The management of venous thromboembolism inpatients with cancer
Rupert M. Bauersachs, MDDept. of Vascular Medicine, Klinikum DarmstadtCenter of Thrombosis and Hemostasis, University of MainzProfessorship for Vulnerable Individuals and Populations (VIP)
Speaker name:
Rupert M. Bauersachs, MDI have the following potential conflicts of interest to report:
Consulting: ASPEN, Bayer, BMS, Daiichi-Sankyo, LEO
Employment in industry
Stockholder of a healthcare company
Owner of a healthcare company
Research support: ASPEN, Bayer, BMS, Daiichi-Sankyo, LEO
I do not have any potential conflict of interest
Disclosure
Munich Vascular Conference (MAC) 2019 2
Management of VTE in patients with cancer
Munich Vascular Conference (MAC) 2019 3
• Challenges of Cancer-associated thrombosis (CAT)• Evidence for LMWH• Evidence for NOACs• Guidelines• Practical implications
In cancer:VTE => leading cause of death5
VTE => worsened prognosis 5
VTE => up to 20% of cancer patients2
VTE in 50% of cancer pts at autopsy3
CancerMalignancy and thrombosis:
a double-sided clinical relationshipVTE
VTE:First sign of cancer 5
20% have active cancer4
VTE - prevention & treatment less effective 5
Epidemiology, pathophysiology
1. Khorana AA, et al. J Thromb Haemost 2007;5:632-4. 2. Farge D, et al. Thromb Res 2010;125(Suppl 2):S108-16.3. Falanga A, Zacharski L. Ann Oncol 2005;16:696-701.4. Monreal M, et al. J Thromb Haemost 2006;4:1950-65. Luxembourg B, Bauersachs R: Malignancy and thrombosis: A double-sided
clinical relationship VASA 2005; 34:225–234.
Wun T, White RH. Cancer Invest 2009;27:63–74
0
2
4
6
8
10
12
14
16
VTE
rate
per
100
pat
ient
-yea
rsVTE Risk Associated with Specific Types of Cancer
0
50000
100000
150000
200000
250000
American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014
Frequencies of Various Types of Cancer
Estimated new cases (US: 2014)
VTE Epidemiology Group Study:Incidence of First VTE in Patients with Active Cancer
Patients with active cancer and a first VTE (N=6592). Active cancer was defined as a primary diagnosis of cancer (excluding non-melanoma skin cancer) as a hospital discharge diagnosis or treatment with radiation, chemotherapy or bone marrow transplantation during hospitalization*Patients allocated to different cancer types when ≥2 were recorded on the same day. For some, no cancer type was specified
Cohen AT et al, Thromb Haemost 2017;117:57–65
0
4
8
12
16
20
Prostate (m) Breast (f) Lung Colon Haematol. Ovarian (f) Bladder Uterus (f) Pancreas Stomach Brain
30
20
10
00 2 4 6 8 10 12
Cum
ulat
ive
prop
ortio
n of
re
curr
ent m
ajor
ble
edin
g, %
Time, m
CancerNo cancer
HR=2.2
12.4%
4.9%
The Challenge of CAT:Recurrences and Bleeding During Anticoagulation
*Defined as overt and associated with either a decrease in the haemoglobin level (at least 2.0 g/dl) or the need for transfusion (≥2 units of blood), if it was retroperitoneal or intracranial, or if the treatment had to be discontinued permanently.
