Post on 07-Apr-2019
Risk assessment of venous thromboembolism in cancer
Cihan Ay
Medical University of Vienna Department of Medicine I
Clinical Division of Haematology and Haemostaseology Vienna, Austria
cihan.ay@meduniwien.ac.at
Disclosures for Cihan Ay
Research Support/P.I. [No relevant conflicts of interest to declare or Company Name(s)]
Employee [No relevant conflicts of interest to declare or Company Name(s)]
Consultant [No relevant conflicts of interest to declare or Company Name(s)]
Stockholder [No relevant conflicts of interest to declare or Company Name(s)]
Advisory Board Daiichi Sankyo, Bayer, Pfizer/BMS
Speakers Bureau Sanofi, Pfizer, Bayer, Daiichi Sankyo
Other (Specify) [No relevant conflicts of interest to declare or Company Name(s)]
Contents of my presentaCon
� Background and epidemiology of venous thromboembolism (VTE) in cancer
� Risk factors and risk assessment for cancer-‐associated VTE � Findings from the Vienna Cancer and Thrombosis Study (CATS)
� Primary thromboprohylaxis in patients with cancer
Brief historical review The cancer and thrombosis connecCon
Armand Trousseau 1801 - 1867
• Close interrelation between cancer thrombosis: „two-‐way“ (clinical) association – Thrombosis can occur as a complication of cancer – Thrombosis can be the first presenting sign of occult cancer – Presence of cancer cells in thrombotic material
Jean Baptiste Bouillaud 1796-1881
Theodor Billroth 1829-1894
Venous thromboembolism and cancer
� Cancer is a strong and independent risk factor for VTE � Risk of VTE in cancer patients is 4-‐ to 7-‐fold increased � Risk of recurrence of VTE is higher in patients with cancer
� VTE aggravates the clinical course of cancer � VTE in cancer patients increases morbidity and mortality � One of the leading causes of death in cancer patients
� Risk stratification and prevention of VTE is of utmost clinical interest
Heit et al, Arch Intern Med 2000; Khorana AA et al, J Clin Oncol 2009; Horsted F PLoS Med. 2012
Vienna Cancer and Thrombosis Study (CATS) Aim and study design
• Aim – To investigate risk factors, specifically biomarkers, for prediction of VTE in cancer patients
• Study design – Prospective, observational and single center cohort study – Inclusion criteria: Newly diagnosed cancer or progression of disease after complete or partial remission and written informed consent
– Outcome measure: Occurrence of VTE, either symptomatic or fatal and objectively confirmed
– Approx. 2000 patients (45% women) – Median age [IQR]: 62 [53-‐68] years – 76% newly diagnosed
Vienna Cancer and Thrombosis Study PaCent populaCon
Rates of VTE in patients with cancer
Ay C et al, J Clin Oncol 2009
� 1 -‐ 20% of paKents with cancer develop VTE during the course of their disease
7.6
2017.6
15.2
8.56.5 5.6 5.1 4.5
1.5 1
8.5
0510152025
VTE-‐incidence (%) during a median follow-‐up of 501 days [IQR, 255-‐731] in 825 patients with different types of cancer
When do thromboCc events occur in paCents with cancer?
CumulaCve probability of VTE
3 months: 4.2%
6 months : 6.1%
12 months : 8.1%
2 years: 9.4%
CATS (unpublished)
Treatment-‐related
PaCent-‐related Biomarkers
Cancer site (primary) Advanced tumor stage High tumor grade IniKal period aTer diagnosis
Major (cancer) surgery HospitalizaKon
AnKcancer treatments (chemotherapy, hormonal therapy, anK-‐agiogenics)
Erythropoiesis-‐sKmulaKng agents
Central venous catheters Transfusions, ….
