giancarlo agnelli internal emergency and vascular medicine ... · agnelli et al., j thromb haemost...

Giancarlo Agnelli

Internal Emergency and Vascular Medicine - Stroke Unit

University of Perugia, Italy

NOACs for VTE treatment in cancer patients

Anticoagulant agents in cancer patients

Clinical settings

• Prophylaxis of venous thromboembolism after cancer

surgery

• Prophylaxis of venous thromboembolism in ambulatory

cancer patients

• Treatment of venous thromboembolism

• The issue

• The benchmark and the current guidelines

• Evidence for NOACs

• The recently published or ongoing NOACs studies

My talk today

Treatment of VTE in patients with cancer

• 15-25% of VTE patients (5% in phase III NOACs RCTs)

• Poor clinical status

• Complexity of clinical care

• Concomitant anticancer treatments

• High risk of recurrence and treatment-related bleeding

VTE treatment in cancer patients

Peculiarities of cancer patients

Recurrent VTE and bleeding during anticoagulant treatment

1 year

0

10

20

30

Re

curr

ent V

TE

, %

Hazard ratio 3.2 (1.9 - 5.4)

Cancer 21%

No Cancer 7%

1 year

0

10

20

30

Ma

jor

Ble

edin

g, %

Cancer 12%

No Cancer 5%

Hazard ratio 2.2 (1.2 - 4.1)

Prandoni et al., Blood 2002

• The issue




My talk today


Dalteparin vs. Warfarin in Cancer patients with VTE

0

Days after randomisation

30 60 90 120 150 180 210 0

5

10

15

20

25

V

TE

re

cu

rre

nce (

%)

Risk reduction=52% p=0.0017

Dalteparin/VKA

Lee et al., N Engl J Med 2003

CLOT Study

Cancer patients with acute DVT and/or PE

n=308

n=298

OAC with VKA Dalteparin

Dalteparin Dalteparin (¾ dose)

4 wks R

Dalteparin

15.8%

8.0%

Lee et al. JAMA 2015

HR: 0.65 [95% CI 0,41-1,03; P=0.07]

10,5%

7.2%

HR: 0.89 [95% CI 0.40-1.99; P=0.77]

Recurrent venous thromboembolism Major bleeding

All-Cause Mortality

HR: 1.08 [95% CI 0.85-1.36; P=0.54]

34.7%

32.2%

The Catch study

Initial treatment LMWH is the

preferred approach

for the initial 5-10

days.

LMWH, UFH or

fondaparinux

according to

patient’s

characeristics and

clinical situation

Weight –adjusted

LMWH,

If creatinine

clearance < 25-30

ml/min either UFH

or LMWH with

antiXa monitoring

LMWH, UFH or

fondaparinux for

the first 10 days, if

severe renal failure

UFH or early VKA

LMWH for the first

3-6 months of long-

term anticoagulant

therapy (Grade 1A)

Long term

treatment

LMWH for at least 6

months; VKA are

acceptable when

LMWH are not

available,

LMWH is preferred LMWH LMWH for 3-6

months; LMWH or

VKA beyond 6

months

Cancer patients

with VTE are

recommended to

receive long-term

LMWH

monotherapy

(grade 2B)

Optimal

duration

Indefinite

anticoagulation in

patients with active

cancer

Indefinite

anticoagulation in


cancer or

persistent risk

factors

for at least 3-6

months

Long term

treatment for


cancer

Not specified indefinitely or until

the cancer is

resolved (Grade

1C)

VTE treatment in cancer patients

• LMWH-associated risk recurrence still significant (10%)

• No reduction in bleeding rate

• Subcutaneous injections uncomfortable and difficult to

maintain long-term (adherence or persistence to/on

treatment)

