A. Roussin MD

Canadian Society of Internal Medicine Annual Meeting 2016

Montreal, QC

◆ 1st workshop: update to VTE guidelines in 2016

◆ 2nd workshop: VTE controversies + new horizons André Roussin MD, FRCP, CSPQ

CHUM and ICM/MHI Associate professor

University of Montreal

A. Roussin MD

Canadian Society of Internal Medicine Annual Meeting 2016

Montreal, QC

The following presentation represents the views of the speaker at the time of the presentation. This

information is meant for educational purposes, and should not replace other sources of information or

your medical judgment.

Andre Roussin MD, FRCP, CSPQ; September 2016

A. Roussin MD

Canadian Society of Internal Medicine Annual Meeting 2016

Montreal, QC

Andre Roussin MD, FRCP, CSPQ; September 2016

Conflict DisclosuresAdvisor or advisory boards:

Bayer, BI, BMS, Leo, Merck, Pfizer, Sanofi Research funding:

Astra-Zeneca and Bayer Speaker:

Bayer, BI, BMS, Leo, Merck, Pfizer and Sanofi

A. Roussin MD

Second Workshop Controversies in VTE and New Horizons

1.  Identify situations when DOACs are not appropriate treatments for VTE

2.  Identify the appropriate, evidence-based workup in a patient with idopathic VTE to r/o underlying malignancy

3.  Recommend when to order a thrombophilia workup in patients with VTE

4.  Recognize new horizons and coming controversies in VTE diagnosis and management

A. Roussin MD

VTE treatment options: AT 10

Warfarin, UFH, LMWH and DOACs

Transition treatment offering immediate AC LMWH sc orUHF iv or sc. orfondaparinux sc

Warfarin INR 2–3 rather than LMWH 2CWarfarin

Specialcases-UFH

LMWHRatherthanVKA2BorDOAC2C

CANCER, (6 months…) LMWH monotherapy

UHF if CrCl < 30 mL/min, increased bleeding risk, need for rapid reversal or if thrombolysis contemplated

DOACRatherthan

VKA2B

Rivaroxaban 15 mg BID for 21 days, then 20 mg DOD

LMWH (UHF) for 5-10 days, then dabigatran 150/110 mg BID

Apixaban 10 mg BID for 7 days, then 5 mg BID 6 months then 2.5 mg BID

DOACs for VTE Phase III studies

Fontana P et al. EHJ 2014

As effective with less bleeding

than VKA

UHF or LMWH

Front line

DOACSandVTEforacutephaseNonhead-to-headcomparisons

Head-to-headstudieshavenotbeenconducted,thereforecomparaIvesafetyandefficacyhavenotbeenestablished.*ComparatorwasLMWHorUFHfollowedbyeitheravitaminKantagonist(warfarinoracenocoumarol)intherivaroxabantrialsorwarfarinintheotherNOACtrials.BID,twicedaily;CRNM,clinicallyrelevantnon-major;QD,oncedaily;LMWH,lowmolecularweightheparin;NOAC,noveloralanIcoagulant;UFH,unfracIonatedheparin;VTE,venousthromboembolism1.AgnelliGetal.NEnglJMed2013;369:799-808;2.TheEINSTEINInvesIgators.NEnglJMed2010;363:2499-510;3.TheEINSTEIN-PEInvesIgators.NEnglJMed2012;366:1287-1297;4.Schulmanetal.NEnglJMed.2009;361:2342–2352;5.Schulmanetal.CirculaIon;2014:129:764-772.

APIXABAN1 RIVAROXABAN2,3 DABIGATRAN4,5

Trialdesign:double-blind Yes No Yes

UseofLMWHand/orUFHlead-in No No Yes

DuraIonoftreatment 6months 3,6,or12months 6months

Non-inferiorefficacyvs.comparator*(recurrentorfatalVTE) Yes

DVT PEYes

Yes Yes

Majorbleedingvs.comparator* ↓ ns ↓ ns

MajororCRNMbleedingvs.comparator* ↓ ns ns ↓

Dosing BID BIDthenQD BID

7

DOACsandVTEprolongedphaseNonhead-to-headcomparisons

BID,twicedaily;NOAC,noveloralanIcoagulant;ns,notsignificant;QD,oncedaily.1.  Agnellietal.NEnglJMed2013;368:699-708.2.  TheEINSTEINInvesIgators.NEnglJMed.2010;363:2499-2510.3.  Schulmanetal.NEnglJMed.2013;368:709-718.

