on CANTOS,COMPASS,VALIDATE Trails Dr.R.Keethika CARE Hospitals, - - PowerPoint PPT Presentation

WINCARS WEBINAR

• n

CANTOS,COMPASS,VALIDATE Trails

Dr.R.Keethika CARE Hospitals, Hyderabad

WINCARS Association www.wincarsassociation.com

Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)

Ridker ACC 2017

Anti-Inflammatory Therapy with Canakinumab for Atherosclerotic Disease

WINCARS Association www.wincarsassociation.com

Low Grade Systemic Inflammation Precedes By Many Years the Onset of Vascular Events

Ridker ESC 2017 WINCARS Association www.wincarsassociation.com

Clinical Impact of Inflammation on Atherosclerosis

• Plasma levels of inflammatory biomarkers including hsCRP and IL-6

robustly predict first and recurrent cardiovascular events, independent of lipid levels.

• Statins are both lipid lowering and anti-inflammatory, and the greatest

benefits of statin therapy accrue to those who not only lower LDLC, but who also lower hsCRP.

• In primary prevention, the JUPITER trial demonstrated that those with

elevated hsCRP but low levels of LDLC markedly benefit from statin therapy.

• In secondary prevention, clinicians now distinguish between those with

“residual cholesterol risk” and those with “residual inflammatory risk”

Ridker PM. JACC 2016;67:712-23

Ridker ESC 2017 WINCARS Association www.wincarsassociation.com

Additional LDL Reduction IMPROVE-IT : Ezetimibe 6% RRR FOURIER/SPIRE: PCSK9 Inhibition q2 weeks 15% RRR Known Cardiovascular Disease LDL 150 mg/dL (3.8 mmol/L) hsCRP 4.5mg/L High Intensity Statin Additional Inflammation Reduction No Prior Proof of Concept

“Residual Inflammatory Risk”

LDL 70 mg/dL (1.8 mmol/L) hsCRP 3.8 mg/L

Ridker ESC 2017

“Residual Cholesterol Risk”

LDL 110 mg/dL (2.8 mmol/L) hsCRP 1.8 mg/L

Residual Inflammatory Risk: Addressing the Obverse Side of the Atherosclerosis Prevention Coin

Ridker PM. Eur Heart J 2016;37:1720-22

WINCARS Association www.wincarsassociation.com

Tailored therapy in CAD

Additional LDL Reduction Known Cardiovascular Disease LDL 150 mg/dL hsCRP 4.5mg/L High Intensity Statin Additional Inflammation Reduction

“Residual Inflammatory Risk”

LDL low hsCRP high LDL high hsCRP low

“Residual Cholesterol Risk” “Residual Thrombotic Risk”

HTPR Additional antiplatelet & anticoagulant therapy

?

WINCARS Association www.wincarsassociation.com

Ridker PM. Circ Res 2016;118:145-156.

From CRP to IL-6 to IL-1: Moving Upstream to Identify Novel Targets for Atheroprotection

Ridker ESC 2017 WINCARS Association www.wincarsassociation.com

Activation of inflammasome - “clinical utility”

Circ Res. 2016;118:145-156 & Ischemia Canakinumab

NLRP3

inflammasome

IL-1β TNF IL-6 hsCRP target converter distributor biomarker

WINCARS Association www.wincarsassociation.com

Canakinumab

• high-affinity human monoclonal anti-human interleukin-1b (IL-

1b) antibody currently indicated for the treatment of IL-1b driven inflammatory diseases (Cryopyrin-Associated Period Syndrome [CAPS], Muckle-Wells Syndrome)

• designed to bind to human IL-1b and functionally neutralize the

bioactivity of this pro-inflammatory cytokine

• long half-life (4-8 weeks) with CRP and IL-6 reduction for up to 3

months

Ridker ESC 2017 WINCARS Association www.wincarsassociation.com

15

• 10
• 20
• 30
• 40
• 50
• 60

Canakinumab Dose (mg/month)

50 100 150 Median Reduction Fibrinogen Interleukin-6 C-reactive Protein Ridker PM, et al; Circulation 2012; 126:2739-2748

Ridker ESC 2017 WINCARS Association www.wincarsassociation.com

Stable CAD (post MI) On Statin, ACE/ARB, BB, ASA Persistent Elevation

• f hsCRP (> 2 mg/L)

