Gerotziafas

Prophylaxis and treatment of VTE in medical patients Grigoris T Gerotziafas

Groupe de Thrombose Equipe de recherche ER2UPMC Interactions cellulaires tumorales et leur environnement et réponses aux agents anticancéreux.

Service d’Hématologie Biologique Hôpital Tenon, APHP, Paris, France

Disclosures Research Support/P.I. Employee Consultant

Sanofi-aventis, Bayer HealthCare, Bristol-Myers Squibb, GlaxoSmithKline, Leo-Pharma, No relevant conflicts of interest to declare

Major Stockholder

Sanofi-aventis, Bayer HealthCare,GlaxoSmithKline, Rovi No relevant conflicts of interest to declare

Speakers Bureau

No relevant conflicts of interest to declare

Scientific Advisory Board

Sanofi-aventis, Bayer HealthCare, GlaxoSmithKline, Leo-Pharma, Pfizer

Agenda • • •

• •

Definitions on VTE and the magnitude of the problem Methods for VTE prophylaxis and treatment 2012: Recommendations for VTE prophylaxis in medical patients VTE Risk stratification of medical patients 2012 : Recommendations for the treatment of VTE

VTE some definitions VTE = DVT and /or PE 70% of patients have DVT + PE 30% of patients have only PE

Pulmonary Pulmonary embolism embolism

thrombosis thrombosisoccurs occursinin pulmonary pulmonaryarteries arteries

Proximal ProximalDVT DVT

when whenthrombus thrombusisis formed formedininfemoral, femoral,iliac, iliac, pelvic pelvicveins veinsor orinferior inferior vena venacava cava

Distal Distal DVT DVT

Venous ThromboEmbolism A silent killer 1 10

Fatal PE Symptomatic PE

50 100 300-1000 Iceberg model

Asymptomatic PE Symptomatic DVT Asymptomatic DVT

Natural history of VTE without treatment in-hospital mortality  20% in patients with PE  3% in patients with DVT

1-year mortality  39% in patients with initial PE  21% in patients with DVT

Deaths/year

VTE : a major health problem 12% 12%of ofthe the cumulative cumulative mortality mortalityin in EU EU

Cohen AT, et al (VITAE). Thromb Haemost 2007; 98: 756–764

VTE is a multifactorial and often silent disease Antiphospholipids Pregnancy

Cancer

Age Smoking

Diabetes

Congenital Thrombophilia HIT

THROMBOSIS A multifactorial accident

Hypertension Others

Acute infection Hyperlipidaemia

Incidence of asymptomatic DVT without prophyalxis Internal Medicine1 General Surgery2,3 AMI2

Stroke4 Oncology2

0%

15 % 25 %

50 % Samama et al, N Engl J Med 1999 ; 341 : 793-800

1

Geerts et al, CHEST 2001 ; 119 : 132S-175S

2

Collins R et al. Br Med J 1996;313:652–9 Councell et al. The Cochrane Library 1999:Issue 2

3 4

Hippocrate 350 b.c.

Το προλαμβάνειν κάλλιον του θεραπεύειν εστι It is better to prevent than to treat

Agenda • • •

• •

Definitions on VTE and the magnitude of the problem Methods for VTE prophylaxis and treatment 2012: Recommendations for VTE prophylaxis in medical patients VTE Risk stratification of medical patients 2012 : Recommendations for the treatment of VTE

Methods of thromboprophylaxis •

•

Mechanical (only prophylaxis) •

Graduated compression stockings

•

Intermittent pneumatic compression

•

Foot pump

Pharmacological (prophylaxis + treatment) •

Unfractionated heparin

•

Low-molecular-weight heparins

•

Fondaparinux

•

Rivaroxaban, apixaban, edoxaban, dabigatran

History of antithrombotic agents 21st century Programmed and designed new antithrombotics aiming at specific targets

2004 : Orally active FXa inhibitorsSemi 2003 specific anti-IIa

2002 Fondaparinux 1983 synthesis of Ultra-LMWHs pentasaccharide

synthetic LMWHs

1980 : LMWHs 1966 : s.c. administration of UFH 20th century 1950 : Clinical use of vitamin K antagonists Discovery by serendipity of heparin in 1940 Discovery of dicoumarol Baltimore and antivitamin K in 1924 -1930 Clinical studies with UFH Wisconsin 1914 Discovery of Heparin 1910

1920 1930 1940 1950 1960 1970 1980 1990

2000

Simple Simple classification classification of of anticoagulants anticoagulants

Factor Xa

Thrombin

AT-dependent inhibitors: Pentasaccharide, heparins, ULMWHs (semuloparin)

