The Art of Medical Prophylaxis, Impacting the Patient Early
Anna Falanga, MDHemostasis and Thrombosis Center
Hematology-Oncology DeptOspedali Riuniti Bergamo, Italy
Satellite Symposium
“Guidelines on Prevention and Treatment of Cancer-Associated Thrombosis”
Stockholm, September 16, 2008
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.
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 in-hospital death2
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
VTE Prevention: We are Failing Our Patients
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
Cancer: 2001FRONTLINE Survey1— 3891 Respondents
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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.
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20
30
40
50
60
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MedicalOnc
US 91 Canada 01 US 02 UK 03 US 07 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.
MEDENOX1 63% 10 Placebo
Enoxaparin 40 mg
PREVENT2 49% 45 Placebo
Dalteparin
ARTEMIS3 47% 20 Placebo
Fondaparinux
Study RRR NNT Prophylaxis Patients with VTE, %
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.
P<0.001
P=0.0015
P=0.029
NNT = number needed to treat; RRR = relative risk reduction.
RRR
63%
45%
47%
14.9* (n=288)
5.5 (n=291)
5.0 (n=1,473)†
2.8 (n=1,518)
10.5‡ (n=323)
5.6 (n=321)
*VTE at day 14; †VTE at day 21; ‡VTE at day 15.
Thromboprophylaxis of Medical Patients: Clear Benefits Over Placebo
MEDENOX PREVENT ARTEMIS
Enox. 2.1 %
Placebo 6.6 %
Dalte. 2.6 %
Placebo 5.0 %
Fond. 1.5 %
Placebo 3.4 %
P = 0.002 P = 0.085P = 0.037
Proximal DVT + Symptomatic VTE at D14-21
REnoxaparin
40 mg s.c. q.d.
Enoxaparin 40 mg s.c. q.d.
Placebo
10±4 38±4Systematic Duplex ultrasound
Days
6-month follow-up
EXCLAIM: Study Design
Prospective, randomized, double-blind 5,090 patients: enrollment completed
Inclusion Criteria
Adapted from Hull et al. J Thromb Thrombolysis. 2006; 22:31-38.
• Age > 75 years OR• History of VTE OR • Diagnosis of cancer
+
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
Level 1 mobility
(total bed rest or sedentary patients)
Level 2 mobility
(Level 1 withbathroom privileges)
or
Initial inclusion criteria
Amended inclusion criteria
4.90
1.00
0.15
2.80
0.300.60
VTE events Major bleeding
P=0.0011
P=0.019
Symptomatic DVT
P=0.0109
121
NNT
NNT = number needed to treat NNH = number needed to harm
0
1
2
3
4
5
6
Inci
den
ce (
%)
224
NNH
46
NNT
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)
Recommended Dose: Venous Thromboembolism Prophylaxis
Management Drug Regimen
Prophylaxis
Patients with cancer receiving medical or surgical treatment while staying in hospital
Unfractionated Heparin (UFH)
5000 U q 8 h
Dalteparin 5000 U daily
Enoxaparin 40 mg daily
Fondaparinux 2.5 mg daily
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).
Patients * Warfarin Placebo p=n=152 n=159
Thromboembolicevents 1 7 0.031
relative risk reduction = 85%
* women receiving chemotherapy for metastatic breast cancer
Adapted from Levine et al., Lancet 1994.
Double Blind Randomized Trial of Very-low-dose Warfarin (INR 1.3-1.9) for Prevention of Thromboembolism in Stage IV Breast Cancer
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 STUDYPancreatic cancer
SCHEDULE
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 non-
randomized trials or randomized studies in other similar high-risk 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* Ann Onc 2006
Dalteparin, 5000 IU od
Placebo
285
140
11 (3.7)
5 (3.4)
Couban S et al*JCO 2005
Warfarin, 1 mg od
Placebo
130
125
6 (4.6)
5 (4.0)
Verso M et al° JCO 2005
Enoxaparin, 40 mg od
Placebo
155
155
22 (14.2)
28 (18.1)
* Symptomatic events°Routine venography at 6 weeks
• 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.
Recommendations for Prophylaxis for CVC – Related Thrombosis
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.