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Satellite Symposium
“Guidelines on Prevention and Treatment of Cancer-Associated Thrombosis”
Stockholm, September 16, 2008
The Art of Medical Prophylaxis,
Impacting the Patient Early
Anna Falanga, MD
Hemostasis and Thrombosis Center
Hematology-Oncology Dept
Ospedali Riuniti Bergamo, Italy
Medical Conditions
• Although VTE is most often considered to be associated
with recent surgery or trauma, 50 to 70% of symptomatic
thromboembolic (TE) events and 70 to 80% of fatal
pulmonary embolism (PE) occur in non-surgical patients1
• PE accounts for 5-10% of deaths in hospitalized patients,
making VTE the most common preventable cause of inhospital death2
Adapted from:
1. ACCP 2004. 1.Geerts WH, et al. Chest. 2004;126:S338–S400,
2. Cohen A et al. Lancet 2008:371;387-394.
Venous Thromboembolism (VTE) Risk
• Hospitalized medical cancer patients are at
increased risk for VTE
• Out of hospital cancer patients receiving
therapy are at risk for VTE
Rate of Appropriate Prophylaxis, %
VTE Prevention: We are Failing Our Patients
Cancer: 2001
FRONTLINE Survey1—
3891 Respondents
60
52
50
50
43
40
33
30
30
29
28
US 02
UK 03
20
10
0
5
Surgical
Onc
Medical
Onc
Adapted from:
1. Kakkar AK et al. Oncologist. 2003;8:381-88.
2. Anderson FA et al. Ann Intern Med. 1991;115:591-95.
3. Rahim SA et al. Thromb Res. 2003;111:215-19
US 91
Canada 01
US 07
4. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-62.
5. Rashid J Royal Soc Med 2005.
6. Spencer FA et al. Arch Intern Med 2007;167:1471-75.
7. Tapson VF, et al. Chest 2007;132:936-45.
World 07
Recommendations for VTE Prophylaxis in Patients with
Cancer Released by International Medical Oncology Societies
• AIOM (Italian Medical Oncology Society) - 2006
• ASCO (American Society of Clinical Oncology) - 2007
• NCCN (National Comprehensive Cancer Network) - 2007, 2008
• ESMO (European Society of Medical Oncology) - 2008
Recommendations for VTE Prophylaxis in
Hospitalized Patients with Cancer
• Hospitalized patients with cancer should be considered
candidates for VTE prophylaxis in the absence of bleeding
or other contraindications to anticoagulation
Contraindications to Anticoagulation
•
•
•
•
•
•
•
•
•
•
Active, uncontrollable bleeding
Active cerebrovascular hemorrhage
Dissecting or cerebral aneurysm
Bacterial endocarditis
Pericarditis, active peptic or other GI ulceration
Severe, uncontrolled or malignant hypertension
Severe head trauma
Pregnancy (warfarin)
Heparin-induced thrombocytopenia (heparin, LMWH)
Epidural catheter placement.
Prophylaxis in Acutely Ill Medical Patients
• No randomized clinical trials designed a priori for
hospitalized medical cancer patients
• Randomized, placebo-controlled trials in acutely ill
hospitalized medical patients
– MEDENOX1- enoxaparin 40 mg daily
– PREVENT2 - dalteparin 5000U daily
– ARTEMIS3 - fondaparinux 2.5 mg daily
Adapted from:
1. Samama et al. N Engl J Med 1999;341:793-800;
2. Leizorovicz et al. Circulation 2004;110:874-79;
3. Cohen et al. Blood 2003; 102(11): 15.
Thromboprophylaxis of Medical Patients:
Clear Benefits Over Placebo
Study
RRR
RRR
NNT
MEDENOX1
63%
63%
10
49%
45%
45
P=0.029
Placebo
Placebo
Dalteparin
P=0.0015
ARTEMIS3
Patients with VTE, %
14.9* (n=288)
Enoxaparin 40 mg
P<0.001
PREVENT2
Prophylaxis
47%
47%
20
5.5 (n=291)
5.0 (n=1,473)†
2.8 (n=1,518)
Placebo
Fondaparinux
*VTE at day 14; †VTE at day 21; ‡VTE at day 15.
Adapted from: 1Samama et al. N Engl J Med 1999;341:793-800.
2Leizorovicz et al. Circulation 2004;110:874-9.
3Cohen et al. Br Med J 2006.
10.5‡ (n=323)
5.6 (n=321)
NNT = number needed to treat;
RRR = relative risk reduction.
Proximal DVT + Symptomatic VTE at D14-21
MEDENOX
PREVENT
ARTEMIS
Enox.
2.1 %
Dalte.
2.6 %
Fond.
1.5 %
Placebo
6.6 %
Placebo
5.0 %
Placebo
3.4 %
P = 0.037
P = 0.002
P = 0.085
EXCLAIM: Study Design
Enoxaparin 40 mg s.c. q.d.
Enoxaparin
40 mg s.c. q.d.
R
Placebo
6-month follow-up
Days
10±4
Prospective, randomized, double-blind
 5,090 patients: enrollment completed

38±4
Systematic Duplex ultrasound
Inclusion Criteria
Initial inclusion criteria
Age  40 years
Recent immobilization ( 3 days)
Acute medical illness
•
Heart failure, NYHA class III/IV
•
Acute respiratory insufficiency
•
Other acute medical conditions including:
– post-acute ischemic stroke
– acute infection without septic shock
– active cancer
Amended inclusion criteria
•
Level 1 mobility
(total bed rest or
sedentary patients)
or
Level 2 mobility
(Level 1 with
bathroom privileges)
Adapted from Hull et al. J Thromb Thrombolysis. 2006; 22:31-38.