Age?, gender?, BMI? Ethnicity
Hereditary risk factors (e.g. factor V Leiden mutaKon)
ComorbidiKes History of VTE Varicose veins
Platelet count Leukocyte count Hemoglobin? soluble P-‐selecKn D-‐dimer Prothrombinfragment 1+2 Factor VIII acKvity Thrombin generaKon potenKal C-‐reac<ve protein? Micropar<cles / Tissue factor? Mean platelet volume
Risk factors for VTE in paCents with cancer
P-‐selecCn in haemostasis and thrombosis
• Cell adhesion molecule P-‐selecKn (CD62) • found in alpha granules of platelets and Weibel-‐Palade bodies of endothelial cells
• promotes thrombus formaKon • exhibits a prothromboKc state
• High levels of soluble P-‐selecKn (sP-‐selecKn) are associated with VTE in paKents without cancer
• Elevated sP-‐selecKn is a risk factor for recurrent VTE
Ay et al, Clin Chem 2007; Rectenwald et al, Thromb Haemost 2005; Blann et al, Br J Haematol 2000; Kyrle et al, Thromb Haemost 2007
P-‐selecKn is a biomarker that has procoagulant properKes and reflects a prothromboKc state in human subjects
3.7%
11.9%
6 months
P=0.002
sP-selectin
Ay et al, Blood 2008
AssociaCon of sP-‐selecCn with VTE in paCents with cancer (n=687)
HR 2.58 (95% CI:1.39-4.89), p=0.003
Elevated D-‐dimer levels are associated with higher probability to develop VTE
Ay et al, J Clin Oncol. 2009; Pabinger et al, Blood 2013
D-‐Dimer (≥75th percenKle)
D-‐Dimer (<75th percenKle)
~4%
~10%
Recent findings Vienna Cancer and Thrombosis Study (CATS)
Clinical and clinicopathological risk factors for VTE in cancer
-‐ Histolgical tumor grade -‐ Tumor stage (solid tumors) -‐ Co-‐morbidiKes and Co-‐medicaKon
Ahlbrecht et al., J Clin Oncol 2012
Histo-‐pathological tumor grade* and associaCon with VTE
Low Grade (G1, G2)
High Grade (G3, G4)
Patienten (n) 468 279
VTE 27 25
VTE / n (%) 5.8% 9.0% P = 0.037
*a measure of cell appearance in a malignant tumor reflecting the biological aggressiveness
Cumulative probability of VTE
after 6 months: Local stage: 2% Regional stage: 7% Distant stage: 7%
Log-rank test P=0.002
Dickmann et al, Haematologica 2013
Tumor stage and risk of VTE Lymph node metastasis (regional stage) increase the risk of VTE
„Venous diseases“ and associaCon with risk of VTE (previous studies)
• Cancer patients: history of VTE – Cancer patients with history of VTE have increased risk of future VTE (Agnelli et al. 2006, Kröger et al. 2006, Mandala et al. 2010)
• General population: – History of superficial vein thrombosis (thombophlebitis)
• Increased risk for VTE (Heit at al. 2000, van Weert et al. 2006)
– Presence of varicose veins • Patients with varicose veins have increased risk of VTE (Heit et al. 2000)
Presence of varicose veins and history of VTE in cancer paCents associated with risk of VTE
Covariate Hazard ratio (95 % CI) p-value
Varicose veins 1.968 (1.212-3.195) 0.006
History of STP 1.815 (0.957-3.441) 0.068
Gender 0.691 (0.457-1.044) 0.079
Age 0.992 (0.977-1.008) 0.337
Obesity 0.650 (0.350-1.205) 0.171
History of VTE 1.534 (0.692-3.400) 0.292
Cumulative probability of VTE. Patients with varicose veins (green line) are compared to patients without varicose veins (blue line). Cumulative probability of VTE. Patients with history of VTE (green line) are compared to patients without history of VTE (blue line)
Varicose veins
History of VTE (>3 months)
Königsbrügge et al, J Thromb Haemost 2013
StaCns and venous thromboembolism
