expanding beyond orthopedics - in1touch

1

Rivaroxaban

Expanding Beyond Orthopedics

Peter Thomson

Clinical Resource Pharmacist, WRHA Medicine Program

Clinical Asst Professor, Faculty of Pharmacy, University of Manitoba

Objectives

Compare key pharmacologic factors with the new oral anticoagulants

Discuss recent regulatory changes with the new oral agents and their potential impact on practice

Identify key factors to assess with patients regarding the use of rivaroxaban in AF prophylaxis and VTE treatment

Review resources for information on the dynamically changing are of oral anticoagulation

2

Disclosures

In the past 2 yrs I have either been sponsored to

speak at education event, introduced speakers

or attended advisory meeting provided advice to

the following pharmaceutical companies:

AstraZeneca Canada

Bayer Canada

Boehringer Ingelheim Canada

Paladin Labs Inc.

Pfizer Canada

Sanofi Aventis Canada

New Oral Agents

Are all small molecules targeted at specific

sites in the coagulation system

Primary target is either

Thrombin; i.e. activated factor II (F IIa)

Activated factor X (F Xa)

3

New Oral Anticoagulants

Direct Thrombin Inhibitors:

Dabigatran (Pradax®, Pradaxa® in other

countries)

Direct F Xa Inhibitors:

Rivaroxaban (Xarelto®)

Apixaban (Eliquis®)


Benefits of new oral agents include:

Predictable pharmacokinetics with low

interpatient variability: LMW Heparin like

Much lower rate of drug interactions

than warfarin

Much faster onset of action than

warfarin - few hrs versus days

Generally, much shorter duration of

action than warfarin

4


Benefits of new oral agents also include a

flatter dose response curve than warfarin.

Should translate into a lower risk of major

bleeding with overshooting the “therapeutic

range”

With warfarin increased bleeding incidence

becomes exponential once INR > 4.5

Palareti G Thromb Haemost 2009

New Orals: Indications

Approved for use in Canada

Hip and knee orthopedic surgery prophylaxis (all 3).

WRHA lists rivaroxaban for this

Atrial fibrillation (dabigatran, rivaroxaban). Only

dabigartran approved on WRHA formulary right now

Deep Vein Thrombosis treatment (rivaroxaban)

5

Rivaroxaban in Orthopedics RECORD 1 – 4 (~ 2,000 – 3,000 pts) total hip or knee arthroplasty. All

given Rivaroxaban 10 mg starting 6 – 8 hr post op vs enoxaparin

Surg Enoxaparin Composite

Endpt (%)

Major VT (%)

Riva Enox Signf Riva Enox Signf

1 THA 40 mg/d start

preop (35 d)

1.1 3.7 < 0.001 0.2 2.0 < 0.001

2 THA 40 mg/d start

preop (14 vs d)

2.0 9.3 0.001 0.6 5.1 0.001

3 TKA 40 mg/d 12 hr

preop (14 d)

9.6 18.9 0.001 1.0 2.6 0.016

4 TKA 30 mg q12h

start 12-24 hr

postop (11-12d)

6.9 10.1 0.012 0.7 1.2 ns

6

Rivaroxaban in Orthopedics

Surg Enoxaparin Major (%) Clinically

Relevant Non-

Major Bleed (%)

Minor (%)

Riva Enox Riva Enox Riva Enox

1 THA 40 mg/d

start preop

0.3 0.1 2.9 2.4 5.8 5.8

2 THA 40 mg/d

start preop

0.1 0.1 3.3 2.7 6.5 5.5

3 TKA 40 mg/d 12

hr preop

0.6 0.5 2,7 2.3 4.3 4.4

4 TKA 30 mg q12h

start 12-24

hr postop

0.7 0.3 2.6 2.0 10.2 9.2

Rivavoxaban Indication & Dose

Prevention of VTE in elective total hip or

knee replacement (THA, TKA)

10 mg daily starting 6 – 10 hr post op for

14 d (knees), 35 d (hips)

8

Case

TT is a 70 yr old female with hypertension and peripheral vascular disease

Just discharged from the HSC with Rx:Levofloxacin 500 mg daily X 4 days

Metoprolol 50 mg bid

Warfarin 5 mg take as directed

Meds on profile:ASA 81 mg once daily

Ramipril 5 mg bid

Common for people to develop following any stress

Many times on medicine wards people come in with something else and leave with A Fib

People usually forget what they were told in the hospital about AF because so much going on, being discussed with them and family