• Treatment after 6 months unclear

After the Clot & Catch studies

Remaining issues

van der Wall et al, J Thromb Haemost 2017

1.0

0.9

0.8

0.7

0.6

0.5

0 30 60 90 120 150 180

Days of trratment

LM

WH

d

isco

nti

nu

ati

on

Number of

patients

372 354 348 325 316 307 293

LMWH discontinuation in patients treated for VTE

• The issue




My talk today


VTE treatment & cancer patients

NOACs studies * 3-8%

Clinical practice: 18-20%

Study population likely not-representative of the full-spectrum of

patients with cancer in the NOACs studies


Level of Evidence

• Sub-group analyses of phase III RCT including patients

with cancer

• Meta-analyses on cancer patients included in phase III

RCT

• Phase III randomized RCT

VTE and VTE related death Major bleeding

Apixaban

Enoxaparin/ Warfarin

Apixaban

Enoxaparin/ Warfarin

Agnelli et al., J Thromb Haemost 2015

Amplify cancer sub-analysis: results by cancer status

6 studies: 1132 patients with cancer at baseline Recurrent VTE

Study or Subgroup

AMPLIFY 2013

EINSTEIN-DVT 2010

EINSTEIN-PE 2012

HOKUSAI 2013

RECOVER I & II 2013

Total (95% CI)

Total events

Heterogeneity: Chi² = 0.36, df = 4 (P = 0.99); I² = 0%

Test for overall effect: Z = 1.62 (P = 0.10)

Events

3

4

2

4

10

23

Total

81

118

114

109

173

595

Events

5

5

3

7

12

32

Total

78

89

109

99

162

537

Weight

15.2%

17.1%

9.4%

22.0%

36.3%

100.0%

M-H, Fixed, 95% CI

0.56 [0.13, 2.43]

0.59 [0.15, 2.26]

0.63 [0.10, 3.85]

0.50 [0.14, 1.77]

0.77 [0.32, 1.83]

0.63 [0.37, 1.10]

DOA Comparator Odds Ratio Odds Ratio

M-H, Fixed, 95% CI

0.01 0.1 1 10 100

Favors DOA Favors comparator

DOACs for cancer-associated VTE: meta-analysis

3.8% vs 5.9%

Vedovati et al., Chest 2015

Study or Subgroup

AMPLIFY 2013

EINSTEIN DVT & PE 2013

HOKUSAI 2013

RECOVER I & II 2013

Total (95% CI)

Total events

Heterogeneity: Chi² = 1.40, df = 3 (P = 0.70); I² = 0%

Test for overall effect: Z = 0.81 (P = 0.42)

Events

2

6

5

6

19

Total

87

232

109

159

587

Events

4

8

3

7

22

Total

80

196

99

152

527

Weight

18.2%

37.7%

13.4%

30.7%

100.0%

M-H, Fixed, 95% CI

0.45 [0.08, 2.51]

0.62 [0.21, 1.83]

1.54 [0.36, 6.61]

0.81 [0.27, 2.47]

0.77 [0.41, 1.44]

DOA Comparator Odds Ratio Odds Ratio

M-H, Fixed, 95% CI

0.01 0.1 1 10 100

Favors DOA Favors comparator

3.2% vs 4.2%

DOACs for cancer-associated VTE: meta-analysis

Vedovati et al., Chest 2015

6 studies: 1132 patients with cancer at baseline Major bleeding

• The issue




My talk today


Dalteparin 150 IU/kg QD

Patients with cancer and objectively confirmed VTE;

Stratified by bleeding risk and dose-adjustment;

1:1 randomization into 2 treatment groups

R A N D O M I Z E

LMWH* Edoxaban QD†

Dalteparin 200 IU/kg QD

Day 5

Day 0 Day 30 Month 12

Planned N ≈ 1000

Planned enrollment is approximately 130 study sites across 13 countries in North America, Europe,

Australia, and New Zealand

Estimated completion date: December 2017 (Final data collection date for primary outcome measure)

*At least 5 days of LMWH. The choice of the LMWH type and lead-in duration will be left to the treating physician; †Edoxaban 60 mg (30

mg QD for patients requiring dose adjustment for CrCL = 30-50 mL/min, body weight 60 kg, and/or concomitant P-gp inhibitor use);

CrCL = creatinine clearance; LMWH = low-molecular weight heparin; P-gp = P-glycoprotein; QD = once-daily; VTE = venous

thromboembolism.