Prandoni P, et al. Blood 2002;100:3484–3488.8
Major Bleeding*30
20
10
00 2 4 6 8 10 12
Cum
ulat
ive
prop
ortio
n of
re
curr
ent V
TE, %
Time, m
CancerNo cancer
HR=3.2
20.7%
6.8%
Recurrent VTE
The Challenge of CAT:Long-term LMWH vs VKA: CLOT Study
Lee AY et al. N Engl J Med 2003;349:146 VKA = vitamin K antagonist; VTE = venous thromboembolism
0
10
20
Dalteparin Dalteparin / VKA
Ble
edin
g (%
)
Major Minor
Dalteparin 200 IU/kg
Oral VKA Target INR 2.5
Dalteparin 200 IU/kg OD Dalteparin ~ 150 IU/kg OD
Oral VKA armN = 338
Dalteparin armN = 338
R
Days 0–5Month 1 Months 2–6
NOAC Phase III VTE TrialsInclusion of Patients with Cancer
Phase III NOAC trials including more than 30,000 patients
van der Hulle T, et al. J Thromb Haemost. 2014;12:1116–1120 Bauersachs RM. Thromb Res. 2015;134:Suppl 1:S16-22
10
0 10.000 20.000 30.000
Cancer
No cancer
1217 patients
2.01 (1.29,3.13)
1.68 (0.86,3.28)
% NOAC VKA
Recurrent- VTECancer 4.1 6.1 RR 0.66 (0.38,1.2)
No cancer 2.6 2.5 RR 0.98 (0.83,1.2)
Major bleeding or CRNMBCancer 15.0 16.0 RR 0.94 (0.70,1.3)
No cancer 7.4 9.1 RR 0.81 (0.64,1.02)
Study RR (95% CI) RR (95% CI)
EINSTEIN 0.63 (0.22,1.79)
Hokusai 1.51 (0.37,6.17)
RE-COVER 0.82 (0.28,2.38)
AMPLIFY 0.46 (0.09,2.44)
Combined* 0.78 (0.42,1.44)
Efficacy and Safety of NOACs vs VKA in the Treatment of CAT
*Random effects model Carrier M, et al. Thromb Res. 2014;134:1214–1219.
11
Study RR (95% CI) RR (95% CI)
EINSTEIN 0.64 (0.23,1.81)
Hokusai 0.52 (0.16,1.72)
RE-COVER 0.78 (0.35,1.76)
AMPLIFY 0.58 (0.14,2.34)
Combined* 0.66 (0.39,1.11)
Major Bleeding Events
0.1 1 100.1 1 10Lower risk with NOAC Higher risk with NOAC
Lower risk with NOAC Higher risk with NOAC
Recurrent VTE
Hokusai-VTE-Cancer: Study Design
Study population: Patients with cancer*
and acute symptomatic or incidental VTE#
Short design: Multinational, prospective, randomized, open-label, blinded endpoint (PROBE), non-inferiority trial
N=10503
12 months
Edoxaban60 mg od‡
Dalteparin150 IU/kg
*Cancer must be other than basal-cell or squamous cell carcinoma of the skin, be active or diagnosed within 2 years prior to randomization and objectively confirmed. Active cancer was defined as any of the following: diagnosis of cancer within the past 6 months; recurrent, regionally advanced or metastatic disease; currently receiving treatment or having received any treatment for cancer during the 6 months prior to randomization; or a haematological malignancy not in complete remission; #symptomatic or incidental VTE;‡dose adjustment to 30 mg od in patients with a body weight ≤60 kg or CrCl 30–50ml/min, or concomitant use of P-glycoprotein inhibitorsRaskob GE et al. N Engl J Med 2017; doi: 10.1056/NEJMoa1711948
R
1 monthDay 0
Day ≥5
LMWH
Dalteparin200 IU/kg
1:1
Primary EP Combination:
• Recurrent VTE plus• Major Bleeding
• Treatment ≥ 6 and ≤ 12 months• Patient characteristics (Edoxaban vs LMWH) comparable• Thrombocytopenia 50.-100.000/µl: 5,3 %• Metastases: 53,0 %; ECOG ≥3: 22% • active anti-cancer treatment: 72,3 %
12,8
7,96,9
13,5
11,3
4
0
5
10
15
20
25
Composite of first recurrent VTE ormajor bleeding
Recurrent VTE Major Bleeding
Patie
nts
(%)
LMWH/edoxabanDalteparin
Hokusai-VTE-Cancer: Primary and Secondary Outcomes
Modified Intention-to-treat population for 12 months (N=1046).
