tailored protection of the vascular patient with rivaroxaban · warfarin at uh, lmwhs &...

Tailored protection of the vascular

patient with Rivaroxaban

Miltos Matsagkas MD, PhD, FEBVS

Professor of Vascular Surgery

University of Thessaly

Conflict of Interest Disclosure Form

❑ I have no potential conflict of interest to report

I have the following potential conflict(s) of interest to report:

Type of affiliation / financial interest Name of commercial company

Receipt of grants/research supports: Bayer, Leo, Medtronic

Receipt of honoraria or consultation fees: Bayer, Elpen, Leo, Pfizer

Participation in a company sponsored speaker’s bureau:

Bayer

Stock shareholder: -

Spouse/partner: -

Other support (please specify): -

The evolution of anticoagulant drugs

AT + Xa + IIa

(1:1 ratio)

Heparin

1930s

AT + Xa

Indirect

Factor Xa

inhibitor

2002

IIa

Oral

direct

thrombin

inhibitors

2004

AT + Xa + IIa

(Xa > IIa)

LMWHs

1980s

II, VII, IX, X

(Protein C, S)

VKAs

1940s

Xa

Oral direct

Factor Xa

inhibitors

2008

IIa

Direct

thrombin

inhibitors

1990s

Perzborn E et al. Nat Rev Drug Discov 2011;10:61-75

Rivaroxaban

Site of Action for anti-coagulant drugs

Fibrin Clot

Intrinsic ExtrinsicXII

VIIVIII

IX

XI

Fibrinogen

II

V

Tissue Factor

X Direct Xa Inhibitors“-xaban”

Rivaroxaban

Direct Thrombin Inhibitors“-gatran”

Warfarin

AT

UH, LMWHs&

Indirect XaInhibitors“-parinux”

Rivaroxaban

for the Vascular patient

A tailored approach for various

clinical situations

Rivaroxaban for VTE treatment

EINSTEIN DVT study

▪ Randomized, open-label, event-

driven, non-inferiority study

▪ 3449 patients

The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510

EINSTEIN PE study

The EINSTEIN–PE Investigators. N Engl J Med. 2012 Apr 5;366(14):1287-97

▪ Randomized, open-label, event-

driven, non-inferiority study

▪ 4832 patients

Current Approved Indications

RivaroxabanApixabanDabigatranEdoxaban

• Stroke prevention in patients with non-valvular atrial fibrillation

• Prevention of VTE in patients undergoing hip or knee replacement

• Acute treatment of DVT/PE• Secondary prevention of DVT/PE

European Medicines Agency (EMA) US Food and Drug Administration (FDA)

Rivaroxaban for the treatment of VTE

Phases of the disease

Intermediate

Acute

Long term

Rivaroxaban treatment for VTE:

Rivaroxaban 20mg x 1

Initial larger dose

Rivaroxaban 15mg x 2for 21 days

DOACs and renal impairment

Renal excretion

▪ Dabigatran

▪ RivaroxabanApixabanEdoxaban

about80%

about30 - 40%

DOACs and renal impairment in VTE

CrCl (mL/min) Dabigatran Rivaroxaban Apixaban Edoxaban

> 50 LMWH for 9 days150md x 2

15mg x 2 (3 weeks) 20mg x 1

10mg x 2 (7 days)5mg x 2

LMWH for 5 days 60mg x 1

30-50 LMWH for 9 days 150mg x 2

* High risk of bleeding

110mg x 2

15mg x 2 (3 weeks) 20mg x 1


15mg x 1


* BW<60Kg + Age>80

2.5mg x 2

LMWH for 5 days 30mg x 1

15-30 Contraindicated 15mg x 2 (3 weeks) 20mg x 1


15mg x 1


* BW<60Kg + Age>80

2.5mg x 2

Contraindicated

< 15 Contraindicated Contraindicated Contraindicated Contraindicated

Konstantinides et al, European Heart Journal, 2014

Treatment choices at non-high risk PE

ACCP Guidelines 2016

Rivaroxaban for extension

of VTE treatment

VTE Treatment Extension

Treatment for index venous thromboembolic event3, 6 or 12 months’ anticoagulation

Continue anticoagulation

EquipoiseShould anticoagulation be

stopped or continue?

Stop treatment

Routine coagulation monitoring, with dose

adjustment and attendant risk of bleeding


Duration of anticoagulant therapy

The optimal treatment duration should be based on the underlying risk factors of VTE recurrence and the benefit–risk of long-term anticoagulant

therapy

Bleeding

VTE

recurrence

EINSTEIN Extension study

▪ Multicenter, randomized,

double-blind, placebo -

controlled, event-driven,

superiority study for

efficacy

▪ 1196 patients


Weitz JI et al, N Engl J Med 2017:376(13):1211–1222

EINSTEIN Choice study

▪ Multicentre, randomized,

double-blind, active-comparator,

event-driven, superiority study

▪ 3396 patients

▪ Male 78 years old with a history of hypertension and

hyperlipidemia

▪ From 3 days complaining of pain and swelling of his

right limb

▪ No history of thromboembolic disease

▪ Under:

➢ Amlodipin 20 mg x 1

➢ Simvastatin 20mg x 1

Case 1

▪ Modified Wells score : 4 (high probability for DVT >2)

▪ D-dimers : 7,7 μg/ml (0,5-1,5)

▪ Color Duplex: acute thrombosis of common and

superficial femoral vein

▪ Ht 42,7%, PLT 287.000 /μl, Cre 1,47 mg/dl, Ure 45 mg/dl,

ALT 17 iu/l, AST 15 iu/l

▪ Weight : 69 Kg

➢ GFR estimation

Case 1

▪ Estimated GFR (e-GFR): 40 ml/min

▪ Hepatic enzymes normal

▪ The patient started therapy with DOACs and particular

with rivaroxaban

➢ For 3 weeks 15mg x 2

➢ Afterwards 20mg x 1

Case 1

Why Rivaroxaban?