Van Es et al. Thromb Haemost 2015

Raskob et al., NEJM 2017

Recurrent VTE & MB

Edoxaban: 12.8%

Dalteparin: 13.5%

HR: 0.97 (0.70-1.36)

P=0.006 for non-inferiority

Raskob et al. NEJM 2017

Recurrent VTE

Edoxaban: 7.9%

Dalteparin: 11.3%

HR: 0.71 (0.48-1.06)

Major bleeding

Edoxaban: 6.9%

Dalteparin: 4.0%

HR: 1.77 (1.77-3.04)

select-d

Rivaroxaban* Cancer patients with

symptomatic DVT and/or PE

without chemotherapy

N~530 Dalteparin#

PE index event or RVT

positive before 6

months N~300

RVT negative before 6

months N~130 No treatment

Fo

llo

w U

p

FPFV: Q4-13 LPLV: 16/17

Indication: VTEx patients with cancer

Short design: Prospective, randomized,

open-label, multicentre pilot phase III study

Rationale: To assess the efficacy and safety of rivaroxaban versus dalteparin for the treatment of VTE in patients with cancer not currently receiving chemotherapy

R

6 months

Rivaroxaban

Placebo

R

12 months

*15 mg bid for 21 days followed by 20 mg od; for patients with CrCl 30–49 ml/min dosing recommendations as in rivaroxaban SmPC; if a patient’s

platelet counts falls to <50,000/mm3, rivaroxaban should be discontinued until the platelet count recovers to above 50,000/mm3; #200 IU/kg od for the

first 30 days of treatment followed by 150 IU/kg od; if a patient’s platelet count falls to 50,000–100,000/mm3 the daily dose of dalteparin should be

reduced by 2500 IU until platelet count returns to ≥100,000/mm3; if a patient’s platelet count falls to <50,000/mm3, dalteparin should be discontinued

until the platelet count recovers to above 50,000/mm3

IIR, Investigator Initiated Research; FU, follow-up; R, randomization; RVT, residual vein thrombosis

http://www2.warwick.ac.uk/fac/med/research/hscience/ctu/trials/cancer/select-d/; EudraCT number: 2012-005589-37

http://www2.warwick.ac.uk/fac/med/research/hscience/ctu/trials/cancer/select-d/



Young A et al, JCO 2018

select-d: VTE recurrence

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)

VT

E r

ec

urr

en

ce (

%)

Outcome at 6 months Rivaroxaban

(n=203) Dalteparin

(n=203)

Lower limb DVT/PE

recurrence,

(95% CI)

3%

(1-7)

9%

(6-15)

select-d: Major, Fatal and CRNM bleeding

*.

Young A et al, JCO 2018

Most Major Bleedings events were Gastrointestinal Bleedings*. No Central Nervous System Bleeding

was observed in rivaroxaban and dalteparin groups.

Clinical outcome studies

• Casta Diva

• Adam

• Canvas

• Caravaggio

Ongoing trials in patients with cancer and VTE

Caravaggio study design

Randomized, open-label, PROBE, non inferiority study

Symptomatic or

unsuspected

proximal lower-limb

DVT

R

Apixaban Apixaban

10 mg bid 5 mg bid

Dalteparin 200 IU/kg od Dalteparin 150 IU/kg od

30 days

observation

period

Day 1 Day 7 Day 30 6 months Symptomatic or

unsuspected PE in a

segmental or more

proximal pulmonary

artery

<72 hours*

Principal Investigator Giancarlo Agnelli

Countries Involved 11

Centers Involved ≈ 140

Sample Size 1168 patients

* Max time allowed between diagnosis and randomization

Conclusions

• Patients with CAT have a higher risk of recurrent VTE and

bleeding than the general population

• Evidence suggests that NOACs could be alternatives to

conventional therapy for VTE in cancer patients

• Edoxaban and rivaroxaban were at least as effective as

LMWH in cancer patients, but were associated with

significantly higher rates of major bleeding or CRNMB

• Ongoing studies of NOACs (vs LMWH) will provide

further information on the role of NOACs CAT patients


giancarlo agnelli internal emergency and vascular medicine ... · agnelli et al., j thromb haemost...

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