9

Atrial Fibrillation

The most common arrhythmia of the heart

that is sustained

Risk of stroke is the same for either

persistent or paroxysmal

Very common, roughly 25% of those over

40 yrs will have it in their life

You JJ Chest 2012; 141

Albers GW Chest 2008; 133

Atrial Fibrillation

Strong predictor of stroke, increases risk 5 fold

A Fib strokes are more devastating than most

other sources of stroke

50,000 new strokes each year in Canada –

average system cost for 1st 6 months $50,000

Total Cost $ 2.5 billion CAN per year

Cost per family up to $200,000 per yr for most

severely affected

Can Stroke Network 2010

10

Atrial Fibrillation

Atrial Fibrillation

Many people are asymptomatic – no

“heart skipped a beat” or “racing”

12

Atrial Fibrillation

Major treatment approaches are either to

restore normal sinus rhythm or to leave in

atrial fibrillation and control ventricular rate

In both, anticoagulation is essential

Rhythm Control Does Not

Replace Anticoagulation

• No evidence that AF reduction via antiarrhythmic

therapy reduces the risk of stroke/thromboembolism

• Patients must continue on appropriate

anticoagulation according to their individual embolic

risk (CHADS2 score)

13

Patients(n = 1733)

Adjusted Stroke Rate (%/yr)

CHADS2

Score

120 1.9 0

463 2.8 1

523 4.0 2

337 5.9 3

220 8.5 4

65 12.5 5

5 18.2 6

CHADS2

Risk Factor Score

Congestive Heart

Failure

1

Hypertension 1

Age ≥ 75 1

Diabetes Mellitus 1

Stroke/TIA/

Thromboembolism

2

Maximum Score 6

Predictive Index for Stroke

CHA2DS2-VASc

Risk Factor Score

Congestive Heart Failure 1

Hypertension 1

Age ≥ 75 2

Diabetes Mellitus 1

Stroke/TIA/Thrombo-embolism 2

Vascular Disease 1

Age 65-74 1

Female 1

Maximum Score 9

16

Overview of Thromboembolic Management

CHADS2 = 0

No antithrombotic may be appropriate in selected young patients with no stroke risk factors

aspirin

*Aspirin is a reasonable alternative in some as indicated by risk/benefit

Dabigatran is preferred OAC over warfarin in most patients.

CHADS2 = 1 CHADS2 ≥ 2

OAC* OAC

Assess ThromboembolicRisk (CHADS2) and

Bleeding Risk (HAS-BLED)

Can Cardiovasc Soc: 2012 A Fib Update

New guidelines expected in next couple of

months

Anticipate changes include:

Predicting Risk – CHADS2 with score of 0 apply

the CHADSVASC factors

Incorporate other new oral anticoagulants:

rivaroxaban and apixaban

Rewording of new oral anticoagulants in

coronary artery disease

ACC Rockies 2012

17

Atrial Fibrillation Trials

Re-LY

(n=18,113)

ROCKET-AF

(n = 14,266)

ARISTOTLE

(n = 18,206)

Drug Dabigatran Rivaroxaban Apixaban

Dose 150, 110 mg BID 20 mg OD 5 mg BID

Entry

Criteria

CHADS > 1

(avg CHADS ~ 2)

CHADS > 2

(avg CHADS > 3)

CHADS > 1

(avg CHADS ~ 2)

Follow Up qs > 2 yrs qs > 2 yrs qs > 2 yrs

Comment

Exclude Clcr < 30

15 mg OD Clcr 30–49

Exclude Clcr < 30

2.5 mg bid if > 80yr,

Wt < 60 kg. Scr > 133

Exclude Scr > 221

Connelly SJ N Engl J Med 2010; 361: 1139-51 Patel MR N N Engl J Med 2011365: 883-91 Granger

CB N Engl J Med 2011; 365: 981-92

WHAT ONE TO USE?

Warfarin

Warfarin

ASA +

Clopidogrel

ASA

Dabigatran

Rivaroxaban

ASA +

Clopidogrel

Rivaroxaban

Rivaroxaban

Dabigatran

ASA +

ClopidogrelDabigatran

ASA

Warfarin

18

What About Guidelines?

Great news!

They May not agree !

