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 thromboembolismAnticoagulant 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
• 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
Recurrent VTE, %
Hazard ratio 3.2 (1.9 - 5.4)
Cancer 21%
No Cancer 7%
1 year 0
10 20 30
Major Bleeding, %
Cancer 12%
No Cancer 5%
Hazard ratio 2.2 (1.2 - 4.1)
Prandoni et al., Blood 2002
• 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
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
VTE recurrence (%)
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 patients with active cancer or
persistent risk factors
for at least 3-6 months Long term treatment for patients with active 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
LMWH discontinuation
Number of patients
372 354 348 325 316 307 293
LMWH discontinuation in patients treated for VTE
• 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
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
NOACs for VTE treatment in cancer patients 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 RCTVTE 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
• 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
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
Follow Up
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
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)
VTE recurrence (%)
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
NOACs for VTE treatment in cancer patients