AT-dependent inhibitors: Heparins, danaparoid, ULMWHs (semuloparin) HCII-dependent inhibitors

Direct inhibitors: Rivaroxaban, apixaban, edoxaban ‌

Direct inhibitors:

Parenteral

Oral

Dabigatran, lepirudin, bivalirudin‌ Gerotziafas GT, Samama MM. Current Pharmaceutical Design, 2005,

Efficacy of antithrombotics in major orthopedic surgery 100

% of DVT

80

Reduction of frequency of DVT with different antithrombotics Warfarin Low Doses UFH

60

40

20

LMWHs

47% 43%

Fondaparinux 27.8%

Rivaroxaban 12.5%

9%

Meta-analysis: Anticoagulant Prophylaxis to Prevent Symptomatic Venous Thromboembolism in Hospitalized Medical Patients •

Sources: MEDLINE (n=382 studies), EMBASE (n=358 studies), Cochrane Library (n=375 studies)

•

Randomized placebo controlled trials

•

Clinical outcomes: symptomatic PE, symptomatic DVT, major bleeding, all cause mortality

•

Anticoagulant regimens: • • • • • •

•

UFH 5000 IU x 2 or 3 s.c.

Enoxaparin 40 mg or 60 mg s.c. od Enoxaparin 30 mg x 2 s.c.

Nadroparin 4000 or 6000 anti-Xa IU s.c. od Dalteparin 5000 anti-Xa IU s.c. od Fondaparinux 2,5 mg s.c. od.

9 studies included in the metaanalysis Dentali et al Ann Intern med 2007;146:278-288

Efficacy outcome for symptomatic DVT during prophylaxis

Dentali et al Ann Intern med 2007;146:278-288

Major bleeding during prophylaxis

Dentali et al Ann Intern med 2007;146:278-288

Agenda • • •

• •

Definitions on VTE and the magnitude of the problem Methods for VTE prophylaxis and treatment 2012: Recommendations for VTE prophylaxis in medical patients VTE Risk stratification of medical patients 2012 : Recommendations for the treatment of VTE

Thromboprophylaxis in acutely ill medical patients ACCP 2012 recommendation

Level of evidence

Intermediate VTE risk

no

1B

High Bleeding risk

no

1B

LMWH, fondaparinux, LDUH, bid or tid GCS IPC Initiation of pharmacological prophylaxis when bleeding risk is low During patient immobilisation or acute hospital stay

1B

Low VTE risk

High VTE risk High VTE/High Bleeding risk

duration

no

1B

2C 2C 2B 2B

Thromboprophylaxis in critically ill medical patients

High VTE risk High VTE/High Bleeding risk

duration

ACCP 2012 recommendation

Level of evidence

GCS IPC Initiation of pharmacological prophylaxis when bleeding risk is low During patient immobilisation or acute hospital stay

2C 2C 2C

LMWH, LDUH, bid or tid

1B

2B

Thromboprophylaxis in medical patients : up to date First step for thromboprophylaxis decision in intensive care unit (ICU) patients.

NO

YES

NO

YES Thromboprophylaxis High risk of fatal PE

PE = Pulmonary Embolism Crit Care Med 2010;38 (suppl):S12

Agenda • • •

• •

Definitions on VTE and the magnitude of the problem Methods for VTE prophylaxis and treatment 2012: Recommendations for VTE prophylaxis in medical patients VTE Risk stratification of medical patients 2012 : Recommendations for the treatment of VTE

Recommandation of the 9th 2012 ACCP Guidelines • Selection of the Padua Prediction Score risk assessment model as the best available basis for judging hospitalized patients’ risk.

• It included a score for bleeding risk factors in hospitalized medical patients

ACCP 2012: Thromboprophylaxis in medical patients Padua Prediction Score risk assessment model

Risk factors for VTE in hospitalized medical patients Risk RiskFactor Factor Active cancer Previous VTE (with the exclusion of superficial vein thrombosis) Reduced mobility Already known thrombophilic condition Recent (≤ 1 mo) trauma and/or surgery Elderly age (³ 70 y) Heart and/or respiratory failure Acute myocardial infarction or ischemic stroke Acute infection and/or rheumatologic disorder Obesity (BMI ³30) Ongoing hormonal treatment

Points Points 3 3 3 3 2 1 1 1 1 1 1

High risk ≥ 4 S.R. Kahn et al Chest 2012;141:e195S-e226S

Risk factors for definite VTE mong Olmsted Country, Minnesota, residents with a first lifetime VTE Surgery Trauma Inpatient Malignant Neoplasm With Chemotherapy Malignant Neoplasm Without Chemotherapy Central Venous Catheter or Pacemaker Neurologic Disease Superficial Vein Thrombosis Varicose Veins (Age 45 y) Varicose Veins (Age 60 y) Varicose Veins (Age 70 y) CHF*, VTE Incidental on Autopsy CHF, Antemortem VTE, or VTE Causal of Death Liver Disease

0 *CHF : congestive heart failure.

