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Slide1
Anticoagulant Options for the Management of Acute Cancer-Associated Thrombosis
Presented by
Slide2Faculty/Presenter DisclosureFaculty:Relationships with commercial interests:
Slide3Disclosure of Commercial SupportThis program has received financial support from Sanofi Canada, in the form of an educational grant.Potential for conflict(s) of interest: All funding for this program was at arms-length and the content was developed by an independent committee of Thrombosis Canada members. The presentation does include reference to medications which the Sanofi markets in Canada.
Slide4Mitigating Potential BiasThe content for this program was developed by a scientific steering committee from Thrombosis Canada. All faculty have been directed that any recommendations involving clinical medicine are to be based on evidence that is accepted within the profession; and all scientific research referred to, reported, or used in the CME/CPD activity in support or justification of patient care recommendations conforms to the generally accepted standards.
Slide5Planning faculty
Marc Carrier,
MD, MSc, FRCPC (Program Chair)
Hematologist
Ottawa, Ontario
Normand
Blais
, MD, MSc, FRCPC
Hematologist, Medical Oncologist
Montreal, Quebec
Mary
DeCarolis
, MD, CFE, MCFP
Oncologist, Hematologist
Ayr, Ontario
Eddy Lang
, MDCM, CCFP(MU), CSPQ
Emergency Physician
Calgary, Alberta
Agnes Lee
, MD, MSc, FRCPC
Hematologist
Vancouver, British Columbia
Laurie
Sardo
, RN,
MScN
, NP, MBA
Nurse Practitioner, Thrombosis
Hamilton, Ontario
Vicky
Tagalakis
, MD, MSc, FRCPC
Internal Medicine
Montreal, Quebec
Slide6Learning objectives
After attending this program, participants will be better able to:
Understand the risk of venous thromboembolism (VTE) in the cancer population;
Discuss best treatment options for cancer associated thrombosis (CAT) recognizing cancer subgroups and bleeding risk;
Define when to consider hospitalization and how this impacts VTE risk;
Discuss risk factors associated with an increased risk of VTE and major bleeding episodes in patients with CAT;
Identify best risk reduction strategies for recurrence of CAT (i.e. patient education on adherence, signs and symptoms recurrence/bleeding, follow-up).
Slide7Cancer-associated Thrombosis
Slide8Defining the terms
Thrombosis:
local coagulation or blood clot within the circulatory system
Venous thromboembolism (VTE):
blood clot (thrombus) that can occur in:
Deep veins of the legs (DVT)
Blood vessels of the lungs (pulmonary embolism; PE)
Arms, especially if a catheter is in place for giving chemotherapy
or taking blood
Organs (e.g. kidney, brain, bowels)
Cancer-associated thrombosis (CAT):
blood clot(s) that occur in patients
living with cancer
Slide9CAT: a frequent and important complication
Patients with cancer have a 4-7x higher risk of VTE
VTE and thrombotic complications are the 2
nd
most frequent cause of mortality in patients with
cancer
Fatal PE is 3x more common in cancer patients
than in patients without cancer
Connolly GC, Francis CW.
Hematology
2013(1):684–91.
Elyamany
G, et al.
Clin Med Insights Oncol 2014;8:129–137.
Slide10Why does CAT occur?
Virchow’s triangle
:
Risk factors are cumulative
Venous stasis
Obesity
Immobility (bed rest)
Tumour compression
Blood hypercoagulability
Malignancy
Hereditary risk factors
Age >40
Vascular injury
Intravasation
of cancer cells
Surgery
Chemotherapy
Trauma
Central catheters
Khalil
J, et al.
World J
Surg
Oncol
2015;13:204-220
.
Slide11When does CAT occur?
CAT most frequently occurs in the first
3-6 months after cancer diagnosis
but can occur anytime
C
hemotherapy can increase
the risk of VTE by 2-6 fold
Connolly GC, Francis CW.
Hematology
2013(1):684–691.
Heit
JA, et al.
Arch Intern Med
2000;160:809–815.
Slide12Treating Cancer-associated Thrombosis
Slide13Current guidelines on treatment of CAT
Current guidelines (ASCO, Thrombosis Canada, Canadian Consensus) recommend low molecular weight heparins (LMWHs) for the treatment of established DVT and PE as well as for long-term secondary prophylaxis for at least 6 months
Direct oral anticoagulants (DOACs) are now being studied and used in the treatment of CAT
Lyman GH, et al.
J
Clin
Oncol
2015;33(6):654-656.
Thrombosis Canada. Cancer and Thrombosis.
http://thrombosiscanada.ca/clinicalguides/#
.
Carrier M et al
.
Curr
Oncol 2015;22(1):49-59.
Slide14Summary: current guideline recommendations on CATASCO, American Society of Clinical Oncology; ACCP, American College of Chest Physicians; ESMO, European Society of Medical Oncology; NCCN, National Comprehensives Cancer Network; LMWH, low molecular weight heparin; UFH,
unfractionated
heparin; VKA, vitamin K agonist; VTE, venous thromboembolism
Adapted in part from Khorana AA, et al.
J
Clin
Oncol
2009;27:4919-4926.
1. Lyman GH, et al.
J
Clin
Oncol
2015;33:654-656. 2. NCCN 2017. https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf 3. Mandala M, et al. Ann Oncol 2011;20(Suppl 6):vi85-92.4. Kearon C, et al. Chest 2016;149(2):315-352. 5. Easaw JC, et al.
Curr Oncol 2015;22:144-155.