Glynn et al. (JUPITER trial), N Engl J Med 2009; Agarwal et al, Int J Pract 2010 Khemasuvan et al, Am J Med 2010
• Favorable effect of statins on VTE risk has been reported in previous studies in the general population
• Effect of statins in reduction of VTE risk in cancer patients – Retrospective analysis in 750 patients with a solid tumour (56 % Africa-‐American) Patients with statins, VTE = 8% Patients without statins VTE= 21%
Odds ratio 0.33; 95% CI 0.19-‐0.57
Lötsch et al, Thrombosis Research 2014
Vienna Cancer and Thrombosis Study StaCn use has an favorable effect on risk of cancer-‐associated VTE
StaCn use is associated with low risk of VTE MulKvariable Fine & Gray regression analysis incorporaKng death as compeKng risk
Variable SHR 95% CI p Statin-use 0.39 0.16 – 0.92 0.031 High+& very high-risk site§ 2.07 1.33 – 3.23 0.001 Antiaggregatory drugs 0.96 0.50 – 1.84 0.891 FVIII (per 10% activity) 1.04 1.02 – 1.06 <0.001 sP-selectin (per 10 ng/L) 1.19 1.11 – 1.28 <0.001 Age 0.99 0.98 – 1.01 0.503 BMI (per kg/m2) 1.04 1.00 – 1-08 0.037 Myocardial Infarction 1.04 0.37 – 2.96 0.936 Diabetes 0.88 0.46 – 1.67 0.697 +Kidney, lung, lymphoma and myeloma §Brain, pancreas and stomach
Lötsch et al, Thrombosis Research 2014
MulCple factors contribute to risk of VTE in
paCents with cancer!
How could risk assessment in cancer be improved?
Khorana et al, Blood 2008
Risk scoring model – „Khorana-‐Score“ • PredicKon of cancer-‐associated VTE during chemotherapy
(follow-‐up 2.4 months)
Score 0 (n=276)
Score 1 (n=229)
Score 2 (n=221)
Score ≥3 (n=93)
6 months
1.5%
3.8%
9.6%
17.7%
Ay et al, Blood 2010
Vienna Cancer and Thrombosis Study ApplicaCon of the „Khorana-‐Score“ for risk straCficaCon of VTE
Total number of paKents included in
this analysis: 819
External ValidaCon of the Khorana Risk Score
Moore et al, J Clin Oncol 2011, Mandala et al, Ann Onc 2012
N=9321 N=1,4152
Ay et al, Blood 2010
Vienna VTE risk assessment score in cancer The Vienna CATS score
• Expansion of the predicKve risk scoring model by Khorana et. al. • Expanded risk score incorporaKng D-‐dimer and sP-‐selecKn
Patient characteristics Risk score Site of cancer very high risk (stomach, pancreas, brain) 2 high risk (lung, lymphoma, kidney, myeloma) 1
Platelet count 350x109/L or more 1 Hemoglobin less than 10 g/dL and/or use of erythropoiesis-stimulating agents 1 Leukocyte count more than 11x109/L 1 BMI of 35 kg/m2 or more 1
Soluble P-selectin 53.1 ng/mL or more 1 D-Dimer 1.44 µg/mL or more 1
Ay et al, Blood 2010
The Vienna CATS score
Score ≥5 (n=30)
Score 4 (n=51)
Score 3 (n=130)
Score 1 (n=218) Score 2 (n=190) Score 0 (n=200)
35.0%
1.0%
6 months
• Expanded risk scoring model for predicKon of cancer-‐associated VTE including D-‐dimer and sP-‐selecKn in 819 paKents
PrevenCon of VTE in cancer paCents Primary thromboprophylaxis
Major cancer surgery
Cancer paCents Clinical seong
HospitalizaKon for acute medical illness
OutpaKents (chemotherapy)
Thromboprophylaxis in hospitalized medical cancer paCents
Summary of Guidelines ASCO (Lyman et al, 2013) 1.1 Hospitalized patients (with acute medical illness or
reduced mobility), in the absence of bleeding or other contraindications. 1.3 Data are inadequate to support routine thrombo-‐prophylaxis in patients admitted for minor procedures or short chemotherapy infusion or in patients undergoing stem-‐cell/bone marrow transplantation.