Case 1

Pts at risk

Rivaroxaban 4150 4018 3969 3924 3604 3579 3283 1237 1163 1148 1102 1034 938

Ενοξαπαρίνη/ΑΒΚ 4131 3932 3876 3826 3523 3504 3236 1215 1149 1109 1071 1019 939

Cumulative analysis EINSTEIN DVT and PE: Efficacy

0.5

3.0

2.5

2.0

1.5

1.0

0.0

Rivaroxaban (n=4150)

Enoxaparin/ΑΒΚ (n=4131)

0 30 60 90 120 150 180 210 240 270 300 330 360

Time to event (days)

Cu

mu

lati

ve e

ven

tsRivaroxaban

n/N (%)

Enoxaparin/ΑΒΚ

n/N (%)

86/4150

(2.1)

95/4131

(2.3)

HR=0.89

95% CI 0.66–1.19

p<0.001-non-inferiority

Prins MH et al, Thromb J 2013,11:21

Cumulative analysis EINSTEIN DVT and PE: Safety endpoint

First major or clinically important non-major bleeding

Pts at risk

Rivaroxaban 4130 3768 3671 3406 3270 3210 1928 1051 1009 936 878 853 453

Enoxaparin/ΑΒΚ 4116 3738 3618 3330 3186 3125 1711 1025 981 907 857 823 369

Cu

mu

lati

ve

eve

nts

(%

)



0 30 60 90 120 150 180 210 240 270 300 330 360

14

10

12

8

6

4

2

0


Rivaroxaban

n/N (%)

Enoxaparin/ΑΒΚ

n/N (%)

HR (95% CI)

value p

388/4130

(9.4)

412/4116

(10.0)

0.93 (0.81–1.06)

p=0.27


Significant reduction of major bleeding events

Pts at risk

Rivaroxaban 4130 3921 3862 3611 3479 3433 2074 1135 1095 1025 969 947 499

Enoxaparin/ΑΒΚ 4116 3868 3784 3525 3394 3348 1835 1109 1065 990 950 916 409

Rivaroxaban

n/N (%)

Enoxaparin/Α

ΒΚ

n/N (%)

HR (95% CI)

value p

40/4130

(1.0)

72/4116

(1.7)

0.54 (0.37–0.79)

p=0.002

0.5

3.0

2.5

2.0

1.5

1.0

0.0



0 30 60 90 120 150 180 210 240 270 300 330 360


Cu

mu

lati

ve

eve

nts

(%

)

HR=0.54

95% CI 0.37–0.79

p=0.002

46% reduction


Similar efficacy and lower risk for major bleeding

0.5

3.0

2.5

2.0

1.5

1.0

0.0



0 30 60 90 120 150 180 210 240 270 300 330 360


Cu

mu

lati

ve

eve

nts

(%

)

Time Rivaroxaban

n (%)

Enoxaparin/ΑΒΚ

n (%)

21 days 39 (0.9) 50 (1.2)

3 months 69 (1.7) 82 (2.0)

12 months 86 (2.1) 95 (2.3)

HR 0.89

95% CI 0.66–1.19

p<0.001


0.5

3.0

2.5

2.0

1.5

1.0

0.0



0 30 60 90 120 150 180 210 240 270 300 330 360

Cu

mu

lati

ve

eve

nts

(%

)

HR 0.54

95% CI 0.37–0.79

p=0.002

Time Rivaroxaban

n (%)

Enoxaparin/ΑΒ

Κ

n (%)

21 days 16 (0.4) 33 (0.8)

3 months 28 (0.7) 49 (1.2)

12 months

20 (1.0) 72 (1.7)

DVT recurrence Major bleeding


Efficacy and safety outcomes in fragile patients with DVT with significant reduction in major bleeding


Major bleeding

Rivaroxaban, but for how long?

Case 1

Which is the optimal treatment duration?

1. The patient should receive therapy for 3 months

2. The patient should receive therapy for 6 months

3. The patient should receive therapy for at least 3 months and after this period reexamine the therapy duration

4. The patient should receive rivaroxaban lifelong

Treatment duration

ACCP Guidelines, CHEST 2016

VTE provoked by surgery 3% recurrence at 5 years

Provoked VTE by a nonsurgical

transient risk factor (eg, estrogen

therapy, pregnancy, leg injury, flight of

> 8 h)

15% recurrence at 5 years

Unprovoked VTE

(also termed “idiopathic”)

30% recurrence at 5 years

VTE associated with cancer (also

termed “ cancer associated

thrombosis”

15% annualized risk of recurrence;

recurrence at 5 years not estimated

because of high mortality from cancer

Recurrence risk

Impact of Clinical Risk Factors in VTE Recurrence

Cumulative proportions of recurrent thrombosis after cessation of anticoagulant therapy* (N=558)

*Patients with malignant disease and antiphospholipid syndrome were excluded from the study

Baglin T et al, Lancet 2003;362:523–526

Provoked by surgery

Provoked by non-surgical

risk factors

Unprovoked

Cu

mu

lati

ve

pro

po

rtio

n o

f re

cu

rre

nt

eve

nts

Time since event (months)

0 4 8 12 16 20 24

0

0.05

0.10

0.15

0.20

Duration of Anticoagulation After VTE in Real-World Clinical Practice: RIETE Registry (N=6944)

Approximately 55% of unprovoked patients are treated for >12 months

Ageno W et al, Thromb Res 2015;135:666–672

55%

19%

Cu

mu

lati

ve

In

cid

en

ce

(%

)

Days

▪ The patient was re-evaluated at 3 months

o There was no change in thrombotic or bleeding profile

o d-Dimers remained positive, even reduced

o Duplex scan showed partial recanalization

▪ We decided for indefinite anticoagulant therapy

Evaluation at 3 months

Indefinite anticoagulant therapy,

with what medication?

Case 1

Which is the treatment of choice for long-term anticoagulation;

1. Switch to VKA with a goal of INR 2-3

2. Switch to VKA with a goal of INR 1.5-1.9

3. Switch to Aspirin 100mg x 1

4. Continuation on Rivaroxaban 20 mg x 1

5. Continue on Rivaroxaban 20mg x 1 for 3 more months (6 months in total) and then reduce to Rivaroxaban 10 mg x 1, indefinitely

Long-term anticoagulation

Study/sub-groupFavours prolonged

treatment

Favours shorter

treatment

Levine 1995

Schulman 1995

Schulman 1997

Kearon 1999

Agnelli 2001

Pinede 2001

Agnelli 2003

Kearon 2004

Total

VTE recurrence with continued versus shorter VKA treatment

Meta-analysis of eight studies of 2,994 patients: consistent reduction in VTE recurrence with prolonged versus shorter treatment (OR=0.18; 95% CI 0.13–0.26)

0.01 0.1 1 10 100

Peto OR and 95% CIsHutten B, Prins M. Cochrane Database Syst Rev 2006

Meta-analysis of four studies (N=808)*: significant increase in major bleeding with prolonged versus shorter VKA treatment (OR=4.87; 95% CI 1.31–18.15)

Study/sub-groupFavours prolonged

treatment

Favours shorter

treatment

Levine 1995

Kearon 1999

Agnelli 2001

Total

Incidence of major bleeding with continued versus shorter VKA treatment

0.001 0.01 0.1 1 10 100 1000

Peto OR and 95% CIs

Hutten B, Prins M. Cochrane Database Syst Rev 2006

VTE treatment with VKAs

Hylek EM, Ann Int Med 1994

Intra-cerebral hemorrhage risk

Kearon et al, NEJM 2003

INR 1.5-1.9

INR 2-3

Low dose VKA treatmentINR: 1.5 – 1.9

Poor adherence in VKA treatment

Rodriguez et al, J Thromb Haemostat 2013

EINSTEIN Extension study

▪ Multicenter, randomized,

double-blind, placebo -

controlled, event-driven,

superiority study for

efficacy

▪ 1196 patients


EINSTEIN Extension

The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; EINSTEIN DVT.

