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Trends and perspectives in the treatment of DVT: Acute phase and secondary prevention Sabine Eichinger Dept. of Medicine I Medical University of Vienna, Austria

18 year old women



Hormone patch since 6 months



Airtravel from Kiev to Buenos Aires



After 1 week cramps, pain left calf  general measures  improvement



4 days later return flight to Kiev



Upon arrival pain, swelling left calf



Sonography  Dx: left proximal DVT



Treatment?

Treatment options  Thrombolysis

hemodynamic unstable PE

 Embolectomy

thrombolysis failed or contraindicated

 Vena cava filter

high bleeding risk

 Anticoagulants

Treatment options ď‚Ž Anticoagulants - Heparin - Fondaparinux - Vitamin K antagonists - New oral anticoagulants

LMWH vs. UFH for treatment of DVT

Studies

Patients

Odds Ratio

95% CI

Recurrence

4451

0.57

0.44 - 0.75

Bleeding

7124

0.57

0.39 - 0.83

van Dongen, Cochrane Database of Systematic Reviews 2004

Fondaparinux vs. Heparin Recurrence MATISSE-DVT

Bleeding

(B端ller, 2004)

Fondaparinux

3.9%

(43/1098)

1.1%

(12/1098)

LMWH

4.1%

(45/1107)

1.2%

(13/1107)

Treatment of DVT: current standard of care

Heparin

Vitamin K antagonists

VKA - % of time outside target INR range 50 40 30

35%

40%

42%

Clinic (1)

Trial (2)

Trial (3)

20 10 0

(1) Eichinger (2012), (2) RECOVER (NEJM 2009), (3) EINSTEIN-DVT (NEJM 2010)

Phase III studies for VTE treatment

Trial name Rivaroxaban EINSTEIN DVT EINSTEIN PE EINSTEIN EXT Dabigatran RE-COVER RE-COVER II RE-MEDY RE-SONATE Apixaban AMPLIFY AMPLIFY-EXT Edoxaban Hokusai-VTE

Design

Initial treatment Long-term with LMWH/ treatment fondaparinux regimen

Status

Open label Open label Double blind

No No --

od od od

Published 2010 Published 2012 Published 2010

Double blind Double blind Double blind Double blind

Yes Yes ---

bid bid bid bid

Published 2009 Abstract 2011 Published 2013 Published 2013

Double blind Double blind

No --

bid bid

Data analysis Published 2012

Double blind

Yes

Data analysis

EINSTEIN-DVT: Rivaroxaban for treatment of DVT

Objectively confirmed DVT without symptomatic PE

N=3449

Rivaroxaban

15 mg bid

20 mg od

R Enoxaparin 1.0 mg/kg bid for at least 5 days, followed by VKA to start ≤48 hours, target INR 2.5 (INR range 2–3) Day 1

Day 21

EINSTEIN Investigators, N Engl J Med 2010

30-day observation period

EINSTEIN DVT Treatment period of 3, 6 or 12 months

EINSTEIN-DVT: recurrent VTE or related death Rivaroxaban (n=1731) First symptomatic recurrent VTE Recurrent DVT Recurrent DVT + PE

n (%) 36 (2.1)

n (%) 51 (3.0)

14 (0.8)

28 (1.6)

1 (<0.1)

Non-fatal PE Fatal PE/unexplained death where PE cannot be ruled out

0.44

Enoxaparin/VKA (n=1718)

0.68

0 (0)

20 (1.2)

18 (1.0)

4 (0.2)

6 (0.3)

1.04 1.00 Hazard ratio

Rivaroxaban superior

p=0.076 for superiority

2.00 Rivaroxaban non-inferior

p<0.0001 for non-inferiority

Rivaroxaban inferior

EINSTEIN-DVT: major and non-major clinically relevant bleeding HR=0.97 (95% CI: 0.76â€“1.22)

9,0

Risk of bleeding (%)

8,0 7,0 6,0 5,0 4,0 3,0 2,0 1,0 0,0

8,1

Rivaroxaban 2x15/20 mg 139/1718

LMWH/VKA 138/1711

Treatment of DVT: past, present, future

Heparin

Rivaroxaban

Vitamin K antagonists

Estimated cumulative risk (%)

