VOYAGER PAD trial

RCT investigating efficacy and safety of rivaroxaban to reduce the risk of

major thrombotic vascular events in patients with symptomatic PAOD

undergoing revascularization – the concept of an event driven trial

Rupert M. Bauersachs Dept. of Vascular Medicine

CTH – Professorship for

Vulnerable Individuals and

Populations (VIP)

Disclosures

Rupert M. Bauersachs

• Research Support / Principal Investigator:

– Bayer, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Leo, Pfizer, Portola

• Consultant & Speakers Bureau:

– Bayer, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Pfizer

Prevalence of PAD is high and

increases significantly with age

The Rotterdam Study

• Patients aged ≥55 years

• 19.1% had PAD

• Prevalence higher in

women (20.5%) than in

men (16.9%)

• Clear increase of PAD

with age

• >50% of patients aged

≥85 years have PAD

PAD=Peripheral artery disease.

Meijer WT, et al. Arterioscler Thromb Vasc Biol. 1998;18:185–92.

55−99 60−64 65−69 70−74 75−79 80−84 ≥85

Age (years)

Pre

va

len

ce

70

60

50

40

30

20

10

0

Men

Women

Prevalence of PAD is high and

continues to increase since 2000

Fowkes FG, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis.

Lancet. 2013 Oct 19;382(9901):1329-40.

0

10

20

30

40

50

60

Age

% Increase in prevalence 2000 => 2010

Natural history – 5-year follow-up

CV=Cardiovascular; MI=Myocardial infarction; WD=Walking distance.

Norgren L, et al. J Vasc Surg. 2007;45 Suppl S:S5–67.

No symptoms

(20–50%)

Interm. claudication

(10–35%)

Other leg pain

(30–40%)

• Stable: 70–80%

• Further reduced WD: 10–20%

• Critical limb ischaemia: 5–10%

• Amputation: <1% annually

Limb prognosis

• Mortality: 10–15%

• (CV: 75%)

• MI/stroke: 20%

General prognosis

CAD and PAD: Overlapping conditions

The REACH registry showed

3 out of 5 patients with PAD

also have CAD and/or CVD

8322 patients had PAD

• ~39% had PAD only

• ~38% had PAD and CAD

• ~10% had PAD and CVD

• ~13% PAD, CAD and CVD

CAD=Coronary artery disease; CVD=Cerebrovascular disease; PAD=Peripheral artery disease.

Cacoub PP, et al. Atherosclerosis. 2009;204:e86–92.

Patients

with

CAD

Patients

with CVD

2 to 3- fold

risk of

stroke

4-fold risk

of fatal MI Patients

with PAD

Current treatment strategies for patients with

PAD

ACE=Angiotensin-converting-enzyme; ASA=Acetylsalicylic acid; CV=Cardiovascular; PAD=Peripheral artery disease.

Symptom Improvement

• Exercise training

• Pharmacological treatments

(e.g. cilostazol, pentoxifylline)

• Endovascular intervention

(e.g. stent placement)

• Surgery

(e.g. revascularisation)

CV risk reduction

• Lipid-lowering drugs

(e.g. statin)

• Antihypersensitive drugs

(e.g. ACE inhibitor)

• Diabetes therapies

• Smoking cessation

• Antiplatelet drugs

(e.g. ASA, clopidogrel)

• Cochrane Review conclusions

• Limited evidence suggesting that restenosis/reocclusion

is reduced by antiplatelet drugs;

• information on bleeding and side effects is lacking.

• Trials are small and of variable quality and side effects

are not addressed.

• Further good quality, large-scale RCTs are required.

Robertson L, Ghouri MA, Kovacs F. Antiplatelet and anticoagulant drugs for prevention of restenosis/reocclusion following

peripheral endovascular treatment. Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD002071. DOI:

10.1002/14651858.CD002071.pub3.

Antithrombotic treatment after intervention

Antithrombotic treatment after intervention

Guidelines

• ACC/AHA and ESC are divergent

• Recommendations often extrapolated from CAD,

or expert opinions

• ACCP recommend single antiplatelet over DAPT

post angioplasty/ and stent in PAD (2C)

• ESC: DAPT with aspirin / thienopyridine for ≥ 1 month after

infrainguinal BMS (IC)

• Anticoagulation after infrainguinal PTA / stenting was assessed

in 3 RCTs: None showed significant improvement in patency

=> anticoagulation cannot be recommended

ACCF/AHA [Anderson et al. 2013] and ESC [Tendera et al. 2011] ACCP [Alonso-Coello et al. 2012].