Rivaroxaban 20 mg od

Placebo

N=1,197

30

-day

ob

serv

atio

n

pe

rio

d

Confirmed symptomatic DVT or PE completing6 or 12 months of rivaroxaban or VKA in EINSTEIN VTE programme

R

Treatment period of 6 or 12 months

Day 1

Confirmed symptomatic DVT or PE completing 6 or 12 months of VKA

~53%

~47%

EINSTEIN Extension Primary efficacy outcome analysis


NNT=151110

5

21C

um

ula

tive e

ven

t ra

te (

%)

34

9

13

678

12

00 30 60 90 120 150 180 210 240 270 300 330 360


HR=0.18; p<0.001, RRR=82%

Placebo (n=594)

Rivaroxaban (n=602)

Number of subjects at risk

Rivaroxaban 602 590 583 573 552 503 482 171 138 132 114 92 81

Placebo 594 582 570 555 522 468 444 164 138 133 110 93 85

EINSTEIN Extension major bleeding


Rivaroxaban

(n=598)

Placebo

(n=590)

n (%) n (%)

Major bleeding 4 (0.7)* 0 (0)

Bleeding contributing to death 0 (0) 0 (0)

Bleeding in a critical site 0 (0) 0 (0)

Associated with fall in haemoglobin

2 g/dl and/or transfusion of 2 units4 (0.7) 0 (0)

Gastrointestinal bleeding 3 (0.5) 0 (0)

Menorrhagia 1 (0.2) 0 (0)

Rivaroxaban Versus Placebo Efficacy and Safety in Extended VTE Treatment

7.1

0.0

1.30.7

0

2

4

6

8

10

Recurrent VTE Major bleeding

Inci

de

nce

(%

)

Placebo

Rivaroxaban


p=0.11

p<0.001

Weitz JI et al, N Engl J Med 2017:376(13):1211–1222

EINSTEIN Choice study

▪ Multicentre, randomized,

double-blind, active-comparator,

event-driven, superiority study

▪ 3396 patients

EINSTEIN CHOICE Evaluated Rivaroxaban Versus ASA for Extended Treatment of VTE

30-dayfollow-up


n=1136

Day 1

ASA 100 mg od

n=1139

12-month plannedtreatment duration†

Population: Patients with confirmed

symptomatic PE/DVT who completed 6–12 months’

anticoagulation*

R

N=3396

Objectives: Compare the efficacy and safety of once daily rivaroxaban (20 or 10 mg) with

aspirin (100 mg) in VTE patients who completed 6 to 12 months of treatment and with equipoise

regarding the need for extended anticoagulation


n=1121

*Completed 6–12 months anticoagulation at randomization with no interruption of anticoagulation >1 week†Patients randomized after the requisite number of primary efficacy outcomes was reached were treated for ≥6 monthsWeitz JI et al, Thromb Hemost 2015;114:645–650; Weitz JI et al, N Engl J Med 2017:doi:10.1056/NEJMoa1700518

Multicentre, randomized, double-blind, active-comparator, event-driven, superiority study

Rationale for Study Arms

Rivaroxaban 20 mg od Rivaroxaban 10 mg od ASA 100 mg od


offered effective

thromboprophylaxis

after elective hip or knee

arthroplasty 2,3

ASA 100 mg od has been shown to reduce the risk of recurrent VTE by more than 30% compared with

placebo, without increasing the risk of

major bleeding4,5

In EINSTEIN EXT, rivaroxaban 20 mg od

reduced the risk of recurrent VTE by 82%

compared with placebo, with similar risk of major

bleeding1

1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; 2. Eriksson BI et al, J Bone Joint Surg [Br] 2009;91-B:636–644; 3. Cohen AT et al, N Engl J Med 2013;368:513–523; 4. Becattini C et al, N Engl J Med 2012; 366:1959–1967; 5. Simes J et al, Circulation 2014;130:1062–1071

Patient Flow

Randomized N=3396

1127

1136 randomized to rivaroxaban 10 mg

1139 randomized to aspirin 100 mg

1131

138 prematurely discontinuedstudy treatment*8 died 14 withdrew consent3 were lost to follow-up

1107

1121 randomized to rivaroxaban 20 mg

1063 10691046

Included in per-protocol analyses

Included in ITT/ safety analyses



8 Did not take study medication



*The other main reasons for premature discontinuation of study medication were adverse events, noncompliance with study drug, protocol violations, and efficacy or safety outcomes. ITT (Intention to treat): all randomized patients who received at least one dose of study medicationWeitz JI et al, N Engl J Med 2017:doi:10.1056/NEJMoa1700518

Both Rivaroxaban Doses Provided Superior Reduction in Recurrent VTE Rates Compared with ASA

Intention-to-treat analysisWeitz JI et al, N Engl J Med 2017:doi:10.1056/NEJMoa1700518

ASA 100 mg od



Days

0

1

2

3

4

5

Cu

mu

lati

ve in

cid

en

ce (

%)

1 30 60 90 120 150 180 210 240 270 300 330 367

Rivaroxaban 20 mg od vs ASA17/1107 (1.5%) vs 50/1131 (4.4%)HR=0.34 (95% CI 0.20–0.59), p<0.001

Rivaroxaban 10 mg od vs ASA13/1127 (1.2%) vs 50/1131 (4.4%)HR=0.26 (95% CI 0.14–0.47), p<0.001

Rates of Major Bleeding Were ≤0.5% and Similar to ASA

Safety analysis. No events after Day 360 up to Day 480Weitz JI et al, N Engl J Med 2017:doi:10.1056/NEJMoa1700518

0

1

2

4

5

3

Days

ASA 100 mg od

Rivaroxaban 20 mg odRivaroxaban 10 mg od

1 30 60 90 120 150 180 210 240 270 300 330 360

Cu

mu

lati

ve in

cid

en

ce (

%)