RE-COVER: risk of recurrent VTE or related death

Number at risk Dabigatran Warfarin

4.0 HR=1.1 (95% CI: 0.65â€“1.84)

3.5 3.0

Dabigatran

2.5 2.0

Warfarin

1.5 1.0 0.5 0 0

1274 1265

1238 1215

2 3 4 Months since randomization 1221 1204

1203 1194

1192 1187

1181 1174

1024 998

Schulman, N Engl J Med 2009

RE-COVER: major bleeding HR=0.82 (95% CI: 0.45â€“1.48) 2,0

p=NS

Percentage

1,5

1,0

0,5

0,0

1,6

1,9

Dabigatran 150 mg bid 20/1273

Warfarin 24/1266

Treatment of DVT: past, present, future

Heparin

Vitamin K antagonists

Rivaroxaban

Apixaban

Heparin

Dabigatran/Edoxaban

18 year old women



Hormone patch since 6 months



Airtravel from Kiev to Buenos Aires



After 1 week cramps, pain left calf  general measures  improvement



4 days later return flight to Kiev



Upon arrival pain, swelling left calf



Sonography  Dx: left proximal DVT



LMWH, vitamin K antagonist



Duration?

VTE â€“ a chronic disease

Case fatality: 4 - 12%

Kyrle & Eichinger, Lancet 2010

Bleeding during anticoagulation for VTE

Time period of AC

Initial 3 months > 3 months

Major bleeding

Intracranial bleeding

(%, 95% CI)

2.06 (2.04-2.08)

1.48 (1.40â€“1.56)

2.74 (2.71-2.77)/yr

0.65 (0.63â€“0.68)/yr

Linkins, Ann Intern Med 2003

Probability of recurrence after VTE

18 months Boutitie, BMJ 2011

Management of patients with unprovoked DVT

 Identifying patients with low recurrence risk • Thrombophilia screening • Residual vein thrombosis • D-Dimer • Prediction models

Nomogram to predict recurrence: Eichinger, Circulation 2010 Vienna Prediction Model

Management of patients with unprovoked DVT

ď‚Ž Identifying of patients with low recurrence risk ď‚Ž Alternative antithrombotic concepts

Long term anticoagulation EINSTEIN ext AMPLIFY ext

Patients, n

Study drug

RE-SONATE

RE-MEDY

Einstein Inv. NEJM 2010

Agnelli NEJM 2012

Schulman NEJM 2013

1197

2486

1343

2856

Rivaroxaban

Apixaban

Dabigatran

1 x 20 mg

2 x 5 mg

2 x 150 mg

Placebo

Warfarin

2 x 2.5 mg

Control

Placebo

Major and clinically relevant non major bleeding

Rivaroxaban vs. placebo Apixaban vs. placebo Dabigatran vs. placebo Dabigatran vs. warfarin

Hazard Ratio

95% CI

5.19

2.3 – 11.7

2.5 mg: 1.20 5.0 mg: 1.62

0.69 – 2.10 0.96 – 2.73

2.92

1.52 – 5.60

0.54

0.41 – 0.71

WARFASA: Aspirin for preventing VTE 1,00

0,75

HR for recurrence: 0.57 (0.35-0.93), p=0.02

0,50

rd z H e tiv la m u C

placebo

HR for major and CRNM bleeding: 0.98 (0.24-3.96), p=0.97

0,25

aspirin 0,00 0

365

730

1095

days

aspirin 205 placebo 197

160 146

97 81

35 30 Becattini, N Engl J Med 2012

Aspirin for longterm prophylaxis of VTE

Becattini, N Engl J Med 2012; Brighton, N Engl J Med 2012

Duration of anticoagulation

stopp: bleeding risk recurrence risk distal DVT provoked* VTE

3 months

proximal DVT unprovoked VTE

long term alternative: Xarelto Aspirin

* Surgery, trauma, immobilisation, pregnancy/puerperium, female hormone intake, long haul travel www.AWMF.org, 6/2010 9th ACCP Consensus Conference on Antithrombotic Therapy, Chest 2012

18 year old women



Hormone patch since 6 months



Airtravel from Kiev to Buenos Aires



After 1 week cramps, pain left calf  general measures  improvement



4 days later return flight to Kiev



Upon arrival pain, swelling left calf



Sonography  Dx: left proximal DVT



LMWH, vitamin K antagonist



Duration  3 months

Treatment of venous thrombosis: challenging aspects

 Optimal duration of anticoagulation  Choice of antithrombotic drug  Single-drug approach  Cancer patients  Patients ‘on the extremes’: advanced age, over/underweight, CrCl <30ml/min  Compliance and adherence  Monitoring