Randomized Canakinumab 150 mg SC q 3 months Randomized Placebo SC q 3 months Primary CV Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE) Key Secondary CV Endpoint: MACE + Unstable Angina Requiring Unplanned Revascularization (MACE+) Critical Non-Cardiovascular Safety Endpoints: Cancer and Cancer Mortality, Infection and Infection Mortality Randomized Canakinumab 300 mg SC q 3 months* Randomized Canakinumab 50 mg SC q 3 months

Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)

N = 10,061 39 Countries April 2011 - June 2017 1490 Primary Events

Ridker ESC 2017 WINCARS Association www.wincarsassociation.com

39 countries > 1000 investigators 17482 Screened 10105 Entered Into Randomization Process 10061 Successfully Randomized

3344 placebo

18.1% discontinued study drug 3335 known final vital status 9 unknown final vital status

2170 canakinumab 50mg

16.7% discontinued study drug 2161 known final vital status 9 unknown final vital status

2284 canakinumab 150mg

19.2% discontinued study drug 2279 known final vital status 5 unknown final vital status

2263 canakinumab 300mg

20.1% discontinued study drug 2259 known final vital status 4 unknown final vital status

Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)

Ridker ESC 2017 7377 Excluded Prior to Entering Randomization Process 146 refused consent 71 child-bearing potential 44 age out of range 251 no documented MI 3390 hsCRP < 2 mg/L 728 exclusionary concomitant disease 1873 tuberculosis risk factors 104 infectious disease 76 immunocompromised state 27 life threatening condition 574 withdrew consent 137 site closure 81 physician decision 49 unable to contact 7 adverse event 11 died 139 other reasons 44 Failed Randomization Process 41 Invalid randomization 3 major GCP violations WINCARS Association www.wincarsassociation.com

Ridker ESC 2017

CANTOS - Baseline Clinical Characteristics Canakinumab SC q 3 months Characteristic Placebo (N=3347) 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263)

Age (years)

61.1 61.1 61.2 61.1

Female (%)

25.9 24.9 25.2 26.8

Current smoker (%)

22.9 24.5 23.4 23.7

Diabetes (%)

39.9 39.4 41.8 39.2

Lipid lowering therapy (%)

93.7 94.0 92.7 93.5

Renin-angiotensin inhibitors (%)

79.8 79.3 79.8 79.6

Prior Revascularization (%)

79.6 80.9 82.2 80.7

LDL cholesterol (mg/dL)

82.8 81.2 82.4 83.5

HDL cholesterol (mg/dL)

44.5 43.7 43.7 44.0

Triglycerides (mg/dL)

139 139 139 138

hsCRP (mg/L)

4.1 4.1 4.2 4.1

WINCARS Association www.wincarsassociation.com

*Statistically significant, adjusted for multiplicity, in accordance with the pre-specified closed-testing procedures CANTOS: Primary Clinical Outcome Effects on MACE and MACE +

Ridker ESC 2017

Canakinumab SC q 3 months Placebo (N=3347) 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263) P-trend Primary Endpoint 4.5 4.1 3.9 3.9 0.020 IR (per 100 person years) HR 1.0 0.93 0.85 0.86 95%CI (referent) 0.80-1.07 0.74-0.98 0.75-0.99 P (referent) 0.30 0.021* 0.031 Secondary Endpoint 5.1 4.6 4.3 4.3 0.003 IR (per 100 person years) HR 1.00 0.90 0.83 0.83 95%CI (referent) 0.78-1.03 0.73-0.95 0.72-0.94 P (referent) 0.11 0.005* 0.004

WINCARS Association www.wincarsassociation.com

Ridker ESC 2017

WINCARS Association www.wincarsassociation.com

CANTOS: Consistency of HRs Across All Cardiovascular Endpoints

Canakinumab SC q 3 months Endpoint Placebo (N=3347) 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263) P-trend

Primary

1.00 0.93 0.85 0.86 0.020

Secondary

1.00 0.90 0.83 0.83 0.002

Myocardial Infarction

1.00 0.94 0.76 0.84 0.028

Urgent Revascularization

1.00 0.70 0.64 0.58 0.005

Any Coronary Revascularization

1.00 0.72 0.68 0.70 <0.001

Stroke

1.00 1.01 0.98 0.80 0.17

Cardiac Arrest

1.00 0.72 0.63 0.46 0.035

CV Death

1.00 0.89 0.90 0.94 0.62

All Cause Mortality

1.00 0.94 0.92 0.94 0.39

Ridker ESC 2017 WINCARS Association www.wincarsassociation.com

Placebo Canakinumab (on treatment hsCRP < median) Canakinumab (on treatment hsCRP > median) HR (95%CI) P 1.0 (referent) (referent) 0.95 (0.84-1.08) 0.47 0.73 (0.63-0.83) 0.0001