ASCO
1
NCCN
2
ESMA
3
ACCP
4
Canadian Consensus
5
Initial treatment
LMWH
is the preferred option for initial 5-10 days
LMWH, UFH or
fondaparinux
according to patient profile and clinical situation
LMWH preferred option
LMWH
LMWH
over VKA,
dabigatran
,
rivaroxaban
,
apixaban
or
edoxaban
In patients with established VTE LMWH is the therapy of choice
Secondary prophylaxis
LMWH for at least 6 months
is preferred
;
> 6 months may be considered in select patients with active cancer (e.g. metastatic disease or receiving chemotherapy
LMWH for at least 6 months as
monotherapy
in patients with advanced or metastatic cancer
Patients with active cancer, under treatments or persistent risk factors indefinitely
LMWH for 6 months
Extended therapy
(> 3 months) is suggested
Patients with recurrent VTE
should receive extended
(>3 months) anticoagulation therapy
Slide15CAT treatment: LMWH vs. VKA data*As per the follow-up period in each study. D =
dalteparin
;
E =
enoxaparin
; OAC – oral anticoagulant; T =
tinzaparin
1. Meyer G, et al.
Arch Intern Med
2002;162:1729-1735. 2. Lee AY, et al.
N Eng J Med
2003;3492:146-153. 3. Lee AY, et al.
JAMA
2015;314:677-686.
4. Hull RD, et al.
Am J Med 2006;119:1062-1072. 5. Deitcher SR, et al. Clin Appl Thromb Hemost 2006;12:389-296.
Study
Design
Length of Therapy (months)
N
Recurrent VTE (%)
Major Bleeding (%)
Deaths* (%)
CANTHANOX (Meyer, 2002)
E (1.5 mg/kg qd)
OAC
3
67
71
4
5
p
=NS
7
16
p
=0.09
11
23
p
=0.07
CLOT
(Lee, 2003)
D (150 IU/kg
qd
)
OAC
6
336
336
8
16
p
=0.002
6
4
p
=0.27
39
41
p
=0.53
LITE
(Hull, 2006)
T (175 IU/kg
qd
)
OAC
3
100
100
6
10
p
=NS
7
7
p
=NS
20
19
p
=NS
CATCH
(Lee, 2015)
T (175 IU/kg
qd
)
OAC
6
449
451
6.9
10.0
p
=NS
2.7
2.4
p
=NS
33.4
30.6
p
=NS
ONCENOX (Deitcher, 2006)
E (1.0 mg/kg
qd
)
E (1.5 mg/kg
qd
)
OAC
6
31
36
34
3
3
7
p
=NS
7
11
3
p
=NS
23
42
32
Slide16CAT treatment: new data on DOACs
Recently, studies assessing the efficacy and safety of DOACs in prevention and treatment of CAT have been published
DOACs vs. VKA
DOACs vs. LMWH
Subgroup analyses of acute treatment trials comparing DOACs to VKA for the management of VTE suggest that DOACs seem to have similar efficacy and safety profiles compared to VKA among cancer patients.
However, very few cancer patients were included in these trials.
These patients seem to have been at low risk of recurrent VTE and major bleeding.
Pabinger
I,
Riedl
J.
Hematology Am Soc
Hematol
Educ
Program 2017;1:136-143.Smrke A, Gross PL.
Frontiers Med 2017;4:142.
Slide17CAT treatment: Meta-analysis of DOACs to VKA in cancer patients with acute VTE
Vedovati
MC, et al.
Chest
2015;147(2):475-483.
CI, confidence interval;
df
, degrees of freedom; M–H, Mantel–
Haenszel
; DOAC, direct oral anticoagulant
Use of DOAC and VTE recurrence in patients with cancer
DOAC
Slide18CAT treatment: Meta-analysis of DOACs to VKA in cancer patients with acute VTE
Vedovati
MC, et al.
Chest
2015;147(2):475-483.
CI, confidence interval;
df
, degrees of freedom; M–H, Mantel–
Haenszel
; DOAC, direct oral anticoagulant
Panel A:
Use of DOAC and major bleeding in patients with cancer
Panel B:
Use of DOAC and clinically relevant bleeding in patients with cancer
DOAC
DOAC
Slide19CAT treatment: Meta-analysis of LMWHs and DOACs to VKA in cancer patients with acute VTE
Risk of recurrent VTE
Posch
F, et al.
Thromb Res
2015;136(3):582-589.
Slide20CAT treatment: Meta-analysis of LMWHs and DOACs to VKA in cancer patients with acute VTE
Posch
F, et al.
Thromb Res
2015;136(3):582-589.
Risk of major bleeding
Slide21Hokusai VTE cancer trial: oral edoxaban vs
dalteparin
Raskob
GE, et al.
N
Engl
J Med
2018;378:615-624
.
Study design
Open-label, noninferiority trial with 1046 patients with cancer who had acute symptomatic or incidental VTE
Treatment
Randomly assigned patients to receive any LMWH for at least 5 days followed by:
Edoxaban
group: oral
edoxaban
60 mg*
od
, or
Dalteparin
group: subcutaneous
dalteparin
200 IU/kg body weight
od
for 1 month followed by dalteparin 150 IU/kg body weight od
Treatment durationAt least 6 months and up to 12 monthsPrimary outcomeComposite of recurrent VTE or thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration
* Edoxaban 30 mg od was used in patients with CrCl 30 to 50 ml/min, or body weight of
<
60 kg or in those receiving concomitant treatment with potent P-glycoprotein inhibitors.
Slide22Hokusai VTE cancer trial: study design
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12-month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
Raskob
GE, et al.
N
Engl
J Med
2018;378:615-624
.
Slide23Hokusai: baseline characteristics
Raskob
GE, et al.
N
Engl
J Med
2018;378:615-624.