NCCN (Streiff, 2010) Consider if active cancer or a high suspicion of cancer and no contraindications
International multidisciplinary working group (Farge et al, 2013)
Consider if decreased mobility: (LMWH or UFH or fondaparinux)
ACCP (Kahn et al, 2012) Recommended if bed-‐bound or acutely ill
ESMO (Mandala et al, 2010) Recommended if bed-‐bound or acute medical complication: (LMWH, UFH or fondaparinux)
These recommendations are extrapolated from large placebo-‐controlled RCT of VTE thromboprophylaxis in broad, mix-‐population of medical inpatients
• PROTECHT study (n=1150)
• SAVE-‐ONCO study (n=3212)
01234
3.9
2
Rate of VTE (%)
01234
3.4
1.2
Rate of VTE (%)
Agnelli et al, N Engl J Med. 2012 Agnelli et al, Lancet Oncol 2009
Randomized placebo-‐controlled interventional trials Primary thromboprophylaxis during chemotherapy (in the ambulatory setting)
Primary thromboprophylaxis in paCents with pancreaCc cancer
Study PaCents AnCcoaguaCon DuraCon
Primary outcome: VTE
Secondary outcome: Overall surival
Conko-‐004, Riess et al., JCO 2009
312 Enoxaparin: 1mg/kg BW once daily for 12 weeks; then 40 mg once daily
12 months
66% risk reducKon
No effect
Maraveyas et al., EJC 2012
123 Dalteparin: 200 IU/kg BW once daily for 4 weeks; then 150 IU/kg BW once daily for 8 weeks
12 weeks 85% risk reducKon
No effect
The Khorana VTE risk assessment score in a retrospecCve analysis of the SAVE-‐ONCO study
George D et al, Blood (ASH Annual Meeting Abstracts) 2011; 118: Abstract 206 Table from: Thaler J , Ay C and Pabinger I, Throm Haemost 2012; 108: 1042–1048
1Lyman GH, et al. J Clin Oncol. 2013, 2NCCN guidelines, 2013, 3Mandala M, et al. Ann Oncol. 2011
PaCents ASCO1 NCCN2 ESMO3
All cancer outpaKents
RouKne prophylaxis not recommended
RouKne prophylaxis not recommended
RouKne prophylaxis not recommended
“High-‐risk” outpaKents
“Risk assessment can be conducted based on a validated risk assessment tool” Oncologists should educate pa<ents regarding risk of VTE
“Consider paKent conversaKon about risks and benefits of prophylaxis in Khorana score ≥3 populaKon”
“Consider in high-‐risk ambulatory cancer paKents. PredicKve model may be used to idenKfy paKents clinically at high risk for VTE”
Guideline RecommendaCons: Primary thromboprophylaxis in outpaKents and idenKfying high-‐risk paKents
PaKents with mulCple myeloma receiving thalidomide-‐ or lenalidomide-‐based regimens with chemotherapy and/or dexamethasone should receive pharmacologic thromboprophylaxis with either aspirin or LMWH for lower risk paKents and LMWH for higher-‐risk paKents.
1Lyman GH, et al. J Clin Oncol. 2013, 2NCCN guidelines, 2013, 3Mandala M, et al. Ann Oncol. 2011
Guideline RecommendaCons: Primary thromboprophylaxis in outpaKents and idenKfying high-‐risk paKents
Patients ACCP4 International Clinical Practice Guidelines5
All cancer outpatients
Routine prophylaxis not recommended Routine prophylaxis not recommended
“High-‐risk” outpatients
Patienten mit soliden Tumoren, die einen zusätzlichen VTE Risikofaktor haben und ein niedriges Blutungsrisiko aufweisen, wird eine prophylaktische Antikoagulation mit einem (niedermolekularen) Heparin empfohlen
Zusätzliche Risikofaktoren: VTE in der Anamnese, Immobilisierung, Hormontherapie oder Therapie mit einem Angiogeneseinhibitor, Thalidomid und Lenalidomid
Primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pancreatic and lung cancer treated with chemotherapy and having a low bleeding risk
4 Guyau et al., Chest 2012, 5Farge et al, J Thromb Haemost 2013
Summary
• VTE is frequent in subgroups of cancer patients – Multiple risk factors contribute to occurrence of VTE in patients with
cancer
• It is possible to identify high risk patients by clinical and laboratory parameters – Risk assessment models seem to be promising
• Primary thromboprophylaxis for prevention of VTE in cancer outpatients is still a matter of debate – Current international guidelines do not recommend primary
thromboprophylaxis in all cancer outpatients – High-‐risk patients might be candidates for thromboprophylaxis with
low molecular weight heparins [during chemotherapy (up to 4 months?)]