Cumulative Incidence (%)

HR 0.73 95%CI 0.63-0.83 P=0.0001

for those with reductions in hsCRP > median at 3-months (1.8 mg/L)

CANTOS: Greater Risk Reduction Among Those With Greater hsCRP Reduction (MACE+)

WINCARS Association www.wincarsassociation.com

* P-value for combined canakinumab doses vs placebo

Ridker ESC 2017

CANTOS: Additional Outcomes (per 100 person years of exposure)

Canakinumab SC q 3 months

Adverse Event Placebo

(N=3347)

50 mg

(N=2170)

150 mg

(N=2284)

300 mg

(N=2263)

P-trend Any SAE

12.0 11.4 11.7 12.3 0.43

Leukopenia

0.24 0.30 0.37 0.52 0.002

Any infection

2.86 3.03 3.13 3.25

0.12 Fatal infection

0.18 0.31 0.28 0.34

0.09/0.02* Injection site reaction

0.23 0.27 0.28 0.30 0.49

Any Malignancy

1.88 1.85 1.69 1.72 0.31

Fatal Malignancy

0.64 0.55 0.50 0.31 0.0007

Arthritis

3.32 2.15 2.17 2.47 0.002

Osteoarthritis

1.67 1.21 1.12 1.30 0.04

Gout

0.80 0.43 0.35 0.37 0.0001

ALT > 3x normal

1.4 1.9 1.9 2.0 0.19

Bilirubin > 2x normal

0.8 1.0 0.7 0.7 0.34

WINCARS Association www.wincarsassociation.com

Sub-clinical chronic inflammation increases cancer risk (hsCRP is also a risk factor for certain cancers, in particular lung cancer) Inflammation in the tumor micro-environment impacts upon tumor initiation, progression, invasiveness, and metastatic progression

Grivennikov, Greten, Karin. Cell 2010;140:883-99.

Ridker ESC 2017

Immunity, Inflammation, and Cancer

WINCARS Association www.wincarsassociation.com

Charles A. Dinarello. Cancer Metastasis Rev 2010;29:317-329. Ron Apte, et al; Cancer Metastasis Rev. 2006;25:387-408. Anne Lewis, et al; J Transl Med. 2006;4:48.

Ridker ESC 2017

Chronic Inflammation, Tumor Progression, and IL-1 Inhibition

WINCARS Association www.wincarsassociation.com

CANTOS and Incident Cancer

The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study

1.The atherosclerosis patients enrolled in CANTOS were at unusually high risk for

certain inflammatory cancers, in particular lung cancer.

2.This is due to several issues including older age, a high prevalence of current

and past smoking, and the enrollment only of those with elevated hsCRP (elevated hsCRP levels are an independent risk marker for lung cancer).

3.The randomized design of CANTOS ensures that prevalent cancers undiagnosed

at trial entry as well as measured and unmeasured cancer risk factors are equally distributed among treatment groups.

4.A Cancer Adjudication Committee of oncologists was established at trial

initiation.

Ridker ESC 2017 WINCARS Association www.wincarsassociation.com

CRP & (non) cardiovascular mortality

Lancet 2010; 375: 132-40

WINCARS Association www.wincarsassociation.com

Ridker ESC 2017

WINCARS Association www.wincarsassociation.com

Conclusions:

The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)

• 1. CANTOS was designed to directly test the inflammatory hypothesis of

atherothrombosis.

• 2. As shown in these data, inhibition of IL-1 with SC canakinumab given once

every three months among patients with a prior myocardial infarction substantially lowered the inflammatory biomarkers hsCRP and IL-6 while having no beneficial impact on atherogenic lipids.

• 3. Concordantly, while the 50 mg dose of canakinumab did not have

cardiovascular efficacy compared to placebo during an average follow-up period of 3.7 years, hazard reductions of 15% for the primary endpoint of MACE (P=0.007) and 17% for the secondary endpoint of MACE+ (P=0.006) were observed for the combined 150mg and 300mg doses groups. The 150mg group met all pre-specified multiplicity adjusted thresholds for statistical significance for both the primary and secondary cardiovascular

• utcomes.

Ridker ESC 2017 WINCARS Association www.wincarsassociation.com

Conclusions:

The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)

4.