Characteristic
Edoxaban
(N = 522)
Dalteparin
(N = 524)
Age; yrs
64.3
+
11.0
63.7
+
11.7
Male gender; no (%)
277 (53.1)
263 (50.2)
Mean weight; kg
Weight ≤60 kg; no (%)
78.8
+
17.9
83 (15.9)
79.1
+
18.1
78 (14.9)
Risk factors for bleeding; no (%) 0
1
2
3
92 (17.6)
148 (28.4)
174 (33.3)
108 (20.7)
92 (17.6)
151 (28.8)
159 (30.3)
122 (23.3)
Active cancer; no (%)
513 (98.3)
511 (97.5)
Metastatic disease; no (%)
274 (52.5)
280 (53.4)
Cancer treatment within previous 4 wks; no (%)
374 (71.6)
383 (73.1)
CrCl of 30-50 mL/min; no (%)
38 (7.3)
34 (6.5)
Platelets 50-100 x 10
9
/L; no (%)
32 (6.1)
23 (4.4)
Lower dose of
edoxaban
; no (%)
122 (23.4)
117 (22.3)
Slide24Hokusai: types of chemotherapies used
Raskob
GE, et al.
N
Engl
J Med
2018;378:615-624
.
Note: Patients could receive more than one anticancer drug. Treatment does not include anticancer therapy initiated after randomization.
Chemotherapies; no (%)
Edoxaban
(N = 522)
Dalteparin
(N = 524)
Antimetabolites
124 (23.8)
118 (22.5)
Platinum-based chemotherapies
105 (20.1)
107 (20.4)
Monoclonal antibodies
42 (8.0)
54 (10.3)
Bevacizumab
13 (2.5)
17 (3.2)
Taxanes
40 (7.7)
47 (9.0)
Hormonal therapy
41 (7.9)
37 (7.1)
Topoisomerases
30 (5.7)
48 (9.2)
Alkylating agents
30 (5.7)
38 (7.3)
Anthracytes
22 (4.2)
25 (4.8)
Vinca alkaloids
16 (3.1)
18 (3.4)
Kinase inhibitors
18 (3.4)
18 (3.4)
Immunomodulating agents
16 (3.1)
9 (1.7)
Proteasome inhibitors
7 (3.1)
8 (1.5)
Antitumour antibiotics
5 (1.0)
5 (1.0)
Miscellaneous
14 (2.7)
14 (2.7)
Slide25Hokusai: Kaplan–Meier cumulative event rates for the primary outcome
Primary outcome: composite of recurrent VTE or major bleeding
Raskob
GE, et al.
N
Engl
J Med
2018;378:615-624
.
Inset: same data on an enlarged y axis
HR 0.97 (0.7 – 1.36)
P=0.006
Slide26Hokusai: results
Primary Edoxaban Dalteparin Hazard Ratio
Outcome (N = 522) (N = 524) (95% CI)
p
Value
Raskob
GE, et al.
N
Engl
J Med
2018;378:615-624
.
Recurrent VTE 67 (12.8) 71 (13.5) 0.97 (0.70–1.36) 0.006 for noninferiority;
or major bleeding 0.87 for superiority
no (%)
Conclusion:
Oral
edoxaban
was
noninferior
to subcutaneous
dalteparin
with respect to the composite outcome of recurrent venous thromboembolism or major bleeding.
Slide27Hokusai: Kaplan–Meier cumulative event rates for secondary outcomes
Recurrent VTE
Major bleeding
Insets: same data on an enlarged y axis
Raskob
GE, et al.
N
Engl
J Med
2018;378:615-624
.
HR 0.71 (0.48 – 1.06); p = 009
HR 1.77 (1.03 – 3.04); p= 0.04
Slide28Hokusai: length of therapy between two groups
Raskob
GE, et al.
N
Engl
J Med
2018;378:615-624
#1 reason for discontinuation: patient preference
Characteristic
Edoxaban
(N = 522)
Dalteparin
(N = 524)
p
value
Treatment duration (median)
211 days
184 days
0.01
Patients completed study treatment at 12 months; n
200
154
Slide29Hokusai: Point estimates for recurrent or major bleeding
Raskob
GE, et al.
N
Engl
J Med
2018;378:615-624
.
Outcomes; no (%)
Edoxaban
(N = 522)
Dalteparin
(N = 524)
Hazard ratio (95% CI)
Recurrent VTE
41 (7.9)
59 (11.3)
0.71 (0.48, 1.06)
p
= 0.09
Recurrent DVT
19 (3.6)
35 (6.7)
0.56 (0.32, 0.97)
Recurrent PE
27 (5.2)
28 (5.3)
1.00 (0.59, 1.69)
Major Bleeding
36 (6.9)
21 (4.0)
1.77 (1.03, 3.04)
p
= 0.04
CRNMB
76 (14.6)
58 (11.1)
1.38 (0.98, 1.94)
MB + CRNMB
97 (18.6)
73 (13.9)
1.40 (1.03, 1.89)
Deaths
206 (39.5)
192 (36.6)
1.12 (0.92, 1.37)
VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; MB, major bleeding; CRNMB, clinically-relevant non-major bleeding
Slide30Hokusai: incidence of GI bleed
GI cancer
Edoxaban
(N = 522)
Dalteparin
(N = 524)
p
value
Yes, n/N (5)
18/136 (13.2)
3/125 (2.4)
0.02
No, n/N (%)
4/386 (3.6)
13/399 (3.3)
Supplement to:
Raskob
GE, et al.
N
Engl
J Med
2018;378:615-624
.
Note: Upper GI bleeding was predominant site in patient with GI cancers
Slide31Hokusai: survival results
Overall 266 (25.5%) patients died
6 deaths in each group were related to VTE or bleeding
No objectively confirmed fatal PEs
Of patients with recurrent PE, 5 (1%) patients in the
edoxaban
group and 3 (0.6%) in the
dalteparin
group had unexplained death (PE could not be ruled out)
Edoxaban
Dalteparin
6-months survival, % (95% CI)
354 (67.8%) 360 (68.7%)
Supplement to:
Raskob
GE, et al.