19

Google: “dabigatran manitoba”

21

Atrial Fib Trials: BleedingRe-LY

(n=18,113)

% Events

ROCKET(n = 14,236)

% Events

ARISTOTLE(n = 18,160)

% Events/yr

Dabi

110/ 150

Warf Riva Warf Apix Warf

Major

bleeding

2.7

3.1

3.4 5.6 5.4 2.1 3.1

Life-

threatening

1.2

1.5

1.8 1.3 1.9

Intracranial 0.2

0.3

0.7 0.8 1.2 0.3 0.8

Gastro-

intestinal

1.1

1.5

1.0 3.2 2.2 0.8 0.9

22

Case

TT is a 70 yr old female with hypertension and peripheral vascular disease

Just discharged from the HSC with Rx:Levofloxacin 500 mg daily X 4 days

Metoprolol 50 mg bid

Warfarin 5 mg take as directed

Meds on profile:ASA 81 mg once daily

Ramipril 5 mg daily

Case

TT still lives at home

Not terribly mobile. Cognition borderline

Home care comes in daily in daily in AM to

help with pills, ADLs

Daughter in law will now have to come

over daily to help with pm meds

Trainer labs will be coming in to draw

blood work

23

A Fib Summary

Very commone cause of stroke, especially disabiling ones

Patients, other health professionals should screen for it

New guidelines coming – expect more encouragement for OCs in lower risk stroke pts and use of new approvals

Some will have strong opinions on which drugs are better than others

24

Case

BB is a 65 yr old male who presents to ER with a

painful swollen right leg

Back of leg has been sore for a number of days,

now that it is swelling up thought he better come

in and get checked out

DM 2, Hypertension, Hypercholesterolemia

Meds on profile: Ramipril 10 mg od, Atorvastatin

10 mg od, EC ASA 81 mg od, Glyburide 5 mg

bid

25

Pathogenesis of Venous

Thromboembolism

Clots arise due to defects of three basic

mechanisms (Virchrow‟s triad):

Blood and its forming elements

Injury to vessel walls

Stasis of blood

Spectrum of VT

DVT

Proximal vs. Distal

PE

Fatal

Both maybe asymptomatic

26

Clinical Risk Factors for VT

Age

Cancer

Chemotherapy

CHF

Central Lines

Estrogen Use

Hypercoaguable States

IBD

Immobility

Major Surgery

Nephrotic Syndrome

Obesity

Paralysis

Pregnancy

Previous VT

Stroke

Trauma

Varicose Veins

Geerts, WH et al. Chest, 2001: 119: 132 S

How should he be treated ?

29

EINSTEIN: Efficacy: Acute DVT

30

EINSTEIN: Safety – Acute DVT

Rivaroxaban Price

15 and 20 mg tabs $ 2.84 ea

31

Pt Issues

Don‟t need bed rest

Important factor for recurrent VTE is therapeutic anticoagulation in first 3 months

Risk esp high if not therapeutic in first month

Drops off to lower level for 2nd and 3rd month

I‟m going to threaten people I will call their MD to put them on warfarin if they fall behind on their refill

If going on warfarin, ask when not if blood being checked next and who and where to find out result

Coagulation Cascade

XIIa

XIa

IXa

Intrinsic Pathway

(surface contact)

Xa

Extrinsic Pathway

(tissue factor)

VIIa

Thrombin (IIa)

Thrombin-Fibrin

Clot

Heparin / LMWH

(AT-III dependent)

Ximelagatran

Dabigatran(direct antithrombin)

Fondaparinux

(AT-III dependent

Pure Anti-Xa)

IX

X

II

TF Pathway

Inhibitor

Apixaban

Rivaroxaban

Warfarin:F II, VII,

IX, X

32

Why warfarin rocks

Strong evidence base for its useapproved for rats in 1948, humans in 1954

Highly effective anticoagulant in a broad range of indicationsatrial fibrillation

venous thromboembolism

mechanical heart valves

No significant off-target toxicities

Cheap

Why warfarin sucks

Narrow therapeutic indexInhibits sequential enzymes (VII, IX, X, and

prothrombin) in a cascade reaction

Hence extremely steep dose-response curve

Works by antagonizing Vitamin K, a trace nutrient present in only a few foodsMoving target

Common genetic polymorphisms (CYP2C9; VKORC1) influence its activity

Many drug interactions (713 by one source, 193 „major‟)

33

More problems with warfarin

For aforementioned reasons, incessant monitoring is essential

Nonetheless, even in good hands, only ~2/3 of INRs will be in target range

Delayed onset and reversal of anticoagulant effect

long half-life of drug (~2d) and of circulating procoagulant proteins (~2.5d for prothrombin)

New oral anticoagulants:

Dabigatran

(Pradax)Oral direct

thrombin inhibitor

little food

interaction

Half life 12-17 hrs

AFib (approved):

110 or 150mg bid

(75 mg in US

↑Scr)

Apixaban

(Eliquis)

Oral direct Factor

Xa inhibitor

little food

interaction

Half-life 9 hrs

AFib: 20mg o.d.