APIXABAN1 RIVAROXABAN2 DABIGATRAN3

Trialdesign:double-blind Yes Yes Yes

Comparator Placebo Placebo Placebo

DuraIonoftreatment 12months 6or12months 6months

Dosing BID QD BID

Dose(s)ofNOACstudied 2.5mgand5mg 20mg 150mg

Superiorefficacy(recurrentorfatalVTE)vscomparator Yes Yes Yes

Majorbleedingvscomparator ns ns ns

Majororclinically-relevantnon-majorbleedingvscomparator ns ↑ ↑

Head-to-headstudieshavenotbeenconducted,thereforecomparaIvesafetyandefficacyhavenotbeenestablished

8

DOACs: Weight and Sex No impact on dosing

Weight/ Sex

Dabigatran Pradaxa™

Rivaroxaban Xarelto™

Apixaban Eliquis™

Weight Exposition to médication

> 120 kg ⬇︎20% ⬇ ︎< 25% ⬇︎< 20-30%

< 50 kg ⬆︎25% ⬆ ︎< 25% ⬆︎< 20-30%

Sex Women vs Men X 1.3 Idem X 1.2

9From Canadian PM and litterature review

DOACs: weight Impact on VTE recurrence and bleeding

VTE recurrence < 50 kgs N= 167

50-100 kgs N=6711

> 100 kgs N= 1393

Coumadin N=4129 2.2% 2.4% 2.0%

Rivaroxaban N=4142 6.7% non ss 1.9% 2.3%

Major bleeding < 50 kgs N= 167

50-100 kgs N=6711

> 100 kgs N= 1393

Coumadin N=4129 4.4% (SS) 1.8% 1.2%

Rivaroxaban N=4142 1.3% 1.0% 0.9%

Prins, AS099, ISTH 2015

DOACs: Renal function Impact on VTE treatment in Canada

Clearance ml/min

Dabigatran Pradaxa™

Rivaroxaban Xarelto™

Apixaban Eliquis™

Dosing in mg

> 50 After UHF or LMWH:

150 ou 110 BID Âge factor:

•  110 BID > 80 years •  110 BID if 75-80 +

bleeding factor

15 BID X 3 weeks Then 20 OD 10 BID X 1 week

Then 5 BID for 6 months followed by

2.5 BID 30-50

25-30 Contraindicated Not recommended

15-25 Limited data

From Canadian PM and litterature review

DOACs: Age Créatinine Clearance is the major contributor

Caracteristics Dabigatran Pradaxa™

Rivaroxaban Xarelto™

Apixaban Eliquis™

AUC ⬆︎⬆︎ X 1.4-1.6 ⬆︎ X 1.5 ⬆︎ X 1.3

C max ⬆︎ X 1.3 ⬆︎ ⬆︎ X 1.3

T max ⬌ ⬌ ⬌

Half-life ⬆︎ ⬆︎ ⬆︎ ?

Dose adjustment Yes after 75 According to clearance, not age

According to Creat, weight and age (2 of 3)

From Canadian PM and litterature review

TAKE HOME MESSAGES DOACs: contraindications

◆  Severe CKD, GFR < 25-30* ml/min, is the most important factor

◆  The risk-benefit ratio is as good for older patients and when GFR > 25-30* ml/min (bleeding) but incertain for extreme weights (> 120 kg and < 50 kg)

◆  The only real contre-indications are pregnancy, breast feeding, GFR < 25-30* ml/min, valvular AF and possibly (pending studies) cancer associated VTE

*25: apixaban, 30: dabigatran et rivaroxaban

Unprovoked VTE workup Screening for occult cancer

◆  History, signs and symptoms ➨ HRT, OC? ➨ Major provoking factor? (surgery, hospitalization) ➨ Overt cancer, inflammatory disease? ➨ Minor provoking factor (trauma, infection, CHF etc)? ➨ Family history of DVT?