+
•
•
Age > 75 years
OR
History of VTE
OR
Diagnosis of cancer
Summary of Efficacy and Safety:
End of the Double-blind Period
Placebo (N=1681 efficacy pop; N=2027 safety pop)
Enoxaparin (N=1666 efficacy pop; N=2013 safety pop)
P=0.0011
NNT
46
6
5
4.90
Incidence (%)
P=0.0109
P=0.019
4
3
NNH
224
NNT
121
2.80
2
1.00
1
0.30
0.60
0.15
0
VTE events
NNT = number needed to treat
NNH = number needed to harm
Symptomatic DVT
Major bleeding
Recommended Dose:
Venous Thromboembolism Prophylaxis
Management
Drug
Regimen
Unfractionated Heparin
(UFH)
5000 U q 8 h
Dalteparin
5000 U daily
Enoxaparin
40 mg daily
Fondaparinux
2.5 mg daily
Prophylaxis
Patients with cancer
receiving medical or
surgical treatment while
staying in hospital
Prophylaxis in Medical Patients:
Ambulatory Cancer Patients
• The role of thromboprophylaxis in ambulatory cancer
patients during chemotherapy and hormone therapy is
not established.
• One double-blind placebo-controlled RCT demonstrated
the efficacy of low-intensity warfarin (INR 1.3-1.9) in
patients receiving chemotherapy for metastatic breast
cancer (Levine MN et al, Lancet 1994).
Double Blind Randomized Trial of Very-low-dose Warfarin (INR 1.31.9) for Prevention of Thromboembolism in Stage IV Breast Cancer
Patients *
Thromboembolic
events
Warfarin
n=152
Placebo
n=159
p=
1
7
0.031
relative risk reduction = 85%
* women receiving chemotherapy for metastatic breast cancer
Adapted from Levine et al., Lancet 1994.
Warfarin Prophylaxis: Limitations
• Very difficult schedule
• Interaction with cytotoxics
• Tested only in breast cancer
Prophylaxis of VTE in Medical Cancer Patients
• LMWH benefits
– Predictable anticoagulant effect
– Single daily administration
– Reduced toxicity (thrombocytopenia, osteoporosis)
– Acceptable safety profile in oncological patient (long
term use in recent studies: FAMOUS, CLOT)
Primary Prophylaxis During Chemotherapy:
LMWH Recent Closed Studies
Study
Cancer
TOPIC-1 1
Breast Cancer
TOPIC-2 1
Non small cell lung cancer
PRODIGE 2
Malignant glioma (grade III or IV)
PROTECHT
Lung, Breast, Gastrointestinal, Ovarian, Head/Neck
cancer
Adapted from: 1 Haas J Tromb Haemost 2005, suppl. 1, Abs OR059; 2 Perry et al. Thromb Res 2007, suppl. 2, Abs PO40.
Primary Prophylaxis During Chemotherapy:
LMWH Ongoing Studies
AUTHOR
STUDY
SCHEDULE
Pancreatic cancer
Maraveyas
Prospective
randomised
Gemcitabine ±
Dalteparin 200U/Kg o.d.
Pelzer
Prospective
randomised
Gemcitabine ±
Enoxaparin 1 mg/Kg
Adapted from ASCO 2007.
Recommendations for Primary VTE Prophylaxis in
Ambulatory Patients with Cancer
• Current guidelines do not recommend:
– Routine prophylaxis with an antithrombotic agent in
ambulatory cancer patients
Special consideration:
Prophylaxis in Multiple Myeloma patients
• Prophylaxis with LMWH or adjusted dose warfarin (INR~1.5) is
recommended in multiple myeloma patients receiving
thalidomide or lenalidomide + chemotherapy or dexamethasone
(high VTE risk).
• However:
– No RCTs available
– Recommendation is based on extrapolation from nonrandomized trials or randomized studies in other similar highrisk categories
– Well-designed RCTs are urgently needed
Adapted from ASCO Guidelines, JCO 2007.
Central Venous Catheter (CVC) – Related Thrombosis
Prophylaxis of CVC - Related Thrombosis
• The presence of CVC is a risk factor for VTE.
• Three recent clinical trials have assessed that the incidence of
CVC-related symptomatic thrombosis is approximately 3% to
4%.
• These trials failed to show a significant effect of prophylaxis with
1 mg fixed dose warfarin, or LMWH dalteparin, or LMWH
enoxaparin in reducing symptomatic and asymptomatic
thrombosis in patients with cancer.
Randomised Controlled Clinical Trials of Prophylaxis
of CVC - Related Thrombosis
Study
Drug
n.
CRT (%)
Karthaus M et al*
Dalteparin, 5000 IU od
Placebo
285
140
11 (3.7)
5 (3.4)
Warfarin, 1 mg od
Placebo
130
125
6 (4.6)
5 (4.0)
Enoxaparin, 40 mg od
Placebo
155
155
22 (14.2)
28 (18.1)
Ann Onc 2006
Couban S et al*
JCO 2005
Verso M et al°
JCO 2005
* Symptomatic events
°Routine venography at 6 weeks
Recommendations for Prophylaxis for CVC –
Related Thrombosis
• Current guidelines agree that extensive, routine prophylaxis to
prevent CVC-related VTE is not recommended. To date
prophylaxis might be tailored according to individual risk level.
Conclusion
• Evidence from epidemiological and clinical studies demonstrates
that not only surgical patients but also medical patients with
acute medical conditions and predisposing risk factors are at
significant risk of VTE.
• Hospitalized cancer patients should be assessed for risk of VTE
and given appropriate thromboprophylaxis.
• Early intervention with thromboprophylaxis (i.e. LMWH) will
impact cancer patient outcome.