(15 mg od ↑Scr)

DVT: 15 mg bid

then 20 mg daily

Rivaroxaban(Xarelto)

● Oral direct Factor

Xa inhibitor

● little food

interaction

● Half-life 12 hrs

● AFib (not

approved): 5mg bid

(2.5 mg bid ↑Scr)

34

New Orals: Other Indications

Other indications likely to see in use:

Pulmonary Embolism (rivaroxaban probably

1st)

Venous thromboembolism (VTE) treatment

(other agents)

New Orals: Other Indications

Possibly see in the future:

Acute Coronary Syndromes

Venous thromboembolism prophylaxis

Valves

35

Pharmacokinetics / dynamics

Dabigatran Rivaroxaban Apixaban

Target Site IIa

(thrombin)

Xa Xa

Absorption Low, but

consistent

~ 70 % but

dose

dependent

~ 60 %

Hrs to Cmax

(i.e full effect)

~ 2

as a prodrug

2 - 4 ~ 2

Pradax Product Monograph

36

PK/PD

Apixaban Dabigatran Rivaroxaban

Liver (CYP)

Metabolism

Yes, multiple

pathways

None CYP 3A4

Renal

Elimination

~ 1/3 80% ~ 1/3

(active drug)

Product Monograph

Apixaban Dabigatran Rivaroxaban

Drug

InteractionsCYP 3A4 & P-gp Strong P-gp CYP 3A4 & P-gp

Wt Extremes

(Δ exposure)< 50 kg ~ 30%

> 120kg ~30%

~ 48 kg: 25%

~ 120 kg 20 %

< 50 kg 24%

> 120 kg < 24%

Rivaroxaban Contraindications

Recent bleeding

Contraindicated in moderate and severe liver

with coagulopathy and severe renal impairment

(Clcr < 30 ml/min)

Contraindicated with agents that are both strong

CYP 3A4 and P-gp inhibitors

Contraindicated in pregnancy and nursing

women

Dosage adjustments for Clcr 30 – 50 ml/min

37

Just not a good idea: NSAIDs

38

Rivaroxaban Monitoring?

anti Xa test coming …. I think

If want to ensure out of system (e.g. going

to surgery) a normal INR is probably ok.

NOT an aPTT (that’s for dabi)

Concern with major drug interaction or

multiple moderate DIs +/- renal dysfunction

Rivaroxaban: effect on Prothrombin time

Kubitza et al., Clin Pharmacol Ther 2005

Healthy human subjects

Time (hours)

PT

(X-f

old

change f

rom

baselin

e)

0 2 4 6 8 10 12 14 16 18 20 22 24

1.0

1.2

1.4

1.6

1.8

2.0

Placebo (n=25)

Rivaroxaban 1.25 mg (n=8)

Rivaroxaban 5 mg (n=6)





39

Enoxaparin

Dalteparin

Dabigatran Rivaroxaban Apixaban

Anti Xa aPTT more

sensitive

INR more

sensitive

Anti-Xa

(potential)

Anti-Xa

(potential)

Monitoring

Note: the new oral drugs are NOT conventionally

monitored

INR and aPTT are NOT adjusted to a target range

Caveats with New Drugs

New agents should not be assumed to be interchangeable with warfarin; each needs to be tested in specific situationsmechanical heart valves

antiphospholipid syndrome

cancer associated thrombosis

acute coronary syndromes

thrombosis in pregnancy

Only loose guidelines available for perioperative management on these agents

No antidote exists for any of them

41

Patient Counselling

Can‟t miss doses otherwise back to

warfarin (or stroke/ PE) for you!

Take with food at 15 and 20 mg doses

Tell everyone who touches you “I am on a

blood thinner”

Know Thy Dose !

10 mg

15 mg

20 mg

Orthopedics

Bid for DVT (Clcr > 30)

Daily for AF or DVT with

Clcr 30 – 49

Daily for AF or DVT and

good renal fn

Not indicated for Clcr < 30 mL/min

42

Questions

Reversal – Call Hematology at HSC or St B

Timing around surgeries and procedures

43

Questions

Use with clopidogrel/ASA or both?

Doubles the bleeding time with clopidogrel

Both antiplatlets increase bleeding risk with riva

44

Questions

Can I crush the pills?

Can I split the pills?

45

Summary

A Fib requires anticoagulation. First thing

is to find it

Role of the new oral anticoagulants

continues to expand. Now have another

agent for A Fib. First one for DVT

treatment

Pharmacists have an important role to

ensure patient safety

Questions

expanding beyond orthopedics - in1touch

Documents