presentations...*hr determined by time-dependent cox model anand ss et al , j am coll cardiol 2018;...

www.phri.caOctober 4, 2017

Finding your COMPASS: Low dose anticoagulants as a new cornerstone therapy for PAD

The Impact of PADo Diseases of the non-cardiac non-intracranial arteries ◦ Predominantly atherosclerotic

o Worldwide prevalence exceeding 200 million; 8 to 12 million Americans

o Patients with PAD are at high risk for Major Adverse Cardiac Events (MACE-4%/yr)

o Patients with PAD are at high risk for Major Adverse Limb Events (MALE-1%/yr)

Finding the Optimal Balance Between Efficacy and Safety in PAD1

APTC, Antiplatelet Trialists’ Collaboration; PAD, peripheral artery disease. 1. Anand SS, et al. J Am Coll Cardiol 2018; 71:2306–15; 2. Hiatt WR, et al. N Engl J Med 2017; 376:32–40; 3. CAPRIE Steering Committee. Lancet 1996; 348:1329–39; 4. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324:74–86; 5. Bonaca MP, et al. N Engl J Med 2015; 372:1791–800; 6. Bonaca MP, et al. JACC: Cardiovasc Interv 2014; 9:2157–64; 7. Bhatt DL, et al. N Engl J Med 2006; 354:1706–17; 8. Anand SS, et al. Lancet 2018; 391:219–29; 9. Eikelboom JW, et al. N Engl J Med 2017; 377:1319–330; 10. WAVE Investigators. N Engl J Med 2007; 357:217–27.

Ischaemic Risk

CAPRIE3

APTC Meta-analysis4

CHARISMA7

TRA2P6

PEGASUS5

EUCLID2 WAVE10

COMPASS1,8,9

Bleeding Risk

Targeting platelets Targeting platelets and coagulation factors

Single antiplatelet therapy Aspirin

P2y12 antagonist

Aspirin

Low-dose anticoagulation

Aspirin

Full-dose anticoagulation

Anand SS 2018

www.phri.ca

COMPASS Design

R

Rivaroxaban 2.5 mg bid + Aspirin 100 mg od

Aspirin 100 mg od

Rivaroxaban 5 mg bid

Expected mean follow up: 3-4 years

Run-in (aspirin plus

rivaroxaban placebo)

Stable CAD or PAD 2,200 participants with a primary outcome event

Bosch J, et al. Can J Cardiol 2017; 33: 1027-1035.

High Risk CAD or PAD


COMPASS trial in patients with CAD or PAD

Eikelboom JW, et al. N Engl J Med 2017; 377: 1319-30.

Eligibility: PAD • Previous revascularization (bypass, angioplasty ±

stenting), or • Previous limb or foot amputation for arterial vascular

disease, or • Intermittent claudication and one or more of:

• ABI <0.90, or • Significant peripheral artery stenosis (≥50%), or

• Previous carotid revascularization or asymptomatic carotid artery stenosis ≥50%

• Plus Asymptomatic PAD: Inclusion CAD and ABI <0.90

Key Efficacy Outcomes • Primary Cardiovascular Outcome: MACE

– Composite of CV death, stroke, or MI • Primary Limb Outcome: Major Adverse Limb

Events (MALE): – Severe limb ischemia leading to an intervention

(angioplasty, bypass surgery, amputation, thrombolysis)

– Major Amputation due to vascular insufficiency above forefoot

PAD Patients in COMPASS

PAD Groups Number of patients All Patients 7,470

Symptomatic PAD Limbs 4,129

Carotid Disease 1,919

CAD + Low ABI (<0.90) only 1,422

Mean Follow-up: 21 months

Eikelboom JW et al, N Engl J Med 2017;377:1319–1330; Anand S et al, Lancet 2018;391:219–229

Baseline characteristics

!9

Characteristic

COMPASS: patients with PAD1 COMPASS: all patients2

Rivaroxaban 2.5 mg bid + aspirin

n (%)

Aspirin n (%)


n (%)

Aspirin n (%)

Age, years (mean) 68 68 68 68

Current smoker (%) 27 27 21 22

Former smoker (%) 46 46 – –

Diabetes (%) 44 44 38 38

Hypertension (%) 79 81 76 75

Prior CAD (%) 69 68 91 91

Secondary prevention treatment received at baseline

Lipid lowering (%) 84 83 89 90

ACE-I/ARB (%) 69 70 71 71


PAD: CV death, stroke, MI

Outcome

R + A N=2,492

A N=2,504

Rivaroxaban + aspirin vs. aspirin

N (%)

N (%)

HR (95% CI) P

MACE 126 (5.1)

174 (6.9)

0.72 (0.57-0.90) 0.005

NNT = 55


PAD: limb outcomes

Outcome

R + A N=2,492

A N=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


PAD: overall outcomes

Outcome

R + A N=2,492

A N=2,504


N (%)