In exploratory analyses, relative hazard reductions of 27% (P<0.001) were

• bserved among those with the lowest levels of on-treatment hsCRP

measured at 3 months. Thus, “lower is better” appears to be true for inflammation as well as LDLC .

5.

Given mild neutropenia and an increase in risk of fatal infection, patients being considered for treatment with canakinumab will require monitoring for early signs and symptoms of infection in a manner similar to that currently done for individuals taking other biologic anti-inflammatory agents.

Ridker ESC 2017 WINCARS Association www.wincarsassociation.com

Conclusions:

The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)

7.

Inflammation is also a determinant of invasiveness, progression, and metastasis for certain cancers. In exploratory analyses within CANTOS, those allocated to canakinumab had large dose-dependent relative risk reductions in deaths due to cancer (P=0.0007), incident lung cancers (P<0.0001), and fatal lung cancer (P=0.0002) such that those in the canakinumab 300mg group had a 50 percent reduction in cancer fatality (P=0.0009). Replication of these data is required.

8.

In conclusion, these randomized placebo-controlled trial data demonstrate that targeting the IL-1 to IL-6 pathway of innate immunity with canakinumab reduces cardiovascular event rates and potentially reduces rates of incident lung cancer and lung cancer mortality.

9.

These data provide proof that inflammation inhibition, in the absence of lipid lowering, can improve atherothrombotic outcomes and potentially alter the progression of some fatal cancers.

Ridker ESC 2017 WINCARS Association www.wincarsassociation.com

Rivaroxaban with or without aspirin in stable cardiovascular disease

COMPASS Steering Committee and Investigators Sponsored by Bayer AG

August 27, 2017

1

WINCARS Association www.wincarsassociation.com

WINCARS Association www.wincarsassociation.com

Background

• CV disease affects 4% of world population (300 million persons)
• Aspirin is the single most widely used preventive treatment but produces only a

19% RRR during the long term

• Warfarin with or without aspirin is more effective than aspirin but increases

bleeding, including intracranial hemorrhage

• Rivaroxaban is safer than warfarin and reduces mortality in patients with

recent acute coronary syndrome

WINCARS Association www.wincarsassociation.com

Objectives

To determine in stable CV disease, whether:

• Rivaroxaban 2.5 mg bid + aspirin 100 mg od, or
• Rivaroxaban 5 mg bid

reduces CV death, stroke or myocardial infarction compared with aspirin 100 mg od

And whether:

• Pantoprazole compared with placebo reduces upper GI events (ongoing)

WINCARS Association www.wincarsassociation.com

COMPASS design

R

Aspirin 100 mg od Rivaroxaban 5 mg bid Expected follow up 3-4 years

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

Rivaroxaban 2.5 mg bid + aspirin 100 mg od Run-in (aspirin)

WINCARS Association www.wincarsassociation.com

Outcomes

• Primary

– CV death, stroke or myocardial infarction

• Secondary

– CHD death, ischemic stroke, myocardial infarction, or acute limb

ischemia,

– CV death, ischemic stroke, myocardial infarction, or acute limb ischemia, – Mortality

• Safety and net clinical benefit

– ISTH major bleeding (modified) – Primary plus fatal or critical organ bleeding

WINCARS Association www.wincarsassociation.com

602 sites, 33 countries

7

Czech Republic N=1553 Italy N=101 8

WINCARS Association www.wincarsassociation.com

Follow up, adherence

• On February 6, 2017 the Data and Safety Monitoring Board recommended

discontinuation of rivaroxaban/aspirin arms for clear evidence of efficacy (combination: Z= -4.59, P<0.00001; rivaroxaban: Z= -2.44, P=0.01)

• Close-out between March and June 2017
• Mean follow up 23 months
• Follow up 99.8% complete

WINCARS Association www.wincarsassociation.com

Baseline characteristics

Characteristic Rivaroxaban + aspirin N=9,152 Rivaroxaban N=9,117 Aspirin N=9,126

• Age, yr
• Blood pressure, mmHg Total cholesterol, L
• CAD PAD
• Diabetes
• Lipid-lowering ACE-I or ARB

68 136/77 4.2 91% 27% 38% 90% 71% 68 136/78 4.2 90% 27% 38% 90% 72% 68 136/78 4.2 90% 27% 38% 89% 71%

WINCARS Association www.wincarsassociation.com

Primary: CV death, stroke, MI

Outcome R + A N=9,152 R N=9,117 A N=9,126 Rivaroxaban + 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) 0.12