Rivaroxaban 20 mg od vs ASA6/1107 (0.5%) vs 3/1131 (0.3%)HR=2.01 (95% CI 0.50–8.04), p=0.32

Rivaroxaban 10 mg od vs ASA5/1127 (0.4%) vs 3/1131 (0.3%)HR=1.64 (95% CI 0.39–6.84), p=0.50

Both Rivaroxaban Doses Reduced Recurrent VTE Rates and had Similar Risk of Bleeding Compared with ASA

Efficacy

*Intention-to-treat analysis; #safety analysis; ‡no events after Day 360 up to Day 480Weitz JI et al, N Engl J Med 2017:doi:10.1056/NEJMoa1700518

0

1

2

4

5

3

Days‡

ASA 100 mg od

Rivaroxaban 20 mg odRivaroxaban 10 mg od

1 30 60 90 120 150 180 210 240 270 300 330 360

Cu

mu

lati

ve in

cid

ence

(%

)

Major bleeding

ASA 100 mg od



Days

0

1

2

3

4

5

Cu

mu

lati

ve in

cid

ence

(%

)

1 30 60 90 120 150 180 210 240 270 300 330 367

Which is the treatment of choice for long-term anticoagulation;


2. Switch to VKA with a goal of INR 1.5-1.9

3. Switch to Aspirin 100mg x 1

4. Continuation on Rivaroxaban 20 mg x 1

5. Continue on Rivaroxaban 20mg x 1 for 3 more months (6 months in total) and then reduce to Rivaroxaban 10 mg x 1, indefinitely

Long-term anticoagulation

Rivaroxaban Efficacy and Safety in the Initial, Continued and Extended Treatment of VTE (N=12,874)

2.31.7

7.1

0.0

4.4

0.3

4.4

0.3

2.1

1.01.3

0.7

1.5

0.51.2

0.4

0

2

4

6

8

10

RecurrentVTE

Majorbleeding

RecurrentVTE

Majorbleeding

RecurrentVTE

Majorbleeding

RecurrentVTE

Majorbleeding

Inci

de

nce

(%

)

EINSTEIN DVT/ EINSTEIN PE1 EINSTEIN EXT2 EINSTEIN CHOICE3

Rivaroxaban20 mg od

Rivaroxaban10 mg od

p=0.41p=0.002

p<0.001

p=0.11 p=0.32 p=0.50

p<0.001p<0.001

1. Prins MH et al, Thromb J 2013;11:21 ; 2. The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; 3. Weitz JI et al, N Engl J Med 2017:doi:10.1056/NEJMoa1700518

LMWH/VKA Placebo ASA Rivaroxaban

Rivaroxaban for the treatment

of Cancer Associated Thrombosis

▪ Woman, 64 years old

▪ Metastatic ovarian cancer (2 liver metastases)

▪ Undergone cytoreductive surgery followed by combination chemotherapy with paclitaxel and carboplatin

▪ During her treatment, she developed shortness of breath

▪ Diagnosed with a large saddle PE

▪ Treated with LMWH for about 8 months

▪ She is now undergoing re-staging and is not taking chemotherapy at the moment

▪ She is anxious to stop the LMWH

Case 2

▪ D-dimers : 6,7 μg/ml (0,5-1,5)

▪ Ht 32,4%, PLT 232.000 /μl, Cre 1,35 mg/dl, Ure 48

mg/dl, ALT 15 iu/l, AST 18 iu/l

▪ Weight : 59 Kg

▪ GFR estimation: 39ml/min

Case 2

Which is the options for long-term anticoagulation in such a cancer patient;

1. Stop anticoagulation

2. Stay in LMWH for the long term


4. Switch to Rivaroxaban 20 mg x 1, no stop schedule

5. Switch to Rivaroxaban 20 mg x 1 until 12 months completion, then re-evaluation

Long-term anticoagulation in Cancer

ACCP 2016 Guidelines: Acute Treatment and Secondary Prevention of VTE

ACCP recommendation Grade of recommendation

Initial anticoagulation

Acute DVT or haemodynamicallystable PE and no cancer

NOAC preferred to LMWH/VKA 2B

LMWH/VKA preferred to LMWH alone 2C

PE with hypotension Thrombolytic therapy (systemic rather than catheter-directed unless bleeding risk is high)

2B (2C)

DVT or PE with cancer LMWH suggested over NOAC or VKA 2C

Duration of anticoagulant therapy

Proximal DVT or PE 3 months recommended over shorter duration 1B

First proximal DVT or PE provoked by surgery or other transient risk factor

3 months 1B (2B if low/moderate

bleeding risk; 1B if high)

Unprovoked DVT or PE Extended therapy if bleeding risk is low/moderate 2B

3 months if bleeding risk is high 1B

DVT or PE associated with active cancer

Extended therapy recommended over 3 months’ therapy (no scheduled stop date)

1B (2B if high bleeding risk)

Kearon C et al, Chest 2016;149:315–352

ITAC-CME 2016 Guidelines

▪ LMWHs are preferred over vitamin K antagonists (VKAs) for the treatment of VTE in patients with cancer (grade 1A). Values and preferences: daily subcutaneous injection might be a burden for patients

▪ LMWH should be used for a minimum of 3 months to treat established VTE in patients with cancer (grade 1A)

During the first 10 days: Any molecule can be used (LMWH, UFH, fondaparinux)

Early maintenance (10 days to 3 months) and long-term (beyond 3 months):

Farge D et al, Lancet Oncol 2016;17:e452-66

Recommendations

ITAC-CME 2016 Guidelines

▪ DOACs can be considered for VTE treatment of patients with stable cancer not receiving systemic anticancer therapy, and in cases where VKA is an acceptable, but not an available, treatment choice (guidance)

▪ After 3–6 months, termination or continuation of anticoagulant (LMWH, VKA, or DOACs) should be based on individual assessment of the benefit-to-risk ratio, tolerability, drug availability, patient preference, and cancer activity (guidance, in the absence of data)

Early maintenance (10 days to 3 months) and long-term (beyond 3 months)

Recommendations

Farge D et al, Lancet Oncol 2016;17:e452-66

Prandoni et al, Blood 2002

Recurrence risk in Ca patients

Risk factors for Cancer-associated Thrombosis

Category Risk Factor Increased Risk

Tumour-related

Site Brain, pancreas, gastric, ovarian, lung, myeloma, lymphoma, renal

Duration of cancer <3 months since diagnosis

Grade High

Stage Advanced

Biomarker Tissue factor, soluble P-selectin, D-dimer, C-reactive protein

Patient-related

Non-specific-cancer Age > 40 years, female, co-morbidities, infection, obesity, anaemia, dehydration, past history of VTE, family history of VTE, inherited hypercoagulable states, concurrent acute illness, pulmonary disease, renal disease, prolonged immobility, smoking