5

10 15 20 25 Odds Ratio (95% CI) Heit et al , Arch

Int

Med

50

quency of VTE risk factors in real-life hospitalised patie

COMPASS Registry

Prophylaxis of VTE in medical cancer patients.

Context

Therapeutic Option

Level of evidence.

hospitalized medical patients with cancer and reduced mobility children with ALL treated with Lasparaginase

Out-patients on chemotherapy Out-patients on chemotherapy locally advanced or metastatic pancreatic cancer lung cancer Patients treated with thalidomide or lenalidomide combined with steroids and/ or chemotherapy (doxorubicin) Values and preferences: subcutaneous injections.

LMWH, UFH or fondaparinux

1B

Prophylaxis can be considered after careful risk assessment based on clinical and biological data (i.e. renal function platelet count, level of Fg, AT etc) No prophylaxis

Poor

Pharmacological thromboprophylaxis

1B

VKA at low or therapeutic doses, LMWH at prophylactic doses low-dose aspirin

2C

1B

ACCP 2012 : Thromboprophylaxis in medical patients Independent risk factors for bleeding in 10.866 hospitalized medical patients Risk Factor Total patients : 10.866 Active gastroduodenal ulcer Bleeding in 3 mo before admission Platelet count < 50X 109/L Age ≥ 85 y (vs < 40 y) Hepatic failure (INR > 1.5) Severe renal failure (GFR < 30 mL/min/m²) ICU or CCU admission Central venous catheter Rheumatic disease Current cancer Male sex

OR (95 % CI) 4.15 (2.21-7.77) 3.64 (2.21-5.99) 3.37 (1.84-6.18) 2.96 (1.43-6.15) 2.18 (1.10-4.33) 2.14 (1.44-3.20) 2.10 (1.42-3.10) 1.85 (1.18-2.90) 1.78 (1.09-2.89) 1.78 (1.20-2.63) 1.48 (1.10-1.99)

Bleeding score ≥ 7 S.R. Kahn et al. Chest 2012;141:e195S-e226S

Frequency of bleeding risk factors in real-life hospitalised patients

COMPASS Registry

RCT of NATA in VTE prophylaxis in medical and oncological patients RCT

Studied populations

Experimental design

MAGELLAN

Acutely ill medical patients

ADOPT

Acutely ill medical patients

Rivaroxaban 10 mg vs enoxaparin 40 mg for 10 d and Rivaroxaban 10 mg vs placebo until the day 35.

Apixaban 2.5 mg b.o.d vs enoxaparin 40 mg for 6 â&#x20AC;&#x201C; 14 d and Apixaban 2.5 mg b.o.d vs placebo until the day 35

SAVEONCO

Oncological patients on chemotherapy

Semuloparin 20 mg o.d vs placebo for 3.5 months.

Efficacy of NATA in VTE prophylaxis

Frequency of VTE

Total Totalstudied studiedpopulation population

NATA comparator

Cancer Cancerpatients patients

Safety* of NATA in VTE prophylaxis Cancer Cancerpatients patients

Frequency of bleeding

Total Totalstudied studiedpopulation population

NATA comparator *Major and clinically relevant bleeding

Descriptive values for the incidence of clinically relevant bleeding consistently favored enoxaparin over rivaroxaban in patients with active cancer

Agenda • • •

• •

Definitions on VTE and the magnitude of the problem Methods for VTE prophylaxis and treatment 2012: Recommendations for VTE prophylaxis in medical patients VTE Risk stratification of medical patients 2012 : Recommendations for the treatment of VTE

Basic principles for the management of VTE with parenteral anticoagulants and VKA * LMWH at therapeutic doses (anti-Xa: 0,5 – 1 UI/ml) (Grade : 1B) or *UFH dose adjusted for aPTT ratio 2 – 3 or anti-Xa 0.3 – 0.6 IU/ml (Grade 1B) or Fondaparinux 7,5 mg 1 injection s.c. per day (Platelet monitoring is not recommended) (Grade 1B) LMWH or fondaparinux over UFH (Grade 2B)