WINCARS Association www.wincarsassociation.com

Primary: CV death, stroke, MI

WINCARS Association www.wincarsassociation.com

Primary components

Outcome R + A N=9,152 A N=9,126 Rivaroxaban + Aspirin vs. Aspirin 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

WINCARS Association www.wincarsassociation.com

Secondary outcomes

* pre-specified threshold P=0.0025

Outcome R + A N=9,152 A N=9,126 Rivaroxaban + Aspirin vs. Aspirin N (%) N (%) HR (95% CI) P* CHD death, IS, MI, ALI 329 (3.6%) 450 (4.9%) 0.72 (0.63-0.83) <0.0001 CV death, IS, MI, ALI 389 (4.3%) 516 (5.7%) 0.74 (0.65-0.85) <0.0001 Mortality 313 (3.4%) 378 (4.1%) 0.82 (0.71-0.96) 0.01

WINCARS Association www.wincarsassociation.com

CAD and PAD Subgroups for primary outcome

14

Outcome R + A N=9,152 A N=9,126 Rivaroxaban + Aspirin

• vs. Aspirin

N (%) N (%) HR (95% CI) CAD 347 (4.2%) 460 (5.6%) 0.74 (0.65-0.86) PAD 126 (5.1%) 174 (6.9%) 0.72 (0.57-0.90)

WINCARS Association www.wincarsassociation.com

Major bleeding

* symptomatic

Outcome R + A N=9,152 R N=9,117 A N=9,126 Rivaroxaban + Aspirin

• vs. Aspirin

Rivaroxaban vs. Aspirin N (%) N (%) N (%) HR (95% CI) P HR (95% CI) P Major bleeding 288 (3.1%) 255 (2.8%) 170 (1.9%) 1.70 (1.40-2.05) <0.0001 1.51 (1.25-1.84) <0.0001 Fatal 15 (0.2%) 14 (0.2%) 10 (0.1%) 1.49 (0.67-3.33) 0.32 1.40 (0.62-3.15) 0.41 Non fatal ICH* 21 (0.2%) 32 (0.4%) 19 (0.2%) 1.10 (0.59-2.04) 0.77 1.69 (0.96-2.98) 0.07 Non-fatal other critical organ* 42 (0.5%) 45 (0.5%) 29 (0.3%) 1.43 (0.89-2.29) 0.14 1.57 (0.98-2.50) 0.06

WINCARS Association www.wincarsassociation.com

Net clinical benefit

Outcome R + A N=9,152 A N=9,126 Rivaroxaban + Aspirin vs. Aspirin N (%) N (%) HR (95% CI) P Net clinical benefit (Primary + Severe bleeding events) 431 (4.7%) 534 (5.9%) 0.80 (0.70-0.91) 0.0005

WINCARS Association www.wincarsassociation.com

Conclusion

Rivaroxaban 2.5 mg bid plus aspirin 100 mg od:

• Reduces CV death, stroke, MI
• Increases major bleeding without a significant increase in

fatal, intracranial or critical organ bleeding

• Provides a net clinical benefit

No significant benefit of rivaroxaban alone

WINCARS Association www.wincarsassociation.com

• Rivaroxaban in stable peripheral or carotid artery disease
• sponsored by Bayer AG

August 27, 2017

WINCARS Association www.wincarsassociation.com

COMPASS PAD rationale

• PAD patients have widespread atherosclerosis and increased risk
• f CV & limb adverse outcomes
• Vascular events are high despite effective interventions
• Few

therapies have clearly reduced both Major Adverse CV Events (MACE) and Major Adverse Limb Events (MALE)

17-07-01

WINCARS Association www.wincarsassociation.com

Primary objectives

To determine in PAD whether:

• Rivaroxaban 2.5 mg bid + aspirin 100 mg od, or
• Rivaroxaban 5 mg bid

reduce the risk of MACE and MALE as compared with aspirin 100 mg od

WINCARS Association www.wincarsassociation.com

Eligibility: PAD

• Peripheral artery revascularization
• Limb or foot amputation for arterial vascular disease
• Intermittent claudication plus:

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

• Previous carotid revascularization, asymptomatic carotid

artery stenosis ≥50%

• CAD + low ABI (<0.90)

WINCARS Association www.wincarsassociation.com

Key Efficacy Outcomes

• Primary Cardiovascular Outcome (MACE):
• CV death, stroke, or MI
• Major Adverse Limb Events (MALE):

– Severe limb ischemia leading to an intervention

(angioplasty, bypass surgery, amputation, thrombolysis)