NOAC (triple) treatment after ACS

Hess CN, James S, Lopes RD, Wojdyla DM, Neely ML, Liaw D, Hagstrom E, Bhatt DL, Husted S, Goodman SG, Lewis BS,

Verheugt FW, De Caterina R, Ogawa H, Wallentin L, Alexander JH. Apixaban Plus Mono Versus Dual Antiplatelet Therapy in

Acute Coronary Syndromes: Insights From the APPRAISE-2 Trial. J Am Coll Cardiol. 2015 Aug 18;66(7):777-87.2015/08/14..

0

2

4

6

8

10

12

14

CV death, MI,or stroke

Stentthrombosis

Major bleeding Major or minorbleeding

% O

utc

om

es

Aspirin Only

Aspirin + Clopidogrel

Apixaban 5 mg bid

therapeutic dose

on top of:

NOAC (triple) treatment after ACS

Hess CN, James S, Lopes RD, Wojdyla DM, Neely ML, Liaw D, Hagstrom E, Bhatt DL, Husted S, Goodman SG, Lewis BS,

Verheugt FW, De Caterina R, Ogawa H, Wallentin L, Alexander JH. Apixaban Plus Mono Versus Dual Antiplatelet Therapy in

Acute Coronary Syndromes: Insights From the APPRAISE-2 Trial. J Am Coll Cardiol. 2015 Aug 18;66(7):777-87.2015/08/14..

0

2

4

6

8

10

12

14

16

CV death, MI,or stroke

Stentthrombosis

Major bleeding Major or minorbleeding

% O

utc

om

es

Apixaban

Placebo

Apixaban 5 mg bid

therapeutic dose

<0.001 0.001 n.s.

n.s.

0

Months

CV-death

NNT = 71

5

0 24

4,1%

2,7%

Placebo

Rivaroxaban 2,5 mg bid

HR = 0,66

mITT p = 0,002

ITT p = 0,005

18 12 6 0

5

Total Mortality

Months

4,5%

2,9%

24 0

Placebo

Rivaroxaban 2,5 bid

HR = 0,68

mITT p = 0,002

ITT p = 0,004

18 12 6

NNT = 63

Months

CV- death/MI/Stroke

Cu

mu

lati

ve

In

cid

en

ce

(%

)

HR = 0,84

mITT p = 0,02

ITT p = 0,007 10,7%

9,1%

Rivaroxaban 2,5 mg bid

Placebo

13

0 24 0 18 12 6

NNT = 63

CV = Kardiovaskulär; HR = Hazard Ratio; MI = Myokardinfarkt; NNT = Number needed to treat

Mega JL et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1112277; Gibson CM et al. Presented at AHA Scientific Sessions 2011

NOAC (triple) treatment after ACS (TIMI 51)

Very low dose Rivaroxaban (2.5 mg bid)

0

1

2

3

0 4 8 12 16 20 24

Months After Randomization

Rivaroxaban (both doses)

HR 0.69

(0.51- 0.93)

ITT p = 0.008

2.9%

2.3%

Es

tim

ate

d C

um

ula

tive

in

cid

en

ce

(%

)

Placebo 2 Yr KM Estimate

ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012

Mega JL et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1112277; Gibson CM et al. Presented at AHA Scientific Sessions 2011

NOAC (triple) treatment after ACS (TIMI 51)

Stent thrombosis

Natural history – 5-year follow-up

CV=Cardiovascular; MI=Myocardial infarction; WD=Walking distance.

Norgren L, et al. J Vasc Surg. 2007;45 Suppl S:S5–67.

No symptoms

(20–50%)

Interm. claudication

(10–35%)

Other leg pain

(30–40%)

• Stable: 70–80%

• Further reduced WD: 10–20%

• Critical limb ischaemia: 5–10%

• Amputation: <1% annually

Limb prognosis

• Mortality: 10–15%

• (CV: 75%)

• MI/stroke: 20%

General prognosis

Objective:

Efficacy and safety of rivaroxaban for the reduction of thrombotic vascular events

in subjects with PAD undergoing peripheral revascularisation procedures

Rivaroxaban 2.5 mg bid +

ASA 100 mg od

ASA 100 mg od

R

N~6500

1:1

Day 1

Population: Patients with symptomatic PAD undergoing peripheral revascularisation

Event-driven study (1.015 events)

MI, ischemic stroke, CV death, ALI,

and major amputation (vascular etiology)

Study design Official study title: An International, Multicenter, Randomized, Double-blind, Placebo-controlled Phase 3 Trial

Investigating the Efficacy and Safety of Rivaroxaban to Reduce the Risk of Major Thrombotic Vascular Events in Patients

with Symptomatic Peripheral Artery Disease Undergoing Lower Extremity Revascularization Procedures

*Mean treatment duration ~30 months. ASA=Acetylsalicylic acid; bid=Twice daily; MI=Myocardial infarction; od=Once daily; PAD=Peripheral artery disease;

R=Randomisation; TIMI=Thrombolysis in myocardial infarction.