N
Engl
J Med
2018;378:615-624
Slide32SELECT-D pilot trial: oral rivaroxaban vs dalteparin
Young AM, et al.
J
Clin
Oncol
2018;36(20):2017-2023.
Study design
Prospective, randomised, open-label, multicentre pilot phase II
Participants
406 patients with active cancer with symptomatic DVT and/or any PE ECOG PS < 2
Treatment groups
Rivaroxaban
group: 15 mg bid for 21 days followed by 20 mg
od
Dalteparin
group: 200 IU/kg
od
for the first 30 days followed by 150 IU/kg
od
Treatment duration
6 months
Primary outcome
To assess VTE recurrence in cancer patients with a first VTE, treated with
rivaroxaban
or
dalteparin
To assess rates of major and clinically relevant non-major bleeding
Slide33SELECT-D: study design
Second randomization was deemed not feasible
The study protocol did not specify central adjudication of suspected VTE events
Young AM, et al.
J
Clin
Oncol
2018;36(20):2017-2023.
Slide34SELECT-D: baseline characteristics
Young AM, et al.
J
Clin
Oncol
2018;36(20):2017-2023.
Characteristic
Rivaroxaban
(N=203)
Dalteparin
(N=203)
Age, years – median (range)
67 (34-87)
67 (22-87)
Male gender; no (%)
97 (48)
109 (54)
BMI, median; kg/m
2
26.7
26.6
Metastatic cancer; no (%)
118 (58)
118 (58)
Currently
receiving cancer treatment; no (%)
140 (69)
142 (70)
ECOG performance status; no (%) 0
1
2
58 (29)
90 (47)
52 (26)
61 (30)
95 (47)
43 (21)
Qualifying VTE; no (%) Symptomatic
Incidental
97 (48)
106 (52)
93 (46)
110 (54)
Slide35SELECT-D: Kaplan–Meier cumulative event rates for primary outcome
Primary outcome: time to recurrent VTE within 6 months
Young AM, et al.
J
Clin
Oncol
2018;36(20):2017-2023.
Slide36SELECT-D: primary outcome results
Primary
Rivaroxaban
Dalteparin
Hazard Ratio
Outcome, n (%) (N = 203) (N = 203) (95% CI)
Young AM, et al.
J
Clin
Oncol
2018;36(20):2017-2023.
VTE recurrence within 6 months 8* 18**
DVT or PE*** 6 16
Other location 2 2
6 month VTE recurrent rate, % (95% CI) 4% (2-9%) 11% (7-16%) 0.43 (0.19–0.99)
* 2 patients experienced symptomatic PE and 1 experienced incidental PE
** 2 patients experienced symptomatic and 6 experienced incidental PE
***One fatal PE in each arm
Conclusion:
Rivaroxaban
was associated with relatively low rate of recurrent VTE
Slide37SELECT-D: Kaplan–Meier cumulative event rates for the secondary outcomeTime to major bleeds within 6 months
Dalteparin
Rivaroxaban
(n= 203) (n=203)
Major* 6 (3%) 11 (5%)
CRNMB** 6 (3%) 25 (12%)
Total 12 (6%) 36 (17%)
Young AM, et al.
J
Clin
Oncol
2018;36(20):2017-2023.
*Most major bleeding events were GI; no CNS bleeds.
**Most CRNMBs were GI or urologic.
Rivaroxaban
was associated with a higher CRNMB compared with
dalteparin
.
Slide38SELECT-D: survival results
Overall 104 (26%) patients died
92 (88%) died from progressive cancer
2 (2%) fatal PEs
Rivaroxaban
Dalteparin
6-months survival, % (95% CI) 75 (69-81%) 70% (63-76%)
Young AM, et al.
J
Clin
Oncol
2018;36(20):2017-2023.
Slide39DOACs vs LMWH for treatment of CAT: systematic review and meta-analysis
DOACs (42/725) had a non-significant lower incidence of 6-month recurrent VTE compared to LMWHs
B.
DOACs (40/725) had a higher incidence of
6-month major bleeding compared to LMWHs
Li A, et al.
Thrombo
Res
2018;doi:10.1016/j.thromres.2018.02.144.
Slide40When to hospitalize?
Estimating risk for adverse outcomes is key
Pulmonary Embolism Severity Index (PESI) and
its simplified version (
sPESI
) are widely validated
(see next slide)
Addition of biomarker data such as
cTnT
, BNP,
NT-
proBNP
, H-FABP as well as echocardiography
may help with risk assessment
There is a trend to outpatient management to reduce strain on inpatient resources
Elias A, et al. BMJ Open 2016;6(4):e010324.
cTnT
, cardiac
troponin
T; BNP, brain
natriuretic
peptide ; NT-
proBNP
, N-terminal
proBNP
; heart-type fatty acid-binding protein, H-FABP
Slide41PESI and sPESI
Thrombosis Canada website.
http://thrombosiscanada.ca/tools/?calc=pesi
;
http://thrombosiscanada.ca/tools/?calc=simplifiedPesi
Tailoring anticoagulation management in patients with acute CAT
Slide43Summary / key learnings: LMWHs vs DOACs for treatment of CAT
Clinical
considerations
Avoid DOACs in certain GI cancers and potentially
urothelial
malignancies
Consider LMWHs in patients with renal dysfunction (
CrCL
< 30 mL/min)
Consider drug-drug interactions when choosing a DOAC
High risk of bleeding (e.g. previous major bleeding episodes, thrombocytopenia)
Current cancer treatment
Patient considerations
Preference
Insurance coverageExtremes of body weights
Noble S. Thromb Res. 2018;164(Suppl 1):S157-S161.