Raskob GE et al. N Engl J Med 2017; doi: 10.1056/NEJMoa1711948
HR (95% CI)
0.97 (0.70–1.36)
p=0.006
HR (95% CI)
0.71 (0.48–1.06)
p=0.09
HR (95% CI)
1.77 (1.03–3.04)
p=0.04
CAT, cancer-associated thrombosis; GI, gastrointestinal Kraaijpoel N et al, Thromb Haemost 2018;118:1439–1449
10
15
20
Maj
or b
leed
ing
even
t (%
)
Number of on-treatment days
0 30 60 90 120 150 180 210 240 270 300 330 360
Edoxaban
Dalteparin
5
0
Patients with GI cancer Patients with non-GI cancer
150120
10
15
20
Maj
or b
leed
ing
even
t (%
)
Number of on-treatment days0 30 60 90 180 210 240 270 300 330 360
EdoxabanDalteparin
5
0
Hokusai-VTE-Cancer: GI-bleeding and cancer type
15
CAT, cancer-associated thrombosis; GI, gastrointestinal Kraaijpoel N et al, Thromb Haemost 2018;118:1439–1449
0% 20% 40% 60% 80% 100%
Esophageal
Stomach
Colorectal
Hepatobilary
Pancreatic
Achs
entit
elMajor GI-Bleeding
Upper Lower None
All were not resected
Hokusai-VTE-Cancer: GI-bleeding and cancer type
Favours NOAC Favours LMWH
StudyNOAC LMWH Risk ratio
Events Patients Events Patients Weight M-H, Random (95% CI)Hokusai-VTE-Cancer 29 522 17 524 73.5% 1.71 (0.95, 3.08)
select-d 11 203 6 203 26.5% 1.83 (0.69, 4.86)
Total 725 727 100.0% 1.74 (1.05, 2.88)Total eventsHeterogeneity: Tau2=0.00; Chi2=0.01, df=1 (p=0.91), I2=0%Test for overall effect: Z=2.17 (p=0.03)
10.01 0.1 10 100
Cancer-Associated Thrombosis: LMWHs Versus NOACs*Recurrent VTE
Major bleedingFavours NOAC Favours LMWH
StudyNOAC LMWH Risk ratio
Events Patients Events Patients Weight M-H, Random (95% CI)Hokusai-VTE-Cancer 34 522 46 524 73.4% 0.74 (0.48, 1.14)
select-d 8 203 18 203 26.6% 0.44 (0.20, 1.00)
Total 725 727 100.0% 0.65 (0.42, 1.01)Total events 42 64Heterogeneity: Tau2=0.02; Chi2=1.21, df=1 (p=0.27), I2=17%Test for overall effect: Z=1.92 (p=0.06)
10.01 0.1 10 100
* Li A et al, Thromb Res 2019;173:158–163
17
CARAVAGGIO: Study Design Prospective, randomized, open-label, multicentre study
Agnelli G et al, Thromb Haemost 2018;118:1668–1678
Apixaban
10 mg bid for 1 week, followed by 5 mg bid for 6 months
Dalteparin
200 IU/kg daily for 1 month, followed by 150 IU/kg for 5 months
Treatment period 6 months
— Patients with symptomatic or unsuspected proximal DVT or PE and cancer
N=~1170
R
Primary outcome: objectively confirmed recurrent VTE occurring during the study period, defined as the composite of proximal DVT of the lower limbs (symptomatic or unsuspected),
DVT of the upper limb (symptomatic) and PE (symptomatic or unsuspected)
bid, twice daily; DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism
18
Management of VTE in patients with cancer
• Challenges of Cancer-associated thrombosis (CAT)• Evidence for LMWH• Evidence for NOACs• Guidelines• Practical implications
ESC Guideline
LMWH should be considered for the first 6 months over VKAs IIa A
Edoxaban considered as an alternative to LMWH in patients without GI cancer IIa B
Rivaroxaban considered as an alternative to LMWH in patients without GI cancer IIa C
Extended AC (> 6 mts) considered for indefinite period (or until cancer is cured) IIa B
Consider to manage incidental PE in the same manner as symptomatic PE (segmental or multiple subsegmental) IIa B
Task Force M, Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, Huisman MV, Humbert M, Jennings CS, Jimenez D, Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N, Ainle FN, Prandoni P, Pruszczyk P, Righini M, Torbicki A, Van Belle E, Zamorano JL, Document Reviewers: Nazzareno Galie JSRGVAWASAAGAFAEBJBABFBJC, Document R. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J. 2019 Aug 31.2019/09/02.
