VKA is still superior to NOAC in some situations

VKA is superior to NOAC in patients with mechanical heart valves Case 1: • 72 year old woman who had a mechanical MVR 21 years earlier • Permanent AF • Stable on VKA for many years but

VKA is still superior to NOAC

Dr Reginald Liew

MA, MBBS (Hons), PhD (Lond), FRCP (UK), FESC, FACC

Senior Consultant Cardiologist, Gleneagles Hospital Asst Prof Duke-NUS Graduate Medical School, Singapore

No conflict of interests to disclose

Warfarin vs placebo 0.33 [0.24, 0.45]

Warfarin vs all FLD warfarin

0.36 [0.23, 0.58]

Warfarin vs Ximelagatran 1.04 [0.77, 1.40]

RR (fixed) [95% Cl]

13 trials reviewed (n=14,423)

AF, atrial fibrillation; ASA, acetylsalicylic acid; CI, confidence interval; FLD, fixed low dose

0.01

Lip et al Thromb Res 2006

Comparison

Warfarin : Effective for stroke prevention in AF

Meta analysis of dose adjusted agents

The promise of new oral anticoagulants

1 Ansell J et al, 2004; 2 Mueck W et al, 2007; 3 Mueck W et al, 2008; 4 Mueck W et al, 2008;

5 Raghavan N et al, 2009; 6 Shantsila E, Lip GY 2008

Less impact on patient’s daily

life

Improved QoL

Less

labour-intensive

Reduced

administrative costs

Improved compliance

Improved efficacy and safety

Reduced potential for food and drug interactions

Simplified dosing regimen

No dietary restrictions Predictable anticoagulation

No need for routine coagulation monitoring

Can be given at fixed doses

RCT data showing that NOAC are:

• As effective as VKA to in stroke/ TE prevention in AF patients

• Associated with lower rates

of ICH

Why then continue to use VKA?

Medical reasons

 Patients with mechanical heart valves

 Patients who need to have anticoagulation quickly reversed if required

 Patients with inherited thromboembolic disease

Socio-economic/ financial reasons

Patient-related reasons

VKA is superior to NOAC in patients with mechanical heart valves

Case 1:

• 72 year old woman who had a mechanical MVR 21 years earlier

• Permanent AF

• Stable on VKA for many years but switched to dabigatran 110mg bd by

GP after a single reading of INR 5 (no active bleeding)

• Admitted to hospital 3 months later with cardiogenic shock; TEE

confirmed large thrombus obstructing MV orifice

• Had immediate MV surgery and MVR but died 3 days post op

Atar et al Chest 2013; 144(1):327-328

VKA is superior to NOAC in patients

with mechanical heart valves

Case 2:

• 73 year old woman who had a mechanical bileaflet MVR 12 years earlier

• Paroxysmal AF

• History of GI bleed, therefore switched from VKA to dabigatran 150mg

bd by GP

• Admitted to hospital 2 months later with acute pulmonary oedema and cardiogenic shock; angiography showed stuck anterior mitral leaflet

• At urgent surgery- large thrombus found obstructing MV

• Patient died 3 hours post op

Atar et al Chest 2013; 144(1):327-328

Dabigatran versus warfarin in patients with

Mechanical Heart Valves (RE-ALIGN STUDY)

Method:

• Phase 2 dose validation study

• Pt groups:

• Population A- mechanical aortic or mitral bileaflet valve replacement within past 7 days

• Population B- mechanical bileaflet mitral valve > 3 months before randomization

• Assigned 2:1 to receive dabigatran (150mg bd, 220mg bd or 300mg bd) or warfarin (target INR 2-3 or 2.5-3.5, depending on TE risk)

• 1ry endpoint trough plasma level of dabigatran

Eikelboom et al NEJM 2013;

369:1206-14

Aim:

• To evaluate the optimal dose of dabigatran in patients post mechanical valve surgery

Eikelboom et al NEJM 2013;

369:1206-14

Dabigatran versus warfarin in patients with

Mechanical Heart Valves- baseline characteristics

Eikelboom et al NEJM 2013;

369:1206-14

Dabigatran versus warfarin in patients with

Mechanical Heart Valves- baseline characteristics

Eikelboom et al NEJM 2013;

369:1206-14

Dabigatran versus warfarin in patients with Mechanical Heart Valves- results

No significant difference in mortality

9 strokes + 3 TIA in Dabigatran group

0 strokes + 2 TIA in warfarin group

Eikelboom et al NEJM 2013;