Slide44Drug-drug interactions: Inducers and inhibitors of CYP3A4 and P-gp
Kinase
inhibitors
CYP3A4
P-
gp
Afatinib
↓
Alectinib
↓
Ceritinib
↓
Crizotinib
↓
Dasatinib
↓
Ibrutinib
↓
Idelalisib
↓
↓
Imatinib
↓
Lapatinib
↓
↓
Nilotinib
↓
↓
Osimertinib
↓
Vemurafenib
↑
↓
Lenvatinib
↑
↑
Chemotherapies
CYP3A4
P-
gp
Doxurubicin
↓
Topotecan
↓
Vinblastine
↓
Mitotane
↑
Venetoclax
↓
Supportive care
CYP3A4
P-
gp
Aprepitant
↓
Methylprednisolone
↓
Dexamethasone
↑
↑
CYP, cytochrome P450; P-
gp
, P-glycoprotein;
↓,
inhibitor;
↑
,induce
r
Inhibitors of CYP3A4 and/or P-gp may increase risk of bleeding on DOACs.
Slide45Patient preference and coverage
Patient preference is important in the choice of any medication or treatment
Needs to take into consideration the balance of risks/benefits in their particular situation
Patients experiencing nausea, vomiting and/or anorexia may not be able to take oral medication
Some patients may have needle phobias or needle fatigue
Cost may be a factor
Slide46Preventing Recurrence: Patient Education
Slide47Risk reduction strategies: patient education
Risk of recurrence after a first episode of VTE is higher in cancer patients than in those without underlying malignancy.
Adherence to anticoagulant treatment plan is important in reducing risk.
Review reasons for anticoagulant (e.g. treat blood clot, prevent more from developing, prevent extension)
Target compliance (e.g. set phone alarm as reminder, use of
dossette
, family member)
Bring medication to medical appointments
Review appropriate LMWH injection technique (i.e. 90 degree angle, do not eject air bubble, inject 1" outside of bruised areas for best absorption)
Khorana AA, et al.
J Thromb Thrombolysis
2016;41:81–91.
Slide48Patient education: signs and symptoms of recurrence
The signs and symptoms of recurrent VTE are usually the same as the first presentation
Signs and symptoms of DVT
Edema - most specific symptom
Leg pain - occurs in 50% of patients but
is nonspecific
Tenderness - occurs in 75% of patients
Warmth or
erythema
Clinical symptoms of PE as the primary manifestation
Dilated superficial veins
Signs and symptoms of PE
Dyspnea,
tachypnea
Pleuritic
chest pain, cough, or
hemoptysis
Tachycardia
Anxiety
Syncope/
presyncope
Slide49Patient education: signs and symptoms of bleeding
Remind patients to seek medical attention if symptoms of bleeding occur
Signs and symptoms of bleeding
Unusual black or melena stool
Hematuria
Hematemesis
Slide50Patient education
Patients need a reasonable level of understanding of risk factors and preventative measures
Allow patients to make informed decisions in partnership with healthcare providers
Address patients’ individual needs and preferences
Clear, consistent patient education materials are beneficial
Sadideen
H, et al.
J R Soc Med
Sh
Rep
2011;2:97.
Slide51Patient education materials: Thrombosis Canada
http://thrombosiscanada.ca/resourcepage/patient-family-information/
Bilingual disease and drug information sheets
Videos for patients
Slide52Questions?
Slide53Case Studies
Slide54Case Study:
Metastatic
Colorectal Cancer
Slide55Mrs RS: Profile
54 year-old high school teacher
Married, mother of 2 adult children
Past medical history: significant for hypertension and hypercholesterolemia, both well controlled with appropriate medications
BMI 31 (height 1.52 m; weight 72 kg)
CBC, Lytes, Ur, Cr and LFTs are all within normal limits
Slide56Mrs RS: Presentation
Metastatic colorectal cancer
Receiving palliative chemotherapy (FOLFIRI and
bevacizumab
) in a stop-and-go fashion for 2 years
Presents with painful, swollen and red lower left limb
Ultrasound confirms a proximal deep vein thrombosis of the left popliteal vein
Slide57Mrs RS: What would you do?
How would you treat Ms RS, and why do you chose this option?
Treat with
dalteparin
only
Treat with
enoxaparin
only
Treat with
tinzaparin
only
Treat with LMWH for 5-7 days with transitioning to warfarin
Treat with LMWH for 5-7 days, then switch to
edoxaban
Treat with rivaroxaban
only
Slide58Mrs RS: What if…?
What if her renal function is decreased with a CrCl 29 mL/min?
Treat with
dalteparin
only
Treat with
enoxaparin
only
Treat with
tinzaparin
only
Treat with LMWH for 5-7 days with transitioning to warfarin
Treat with LMWH for 5-7 days, then switch to
edoxaban
Treat with
rivaroxaban
only
Slide59Anticoagulation and renal dysfunction
Renal function surveillance should be exercised in
patients with
CrCl
<50 mL/min
Therapeutic doses of LMWH should be avoided in
cases of severe renal disease (CrCl <30 mL/min)
unless monitored by anti–factor
Xa
heparin levels
LMWH should be used with extreme care in patients with end-stage renal disease requiring dialysis.
Carrier M, et al.
Curr
Oncol
2015; 22:49-59.