ISTH, International Society of Thrombosis and Haemostasis; LMWH, low molecular weight heparin; NOAC, non-vitamin K antagonist oral anticoagulant; VTE, venous thromboembolism
Khorana AA et al, J Thromb Haemost 2018;16:1891–1894
ISTH Guidance for Treatment of Cancer-Associated VTE— NOACs suggested for patients with CAT and low risk of bleeding and no
DDI with current systemic therapy— Edoxaban and rivaroxaban are the only NOACs with RCT evidence
compared with LMWH in CAT— LMWH remains acceptable alternative
— LMWH suggested for patients with CAT and high risk of bleeding, including:• luminal GI cancers with intact primary, or with active GI mucosal
abnormalities (duodenal ulcers, gastritis, esophagitis, or colitis…)— NOACs may be acceptable alternative if no DDI with current systemic Tx
Summary
Patients with active cancer have a high risk of VTE recurrence1
• Prevalence and incidence of CAT vary by cancer type2,3
Randomized clinical trials suggest that NOACs are as effective as LMWH for the treatment of CAT to prevent VTE recurrence4,5
Current clinical guidance/guidelines recommended the use of NOACs and LMWH for treatment of patients with CAT, based on the individual clinical profile and patient preferences6
In patients with high risk of bleeding LMWH are preferred over NOACs. NOACS are contraindicated in case of malignant neoplasms at high risk of bleeding.
1. Cohen AT et al, Thromb Haemost 2017;117:57–65; 2. Cohen AT, et al. Thromb Haemost 2017;117:57-65; 3. Horsted F et al, PLoS Med 2012;9:e1001275; 4. Young A et al. J Clin Oncol 2018;36:2017–2023; 5. Raskob GE et al. N Engl J Med 2017;378:615–624; 6. Khorana AA et al, J Thromb Haemost 2018;16:1891–1894
LMWH
Unstable;high
bleeding risk
• E.g. acute leukaemia, active GI/UG lesion, oesophagus/stomach, not resected
• CrCl <30 ml/min; LFT >3x ULN• Antiplatelet agent• CNS neoplasm: primary/metastatic
• ECOG 4, poor prognosis• Acute chemotherapy; sepsis;
vomiting; mucositis; platelets <50,000 per μl
• Post-surgery <2 weeks• DDI
• Pancreatic cancer• Hepatic/renal cancer• Prostate cancer• Thyroid cancer• Lung/ovarian cancer• Chronic leukaemia• Uterine/breast cancer• Melanoma
NOAC
Stable;low
bleeding risk
• Preventive radiotherapy• Chronic chemotherapy• No active anticancer treatment; stable
disease
NOACs in Treatment of CAT: Treatment matrix
LMWH vs NOAC: no permanent decision! Adjustment to type/phase of malignancy and treatment, patient situation: Unstable, chemotherapy, vomiting, thrombocytopenia: NOAC LMWH Stable, low risk for complications and high QoL: LMWH NOAC
Bauersachs R. Akuttherapie und Prolongierte Sekundärprävention Venöser Thromboembolien. In: Lindhoff-Last E, Debus ES, KellersmannR, Tepe G, editors. med publico GmbH; 2019. p. 1-44.
24
Thank you very much for your attention!
256. - 7. SEPTEMBER 2019
Thank you very much for your attention!
26
Thank you very much for your attention!
Top Related