Cancer-specific Thrombocytosis, leucocytosis, anaemia, hospitalization, acquired protein C resistance

Treatment-related

Surgical Major laparotomy or laparoscopy lasting more than 30min; major abdominal or pelvic operation

Pharmacological Aggressive chemotherapy, anti-angiogenic medication, growth factors, blood product

Indwelling venous catheter-related

Central venous catheter, femoral venous catheter, peripheral venous catheter

Adapted from Barsam SJ, Patel R, Arya R. B J Haem 2013;161:764-777

Extended Treatment in Cancer Associated Thrombosis: Challenges in the Real World

Only 28% of cancer patients are treated for >12 months

Ageno W et al, Thromb Res 2015;135:666–672

28%

9%

Cu

mu

lati

ve

In

cid

en

ce

(%

)

Days

Higher Persistence on Index Therapy in Cancer Patients Using Rivaroxaban or Warfarin Versus LMWH

*Discontinuation was defined as a gap of no more than 60 days between the end of the days of supply of a dispensing and the start date of the next dispensing of the index therapy, if any

Khorana AA et al, Res Pract Thromb Haemost 2017;1:14–22

Cohort Median treatment duration

Kaplan–Meier rates

6 months 12 months

LMWH 3.3 37% 21%

Warfarin 7.9 61% 35%

Rivaroxaban 7.9 61% 36%

Warfarin (n=1403)

Rivaroxaban (n=709)

LMWH (n=735)

100

75

50

25

0

Pro

po

rtio

n o

f p

atie

nts

sti

ll o

n in

dex

th

erap

y (%

)

0 2 4 6 8 10 12

Time (months)

EINSTEIN DVT and PE Pooled Analysis Outcomes: Cancer

Active cancer at baseline

(n=462)

ITT analysis(n=8281 )

Active cancer during study

(n=193)

History of cancer

(n=469)

No known cancer:

(n=7157)

Safety analysis (n=8246)

8281 patients randomized

1. Prins MH et al, Lancet Haematol 2014;1:e37–e46

7.0

5.0

13.0

5.0

2.0

7.0

0

2

4

6

8

10

12

14

Recurrent VTE Majorbleeding

Net clinicalbenefit

Eve

nt

in p

atie

nts

wit

h

acti

ve c

ance

r* (

%)

EINSTEIN PE/DVT: Effective Treatment in Patients with Active Cancer, with Significant Reduction in Major Bleeding

0.1 1 10

n=16 n=20 n=8 n=15 n=25 n=38

p=0.047

p=0.018

# #,§‡

Efficacy#

Major bleeding‡

Net clinical benefit#§

Rivaroxaban

Enoxaparin/VKA

Favoursrivaroxaban

Favours enoxaparin/VKA

*At baseline or during the study period; #ITT population: N=8281; patients with active cancer, n=655; ‡safety population: N=8246; patients with active cancer, n=651; §composite of recurrent VTE and major bleeding


EINSTEIN PE/DVT: Major Bleeding in Patients with Active Cancer According to Renal Function

2.7

5.0

13.0

2.4 2.2 2.1

0

2

4

6

8

10

12

14

>80 50−80 <50

Maj

or

ble

ed

ing

(%)

Creatinine clearance (ml/min)

Enoxaparin/VKA

Rivaroxaban


SELECT-D study

▪ Randomized, open label,

pilot study for efficacy

▪ 203 patients

Young AM et al, J Clin Oncol 36, 2018

Select-d Primary Outcome: Lower Incidence of Recurrent VTE with Rivaroxaban Versus Dalteparin

Dalteparin

Rivaroxaban

Number at risk

Dalteparin 203 171 139 115

Rivaroxaban 203 174 149 134

40

35

30

25

20

15

10

5

0

0 1 2 3 4 5 6

Time from trial entry (months)

VTE

rec

urr

ence

(%

)

Outcome at 6 months

Rivaroxaban (n=203)

Dalteparin (n=203)

VTE recurrence, % (95% CI)

4 (2–9) 11 (7–16)

Lower limb DVT/PE recurrence,% (95% CI)

3 (1-7) 9 (6-15)


Select-d Secondary Outcome: More Major Bleeding with Rivaroxaban but Similar Rate of Fatal Bleeding

2.9

0.5

5.4

0.5

0

5

10

15

20

Major bleeding Fatal bleeding

Pa

tie

nts

(%

)

Dalteparin Rivaroxaban

*All bleeding events were adjudicated. The rate of clinical major bleeding events in the rivaroxaban group was 12.3% versus 2.9% in the daltaparin group. Overall survival at 6 months was 70% (63–76%) in the rivaroxaban group and 75% (69–81%) in the dalteparin group

Most major bleeding events were gastrointestinal bleeding.* No CNS bleeding was observed in the rivaroxaban or dalteparin groups


Which is the options for long-term anticoagulation in such a cancer patient;

1. Stop anticoagulation

2. Stay in LMWH for the long term


4. Switch to Rivaroxaban 20 mg x 1, no stop schedule

5. Switch to Rivaroxaban 20 mg x 1 until 12 months completion, then re-evaluation

Long-term anticoagulation in Cancer

Further Evidence Will Come from the CALLISTO Programme

Trial Design Dose Duration Population

VTE prevention

Prospective, randomized,double-blind superiority

Rivaroxaban 10 mg od vs placebo 6 monthsCancer patients at high VTE risk

planned to initiate chemotherapy

PRO-LAPS 23Randomized,double blind

Rivaroxaban 10 mg od vs placebo

Extended antithrombotic prophylaxis (3

weeks)

Colorectal cancer patients after laparoscopic surgery

VTE treatment

Randomized, open-label, multicentre pilot

-Rivaroxaban vs dalteparin-Rivaroxaban vs placebo

6 months

6 months

-Cancer patients with symptomatic VTE

-PE and RVT-positive patients

CASTA-DIVA6Randomized,

open labelRivaroxaban vs dalteparin 3 months

Patients with active cancerat high risk of VTE recurrence

Prospective, randomized,open-label, multicentre

Rivaroxaban vsLMWH

3 monthsPatients with active cancer

and newly diagnosed VTE event

QAI9 Following-up 200 CAT patients with VTE whose full anticoagulation course was with rivaroxaban for 6 months

Patient-reported outcomes, follow-up for 6 months

2nd CAT survey for professionals in the oncology/haematology field to identify current practice