Duration of anticoagulation after VTE

Different intermediate durations - Summary

 4 studies, n= 1881  VKA for 6 or 12 mo vs. 3 mo  Recurrence:  Major bleeding:

RR 0.95

(95% CI 0.7 - 1.3)

RR 2.53

(95% CI 1.2 - 5.5)

Kearon, Chest 2008

Risk Factors of Recurrence

95% CI

Men vs. women

2.7

1.8 - 4.2

Idiopathic vs. provoked

1.9

1.2 - 2.9

Laboratory abnormality Any vs. none

1.4

0.9 - 2.3

Christiansen S, JAMA 2005

Risk of recurrent VTE

Laboratory markers Evidence High clotting factors

Strong

Hyperhomocysteinemia

Strong

Factor V Leiden

Strong

Factor II G20210A

Strong

AT-, PC-, PS-deficiency

Weak

Phospholipid antibodies

Weak

Single nucleotide polymorphisms

Needs confirmation

Thrombin generation

Strong Modified after Kyrle & Eichinger, Lancet 2010

Risk of recurrent VTE

Laboratory markers Evidence

Clinical Relevance

High clotting factors

Strong

Uncertain

Hyperhomocysteinemia

Strong

Uncertain

Factor V Leiden

Strong

None

Factor II G20210A

Strong

None

AT-, PC-, PS-deficiency

Weak

Uncertain

Phospholipid antibodies

Weak

Uncertain

Single nucleotide polymorphisms

Needs confirmation

None

Thrombin generation

Strong

Uncertain Modified after Kyrle & Eichinger, Lancet 2010

Risk factors (RF) in 158 pts with a second VTE

24%

35% 40%

no RF 1 RF 2 RF 3 RF 4 RF

factor V Leiden, factor II G20210A, HHC, high factor VIII or IX

EINSTEIN-PE: patient characteristics

Males (%) Age, mean (years) Body mass index, mean (kg/m2) Creatinine clearance (%) <30 ml/min 30–49 ml/min 50–79 ml/min ≥80 ml/min Previous VTE (%) Patients with active cancer (%) Intended treatment duration (%) 3 months 6 months 12 months Pretreatment for maximum of 48 hours with LMWH, heparin/fondaparinux (%) Concomitant DVT (%)

Rivaroxaban (N=2419) 54.1 57.9 28.3

Enoxaparin/VKA (N=2413) 51.7 57.5 28.4

0.2 8.6 26.3 64.3 18.8 4.7

<0.1 7.9 24.6 67.0 20.3 4.5

5.3 57.3 37.4

5.1 57.5 37.5

92.5

92.1

24.9

24.3

ITT population EINSTEIN–PE Investigators, N Engl J Med 2012

EINSTEIN DVT and PE pooled analysis: recurrent VTE or related death Rivaroxaban (N=4150) First symptomatic recurrent VTE Recurrent DVT Recurrent DVT + PE Non-fatal PE Fatal PE/unexplained death where PE cannot be ruled out

0.66

0.87

n 86 32 1 43

(%) (2.1) (0.8) (<0.1) (1.0)

n 95 45 2 38

(%) (2.3) (1.1) (<0.1) (0.9)

(0.4)

(0.3)

1.19

1.00 HR Rivaroxaban superior

p=0.41 for superiority (two-sided) ITT population

Enoxaparin/VKA (N=4131)

1.75 Rivaroxaban non-inferior

p<0.0001 for non-inferiority (one-sided)

Rivaroxaban inferior

EINSTEIN DVT and PE pooled analysis: bleeding and mortality

 First major or non-major clinically relevant bleeding • HR=0.93 (95% CI: 0.81 - 1.06)  Major bleeding • HR=0.54 (95% CI: 0.37 - 0.79), p=0.0018  All-cause mortality • HR=0.90 (95% CI: 0.68 - 1.19)

Management of VTE: challenging aspects ď‚Ž Optimal duration of anticoagulation ď‚Ž Single-drug approach

Management of VTE: challenging aspects  Optimal duration of anticoagulation  Single-drug approach  Outpatient treatment

Pulmonary Embolism Outpatient vs. inpatient treatment Outpatients

Inpatients

N = 171

N = 168

Recurrence

1 (0.6%)

n.s

Death

1 (0.6%)

n.s.

Bleeding

3 (1.8%)

n.s.