Acknowledgments
Ingrid Pabinger Johannes Thaler
Rainer Vormittag
Ralph Simanek Alexandru Chiriac
Eva-Maria Reitter
Tanja Altreiter
Roman Kanz
Johanna Haselböck Gülay Algül Magdalena Pabinger
Laura Ovissi
Silvia Koder
Julia Riedl Daniela Dunkler
Alexandera Kaider
Jonas Ahlbrecht
Boris Dickmann Felix Lötsch
Vera Tiedje
Hanna Obermeier
Clinical Division of Haematology and Haemostaseology
Clinical Division of Oncology
Department of Laboratory Medicine
Contributors from the Medical University of Vienna to CATS
Oliver Königsbrügge
Florian Posch
Tumor cells Thrombosis Activation of blood coagulation
and induction of hypercoagulability
Prothrombotic properties of cancer cells are leading to hypercoagulability and contribute to thromboegenesis in cancer.
Cancer cells are able to activate blood coagulation through direct and indirect mechanisms.
Biomarkers invesCgated to idenCfy paCents at high/low risk of VTE
Biomarkers and laboratory tests invesKgated for predicKon of cancer-‐associated VTE in CATS Platelet count Simanek et al, JTH 2009 + soluble P-selectin Ay et al, Blood 2008 + D-Dimer Prothrombinfragment 1+2 Ay et al, J Clin Oncol 2009
+ +
C-reaktive Protein Kanz et al, JTH 2011 (+) Factor VIII activity Vormittag et al, ATVB 2009 + Thrombin Generation Assay Ay et al, J Clin Oncol 2011 + Microparticles/Tissue factor bearing microparticles Thaler et al, JTH 2012 -/+ ? Fibrinogen Tiedje et al, Thromb Haemost 2011 --
Reviewed in: Pabinger, Thaler and Ay, Blood 2013
Padua Prediction Risk Score – high risk defined as a score > 4 ACCP Practice Guidelines
Risk Score Points Active cancer Previous VTE Reduced Mobility (bed rest > 3 days) Known thrombophilic condition Recent trauma and/or surgery Elderly age (> 70 years) Heart and/or respiratory failure Acute MI or ischemic stroke Obesity (BMI > 30) Ongoing hormone treatment
3 3 3 3 2 1 1 1 1 1
Primäre Thromboseprophylaxe bei hospitalisierten internisCschen PaCenten (basierend auf Risikoevalierung)
Guyatt et al., Chest 2012; Barbar S et al., J Thromb Haemost 2010
Primäre Thromboseprophylaxe nach tumorchirurgischen OperaConen
Zusammenfassung der Guidelines ASCO (Lyman et al, 2013) Consider for major surgery: at least 7 d LMWH post-operative
and consider extended use in higher risk patients
NCCN (Streiff, 2010) Consider for major surgery: at least 4 weeks LMWH post-operative, especially for high risk abdominal or pelvic surgery
International multi-‐disciplinary working group (Farge et al, 2012)
All patients undergoing surgery should have either LMWH or UFH 12–24 h pre-operatively and 7–10 d post-operatively, which should be extended to 4 weeks post laparotomy if there is a risk of VTE and no risk of bleeding
ACCP (Kahn et al, 2012) All patients undergoing major surgery who are at high risk should receive 3 d UFH, fondaparinux or LMWH and up to 28 d if they are also high risk
ESMO (Mandala et al, 2010) Consider for major laparotomy or laparoscopy of >30 min duration: LMWH, UFH or fondaparinux for at least 10 d post-op; and major abdominal or pelvic surgery LMWH for >1 month post-op