1,2

7,8

10,11

12

4,5

Rivaroxaban for the treatment

of PAD patients

Plaque disruption and thrombosis

Normal artery

‘Fatty streak’

Atheroscleroticplaque

Fibrous plaque

Flow-limiting stenosis

Symptoms with exercise,

e.g. stable angina and

intermittent claudication

Atherothrombosis

◆ MI

◆ Stroke

◆ CV death

◆ Limb ischaemia

Atherosclerosis Is a Progressive Disease Leading to Atherothrombosis and Ischaemia

154million 120

million

0

20

40

60

80

100

120

140

160

180

CAD PAD

Pre

vale

nce

(m

illio

ns)

PAD Affects Millions of Patients Worldwide

Global burden of disease study 20161

1. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators, Lancet 2017;390:1211–1259; 2. McDermott MM et al, J Am Heart Assoc 2013;2:e000257

~5% of patients with PAD

have classical symptoms of

intermittent claudication2

Asymptomatic

65%

Non-classical

symptoms

30%

REACH: More than 3 in 5 patients with PAD have

atherothrombotic disease also in other arterial territories

CAD

PAD

CeVD

61.5% of patients

with PAD had

concomitant

disease in other

vascular beds

24.7% of patients

with CAD had

concomitant

disease in other

vascular beds

Percentages are calculated from the total population included in the REACH Registry. N=67,888

Bhatt DL et al, JAMA 2006;295:180–189

Atherosclerosis Is a Polyvascular Disease

Prevention of MACE in PAD Requires a Combination of Risk Factor Management and Antithrombotic Therapy

Vascular protection

Control of CV risk factors to limit atherosclerosis progression

and stabilize existing plaques

Lifestyle changes

• Smoking cessation

• Regular exercise

• Healthy diet

• Weight management

• Psychosocial support

Medical therapies

• Lipid control – statins

• Hypertension control – ACE

inhibitors/ARBs

• Diabetes control –

insulin/anti-glycaemic drugs

Prevention of blood clot

formation over ruptured/eroded

atherosclerotic plaques

Antithrombotic therapy

• Single antiplatelet therapy

with aspirin or clopidogrel

Montalescot G et al, Eur Heart J 2013;34:2949–3003; Aboyans V et al, Eur Heart J 2018;39:763–816; Cortés-Beringola A et al, Eur J Prevent Cardiol 2017;24:22–28

Antithrombotic Options for PAD Are Limited

Recommendation Class Level

2017 ESC/ESVS guidelines1

Long-term single antiplatelet therapy is recommended in symptomatic patients I A

In patients requiring antiplatelet therapy, clopidogrel may be preferred over aspirin IIb B

2016 AHA/ACC guidelines2

Antiplatelet therapy with aspirin alone (75–325 mg per day) or clopidogrel (75 mg per day) is recommended to reduce MI, stroke and vascular death in patients with symptomatic PAD

I A

The effectiveness of DAPT (aspirin and clopidogrel) to reduce the risk of CV ischaemic events in patients with symptomatic PAD is not well established

IIb B-R

The overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain

IIb B-R

Anticoagulation should not be used to reduce the risk of CV ischaemic events in patients with PAD

III(Harm)

A

Current guidelines for the use of antithrombotics in patients with PAD

1. Aboyans V et al, Eur Heart J 2018;39:763–816; 2. Gerhard-Herman MD et al, J Am Coll Cardiol 2017;69:e71–e126

Pharmacological therapy in PAD

Selection of antiplatelet therapy

Katsanos et al, PloS one 2015

49 RCTs34.518 PAD pts

Aspirin Is the Most Commonly Prescribed Antiplatelet Agent in Patients with PAD

Antiplatelet use in US patients with PAD enrolled in the REACH registry

Cannon CP et al, Am J Card 2010;105:445–452

COMPASS trial

ATLAS ACS 2 TIMI 51: Rivaroxaban Vascular Dose Reduced CV Events and Death in Patients with ACS

Patients with elevated cardiac biomarkers and no prior stroke/transient ischaemic attack

CAD

CV death, MI or stroke

12

Days

2-y

ea

r K

ap

lan

–M

eie

r e

sti

ma

te (

%) HR=0.80

(95% CI

0.68–0.94);

p=0.007

Rivaroxaban

2.5 mg bid

Placebo

0

7200 540360180

10

8

6

4

2

CV death

0

5

Days

HR=0.55

(95% CI

0.41–0.74);

p<0.001

NNT=50

Rivaroxaban

2.5 mg bid

Placebo

7200 540360180

4

3

2

1

All-cause death

5

Days

HR=0.58

(95% CI

0.44–0.77);

p<0.001

NNT=49

Rivaroxaban

2.5 mg bid

Placebo

0

7200 540360180

4

3

2

1

Mega JL et al, Eur Heart J 2014;35(Suppl.):992.

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

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

Antithrombotic investigations* were stopped 1 year ahead of expectations in Feb 2017 due to overwhelming efficacy in the rivaroxaban 2.5 mg bid + aspirin arm

Rivaroxaban 5.0 mg bid

Aspirin 100 mg od

Rivaroxaban 2.5 mg bid + Aspirin 100 mg od

30-day

washout

period

30-day run-in,

aspirin 100 mg

Final

follow-up

visit

R

Final

washout

period visit

1:1:1

N=27,395

Population:

Chronic CAD (91%)PAD (27%)

*Patients who were not receiving a proton pump inhibitor (PPI) were randomized to pantoprazole or placebo (partial factorial design); the PPI pantoprazole component of the study is continuing; data will be communicated once complete

1. Eikelboom JW et al. N Engl J Med 2017; DOI: 10.1056/NEJMoa1709118; 2. Bosch J et al. Can J Cardiol 2017;33(8):1027–1035

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

Factorial design ± pantoprazole*

Modified ISTH Major Bleeding Definition Applied

at Regulators’ Request with the Intent of Capturing

all Bleeding that Required Medical Attention

Modified ISTH major bleeding

(COMPASS)

◆ 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

1. Schulman S et al, J Thromb Haemost 2005;3:692–694

ISTH major bleeding1

◆ Fatal bleeding, and/or

◆ Symptomatic bleeding in a critical area or organ (such as intracranial), and/or

◆ Bleeding causing a drop in haemoglobin level of ≥20 g/l, or leading to transfusion of ≥2 units of whole blood or red cells

Unlike the standard ISTH criteria, all bleeding that led to presentation

to an acute care facility or hospitalization were considered as major

compared with the standard ISTH major bleeding definition

Dual Pathway Inhibition with Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin Reduced CV Death, Stroke and MI