369:1206-14

Dabigatran versus warfarin in patients with Mechanical Heart Valves- results

Increased bleeding in the dabigatran group (P<0.01)

Eikelboom et al NEJM 2013;

369:1206-14

Results:

• Composite of stroke, TIA, systemic embolism, MI or death:

• Dabigatran group- 15 patients (9%)

• Warfarin group- 4 patients (5%)

• HR 1.94, 95% CI 0.64-5.86; P=0.24

• Statistically increased bleeding events in dabigatran group (A and B)

• All major bleeding occurred in population A

• Trial was stopped early due to excess of bleeding and thromboembolic events in dabigatran group

• All patients subsequent changed to non-trial VKA

Dabigatran versus warfarin in patients with

Mechanical Heart Valves- results summary

Eikelboom et al NEJM 2013;

369:1206-14

Dabigatran versus warfarin in patients with

Mechanical Heart Valves- conclusions

• Possible explanation: mechanisms of thrombosis in pts with mechanical heart valves is different to that in pts with AF

• Involves different factors of the coagulation cascade which warfarin is better at inhibiting (dabigatran just inhibits thrombin formation)

• Data from NOAC benefits in stroke prevention in AF trials cannot be extrapolated to patients with mechanical heart valves

Effects of VKA can be reversed more quickly than NOAC

Case example:

• 63 year old man with PAF presented with left sided weakness (not

on anticoagulation)

• MRI brain showed right MCA thromboembolic stroke

• Unable to thrombolyze as initial presentation was 3 days prior

• Co-morbidities: hypertension, diabetes, CAD

• CHADS2Vasc score- 5

• Echo- preserved LV systolic function; no sig valve lesions

• Managed with supportive care and neuro rehab (physio, speech therapy)

• Intermittent AF on ward- started on oral amiodarone

When would you start anti-coagulation?

What drug would you use?

Effects of VKA can be reversed more quickly than NOAC

Case example (cont.):

• CT head at day 8 showed no brain oedema or bleeding

• Discussed with neurologist, decided to start warfarin at day 10

aiming for target INR of 1.5 initially

• 3 days after starting warfarin, patient became more drowsy

• Repeat CT head showed hemorrhagic conversion of CVA

• INR measured 1.5- corrected with iv vit K and FFP

• Patient recovered after 5 days

• Further anticoagulation withheld

• Repeat CT head 10 days later showed hemorrhagic conversion

improving

Benefit of using warfarin- able to titrate to only a low level of

anticoagulation; bleeding was quickly and effectively reversed

VKA may be more effective than NOAC for treatment/ prevention of TE events in patients with inherited

clotting disorders

Case example:

• 43 year old man- history of Crohn’s disease

• DVT aged 26 – treated with 3 months warfarin (not further

investigated at the time)

• Pulmonary embolus (PE) 2 years ago after long haul flight- PE

confirmed on CT PA and DVT found in leg

• Treated with LMWH initially and then NOAC indefinitely

How would you manage this patient?

What anticoagulation should be used?

• Saw me 4 months ago – leg still slightly swollen; repeat USS leg

showed small residual DVT

• Thrombophilia screen for inherited clotting disorder showed

abnormal protein S level (48%)

VKA may be more effective than NOAC for treatment/ prevention of TE events in patients with inherited

clotting disorders

Case example (cont.):

• Decided to change NOAC to warfarin

• Treated with target INR 2-3

• Repeat USS leg after 3 months, thrombus no longer visible

• Patient remains well and recommend to take life-long warfarin

• To consider thrombophilia screen in first degree family members

• Efficacy of NOAC in patients with inherited clotting disorders not known or well tested

• Warfarin is still indicated in these cases and may be superior

Conclusions

NOAC are superior to warfarin in stroke prevention

in AF and have an important clinical role to play

1. Patients with mechanical heart valves

2. Patients who need to have anticoagulation quickly

reversed if required

3. Patients with inherited thromboembolic disease

 BUT, VKA still have an important clinical role to play and may be superior to NOAC in the following

clinical situations:

Gleneagles Hospital,

#03-37C, Annexe Block

6A Napier Road, Singapore

T +65 6472 3703

Email: reginald.liew@hscs.com.sg

www.theharleystreetclinicsingapore.com

Mount Elizabeth Novena Specialist Centre

#07-41, 38 Irrawaddy Road, Singapore

T +65 6694 0050