Slide60LMWH in patients with CAT and RIVTE and bleeding outcomes
Variable
Treatment
Events
n/N
%
Hazard ratio
(95% CI)
p
– value
VTE (ITT)
(N
= 162)
Dalteparin
2/74
2.7
0.15
(0.03,
0.65)
0.01
VKA
15/88
17.0
Major bleeding
(N
= 161)
Dalteparin
7/749.51.29(0.43, 3.83)0.65VKA6/87
6.9
CI = confidence interval; CrCl = creatinine clearance; CRNMB = clinically-relevant non-major bleeding;
ITT = intent to treat; NS = not significant
Variable
Treatment
Events
n/N
%
Hazard ratio
(95% CI)
p
– value
VTE (ITT)
(N
= 131)
Tinzaparin
9/69
13.0
0.90
(0.38, 2.12)
NS
VKA
9/62
14.5
Major bleeding
(N
= 131)
Tinzaparin
3/69
4.3
0.54
(0.13, 2.16)
NS
VKA
5/62
8.1
CATCH patients with
CrCl
20–59 mL/min
2
CLOT patients with CrCl <60 mL/min
1
1. Woodruff S et al.
J Thromb Thrombolysis
2016;42(4):494–505; 2. Bauersachs R et al.
Thromb
Haemost
2018;118(5):914-921.
Slide61Mrs RS: What if…?
What if she was receiving adjuvant FOLFOX chemotherapy and her platelets were chronically in the 75-80 range?
Treat with
dalteparin
only
Treat with
enoxaparin
only
Treat with
tinzaparin
only
Treat with LMWH for 5-7 days with transitioning to warfarin
Treat with LMWH for 5-7 days, then switch to
edoxaban
Treat with
rivaroxaban
only
Slide62Anticoagulation and thrombocytopenia
Heparin-induced thrombocytopenia must be excluded in patients developing thrombocytopenia during heparin therapy
The risk-benefit balance of anticoagulation should be reassessed in the presence of thrombocytopenia
The risk of VTE recurrence is particularly high in the first 3 months after thrombosis; safe administration of anticoagulant therapy is recommended
Full anticoagulation (DOACs or LMWH)
does not pose excessive risk when platelet count remains above 50 x 10
9
/L
Watson HG, et al. Br
J
Haematol
2015;170(5):640-648.
Slide63Platelets < 50 X 10
9
/L
Able to maintain platelets
with transfusion (≥ 50)
Therapeutic doses
Unable to maintain
platelets
20-50
50% dose
LMWH
< 20
Hold LMWH
Samuelson
Bannow
BT, et al.
J
Thromb
Haemost
2018;16(6):1246-1249
.
Thrombocytopenia in patients with acute VTE
(< 1 month)
Slide64Thrombocytopenia in patients with acute VTE (≥ 1 month)
ISTH SSC suggest reducing the dose of LMWH to 50% of the therapeutic dose or using a prophylactic dose of LMWH in patients with a platelet count of 20–50 X 10
9
/L
ISTH SSC suggest discontinuing anticoagulation in patients with a platelet count of < 20 X 10
9
/L
Samuelson
Bannow
BT ,et al.
J
Thromb
Haemost
2018;16(6):1246-1249.
Slide65Mrs RS: What if…?
What if she is visually impaired such that she cannot safely self-administer LMWH?
What if she has a needle phobia and will not agree to LMWH injections for any length of treatment?
What if her disease is stable for several months such that her chemotherapy is held. Would you consider switching her to a DOAC? If you did, would you switch her back to LMWH when you need to restart IV chemotherapy?
Slide66Case Study:
Recurrent Thrombosis In Aggressive Colorectal Cancer
Slide67Mr NN: Profile
39-year-old accountant
Married, three children
Non-smoker, non-drinker
Past medical-surgical history
Abdominal hernia repair and vasectomy
Family history:
Maternal grandmother: colorectal cancer
Paternal grandmother: breast cancer
BMI 23 (height 1.84 m; weight 78 kg)
Mr NN: Presentation
March 10: presents in the ER
1 week progressive shortness of breath and cough, non-responding to oral antibiotic (Levaquin)
Normal CBC, LFTs and electrolytes:
HGB 155 (140-175), WBC 9.2 ANC 4.5,
PLT 189
,
PT 13.7
(9.4–12.9),
INR 1.2
, creatinine 88,
eGFR >60
, CEA 4.8 (0–3.0)
CT scan of chest
: enlarged mediastinal LNs, right hilar lymph nodes, retroperitoneal LNs, and right middle lobe
bronchovesicular thickening Refer to ENT for diagnosis and biopsy
Slide69Mr NN
March 13: returns to ER
Progressive right upper extremity swelling and pain for 2 days
Right doppler US of the right upper extremity: acute DVT in axillary, subclavian and internal jugular vein
Mr NN: What would you do?
How would you treat Mr NN, and why do you chose this option?
Hospitalize with LMWH
Outpatient treatment with
dalteparin
only
Outpatient treatment with
enoxaparin
only
Outpatient treatment with
tinzaparin
only
Outpatient treatment with LMWH for 5-7 days with transitioning to warfarin
Outpatient treatment with LMWH for 5-7 days, then switch to
edoxaban
Outpatient treatment with rivaroxaban only
Slide71Mr NN
Treated with therapeutic dose of LMWH
March 22
FNAB right neck LN: metastatic adenocarcinoma consistent with colorectal origin
C-scope: semi-circumferential indented mass in proximal transverse colon
Low-grade colorectal adenocarcinoma, KRAS WT, NRAS WT, MSS, V600 BRAF mutated
Slide72Mr NN
April 20
New right upper extremity symptoms (worsening of swelling)
Doppler confirmed extension of the previously described thrombus
Confirm patient compliance of LMWH and heparin induced thrombocytopenia was excluded
LMWH increased by 25% (up to 125% of weight-base)
Slide73Recurrent VTE
Subtherapeutic doses
Therapeutic doses
Switch to full doses
↑ doses by 20-25%
Reassess in 5 to 7 days
Same
Better
?
Another dose
Escalation?
Yes
No
Recurrent VTE despite LMWH
Carrier M, Khorana AA,
Zwicker
JI, et al.
J
Thromb
Haemost
2013;11(9):1760-1765.