– Major Amputation above forefoot due to vascular cause

WINCARS Association www.wincarsassociation.com

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

WINCARS Association www.wincarsassociation.com

Baseline Characteristics

Characteristic Riva + aspirin N=2,492 Rivaroxaban N=2,474 Aspirin N=2,504 Age, years (mean) 68 68 68 Current Smoker 27% 28% 27% Former Smoker 46% 47% 46% Diabetes 44% 44% 44% Hypertension 79% 78% 81% Prior CAD or Stroke 69% 69% 68% Lipid Lowering 84% 84% 83% ACE-I/ARB 69% 71% 70%

WINCARS Association www.wincarsassociation.com

Primary outcome & components

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 MACE 126 (5.1) 149 (6.0) 174 (6.9) 0.72 (0.57-0.90) 0.005 0.86 (0.69-1.08) 0.19 MI 51 (2.0) 56 (2.3) 67 (2.7) 0.76 (0.53-1.09)

• 0.84

(0.59-1.20)

• Stroke

25 (1.0) 43 (1.7) 47 (1.9) 0.54 (0.33-0.87)

• 0.93

(0.61-1.40)

• CV Death

64 (2.6) 66 (2.7) 78 (3.1) 0.82 (0.59-1.14)

• 0.86

(0.62-1.19)

• WINCARS Association

www.wincarsassociation.com

Limb outcomes

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

MALE

30 (1.2) 35 (1.4) 56 (2.2) 0.54 (0.35-0.84) 0.005 0.63 (0.41-0.96) 0.03

Major amputation

5 (0.2) 8 (0.3) 17 (0.7) 0.30 (0.11-0.80) 0.01 0.46 (0.20-1.08) 0.07

WINCARS Association www.wincarsassociation.com

Key Composite Outcome

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 MACE, MALE

• r Major

amputation 157 (6.3) 188 (7.6) 225 (9.0) 0.69 (0.56-0.85) 0.0003 0.84 (0.69-1.02) 0.08

WINCARS Association www.wincarsassociation.com

Cumulative Hazard Rate 0.0 0.05 0.10 0.15

Aspirin Rivaroxaban Rivaroxaban + Aspirin

• No. at Risk

1 Ye 2 ar 3

Riva + ASA 2492 2069 893 124 Riva 2474 2023 864 147 ASA 2504 2034 911 113

Rivaroxaban + Aspirin vs. Aspirin HR: 0.69 (0.56-0.85) P=0.0003

Rivaroxaban vs. Aspirin HR: 0.84 (0.69-1.02) P=0.08

MACE or MALE or Major Amputation

WINCARS Association www.wincarsassociation.com

Major bleeding

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 Major Bleeding 77 (3.1) 79 (3.2) 48 (1.9) 1.61 (1.12-2.31) 0.009 1.68 (1.17-2.40) 0.004 Fatal 4 (0.2) 5 (0.2) 3 (0.1)

• Non-Fatal ICH

4 (0.2) 3 (0.1) 8 (0.3)

• Non-fatal
• ther critical
• rgan*

13 (0.5) 18 (0.7) 8 (0.3) 1.55 (0.64-3.74) 0.33 2.15 (0.94-4.96) 0.06

* symptomatic

WINCARS Association www.wincarsassociation.com

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 August 14, 2017

WINCARS Association www.wincarsassociation.com

Overall COMPASS Overall PAD Symptomatic PAD PAD Lower Extremeties Carotid Artery Disease 1.0 0.5 Riva 2.5 + ASA better 1.5 ASA only better

MACE, MALE or Major Amputation

WINCARS Association www.wincarsassociation.com

Conclusions

Rivaroxaban 2.5 mg BID plus aspirin is:

• Significantly superior to aspirin alone in

reducing MACE or MALE or major amputation (31% RRR)

• Increased major bleeding, but no significant

increase in fatal or critical organ bleeding

17-07-01

WINCARS Association www.wincarsassociation.com

Bivalirudin versus Heparin Monotherapy in Myocardial Infarction The VALIDATE- SWEDEHEART trial

David Erlinge, MD, PhD Professor Cardiology, Lund University Department of Cardiology Skåne University Hospital Lund, Sweden

WINCARS Association www.wincarsassociation.com

Background

• Three previous trials evaluating bivalirudin versus heparin

without planned use of glycoprotein IIb/IIIa inhibitors (GPI) in acute coronary syndromes have yielded conflicting results.