PADCAD

*Rates as at mean follow up of 23 monthsEikelboom JW et al. N Engl J Med 2017; DOI: 10.1056/NEJMoa1709118

MACE* % HR (95% CI) p-value

Aspirin 100mg OD 5.4 - -

Rivaroxaban 5mg BID 4.9 0.90 (0.79-1.03) 0.12

Rivaroxaban 2.5mg BID + Aspirin 100 mg OD

4.1 0.76 (0.66-0.86) <0.001

Cu

mu

lati

ve

in

cid

en

ce

(%

)

0

2

4

6

8

10

0 1 2 3

Rivaroxaban 2.5mg bid + Aspirin 100mg od

Rivaroxaban 5mg bid

Aspirin 100mg od

Number at riskAspirin 100mg od 9126 7808 3860 669Riva 5mg bid 9117 7824 3862 670Riva 2.5mg bid + Aspirin 100mg od

9152 7904 3912 658

Year

Dual Pathway Inhibition with Rivaroxaban 2.5 mg bid + Aspirin:

Significantly Reduced CV Events by 24% Versus Aspirin

Outcomes, n (%) Rivaroxaban 2.5 mg bid +

aspirin 100 mg N=9152

Aspirin 100 mgN=9126

Rivaroxaban 2.5 mg bid +aspirin 100 mg vs aspirin 100 mg

HR (95% CI) p-value

CV death, stroke,

or MI379 (4.1) 496 (5.4) 0.76 (0.66–0.86) <0.001

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

PADCAD

Outcomes, n (%) Rivaroxaban 5 mg bidN=9117

Rivaroxaban 5 mg bid vs aspirin 100 mg

HR (95% CI) p-value

CV death, stroke,

or MI448 (4.9) 0.90 (0.79–1.03) 0.12

CV death 195 (2.1) 0.96 (0.79–1.17) 0.69

Stroke 117 (1.3) 0.82 (0.65–1.05) 0.12

MI 182 (2.0) 0.89 (0.73–1.08) 0.24

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

Bleeding Rates Increased, but Low

with Rivaroxaban 2.5 mg bid + Aspirin Versus Aspirin Alone,

with No Differences Seen in Fatal and Intracranial Bleeding

PADCAD

Rates at mean follow-up of 23 months

Rivaroxaban 2.5 mg bid +


Rivaroxaban 5 mg bidN=9117

Aspirin 100 mg

N=9126

Modified major ISTH bleeding 288 (3.1%) 255 (2.8%) 170 (1.9%)

Fatal 15 (0.2%) 14 (0.2%) 10 (0.1%)

Non-fatal ICH* 21 (0.2%) 32 (0.4%) 19 (0.2%)

Non-fatal other critical organ* 42 (0.5%) 45 (0.5%) 29 (0.3%)

Rates at mean follow-up of 23 months

Rivaroxaban 2.5 mg bid + aspirin 100 mg

vs aspirin 100 mg

Rivaroxaban 5 mg bid vsaspirin 100 mg

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

Modified ISTH major bleeding 1.70 (1.40–2.05) <0.001 1.51 (1.25–1.84) <0.001

Fatal 1.49 (0.67–3.33) 0.32 1.40 (0.62–3.15) 0.41

Non-fatal ICH* 1.10 (0.59–2.04) 0.77 1.69 (0.96–2.98) 0.07

Non-fatal other critical organ* 1.43 (0.89–2.29) 0.14 1.57 (0.98–2.50) 0.06

The use of the standard ISTH major bleeding definition

would have led to approximately one third fewer major bleeding events

than with the use of the modified ISTH definition

Each event is counted in the most severe hierarchical category (fatal; critical organ bleeding; bleeding into surgical site requiring

re-operation; bleeding leading to hospitalization) only. For each outcome, the first event experienced per patient is considered. Subsequent events of

the same type are not shown. Therefore subcategories do not necessarily sum up to overall category. *Symptomatic


Net Clinical Benefit: 20% RRR

with Rivaroxaban 2.5 mg bid + Aspirin Versus Aspirin

◆ Definition: composite of CV death, stroke, MI, fatal bleeding or

symptomatic bleeding into a critical organ

• In other words, net clinical benefit represented the composite

of fatal and non-fatal events of irreversible harm

PADCAD

Outcome Rivaroxaban 2.5 mg bid +


Aspirin 100 mgN=9126

Rivaroxaban 2.5 mg bid + aspirin 100 mg

vs aspirin 100 mg

HR (95% CI) p-value

Net clinical benefit

431 (4.7%) 534 (5.9%) 0.80 (0.70–0.91) <0.001


Study / Treatment armControl Intervention

HR HR (95% CI) p-value%/year %/year

COMPASS1

Rivaroxaban 2.5 mg bid 2.1† 1.8† 0.82 0.01

CHARISMA2

Clopidogrel 75 mg od 2.3‡ 2.1‡ 0.91 0.32

PEGASUS3

Ticagrelor 90 mg bid 1.7¶ 1.7¶ 1.00 0.99

Ticagrelor 60 mg bid 1.7¶ 1.6¶ 0.89 0.14

TRA2P-TIMI 504

Vorapaxar 2.5 mg od 1.8¶ 1.7¶ 0.95 0.41

0.5 1 2

Rivaroxaban 2.5 mg bid + Aspirin Improved Overall

Survival in Patients with CAD or PAD

Favoursintervention

Favourscontrol

1. Eikelboom JW et al. N Engl J Med 2017; DOI: 10.1056/NEJMoa1709118; 2. Bhatt DL et al. J Am Coll Cardiol 2007;49:1982–1988;

3. Bonaca MP et al. N Engl J Med 2015;372:1791–1800; 4. Morrow DA et al. N Engl J Med 2012;366:1404–1413

PADCAD

COMPASS PAD Analysis

Inclusion and Exclusion Criteria Ensure That Patients Are Chronic CAD and PAD Patients

#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 considered

www.clinicaltrials.gov/ct2/show/NCT01776424 [accessed 21 Mar 2017]; Bosch J et al, Can J Cardiol 2017;33:1027–1035

Key exclusion criteria‡

◆ Stroke ≤1 month or any haemorrhagic or lacunar stroke

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

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

◆ eGFR <15 ml/min

Key inclusion criteria*

◆ PAD• Aortofemoral bypass surgery, limb

bypass surgery, percutaneous transluminal angioplasty, revascularisation of the iliac, or infrainguinal arteries

• Limb or foot amputation for arterial vascular disease

• Intermittent claudication

• Ankle brachial index (ABI) of less than 0·90

• Peripheral artery stenosis (≥50%) documented by angiography or duplex ultrasound