Slide74Case Study:
Lung Cancer-
associated
Venous
Thromboembolism
Slide75Mr JD: Profile
56-year-old theater producer
Divorced, 2 teenaged children
Active
50 pack year smoker; occasional THC;
no alcohol
Reports reduced exercise tolerance lately limited by dyspnea
No previous medical history
No current medication
BMI 26 (height 1.70 m; weight 75 kg)
Slide76Mr JD: Presentation
Presents to the ED with right-sided pleuritic chest pain
VS: HR = 90; BP 140/80; RR 20/min / Sat 93%
EKG – sinus with RV strain
CXR shows hyperinflation and possible RUL mass
hsTnT marginally +ve at 20 nmol/L / d-Dimer > 5.0 (n < 0.5)
CTPA show bilateral segmental emboli (RML and LLL)
Presence of a right apical mass, possible mediastinal invasion
Neutrophilia on CBC
Normal renal and liver function
Well-established lung mass follow-up outpatient program
Patient feels well after analgesia – big play tomorrow night – wants to go home
Slide77PESI and sPESI
Thrombosis Canada website.
http://thrombosiscanada.ca/tools/?calc=pesi
;
http://thrombosiscanada.ca/tools/?calc=simplifiedPesi
Mr JD: PESI Score
Class IV = 4-11% 30d mortality
Slide79Mr JD: What would you do?
How would you treat Mr JD, and why do you chose this option?
Admit with IV UFH
Admit with LMWH
Discharge with
dalteparin
only
Discharge with
enoxaparin
only
Discharge with
tinzaparin
only
Discharge with LMWH for 5-7 days, then switch to warfarin
Discharge with LMWH for 5-7 days, then switch to edoxaban
Discharge with rivaroxaban only
Slide80Mr JD: Investigations
Mild COPD on PFTs
PET scan confirms findings
Thoracic MRI confirms mediastinal contact, apical invasion but no brachial plexus involvement
Endobronchial ultrasound (EBUS) is scheduled
What is your
peri
-procedural anticoagulation recommendation?
EBUS turns out negative
Slide81Mr JD: Investigations
Transthoracic needle biopsy (TTMB) is scheduled
What is your peri-procedural anticoagulation recommendation?
TTNB confirms squamous cell lung carcinoma (PD-L1 negative)
Staging concludes T4N0M0 SC-NSCLC
How do you approach anticoagulation at this point (post-discharge)?
Slide82Mr JD: Oncology treatment plan
Pre-operative chemotherapy and radiation
Cisplatin-etoposide days 1-5 and day 8 every 3 weeks x 2 cycles
Chest radiation 45
Gy
(25 fractions of 1.8
Gy
)
Surgery planned on week 10-12
Post-operative cisplatin-etoposide x 2 cycles
What is your peri-operative anticoagulation recommendation?
Slide83Mr JD: Progression
At 3 months post-end of chemotherapy:
Seizure
Brain CT shows necrotic left frontal-parietal brain metastasis (slightly hyper dense material – mild bleeding?)
CT thorax-abdomen-pelvis: no sign of recurrence
Would you change the type of anticoagulants (DOACs or LMWH) and why?
Confirmed single brain metastasis – operable
What are your peri-operative anticoagulation recommendations?
Slide84Primary or metastatic brain tumours and anticoagulation
Primary or metastatic brain tumours confer an
increased risk of developing venous thromboses.
Potential benefit of anticoagulation must be weighed
against the potential complication of intracranial
hemorrhage.
For most primary and treated metastatic brain
tumours, the risk of spontaneous bleeding is
acceptable and not further increased by careful anticoagulation with LMWH or DOACs, although thrombocytopenia (platelet count <50,000/
μL
) and other coagulopathies are relative contraindications.
Lin RJ, et al.
Oncologist
2018;23(4):468-473.
Slide85Metastatic brain disease on anticoagulation
Risk of intracranial bleeding episode: OR = 1.07 (95% CI: 0.61–1.88;
p
= 0.81; I
2
= 0%)
CI = confidence interval; OR = odds ratio
Zwicker
JI ,et al,
J
Thromb
Haemost
2016;14:1736–1740
.
Slide86Primary brain tumour/gliomas on anticoagulation
Risk of intracranial bleeding episode: OR = 3.53 (95% CI: 1.34–9.02;
p
= 0.81; I
2
= 28.2%)
CI = confidence interval; OR = odds ratio
Zwicker
JI, et al,
J
Thromb
Haemost
2016;14:1736–1740.
Slide87Mr JD: Further progression
At 9 months follow-up after brain surgery
In-field recurrence in the brain
Has developed progressive left lower limb palsy
Still on anticoagulation (DOACs vs. LMWH)
Receives further stereotactic brain radiation
Condition worsens after 2 more months –
radionecrosis
vs progressive disease
Mr JD requests transfer to hospice
What is your recommendation in regards to anticoagulation?
Slide88Anticoagulation: continuation beyond 6 months
Beyond 6 months is the preferred option in patients with active advanced cancer in the absence of a contraindication to anticoagulation.
A reasonable option in patients with advanced cancer in complete remission for whom the short-term risk of cancer recurrence is high, or in the presence of other ongoing major risk factors for thrombosis.
Required in most circumstances if an indication for anticoagulation was present before the incident cancer (e.g. AF, VTE not related to malignancy). Chosen therapy should be adapted to the situation.
Carrier M, et al.
Curr
Oncol
2015; 22:49-59.
Slide89Anticoagulation: discontinuation beyond 6 months
Anticoagulation
can be terminated after a minimum of 6 months of anticoagulant therapy if the underlying cancer has been treated with curative intent and any ongoing therapy is associated with a low risk of thrombosis.
Carrier M, et al.
Curr
Oncol
2015; 22:49-59.
