The Art of Medical Prophylaxis, Impacting the Patient Early

1
The Art of Medical Prophylaxis, Impacting the
Patient Early
Satellite Symposium Guidelines on Prevention and
Treatment of Cancer-Associated Thrombosis Stockho
lm, September 16, 2008

• Anna Falanga, MD
• Hemostasis and Thrombosis Center
• Hematology-Oncology Dept
• Ospedali Riuniti Bergamo, Italy

2
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

Adapted from 1. ACCP 2004. 1.Geerts WH, et al.
Chest. 2004126S338S400, 2. Cohen A et al.
Lancet 2008371387-394.
3
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

4
VTE Prevention We are Failing Our Patients
Cancer 2001 FRONTLINE Survey1 3891 Respondents
60
52
50
50
43
40
33
Rate of Appropriate Prophylaxis,
30
29
28
30
20
10
5
0
Surgical
Medical
US 91
Canada 01
US 02
UK 03
US 07
World 07
Onc
Onc
Adapted from 1. Kakkar AK et al. Oncologist.
20038381-88. 2. Anderson FA et al. Ann Intern
Med. 1991115591-95. 3. Rahim SA et al. Thromb
Res. 2003111215-19
4. Goldhaber SZ et al. Am J Cardiol.
200493259-62. 5. Rashid J Royal Soc Med
2005. 6. Spencer FA et al. Arch Intern Med
20071671471-75. 7. Tapson VF, et al. Chest
2007132936-45.
5
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

6
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

7
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.

8
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
1999341793-800 2. Leizorovicz et al.
Circulation 2004110874-79 3. Cohen et al.
Blood 2003 102(11) 15.
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Thromboprophylaxis of Medical Patients Clear
Benefits Over Placebo
RRR 63 45 47
Study RRR NNT Prophylaxis Patients with
VTE,
MEDENOX1 63 10 Placebo Enoxaparin 40
mg PREVENT2 49 45 Placebo Dalteparin A
RTEMIS3 47 20 Placebo Fondaparinux
14.9 (n288)
Plt0.001
5.5 (n291)
5.0 (n1,473)
P0.0015
2.8 (n1,518)
10.5 (n323)
5.6 (n321)
P0.029
VTE at day 14 VTE at day 21 VTE at day 15.
NNT number needed to treat RRR relative
risk reduction.
Adapted from 1Samama et al. N Engl J Med
1999341793-800. 2Leizorovicz et al.
Circulation 2004110874-9. 3Cohen et al. Br Med
J 2006.
10
Proximal DVT Symptomatic VTE at D14-21
MEDENOX
PREVENT
ARTEMIS
Dalte. 2.6
Fond. 1.5
Enox. 2.1
Placebo 6.6
Placebo 5.0
Placebo 3.4
P 0.002
P 0.085
P 0.037
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EXCLAIM Study Design
Enoxaparin 40 mg s.c. q.d.
Enoxaparin 40 mg s.c. q.d.
R
Placebo
6-month follow-up
104
384 Systematic Duplex ultrasound
Days

• Prospective, randomized, double-blind
• 5,090 patients enrollment completed

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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)
Level 2 mobility (Level 1 withbathroom
privileges)
or
Adapted from Hull et al. J Thromb Thrombolysis.
2006 2231-38.
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Summary of Efficacy and SafetyEnd of the
Double-blind Period
P0.0011
6
5
P0.019
P0.0109
4
Incidence ()
3
2
1
0
VTE events
Major bleeding
Symptomatic DVT
NNT number needed to treat NNH number needed
to harm
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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
Patients with cancer receiving medical or surgical treatment while staying in hospital Dalteparin 5000 U daily
Patients with cancer receiving medical or surgical treatment while staying in hospital Enoxaparin 40 mg daily
Patients with cancer receiving medical or surgical treatment while staying in hospital Fondaparinux 2.5 mg daily
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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).

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Double Blind Randomized Trial of Very-low-dose
Warfarin (INR 1.3-1.9) for Prevention of
Thromboembolism in Stage IV Breast Cancer
Patients
Warfarin
Placebo
p
n152
n159
Thromboembolic
events
1
7
0.031
relative risk reduction 85
women receiving chemotherapy for metastatic
breast cancer
Adapted from Levine et al., Lancet 1994.
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Warfarin Prophylaxis Limitations

• Very difficult schedule
• Interaction with cytotoxics
• Tested only in breast cancer

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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)

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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.
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Primary Prophylaxis During ChemotherapyLMWH
Ongoing Studies
AUTHOR STUDY Pancreatic cancer SCHEDULE
Maraveyas Prospective randomised Gemcitabine Dalteparin 200U/Kg o.d.
Pelzer Prospective randomised Gemcitabine Enoxaparin 1 mg/Kg
Adapted from ASCO 2007.
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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

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Special consideration Prophylaxis in Multiple
Myeloma patients

• Prophylaxis with LMWH or adjusted dose warfarin
  (INR1.5) 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.
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Central Venous Catheter (CVC) Related Thrombosis
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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.

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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 alJCO 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
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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.

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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.