or Stroke (%

)

3 6 9 120 15 18 21 24 27 30 33 36


P=0.008

Placebo (9.0%)

Ticagrelor 90 (7.8%)Ticagrelor 60 (7.8%)

6

5

4

3

10

9

8

7

2

1

0

N = 21,162Median follow-up 33 months

Bonaca MP et al., NEJM 2015

Residual Risk in ‘Stable CAD PatientsTicagrelor - Time to First Primary Efficacy Event:Composite of Cardiovascular Death, MI or Stroke

Adverse events leading to discontinuation

1. Eikelboom JW, et al. N Engl J Med 2017;; DOI: 10.1056/NEJMoa1709118;;

Documents

SUN 03 ACC R Welsh 2018 R Welsh 201… · Alexander et al., N Engl J Med 2011;365:699-708 Patients (n=7392) with recent STEMI or NSTEACS (80% on dual antiplatelet therapy) and ≥2