Slide90Summary / key learnings: LMWHs vs DOACs for treatment of CAT
Clinical
considerations
Avoid DOACs in certain GI cancers and potentially
urothelial
malignancies
Consider LMWHs in patients with renal dysfunction (
CrCL
< 30 mL/min)
Consider drug-drug interactions when choosing a DOAC
High risk of bleeding (e.g. previous major bleeding episodes, thrombocytopenia)
Current cancer treatment
Patient considerations
Preference
Insurance coverageExtremes of body weights
Noble S. Thromb Res. 2018;164(Suppl 1):S157-S161.
Slide91Supplementary Slides
Slide92Risk Factors for CAT
Slide93Risk factors for VTE in cancer
Elyamany
G, et al.
Clin
Med Insights
Oncol
2014;8:129–137.
Blom
JW, et al.
JAMA
2005;9;293(6):715–722.
Increased risk varies from 1 – 30% depending on:
Patient characteristics
Cancer-related factors
Treatment-related
factors
Female gender
Older age
Race (black ethnicity)
Previous VTE
Common comorbidities,
e.g. diabetes, obesity,
inflammation, pulmonary disease, renal disease,
others
Genetic mutations
Site of tumour(s)
Tumour histologyStage and gradeInitial period after diagnosisDuration of cancerMajor surgeryHospitalizationImmobilizationChemotherapyRadiation therapyErythropoiesis-stimulating agentsAntiangiogenic
agents
Indwelling central catheters
Slide94VTE risk: predictive model for CAT
Khorana AA, et al.
Blood
2008;111(10):4902–4906.
Khorana AA, et al.
Thromb Res
2018;164 (Suppl 1):S70-S76..
Slide95VTE risk: post-surgical
VTE is a common complication of cancer surgery
@RISTOS study:
A prospective observational study that assessed
the incidence of VTE in 2372 patients undergoing
cancer surgery
A total of 50 patients (2.1%) experienced VTE
40% of the events occurred later than 21 days from surgery.
Overall death rate was 1.72%; 46.3% of these were caused by VTE
Agnelli
G, et al.
Ann
Surg
2006;243(1):89–95.
Slide96Risk factors: post-surgical VTE
Agnelli
G, et al.
Ann
Surg
2006;243(1):89–95.
Risk Factors for VTE
Odds Ratio (95% CI)
Previous history of VTE
6.0 (2.1 – 16.8)
Anesthesia lasting
>
2 hours
4.5 (1.1 – 19.0)
Bed rest post-op
>
4 days
4.4 (2.5 – 7.8)
Advanced
tumour
2.7 (1.4 – 5.2)
Age
>
60
2.6 (1.2 – 5.7)
Results from @RISTOS
Slide97VTE risk: hospitalization and immobilization
The risk of VTE due to vessel stasis increases with length of hospitalization/immobilization in patients with cancer who have and who have not had surgery
Increased risk of VTE
Khalil J, et al.
World J Surg Oncol
2015;13:204-220.
Slide98VTE risk: cancer treatment
Mandala
M, et al.
Annals
Oncol
2011;22(
Suppl
6):vi85–vi92.
Chemotherapy increases the risk of VTE by at least four mechanisms:
acute damage to vessel walls
non-acute damage of the endothelium
a decrease in natural coagulation inhibitors (reduced level
of C, protein S or
antithrombin
III)platelet activationAntiangiogenic agents such as bevacizumab, thalidomide and lenalidomide contribute to thrombosis, through endothelial cell and platelet activation and damage to the vascular endothelium
Slide99VTE risk: cancer treatment examples
Khalil
J, et al.
World J
Surg
Oncol
2015;13:204-220
. ;
Palumbo A, et al.
J
Clin
Oncol
2011;29:986–993.Carrier M, et al. J Thromb Haemost 2011;9:653–663.; Lyman GH, et al. The Oncologist 2013;18(12):1321–1329. Mandala M, et al. Annals Oncol 2011;22(Suppl 6):vi85–vi92.
Examples:Bevacizumab administered concomitantly with chemotherapy is associated with a 33% relative increase of VTE. The overall incidence of any-grade and high-grade VTE in patients receiving bevacizumab was 11.9 and 6.3%, respectively.
In patients with multiple myeloma, the incidence of thromboembolic events is 14% to 26% in patients receiving thalidomide plus dexamethasone and 10% to 20% in patients receiving thalidomide plus melphalan
Slide100VTE risk with chemotherapy: a retrospective analysis
Lyman GH, et al.
The Oncologist
2013;18(12):1321–1329.;
Blom
JW, et al.
J Thromb
Haemost
2004;2:1760-1765.
VTE incidence (%)
*Adenocarcinomas are associated with higher risks of VTE than squamous cell carcinomas
Slide101VTE risk: cancer site
Lyman GH, et al.
The Oncologist
2013;18(12):1321–1329
.
Risk of VTE in Cancer Patients Receiving Chemotherapy
Slide102VTE risk: hematologic cancers
Patients with a hematological cancer have a six-fold increased risk of developing VTE compared to the matched controls with no hematological cancer.
Highest to lowest risk of developing VTE:
aggressive non-Hodgkin lymphoma
multiple myeloma
acute leukemia (myeloid and lymphoblastic)
chronic
myeloproliferative
neoplasms
and
myelodysplastic
syndrome
chronic lymphocytic leukemia
Hodgkin lymphoma
Gade IL, et al.
Blood
2015;126:628.
Slide103VTE risk: tumour stage
Cancer
Distant Metastases
Adjusted OR
(95% CI)
Adjusted OR
(95% CI)
No
No
1.0
Yes
No
3.9
(2.5 – 6.0)
1.0
Yes
58.0
(9.7 – 346.7)
19.8
(2.6 – 149.1)
Patients with metastatic disease have 20-fold risk of VTE compared with those without
Blom
JW, et al.
JAMA
2005;9;293(6):715–722.