Platelet count*

D3*

D5*

UFH, LMWH, Fondaparinux

Initiation phase

Treatment with VKA INR: 2 - 3 D2 D3

D4

D5

D2 D2

Once/week Once/month

Effect of initial dose of warfarin (5 mg or 10 mg) on vitamin K dependent clotting factors Loading Dose then Maintenance Dose

Daily Dose

PC

Maintenance Dose Only

Daily Dose

PC

Thrombin generation in patients on VKA treatment ETP (nMxmin)

control

VKA/enoxa INR 2,7; aXa 0,6 IU/ml

VKA INR 2,1

VKA INR 6 Severe hemophilia FVIII = 2%

time (min) Gerotziafas et al Thromb Haemost. 2009;102:42-8.

ACCP 2012 : Treatment of VTE ACCP 2012 recommendations Anticoagulants over Catheter directed thrombolysis

Level of evidence 2C

Anticoagulants over systemic thrombolysis

2C

Anticoagulants over venous thrombectomy

2C

Against IVC filter in addition to anticoagulant treatment

2C

IVC filter when anticoagulant treatment is contraindicated

2C

If IVC filter is placed the anticoagulant treatment should be continued

2C

9th ACCP: Duration of antithrombotic treatment Clinical manifestation 1st épisode of DVT

Risk Factor Duration of treatment Absent

Absent

3 months > low or moderate bleeding risk 3 months > High bleeding risk Long term > moderate bleeding risk Long term > High bleeding risk Long term > low bleeding risk Long ter ; > moderate bleeding risk 3 mois > High bleeding risk 3 months > low or moderate bleeding risk 3 mois > High bleeding risk Long term> low bleeding risk

Transitory

Long term > moderate bleeding risk 3 mois > High bleeding risk 3 months

Cancer

Recidivant DVT

1st épisode of PE

2nd épisode of PE

1st ep or peripheral DVT

Absent

Absent

Level of recommendation 2B 1B 1B 2B 1B 2B 2B 2B 1B 1B 2B 2B 1B

Risk of recurrence of VTE after treatment interruption according to the nature of the risk factor

Risk of recidivant VTE in relation the presence of known risk factors High risk or recurrence Risk factors Active cancer

Increase of the Relative Risk >6

Homozygous mutation of FV Leiden

4

Hereditary deficiency of AT

3

Homozygous mutation of FIIG20210A Mixed thrombophilia

2-4 4

Heterozygous FIIG20210A + Heterozygous FV Leiden Increased Ddimers after treatment interruption (> 500 ng / ml) Increased Thrombin Generation (CAT)

2-5

Significant residual clot after DVT

2-5

5 2-4

Antiphospholipide syndrom

3

Permanent risk factor

>2

Risk of recidivant VTE in relation the presence of known risk factors Low risk or recurrence Risk factors Heterozygous mutation of FV Leiden Hereditary deficiency of protein C

Increase of the Relative Risk 1-2 1.5-2

Heterozygous mutation FIIG20210A

1-2

Protein S deficiency

1.5

BMI> 30

1.9

FVIII> 150 UI / dL

1.3

Age : 11.1 increase of the risk for every 10 ys

1.1

Immobilisation

0.9

Transient risk factor

<0.5

Bleeding risk factors during treatment with VKA Intensity of treatment Patients’ characteristics

Underlying disease

Bleeding risk factors during treatment with VKA Target INR

Elderly Polymorphismes *2 and *3 of the CYP2C9 subunit of the cytochrome P450 induce a delayed métabolisme resulting in accumulation Mutation VKORC1 (C1173Tp) at the gene of époxyde réductase of vitamin K • Low social class • Difficile of the access to hemlab • Mental disorders Renal insufficiency

Hemorragic risk If INR> 3 the risk is 2-fold higher vs INR 2-3 INR> 4: the risk increases x2 for each unit of augmentation of the INR > 75 ys the bleeidng risk is x2 the risk of intracrnial bleeding is x2.5 vs patients with the same INR and age<75 ys x2 vs patients withot the polymorphisms CYP2C9 *2 or *3 x2 vs patients without the polymorphisms VKORC1

x2,5

Liver insufficiency

x2,5

Hypertension

x1,5

Diabetes Recent bleeding Interactions médicamenteuses

Antiplaquettaires

x3

Anti-inflammatoires non-stéroïdiens antiVIH

x 11

Platelet monitoring for early HIT diagnosis Risk for HIT High risk for HIT (>1%) Low risk for HIT (<1%)