• These trials differed in the use of pre-randomization heparin,

post-PCI infusion of bivalirudin, and potent P2Y12 inhibitors.1-3

1Shahzad et al., Lancet 2014; 2Han et al., JAMA 2015; 3Schulz et al., EHJ 2014

WINCARS Association www.wincarsassociation.com

Aim and end points

• The aim was to investigate bivalirudin compared to heparin in patients

with STEMI or NSTEMI using a modern strategy with:

• mandatory use of potent P2Y12 inhibitors prior to PCI
• recommended low dose of heparin prior to randomization
• no planned GPI use
• predominantly radial-artery access for PCI
• The primary end point was the composite of death, myocardial infarction, or major bleeding events at

180 days.

• Secondary end points included the primary end point in the NSTEMI and STEMI strata, and its

individual components, stroke and stent thrombosis in the total material.

WINCARS Association www.wincarsassociation.com

Study design

STEMI (n=3005) or NSTEMI (n=3001) Treatment with Ticagrelor, Prasugrel or Cangrelor Angiography performed: PCI intended Primary Endpoint: NACE: Death, Myocardial Infarction or Bleeding events (BARC 2, 3 or 5) at 180 days Heparin only (70-100U/kg) (no planned GPI) Bivalirudin (5000U Heparin pre-hospital

• r 3000U pre-PCI)

R 1:1

Coordinating PI: Chairman: David Erlinge, Lund University, Sweden Stefan James, Uppsala University, Sweden Clinicaltrials.gov: NCT02311231 Trial design: Erlinge et al., Am Heart J 2014

WINCARS Association www.wincarsassociation.com

Inclusion criteria (main)

• Diagnosis of NSTEMI (positive troponin) or STEMI if PCI of culprit

lesion intended after angiography

• Bolus dose of ticagrelor, prasugrel or cangrelor before start of PCI
• Ability to provide informed consent

WINCARS Association www.wincarsassociation.com

Exclusion criteria (main)

• Known terminal disease with life expectancy < 1 year
• Ongoing bleeding
• Severe renal (GFR < 30 ml/min) or liver dysfunction
• Thrombocytopenia or thrombocyte function defect
• Heparin
• >5000U before arriving to PCI lab or
• >3000U during angiography before randomization
• GPI
• given or pre-planned before the procedure

WINCARS Association www.wincarsassociation.com

Methods Registry-based Randomized Clinical Trial (RRCT)

• We utilized pre-existing health care

registries (SWEDEHEART including SCAAR and Swedish National Population registry) for screening, enrollment, randomization, case report forms, and follow-up.

• Follow up was also done by phone calls

by study nurses at day 7 and 180 with registration of bleeding events and myocardial infarction.

• Central adjudication of clinical events

Randomized in VALIDATE

SWEDEHEART register follow up

CEC DSMC Comparison of 180 days endpoint data Background data from SCAAR Periprocedural characteristics, in hospital complications, discharge medication data from SCAAR

Erlinge et al., Am Heart J 2014

Inclusion CRF 7 days CRF Phone call 7 days CRF Study data base Phone Call 180 days CRF

WINCARS Association www.wincarsassociation.com

Results

• 25 PCI centers out of 29 in Sweden

participated in the trial

• 47.8% (6006 of 12,561) of all patients

in Sweden presenting at enrolling hospitals with an initial diagnosis of STEMI or NSTEMI planned for PCI were randomized.

• Of all patients potentially eligible for

enrollment, 70.0% (6006 of 8585) were randomized.

STEMI or NSTEMI ENROLLED

WINCARS Association www.wincarsassociation.com

Baseline Characteristics and Clinical Presentation

Bivalirudi n Heparin Screened, not randomized* N 3004 3002 6555 STEMI, (%) 50.0 50.0 35.4 Male sex, (%) 74.2 72.5 69.5 Age (years), median (Q1-Q3) 68.0 68.0 71.0 BMI, median (Q1-Q3) 26.8 26.9 26.9 Weight <60kg, (%) 4.6 5.2 7.2 Current smoker, (%) 23.8 23.7 20.8 Diabetes, (%) 16.3 16.9 24.9 Hypertension, (%) 51.8 51.6 62.2 Hyperlipidemia, (%) 31.7 31.2 44.1 Previous MI, (%) 16.3 16.1 27.9 Previous PCI, (%) 15.2 14.2 21.9 Previous CABG, (%) 5.1 4.7 10.0 Previous stroke, (%) 3.8 4.2 7.1 CPR before arrival, (%) 0.9 0.7 1.3 Killip class II-IV, (%) 3.6 2.9 7.9

*All patients with an initial diagnosis of STEMI or NSTEMI not included.