◆  Additional workup ➨ Imaging: depending on signs and symptoms ➨ Thrombophilia workup: almost always useless

“THE RISK OF A DIAGNOSIS OF CANCER AFTER PRIMARY DEEP VENOUS THROMBOSIS OR PULMONARY EMBOLISM” Sorensen H T et al. NEJM 1998: 338: 1169-73

26,653 ptsCancer:11.3%

PancreasOvary

LiverBrain

“INCIDENCE OF CANCER AFTER PROPHYLAXIS WITH WARFARIN AGAINST RECURRENT VENOUS THROMBOEMBOLISM”

Schulman S et al. NEJM 2000; 342: 1953-8

Incidence newly diagnosed cancer

Mean F-up8.1 years

1st cancer diagnosed

13.0%

Thrombosis and cancer Pathology vs Clinical presentation

◆ Cancers strongly associated to VTE ➨  Ovary 120 for 10,000 ➨  Brain 117 for 10,000 ➨  Pancreas 110 for 10,000

◆ Cancers most frequent in TEV ➨  Breast ➨  Colorectal ➨  Lung

Levitan N, et al. Medicine 1999;78:285-291.

Otten, et al. Haemostasis 2000;30:72-76. Lee & Levine Circulation 2003;107:I17-I21.

VTE incidence for certain cancers Incidence according to clinical situation

Types of cancer Incidence

Breast cancer (Stage I & II) w/o systemic treatment 0.2% Breast cancer (Stage I & II) w/ chemo 2% Breast cancer (Stage I & II) w/ chemo and tamoxifen 5% Breast cancer (Stage IV) w/ chemo 8% High-grade glioma 26% Multiple myeloma (thalidomide + chemo) 28% Renal cell carcinoma (thalidomide + chemo) 43% Solid tumors (anti-VEGF + chemo) 47%

Cancer screening impact SOME study, NEJM 2015

Limited screening or with CT (complete abdo.) SOME study: nothing significant

Multicenter study, open, randomized, canadian

Limited screening: blood, chest XR,

testing for breast, cervical and

prostate cancer

Limited screening + abdominal-pelvic CT with virtual gastric and colon imaging

Number of patients (854) 431 423 Number of cancers 33 (3.9%) Cancers on initial screening 10 14 Occult cancers at 1 year 14 (3.2%) 19 (4.5%)

Cancers missed by first screening 4 (29%) 5 (26%)

Mean time to cancer diagnosis 4.2 months 4.0 months Mortality 1.4% 0.9% Occult cancer at 1 year 0.93% 1.18%

Sun LM et ak JTH 2016; 14: 495-503

Thrombophilias overview

Defect Prevalence % Attributable Risk (% of patients with VTE) RR of thrombosis

Protein C deficiency 0.2 – 0.4 2 4 - 5

Protein S deficiency 0.7 – 2.3 <1 4 - 5

Antithrombin deficiency .02 <1 10

Factor V Leiden heteroor homozygous

2 - 10.02

25 4 - 530 - 140

Prothrombin G20210A 2 - 4 4 3 - 4

Elevated factor VIII 11 16

Elevated Factor XI 10 11

SNPs Frequent 10 – 84 1.15 – 1.39

Relative risk and incidence of 1st DVT

Variable RR Annual incidence : %Normal 1 0.008

Homocysteinemia 2.5 0.02

PT G20210 A mutation 2.8 0.02

Oral contraceptive 4.8 0.03

Factor V Leiden heteroz. 7 0.06

OC and Factor V mutation 35 0.3

Factor V Leiden homoz. 80 0.5 - 1

Baue K A. Ann Intern Med. 2001;135: 367-373.