ACCP 2012 recommandations Platelet count every 2 â&#x20AC;&#x201C; 3 days from d4 to d14 No monitoring of platelet count

Level of evidence 2C 2C

Alternative antithrombotic treatment

HIT Thrombosis HITT + renal insufficiency

Lepirudin, argatroban, danaparoid

1C

argatroban

2C

Initiation of VKA only when Plt>150 G/L Parenteral anticoagulant treatment + VKA (wrfarin 5 mg) for minimum 5 days

1C

Alg Au eria Ba stra ng l lad ia es h Bra Bu zil lg Co aria lo Cz mbia ech Re p Eg y Fra pt Ge nce rm an Gr y ee H u ce ng ary In d Ire ia lan Ku d wa Me it Pa xico kis ta Po n la Po nd rtu Ro gal ma nia Sa Rus s ud i A ia rab Slo ia va ki a S Sw p it ze ain rl Th and aila n Tu d nis i Tu a rke y UA E UK Ve USA ne zu ela

%

% Use of ACCP recommended Px among Medical patients at Risk for VTE per Country

100

80

60

Mean=48%

40

20

0

Working group for guidelines implementation •

Multidisciplinary group with medical members from •

Thrombosis/Haemostasis Unit

•

Emergency department

•

Surgery

•

Internal medicine

•

Anesthesiology departement

•

Clinical epidemiology serviceist

•

Hospital pharmacy Scaglione L et al Haematologica 2005; 90:678-684

Minimally effective strategies Traditional didactic continuing medical education lectures Dissemination of newsletters Dissemination of clinical practice guidelines Computerized guidelines Training in critical appraisal Medication profiles Drug utilization review, retrospective or prospective

More effective strategies •

Audit and feedback with comparison to local peers

•

Real-time clinical reminders, computerized or paper based

•

Face-to-face educational outreach (academic detailing)

•

Local opinion leaders

•

Disease management approaches

•

Computerized physician order entry

•

Use of Risk Assessemnt models (i.e. DecisionMatrix etc)

Optimisation of antithrombotic prophylaxis •

National and International Guidelines

•

Risk assessment

•

•

Individualized

•

Groups of patients (i.e. major orthopedic surgery

Methods of thromboprophylaxis •

Which antithrombotic agent

•

Timing of the first injection

•

Duration of thromboprophylaxis

grigoris.gerotziafas@tnn.aphp.fr

Groupe de Thrombose quipe de recherche ER2UPMC Interactions cellulaires tumorales et leur environnement et réponses aux agents anticancéreux.

Service d’Hématologie Biologique Hôpital Tenon, APHP, Paris,

Classification of recommendations Recommendati on

Definition

Strong (Grade 1)

The panel is confident that the desirable effects of adherence to a recommendation outweigh the undesirable effects

Weak (Grade 2)

The panel concludes that the desirable effects of adherence to a recommendation probably outweigh the undesirable effects, but is not confident

Best clinical practice (Guidance)

In the absence of any clear scientific evidence and because of undetermined balance between desirable and undesirable effects, judgment was based on the professional experience and consensus of the international experts within the

Drug

Dosage and duration

Study

Enoxaparin

1.5 mg kg)1 per day for 3 months

CANTHANOX [MEYER2002]

Dalteparin

200 IU kg)1 per day for 1 month, 150 IU kg)1 per day for 5 months

CLOT [LEE2003]

Tinzaparin

175 IU kg)1 per day for 3 months

LITE [HULL2006]

Idraparinux

2.5 mg per week first dose, then 2.5 mg per week or VANGOGH 1.5 mg per week subgroup if creatinine clearance < 30 mL min)1 for 3 or 6 month [VANDOORMAAL2 010]

Treatment of established VTE Therapeuti Option

Level of evidence.

LMWH

1B

Fondaparinux UFH Thrombolysis To be considered on a case-by-case basis

2D

vena cava filters in the case of contraindication for anticoagula- tion or in the case of PE recurrence under optimal anticoagulation.

poor

poor

Values and preferences LMWHs are easier to use than UFH fondaparinux is easier to use than UFH pecific attention paid to contraindications, especially bleeding risk (brain metastasis)

Secondary prevention of established VTE Early maintenance : 10 days to 3 months and long-term treatment : > 3 months Therapeuti Option

Level of

Values and preferences

evidence.