WINCARS Association www.wincarsassociation.com

In-hospital procedures

Bivalirudin Heparin

N 3004 3002 TIMI flow prior to PCI, (%) TIMI 0 39.2 37.1 TIMI 1 7.4 7.3 TIMI 2 16.1 16.2 TIMI 3 37.1 39.2 Time from administration of ticagrelor

• r prasugrel to PCI (%)

0-1 h 38.2 37.6 1-2 h 19.6 20.1 > 2 h 41.7 41.8 Radial approach, (%) 90.1 90.5 P2Y12 inhibitor, (%) Ticagrelor 94.9 94.9 Prasugrel 1.9 2.3 Cangrelor 0.3 0.3

WINCARS Association www.wincarsassociation.com

Treatment in relation to the invasive procedure

Bivalirudin Heparin Treatment in relation to the invasive procedure N 3004 3002 Heparin pre-treatment, (%) 35.6 37.6 Heparin during procedure, (%) 54.2* 95.4 Heparin before or during procedure, (%) 91.0* 99.8 Crossover after randomization, (%) 0.6 0.4 First dose heparin in lab (U/kg), mean 22 84 Max ACT during PCI (s), mean 386 305 Bailout GPI, (%) 2.4 2.8 Bivalirudin infusion after PCI, (%) 65.3 N/A Time prolonged (min), mean 57.3 N/A

*Prior to randomization

WINCARS Association www.wincarsassociation.com

Primary Endpoint at 180 days

WINCARS Association www.wincarsassociation.com

Primary Endpoint at 180 days

HR 0.96 95% CI, 0.83 – 1.10 P=0.54

WINCARS Association www.wincarsassociation.com

Mortality at 180 days

HR 1.05 95% CI, 0.78 – 1.41 P=0.76

WINCARS Association www.wincarsassociation.com

Myocardial Infarction at 180 days

HR 0.84 95% CI, 0.60 – 1.19 P=0.33

WINCARS Association www.wincarsassociation.com

Bleeding events (BARC 2,3,5) at 180 days HR 1.00 95% CI, 0.84 – 1.19 P=0.98

WINCARS Association www.wincarsassociation.com

Bleeding events

30 days

180 days

• BARC Type 2
• BARC Type 3
• BARC Type 5

e Major bleeding (BARC Typ 2,3,5) 9 8 7 6 5 4 3 2 1

• BARC Type 2
• BARC Type 3
• BARC Type 5

Major bleeding (BARC Type 2,3,5) 9 8 7 6 3 2 1

NS NS NS NS

5

%

4

5.1 5.6 5.7 6.0 3.1 NS 0.2 0.1 2.9 8.6 8.6 NS 0.1 0.1 NS 3.3 3.8

BARC 2 BARC 2,3 & 5 BARC 5

NS 1.8 1.8

BARC 3 BARC 2 BARC 2,3 & 5 BARC 5 BARC 3

Bivalirudin Heparin

WINCARS Association www.wincarsassociation.com

Definite ST Probable ST Possible ST All stent thrombosis (ST)

1 2 3

Definite ST Probable ST Intraprocedural ST (operator reported) All stent thrombosis (ST)

3 2 1

Stent thrombosis (ST)

30 days

180 days

P=0.03

P=0.09 NS NS NS NS NS NS

%

0.3 0.7 1.0 0.8 0.4 0.4 1.7 1.8 0.4 0.7 0.1 0.1 0.4 0.4 1.9 2.0 NS 1.0 0.8

Intraprocedural ST (operator reported)

Bivalirudin

Heparin

WINCARS Association www.wincarsassociation.com

Primary Endpoint at 180 days in pre-specified subgroups No significant interaction for any subgroup, although borderline significant for female sex

WINCARS Association www.wincarsassociation.com

Conclusions

• VALIDATE-SWEDEHEART was a registry-based randomized

clinical trial that compared bivalirudin with heparin monotherapy in patients presenting with STEMI or NSTEMI and treated with PCI using predominantly radial approach and high-intensity platelet inhibition.

• We found no significant differences between bivalirudin and

heparin treatment with respect to mortality, re-infarction, or major bleeding events during 180 days of follow-up.

WINCARS Association www.wincarsassociation.com

NEJM

WINCARS Association www.wincarsassociation.com

Thank you

WINCARS Association www.wincarsassociation.com