Recurrence risk: role of an isolated thrombophilia Prospective / retrospective studies, mostly non-randomized

Antithrombin, protein C or S 10-17% / 1st year then 2.7% / yr

Facteur V Leiden homozygous Antiphospholipid (APS)

48% / 4 yrs 29 to 53% / 4-5 yrs

Factor VIII Hyperhomocysteinemia Factor V Leiden heterozygous Mutation II 20210A

RR 6.7 RR 2.7

RR 1.0 to 4.7 RR 1.0 to 4.9

Factor IX, XI ?

Recurrence: FVL + Prothrombin G20210A Wai K H et al. Arch Intern Med 2006; 166: 729-736

Recurrence: FVL + Prothrombin G20210A

Wai K H et al. Arch Intern Med 2006; 166: 729-736

Heterozygous FVL and prothrombin G20210A are each associated with a significantly increased risk of recurrent VTE after a first event, but the magnitude of the increase in risk is modest and by itself is unlikely to merit extended-duration anticoagulation. These data call into question the cost-effectiveness of routine testing for these common inherited thrombophilic polymorphisms among patients with a first episode of VTE

Risk factors synergy V Leiden and OC

Risk factor RR Annual incidence

Nil 1 0.8 / 10 000

OC 4 3.0 / 10 000

V Leiden 7 5.7 / 10 000

OC + V Leiden 35 28.5 / 10 000

Vandenbroucke JP et al. NEJM 2001; 344: 1527-1535

Van Vlijmen EFW et al. JTH 2016; 14: 1393 - 1403

Thrombophilia work-up: « Recommended »

◆  Recurrent VTE◆  1st VTE before 50 yrs◆  Unprovoked VTE any age◆  1st VTE unusual site◆  1st VTE pregnancy, childbirth or with OC/HRT◆  2 or more unexplained abortions◆  COMMENTS:

➨ All these recommendations are debatable➨ What is the impact on treatment

Colman et al. Ed. Hemostatis and Thrombosis. Lippincott 2006

Thrombophilia work-up: « To consider »

◆  Asymptomatic person in affected family➨ Especially if early severe event

◆  Asymptomatic woman in affected family➨ When OC or pregnancy ongoing or contemplated

◆  COMMENTS:➨ Think about impact on insurability➨ Rarely a contraindication to OC

Colman et al. Ed. Hemostatis and Thrombosis. Lippincott 2006

Thrombophilia work-up: « Controversial »

◆  Young women < 50 yrs with MI

◆  Pts > 50 yrs with 1st provoked VTE without cancer

◆  1st VTE while on tamoxifen

◆  Atypical obstetrical cases

◆  COMMENT:➨ Almost always useless

Colman et al. Ed. Hemostatis and Thrombosis. Lippincott 2006

Thrombophilia work-up: « Not recommended »

◆  General screening◆  Screening before OC, HRT or tamoxifen◆  As pre-natal test◆  Pre-adolescent screening if asymptomatic◆  As ASO work-up

➨ Except in young adults with early CAD without ASO

◆  COMMENTS:➨ In doubt, refrain and consult a specialist

Colman et al. Ed. Hemostatis and Thrombosis. Lippincott 2006

“Aggressive” approach to thrombophilia

Martinelli I et al. Nat. Rev. Cardiol 2014; 11: 140–156

Stepwise approach to thrombophilia testing

Piazza G. Circulation 2014; 130: 283-7

Stepwise approach to thrombophilia testing TIPS from G. Piazza, Boston

Piazza G. Circulation 2014; 130: 283-7

New horizons and coming controversies

◆  Antidotes: Idarucizumab (Praxbind™) and Andexanet ◆  DOACs or LMWH for cancer VTE: patient selection ◆  Edoxaban in Canada? What advantage for VTE?

➨ Less major and CRNM bleeding ➨ Less recurrence in EP with elevated NT-proBNP

◆  APS: Case series encouraging but not conclusive ➨ RAPS published and TRAPS underway

◆  IXa and XIa inhibition: possible targets upstream

VTE REFERENCES

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2016

THROMBOSIS CANADA: « App »

www.thrombosiscanada.ca @ThrombosisCan

References: "App"