LMWHs are preferred over VKA

1A

LMWH should be used for a minimum of 3 months After 3–6 months, termination or continuation of anticoAgulation should be based on individual evaluation of the benefit-risk ratio, tolerability, patients preference cancer activity

1A No data

daily subcutaneous injection may represent a burden for patients Best clinical practie – experts’ suggestions

Treatment of VTE recurrence in cancer patients under anticoagulation Early maintenance : 10 days to 3 months and long-term treatment : > 3 months Therapeuti Option

Level of

Values and preferences

evidence.

switch from VKA to LMWH in patients treated with VKA increase in LMWH dose in patients treated with LMWH vena cava filter insertion

poor

individual decision.

New oral anticoagulant agents (NOAC) â&#x20AC;˘

The experts of the working group acknowledge the potential benefit of new oral anticoagulant agents for the treatment of VTE in cancer patients. However, the group considered it was premature to issue recommendations or guidance on the use of these new agents in this setting

Prophylaxis of VTE in surgical cancer patients.

Therapeuti Option

Level of evidence.

Values and preferences

Dosage regimen evaluated in clinical trials of thromboprophylaxis in surgical Studie cancer patients s (n)

LMWH

Dalteparin 5000 IU per day for 8–9 days Dalteparin 2500 IU per day for 7 days Nadroparin 2850 IU per day for 7–11 days Enoxaparin 40 mg per day for 10 ± 2 days Enoxaparin 25 mg per day for 10 ± 2 days

3 1 1 3 1

Factor Xa inhibitors LMWH

Fondaparinux 2.5 mg per day for 5–9 days

1

extended use

Tinzaparin 3500 IU per day for 3 weeks (after 7 days postoperatively) Enoxaparin 40 mg per day for 25–31 days (28 days) Dalteparin 5000 IU per day for 21 days (after 7 days postoperatively) Bemiparin sodium 3500 IU per day for 28 days

1 1 1 1

Prophylaxis of VTE in surgical cancer patients.

Therapeutic Option

Level of

Values and preferences

evidence.

LMWH once a day or a low dose of UFH 3 times a day

1A

No evidence for fondaparinux as alternative to LMWH

1C

Dose of LMWH highest prophylactic dose of LMWH Initiation of LMWH 12â&#x20AC;&#x201C;2 h preoperatively Duration at least 7â&#x20AC;&#x201C;10 days 4 weeks after major laparotomy if VTE risk is high and bleeding risk is low

1A 1A

1A 2B

there are no data allowing conclusions regarding the superiority of one type of LMWH over another [Grade 1A].

LMWH once a day is more convenient

•

The use of LMWH for the prevention of VTE in cancer patients undergoing laparoscopic surgery may be recom- mended in the same way as for laparotomy [Best clinical practice, based on a balance between desirable and unde- sirable effects indicating an increased bleeding risk].

•

Values and preferences: daily injections.

•

Costs: In some countries, the price of LMWH may influence the choice.

•

Mechanical methods are not recommended as monotherapy except when pharmacological

Prophylaxis of VTE in medical cancer patients.

Context

Therapeutic Option

Level of evidence.

hospitalized medical patients with cancer and reduced mobility children with ALL treated with Lasparaginase

Out-patients on chemotherapy Out-patients on chemotherapy locally advanced or metastatic pancreatic cancer lung cancer Patients treated with thalidomide or lenalidomide combined with steroids and/ or chemotherapy (doxorubicin) Values and preferences: subcutaneous injections.

LMWH, UFH or fondaparinux

1B

Prophylaxis can be considered after careful risk assessment based on clinical and biological data (i.e. renal function platelet count, level of Fg, AT etc) No prophylaxis

Poor

Pharmacological thromboprophylaxis

1B

VKA at low or therapeutic doses, LMWH at prophylactic doses low-dose aspirin

2C

1B

Special situations •

brain tumor per se is not a contraindication for anticoagulation for established VTE [Grade 2C].

•

Treatment with LMWH is prefered [this opinion reflects the views of the panel group.

•

]

Thromboprophylaxis in cancer patients ACCP 2012 recommandations no

Level of evidence 1B

Intermediate VTE risk

no

1B

High Bleeding risk

no

1B

LMWH, fondaparinux, LDUH, bid or tid GCS IPC Initiation of pharmacological prophylaxis when bleeding risk is low During patient immobilisation or acute hospital stay

1B

Low VTE risk

High VTE risk High VTE/High Bleeding risk

duration

2C 2C 2B 2B

Thromboprophylaxis in cancer outpatients

Only cancer Cancer + VTE risk factors Low bleeding risk Cancer and CVC duration

ACCP 2012 recommendation no

Level of evidence 2B

LMWH or LDUH No LMWH No VKA ?