P-value

Aujesky, Lancet 2011

Management of VTE: challenging aspects  Optimal duration of anticoagulation  Single-drug approach  Outpatient treatment  Cancer patients  Pregnancy/breastfeeding  Patients ‘on the extremes’: over/underweight, CrCl <30ml/min, advanced age

EINSTEIN-DVT/PE: patient age EINSTEIN-DVT Rivaroxaban Enoxaparin/VKA (n=1731) (n=1718) Age, mean (years)

55.8 + 16.4

56.4 + 16.3

EINSTEIN-PE Rivaroxaban Enoxaparin/VKA (n=1731) (n=1718) Age, mean (years)

57.9 + 7.3

57.5 + 7.2

EINSTEIN EXT: rivaroxaban for extended thromboprophylaxis after VTE

Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA in EINSTEIN VTE programme Confirmed symptomatic DVT or PE completing 6 or 12 months of VKA

Treatment period of 6 or 12 months

N=1197

Rivaroxaban 20 mg od

R Day 1

EINSTEIN Investigators, N Engl J Med 2010

Placebo

30-day observational period

Randomized, double-blind, placebo-controlled

EINSTEIN EXT: patient characteristics

Males (%) Age, mean (years) Body mass index, mean (kg/m2) Creatinine clearance (ml/min) <50 50–<80 ≥80 Index event DVT PE with or without DVT Risk factors Patients with idiopathic DVT/PE Patients with risk factors ITT population

Placebo (n=594)

Rivaroxaban (n=602)

57 58 28

59 58 28

49 (8%) 121 (20%) 373 (63%)

37 (6%) 134 (22%) 371 (62%)

350 (59%) 233 (39%)

376 (63%) 213 (35%)

358 (60%) 236 (40%)

344 (57%) 258 (43%)

EINSTEIN EXT: recurrent VTE or related death Placebo (n=594) Symptomatic recurrent VTE* Recurrent DVT Non-fatal PE

Rivaroxaban (n=602)

42 7.1%

8 1.3%

5.2%

5 0.8%

13 2.2%

2 0.3%

Fatal PE

1 0.2%

Unexplained death (where PE cannot be excluded)

1 0.2%

ITT population; *Some patients experienced more than one event

Cumulative event rate for primary efficacy outcome (%)

EINSTEIN EXT: recurrent VTE or related death 10 8

p<0.001 for superiority

6 4

Rivaroxaban (N=602)

2 0 0

Number at risk Rivaroxaban Placebo

Placebo (N=594)

NNT: 15

120

150 180 210 240 270 300 330 360 Days

602 594

590 582

583 570

573 555

552 522

503 468

482 444

171 164

138 138

132 133

114 110

92 93

81 85

EINSTEIN EXT: major bleeding Placebo (n=590)

Rivaroxaban (n=598)

4 (0.7%)*

Bleeding contributing to death

Bleeding in a critical site

Gastrointestinal bleeding

3 (0.5%)

Menorrhagia

1 (0.2%)

Major bleeding

Associated with fall in haemoglobin â‰Ľ2 g/dl and/or transfusion

*p=0.1 NNH: 139

Extended thromboprophylaxis after VTE New oral anticoagulants RE-SONATE Schulman, ISTH Congress 2011

RE-MEDY Schulman, ISTH Congress 2011

Patients, n

1343

2856

Study drug

Dabigatran 2 × 150 mg

Placebo

Warfarin INR 2.0–3.0

Control

RE-SONATE: study results Dabigatran (n=681)

Placebo (n=662)

n (%)

HR (95% CI)

Recurrent VTE or related death

3 (0.4)

37 (5.6)

0.08 (0.02–0.25) p<0.0001

Major bleeding

2 (0.39)

Events

Clinically relevant bleeding

36 (5.3)

0 12 (1.8)

(0.04–1.05) p=0.5 2.9 (1.5–5.6) p=0.001

RE-MEDY: study results Dabigatran (n=1430) Events

Warfarin (n=1426) HR (95% CI)

n (%)

Recurrent VTE or related death

26 (1.8)

18 (1.3)

1.44 (0.78–2.64) p=0.03 for non-inferiority

Major bleeding

13 (0.9)

25 (1.8)

0.52 (0.27–1.01)

Any bleeding Acute coronary syndromes

277

(19)

13 (0.9)

373

(26)

3 (0.2)