ClinicalTrials.com Identifier: NCT02504216. Available at https://clinicaltrials.gov/ct2/show/NCT02504216 (accessed November 2015).

Up to 7 days

DAPT

Mean 30 months

Primary endpoints and inclusion/exclusion

criteria

ALI=Acute limb ischaemia; CV=Cardiovascular; DAPT=Dual antiplatelet therapy; MI=Myocardial infarction; PAD=Peripheral artery disease;

TIMI=Thrombolysis in myocardial infarction.

ClinicalTrials.com Identifier: NCT02504216. Available at https://clinicaltrials.gov/ct2/show/NCT02504216 (accessed November 2015).

Primary efficacy endpoints

• Composite of MI, stroke or CV death,

ALI, and major amputation due to

vascular etiology

Primary safety endpoints

• TIMI major bleeding events

Key inclusion criteria

• Age ≥50 years

• Symptomatic and haemodynamic PAD

• Technically successful peripheral

infrainguinal revascularisation within

last 7 days prior to randomisation

Key exclusion criteria

• Asymptomatic PAD or mild claudication

• Major tissue loss/gangrene beyond the

forefoot

• Prior revascularisation within 8 weeks

• ALI within 2 weeks

• Planned DAPT >30 days

• Planned DAPT for any other indication

• Systemic anticoagulation

Study design (contd)

• Event-driven (~1015 endpoint events)

• ITT

• 6,500 patients

• Enrollment period: ~18 months

• Start: Q4 2015; last patient: Q1 2017

ASA=acetylsalicylic acid; ITT=intention-to-treat.

ClinicalTrials.com Identifier: NCT02504216.

• Randomisation / stratification by procedure and clopidogrel use

Surgical

Endovascular

w/Clopidogrel Endovascular w/o

Clopidogrel

Rivaroxaban

& ASA Rivaroxaban

& ASA

Rivaroxaban

& ASA

Placebo

& ASA Placebo

& ASA

Placebo

& ASA

Committee chairs

Executive Committee

William R. Hiatt, MD – Chair University of Colorado and CPC

Rupert M. Bauersachs, MD – Co-Chair Klinikum Darmstadt GmbH

Independent Data Monitoring

John Dormandy, MD – Chair St. George’s Hospital Medical School

Independent Clinical Adjudication

Warren Capell, MD – Chair CPC Clinical Research

International Steering Committee

Richard Powell, MD – Co--Chair Dartmouth-Hitchcock Medical Center

Dierk Scheinert, MD – Co--Chair University Hospital Leipzig

National lead investigators

Argentina A. Alarcon

Austria M. Brodmann

Belgium F. Vermassen

Brazil D. Brasil

Bulgaria V. Chervenkoff

Canada D. Szalay

China TBD

Czech Republic K. Roztocil

Denmark H. Sillesen

France J. B. Ricco

Germany D. Scheinert

Hungary L. Matyas

Japan H. Shigematsu & Y. Yonemitsu

Italy C. Rabbia

Netherlands F. Moll

Poland A. Jawien

Portugal A. Mansilha

Romania I. Coman

South Korea D. Choi

Spain V. Riambau

Sweden L. Norgren

Switzerland I. Baumgartner

Taiwan S. Wang

Thailand P. Mutirangura

United Kingdom G. Hamilton

United States R. Powell, A. Hirsch,

J. Mustapha & J. Mills

Conclusion

Unmet needs in PAD

PAD remains a frequent and serious disorder with a high rate

of severe thrombotic complications,

including AMI, stroke, CV death, ALI and amputation

The risk is particularly high in incident patients, i.e. patients

undergoing revascularisation

VOYAGER PAD is the largest antithrombotic trial ever

performed in PAOD patients undergoing revascularization

VOYAGER PAD will also provide important long-term and

large-scale outcome data in patients undergoing

revascularisation procedures for PAD

VOYAGER PAD is

the first trial to

examine the effect

of a very low dose

anticoagulant (2.5

mg Rivaroxaban

bid) on top of

standard treatment

to improve limb and

systemic outcomes

after intervention or

surgery

Thank you very much for your attention!

Thank you very much for your attention!