2B

2B 2C

Khorana score A validated predictive model for chemotherapy-associated VTE Patient characteristics

Risk score

 Site of cancer 

very high risk (stomach, pancreas)

2



high risk (lung, lymphoma, gynaecologic)

1

pre-chemotherapy platelet count ≥ 350 000/mm3

1

haemoglobin < 10 g/dl or use of red cell growth factors1 pre-chemotherapy leucocyte count > 11 000/mm3

1

Body mass index ≥ 35 kg/m²

1

core : 0 = Low Risk

1-2 = Intermediate Risk

≥ 3 = High Risk

T. Sousou; A. Khorana Hämostaseologie 2009; 29: 121-124

Khorana Score : Risk Model Validation

Agenda • • •

• • • •

Definition on VTE and the magnitude of the problem Methods for VTE prophylaxis and treatment 2012: Recommendations for VTE prophylaxis in medical patients VTE Risk stratification of medical patients VTE prophylaxis in cancer patients New AntiThrombotic Agents in medical and cancer patients 2012 : Recommendations for the treatment of VTE

Main drug interactions and contraindications of the NATA Rivaroxaban

Apixaban

drug interactions

contraindications

Inhibitors

creatinin clearance < 30 ml/min or liver impairment ketokonazol co-administration creatinin clearance < 30 ml/min in liver impairement : Possibly safe as no hepatic metabolism but caution advised ketokonazol co-administration

of CYP3A4 : imatinib -azoleâ&#x20AC;? drugs : i.e antimycotics like ketokonazol traconazole, voriconazole, posaconazole, except fluconazole, selective serotonin reuptake inhibitors, diltiazem, and cimetidine HIV protease inhibitors (i.e ritonavir) of P-glycoprotein Cyclosporine, lapatinib, nilotinib, sunitinib, tamoxifen rifampycine amiodaron, quinidin, clarithromicine, verapamil, macrolides (clarithromycine), phenytoine, phenobarbital, St. Johnâ&#x20AC;&#x2122;s wort

Inducers

Dabigatran

of CYP3A4 dexamethasone of P-glycoprotein dexamethasone, doxorubicin, vinblastin Inhibitors of P-glycoprotein Minor interactions with atorvastatin

Lower dose if creatinin clearance is 15 â&#x20AC;&#x201C; 30 ml/min Contraindication if creatinin clearance < 30 ml/min

Interactions cellulaires tumorales et leur environnement et rĂŠponses aux agents anticancĂŠreux.

New antithrombotic agents in the treatment of VTE; a subgroup analysis of the Phase III randomized clinical trials.

Grigoris T Gerotziafas, Michel M Samama, Ismail Elalamy

Randomized Controlled Trials with NATA in VTE treatment

RCT

Studied populations

Experimental design

EINSTEIN Acute DVT

treatment of sympromatic DVT for 3, 6 or 12 months

Rivaroxaban 15 mg b.i.d x 3 weeks and then 20 mg o.d versus Enoxaparin 1 mg/kg bid s.c./VKA for 6 months

EINSTEIN DVT extension

Duration more 6 months after completing the first phase of treatment.

Rivaroxaban 20 mg o.c versus placebo

EINSTEIN-PE

treatment of sympromatic PE Rivaroxaban 15 mg b.i.d x 3 weeks and for 3, 6 or 12 month then 20 mg o.d versus Enoxaparin 1 mg/kg bid s.c./VKA

RECOVER

Treatment of sympromatic acute proxymal DVT orPE who were initially given parenteral anticoagulant therapy Duration of treatment 6 months

Dabigatran 150 mg b.i.d versus dose adjusted warfarin INR 2-3

Cancer patients in the RCT with direct NATA in VTE treatment RCT

Total studied population

Patients with cancer

EINSTEIN Acute DVT

Rivaroxaban = 1731

Rivaroxaban = 6.8%

Enox/VKA= 1718

Enox/VKA = 5.2%

Rivaroxaban= 602

Rivaroxaban = 4.5%

placebo= 594

Placebo = 4.4%

Rivaroxaban= 2419

Rivaroxaban = 4.7%

Enox/VKA= 2413

Enox/VKA= 4.5%

Dabigatran = 1274

Dabigatran = 5%

VKA = 1265

VKA = 4.5%

EINSTEIN DVT extension

EINSTEIN-PE

RECOVER

Efficacy of direct NATA in VTE treatment

Frequency of VTE

Total Totalstudied studiedpopulation population

NATA comparator

Cancer Cancerpatients patients

Safety* of direct NATA in VTE treatment

Frequency of bleeding

Total Totalstudied studiedpopulation population

NATA comparator *Major and clinically relevant bleeding

Cancer Cancerpatients patients

RCT with antithrombin-dependent NATA in VTE treatment

RCT

Studied populations

Experimental design

MATISSE-PE

Treatment of sympromatic PE

Fondaparinux 7.5 mg s.c. o.d. followed by VKA versus UFH i.v./VKA for 6 months

MATISSE-DVT

Treatment of sympromatic acute DVT

Fondaparinux 7.5 mg s.c. o.d. followed by VKA versus Enoxaparin 1 mg/kg bid s.c./VKA