N (%)

HR (95% CI) P

MACE or MALE plus Major amputation

157 (6.3)

225 (9.0)

0.69 (0.56-0.85) 0.0003

NNT= 37

Safety outcomes in the PAD population: Modified ISTH bleeding

*Modified ISTH definition: fatal bleeding, and/or symptomatic bleeding in a critical area or organ (such as intracranial), or bleeding into the surgical site requiring re-operation, and/or bleeding leading to hospitalization; ‡symptomatic Anand S et al, Lancet 2018;391:219–229

Outcome Rivaroxaban 2.5 mg bid + aspirin

N=2492

Aspirin N=2504


vs aspirin

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

Modified ISTH major bleeding* 77 (3.1) 48 (1.9) 1.61

(1.12–2.31) 0.0089

Fatal 4 (0.2) 3 (0.1) – –Non-fatal ICH‡ 4 (0.2) 8 (0.3) – –

Non-fatal other critical organ* 13 (0.5) 8 (0.3) 1.55

(0.64–3.74) 0.33

ISTH major bleeding 64 (2.6) 40 (1.6) 1.61

(1.08–2.39) –

Net Clinical benefit in PAD

Outcome

R + A N=2,492

R N=2,474

A N=2,504 Riva + aspirin vs. aspirin Riva vs. aspirin

N (%)

N (%)

N (%)

HR (95% CI) P HR

(95% CI) P

Net Clinical Benefit 169 (6.8) 207 (8.4) 234 (9.3) 0.72

(0.59-0.87) 0.0008 0.89 (0.74-1.07) 0.23


PAD subsets

Overall COMPASS

Overall PAD

Symptomatic PAD

PAD Lower Extremeties

Carotid Artery Disease

MACE + MALE + Major Amputation

0 0.5 1.0 1.5

Riva 2.5 + ASA better

ASA only better

Hazard Ratio of MALE on Subsequent Events

Outcome Hazard Ratio P Value

Hospitalizations 7.21 < 0.0001

Amputation 197.5 < 0.0001Death 3.23 < 0.0001MACE 1.52 0.27MACE or Amputation 7.56 < 0.0001

Anand SS et al, J Am Coll Cardiol 2018; doi: 10.1016/j.jacc.2018.03.008;

Prognosis of MALE by Randomized Treatment Group(incidence rates / 100 person-years)

Riva/Aspirin Aspirin Only

0.1

11.33

22.55

33.78

45

Death Total Amp Mace/Total Amp

BeforeAfter

•* HR=0.89; P=0.91

0

10

20

30

40

Death Total Amp Mace/Total Amp

BeforeAfter •* HR=5.97; P=<0.0001

* HR=10.2; P=<0.0001

* HR=2.05; P=0.32

*HR determined by time-dependent Cox modelAnand SS et al, J Am Coll Cardiol 2018; doi: 10.1016/j.jacc.2018.03.008; Anand S et al, ACC 2018:Oral presentation 407-16

Summary N=121 pathological specimens from 95 AKA or BKA patients

Narula et al. JACC, 2018

Histopathological characterization of lower leg vessels reveals thrombotic occlusion commonly with insignificant atherosclerosis

www.phri.caEikelboom J, et al. N Engl J Med 2017; 377: 1319-1330. 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. Dagenais GR, et al. Lancet. 2006; 368:581-8. Schwartz GG, et al. N Engl J Med 2018;379:2097-2107. Zinman B, et al. N Engl J Med 2015; 373: 2117-2128.

Rivaroxaban + aspirin

Lipid-lowering

(1mmol/L)

BP- lowering

(10mm Hg)ACE

SGLT2 inhibitor

(Empagliflozin)

PCSK9 inhibitor

(Alirocumab)

Triple outcome -24% -21% -20% -18% -14% -14%

Death -18% -9% -13% -14% -32% -15%

Stroke -42% -15% -27% -23% +18% -27%

MI -14%* -24% -17% -18% -13% -12%

COMPASS in context of other proven secondary prevention therapies

*Not significant

Events Prevented Per 1,000 Patients Treated with Rivaroxaban + Aspirin Over 30 Months

.Anand SS. In Press JACC July 2019.

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Presence Absence

Who are the Highest Risk Patients who benefits most?

Therapies for PAD in 2019

Preventing CV Events

Antiplatelets

Rivaroxaban and aspirin Cholesterol lowering – “statins/iPCSK-9”

ACE Inhibitors

Behaviour: Smoking/Exercise

Reducing Leg Symptoms/MALE • Smoking Cessation/Exercise • Cilostazol • Statins/iPCSK-9 • Catheter-based interventions • Graft surgery • Rivaroxaban and aspirin

presentations...*hr determined by time-dependent cox model anand ss et al , j am coll cardiol 2018;...

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