0.71 (0.61–0.83) p=0.02

RE-COVER: patient characteristics Dabigatran (N=1273)

Heparin/warfarin (N=1266)

738 (58)

746 (59)

Age, mean (years)

55.0

54.4

BMI, mean (kg/m2)

28.9

28.4

Creatinine clearance, mean (ml/min)

105.8

104.4

64 (5.0)

57 (4.5)

Before randomization

3.0

After randomization

6.0

Males, n (%)

Cancer, n (%) Parenteral pre-treatment, median (days)

EINSTEIN-DVT: patient characteristics Rivaroxaban Enoxaparin/VKA (n=1731) (n=1718) Males (%) Age, mean (years) Body mass index, mean (kg/m2) Creatinine clearance (%) <50 ml/min 50â€“<80 ml/min â‰Ľ80 ml/min Patients with secondary DVT (%) Patients with active cancer (%) Intended treatment duration (%) 3 months 6 months 12 months Pre-treatment for maximum 48 hours with LMWH/fondaparinux (%) EINSTEIN Investigators, N Engl J Med 2010

57 56 28

56 56 28

7 23 69 39 7

7 23 68 37 5

12 63 25 73

12 63 25 71 ITT population

EINSTEIN-DVT & RE-COVER: overview EINSTEIN N=3449 Design Parenteral anticoagulation Dosing regimen Primary efficacy outcome

Open, non-inferiority

RE-COVER N=2564 Double-blind, non-inferiority

Yes

20 mg od (15 mg bid for 3 weeks)

150 mg bid

Recurrent VTE and related death

Primary safety outcome

Major and non-major clinically relevant bleeding

Major bleeding

Time in target INR (%)

57.7

59.9

Below

Above

EINSTEIN-DVT & RE-COVER: overview EINSTEIN-DVT N=3449

RE-COVER N=2564

Rivaroxaban

Dabigatran

Study drug Design Parenteral anticoagulation

Open,

inferiority

non-

Double-blind, inferiority

Yes

20 mg od (15 mg bid for 3 weeks)

150 mg bid

57.7

59.9

Below

Above

Dosing regimen Time in target INR (%)

non-

EINSTEIN-PE: major and non-major clinically relevant bleeding

LMWH daily dose

<50 kg

50-100 kg

> 100 kg

< 175 IU/kg

(22)

2516

(33)

178 (74)

175 - 200 IU/kg

(24)

3492

(46)

62 (26)

> 200 IU/kg

(54)

1551

(21)

2 (0.8)

Management of VTE: challenging aspects

Thrombolysis for PE: Metaanalysis of 11 studies Thrombolysis n/n

Heparin n/n 16/374 (4.3%)

OR (95% CI)

Recurrrent PE

10/374 (2.7%)

Death

16/374 (4.3%)

22/374 (5.9%)

0.70 (0.37-1.30)

Thrombolysis n/n

Heparin n/n

OR (95% CI)

Major bleeding

34/374 (9.1%)

ICB

2/374 (0.5%)

23/374 (6.1%)

1/374 (0.3%)

0.67 (0.33-1.37)

1.42 (0.81-2.46) 1.04 (0.36-3.04)

Wan, Circulation 2004

DVT - current standard of care

LMWH

Duration > 5 d

VKA for > 3 mo

Langzeitantikoagulation und Blutungsrisiko

Bleeding*

HR (95% CI) vs. placebo

EINSTEINext n = 1197 5.19

(2.3–11.7)

Resonate 2.92 (1.52-5.60) 0.54 (0.41–0.71)

*major and clinically relevant non major

AMPLIFYext n = 2486 2.5 mg: 1.20 5.0 mg: 1.62

(0.69–2.10) (0.96–2.73)

Recurrence risk HR (95% CI)

Rivaroxaban vs. placebo

Dabigatran vs. placebo Dabigatran vs. warfarin

0.18 (0.09 – 0.4)

0.08 (0.02 – 0.25)

1.44 (0.8 – 2.6)

P-value

< 0.001 superiority

< 0.001 superiority 0.03 Non-inferiority

Duration of anticoagulation Patient preference

Risk of bleeding â†‘ Distal DVT Provoked* VTE 3 months

Proximal DVT Unprovoked VTE Long term

* Surgery, trauma, immobilisation, pregnancy/puerperium, female hormone intake, long haul travel

www.AWMF.org, 6/2010 9th ACCP Consensus Conference on Antithrombotic Therapy, Chest 2012