EQUINOX

Treatment of sympromatic acute DVT

Idrabiotapariux 3 mg s.c./week Versus Idraparinux 2.5 mg s.c./ week

Van-Gogh

Treatment of sympromatic acute

Idraparinux 2.5 mg s.c. once weekly versus LMWH s.c./VKA total duration of treatment 3 months (22% of patients) or 6 months (78%)

Cancer patients in RCT of Antithrombin-dependent NATA in VTE treatment

RCT

Total studied population

Patients with cancer

MATISSE-PE

Fondaparinux = 1103

Fondaparinux = 10%

UFH/VKA= 1110

UFH/VKA= 10%

Fondaparinux = 1098

Fondaparinux = 11%

Enoxaparin/VKA= 1107

UFH/VKA = 11%

idrabiotaparinux= 386

Idrabiotaparinux = 4.7%

idraparinux= 371

Idraparinux = 5.7%

Idraparinux = 1452

Idraparinux = 15%

LMWH/VKA = 1452

LMWH/VKA =14.5%

MATISSE-DVT

EQUINOX

Van-Gogh

Efficacy of AT-dependent NATA in VTE treatment

Frequency of VTE

Total Totalstudied studiedpopulation population

NATA comparator

Cancer Cancerpatients patients

Influence of cancer stage on the efficacy of fondaparinux

NATA comparator

Safety* of AT-dependent NATA in VTE treatment

Frequency of bleeding

Total Totalstudied studiedpopulation population

NATA comparator *Major and clinically relevant bleeding

Cancer Cancerpatients patients

Agenda • • •

• • • •

Definition on VTE and the magnitude of the problem Methods for VTE prophylaxis and treatment 2012: Recommendations for VTE prophylaxis in medical patients VTE Risk stratification of medical patients VTE prophylaxis in cancer patients New AntiThrombotic Agents in medical and cancer patients 2012 : Recommendations for the treatment of VTE

Thromboprophylaxis in immobilized outpatients

Chronically immobilized patients without RF for VTE

ACCP 2012 recommendation no

Level of evidence 2C

ENDORSE: a Worldwide Study

32 Countries - 358 Hospitals â&#x20AC;&#x201C; 68 183 Patients

Use of ACCP Recommended Px in Patients at Risk for VTE Overall ( n= 68 183 ) Primary objectives

52% at Risk for VTE (n=35 689)

50% receiving ACCP Secondary objectives

Rec. Px

Surgical (n = 30 827)

64% at Risk for VTE

(n=17 732)

Medical (n = 37 356)

42% at Risk for VTE (n=15 847)

(n=19 842)

59% receiving ACCP Rec. Px

(n=11 613)

39% receiving ACCP Rec. Px

(n=6 119)

Alg Au eria Ba stra ng l lad ia es h Bra Bu zil lg Co aria lo Cz mbia ech Re p Eg y Fra pt Ge nce rm an Gr y ee H u ce ng ary In d Ire ia lan Ku d wa Me it Pa xico kis ta Po n la Po nd rtu Ro gal ma nia Sa Rus s ud i A ia rab Slo ia va ki a S Sw p it ze ain rl Th and aila n Tu d nis i Tu a rke y UA E UK Ve USA ne zu ela

%

% Use of ACCP recommended Px among Medical patients at Risk for VTE per Country 100

80

60

Mean=48%

40

20

0

Agenda • • •

• • • •

Definition on VTE and the magnitude of the problem Methods for VTE prophylaxis and treatment 2012: Recommendations for VTE prophylaxis in medical patients VTE Risk stratification of medical patients VTE prophylaxis in cancer patients New AntiThrombotic Agents in medical and cancer patients 2012 : Recommendations for the treatment of VTE

Groupe de Thrombose Equipe de recherche ER2UPMC Interactions cellulaires tumorales et leur environnement et réponses aux agents anticancéreux.

Service d’Hématologie Biologique Hôpital Tenon, APHP, Paris, France