• Carotid revascularisation

• Asymptomatic carotid artery stenosis of at least 50% diagnosed by duplex ultrasound or angiography

31% RRR in MACE or MALE Including Major Amputation

with Rivaroxaban 2.5 mg bid + Aspirin Versus Aspirin

in Patients with PAD

PAD

Number at riskRivaroxaban + aspirin 2492 2069 893 124

Rivaroxaban 2474 2023 864 147

Aspirin 2504 2034 911 113

Rivaroxaban 2.5 mg bid + aspirin 100 mg vs aspirin 100 mg: HR 0.69 (0.56–0.85), p=0.0003

Rivaroxaban 5 mg bid vs aspirin 100 mg: HR 0.84 (0.69–1.02), p=0.08

Anand SS et al. ESC 2017, Abs 1157; Available at:

http://spo.escardio.org/SessionDetails.aspx?eevtid=1220&sessId=22247&subSessId=0;

Anand SS et al. Lancet 2017;In Press

http://spo.escardio.org/SessionDetails.aspx?eevtid=1220&sessId=22247&subSessId=0

Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin Significantly Reduced Both MACE and MALE


*Crude incidence over mean follow-up of 21 months

Anand S et al, Lancet 2018;391:219–229Rivaroxaban 2.5 mg bid + aspirin significantly reduced major amputation

by 70% versus aspirin

Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin Resulted in Low Increases in Major 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

• Indication to include prevention of atherothrombotic events in adult patients

with coronary artery disease (CAD) or symptomatic peripheral artery disease

(PAD) at high risk of ischaemic events for Xarelto 2.5 mg co-administered with

acetylsalicylic acid;

Case 3

• Male 72 yo

• Hypertension, dislipidemia, DM

• Calf intermitted claudication at 400m in the left leg (stable)

• ABPI at 0,7

• Duplex scan: SFA occlusion

• On Clopidogrel 75mg x 1

Case 3

• 3 years later (75 yo)

• AMI

• Primary PCI – stenting (DES) in the left main

• On DAPT (Clopidogrel 75mg x 1 + ASA 100mg x 1)

Case 3

• 1 year after MI (76 yo)

• Re-evaluation

• SPECT: ok, fixed irreversible perfusion defect

• Decision made to stop DAPT

• Stable PAD (IC Lt calf 400m, ABPI=0.7)

Case 3

What will be the antithrombotic treatment further on?

• ASA 100mg x 1

• Clopidogrel 75mg x 1

• Ticagrelor 90mg x 2

• Compass therapy (Riva 2.5mg x 2 + ASA 100mg x 1)

Patients With Both CAD and PAD Are at Increased Risk of MACE

Compared with Patients with Either CAD or PAD

1-year outcomes in patients with CAD alone, PAD alone or CAD+PAD (REACH registry)

Steg PG et al, JAMA 2007;297:1197–1206

2.41.6 1.4 0.9

3.6

13.0

2.41.4 1.0 0.8

3.1

17.4

4.63.2

1.5 1.2

5.5

23.1

0

5

10

15

20

25

All-causemortality

CV death Non-fatal MI Non-fatalstroke

CV death, MIor stroke

CV death, MI ,stroke or

hospitalization

1-y

ea

r in

cid

en

ce

ra

tes

(%

) CAD alone (n=28,867)

PAD alone (n=3246)

CAD+PAD (n=3264)

Patients With Both CAD and PAD Are at Increased Risk of MACE

Compared with Patients with Either CAD or PAD

Incidence of the primary efficacy and safety outcomes in patients with CAD plus PAD and in patients with CAD only in COMPASS

Rivaroxaban 2.5 mg bid plus Aspirin Significantly Reduced the Risk of MACE in Patients with Polyvascular Disease

Connolly SJ et al, Lancet 2018;391:205–218

➢ Patients with Polyvascular Disease

➢ Patients suffering from PAD + CAD

Patients with PAD at High Risk of MACE

Case 3

What will be the antithrombotic treatment further on?

• ASA 100mg x 1




Case 4

• Male 67 yo

• Hypertension, dislipidemia, ex-smoker, DM

• Calf intermitted claudication at 200m in the right leg (stable)

• ABPI at 0.5

• Duplex scan: SFA occlusion, tibial stenoses

• On Clopidogrel 75mg x 1

Case 4

• 2 years later (69 yo)• CLI (1st toe gangrene + rest pain)• ABPI at 0.3• DSA: SFA occlusion, ATA - PerA patent with

moderate stenoses, PTA occluded

• Decision to perform a below-knee bypass with GSV

• Successful revascularization, 1st toe amputation, no rest pain any more

• IC at 500m, ABPI=0.7

Case 4

What could be the antithrombotic treatment beyond this point?

• SAPT with ASA 100mg x 1



• DAPT (ASA 100mg x 1 + Clop 75mg x 1)



2-year outcomes in US patients with PAD enrolled in the REACH registry according to PAD status at baseline

1021

37

8

60

09

24

46

11

5948

11

30

108

22

149

74

17

34

9990

61

42

0

20

40

60

80

100

120

140

160

180

CV death/MI/stroke

CV death/MI/stroke/CV

hospitalization

Worsening ofclaudication

Lower-limbamputation

Peripheralangioplasty/

stenting

Peripheralbypass graft

2-y

ea

r ra

tes

pe

r 1

00

0 p

ati

en

ts

Asymptomatic (n=134)

Claudication (n=539)

Prior revascularization (n=692)

Prior amputation (n=312)

Despite Current Therapy, Patients with a Prior Revascularization

Remain at Risk of MACE and MALE

Mahoney EM et al, Circ Cardiovasc Qual Outcomes 2010;3:642–651

Despite Guideline-Recommended Therapy, Outcomes Are Significantly Poorer

After MALE than Before

Anand SS et al, J Am Coll Cardiol 2018

➢ PAD Patients with a Prior Revascularization

Patients with PAD at High Risk of MALE

Case 4

What could be the antithrombotic treatment beyond this point?




• DAPT (ASA 100mg x 1 + Clop 75mg x 1)



Compass – PAD treatment

• Which patients should we treat most?

➢ Patients with Polyvascular Disease

➢ Patients suffering from PAD + CAD

➢ Symptomatic PAD patients with Disease Progression

➢ PAD patients with a Prior Revascularization

➢ PAD patients with HF

➢ PAD patients with low eGFR

➢ PAD patients with DM

tailored protection of the vascular patient with rivaroxaban · warfarin at uh, lmwhs &...

Documents