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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30

40

50

60

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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.