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Inter-hospital Geriatric Meeting –

Emerging Drugs for an Old Problem

Presenter: LAI King-Son (TPH)

Chairperson: Dr. CHUI Pui-Yuk (TPH)

28th September 2012

Case Presentation

Introduction

• Ms. C , 80 years old

• Non-smoker , non-drinker

• Right-handed

• Premorbid walked unaided

• Emigrated to Canada with family in 1997

• Returned to Hong Kong in 2005

• Lived with family (private housing)

• Financial support by children

Past Medical History

• Atrial fibrillation with sick sinus syndrome

– Discovered in 1997

– Presented with syncope / LOC

– Echocardiogram: Normal LVEF , mild global

hypokinesia , mild to moderate MR/TR

– Pacemaker insertion in 1997 in Canada

– On metoprolol

– Opted for warfarin as thromboembolic prophylaxis

thereafter

Past Medical History

• Gout

– Intermittent gouty attack over right index finger PIP

– Frequency ~ 4x per year

– Started allopurinol in 2009

– Warfarin adjusted accordingly

Drug List

• Warfarin (adjusted dose)

• Metoprolol 50mg BD

• Allopurinol 100mg daily

INR Status

Date INR Warfarin dosage

5/2005 (first visit after back to HK) 2.1 2mg daily

1/2006 1.8 2mg daily

4/2007 1.8 2mg daily

6/2008 1.9 2mg daily

12/2008 1.9 2mg daily

4/2009 1.7 2mg daily

8/2009 (allopurinol added) 2.0 1.5mg daily

12/2009 1.3 1.5mg / 2mg alternate day



7/2011 (told ↑ vegetables intake) 1.4 2mg daily

10/2011 1.8 2mg daily

3/2012 2.0 2mg daily

15/6/2012 , 2am

• ↓ right limb movement

• ↓ walking ability

• Slurring

• Still alert , no witnessed LOC / seizures

• No other systemic complaints

AHNH (Tai Po) Medical Ward , 7am

• GCS 15/15 , PEARL

• BP 139/89 mmHg , pulse 69 bpm

• Afebrile , SaO2 98% on room air

• RUL power 2/5 , RLL 3/5 ; left limb power full

• No cerebellar signs

• No sensory signs

• No heart murmurs

• No carotid bruits

Blood Tests

• RFT – Na 140 / K 4.0 / urea 5.7 / creatinine 84

• LFT – alb. 35 , bil. 15 , ALP 100 , ALT 15

• Fasting glucose 5.0

• Lipids – TC 5.0 , LDL 3.0 , HDL 1.5 , TG 1.1

• Hb 12.1 , WBC 5.7 , platelet 225

• INR 3.3

• TSH 1.2 (5/2005)

Further Investigations

Plain CT-Brain

• Left insular cortex infarct

• No haemorrhage

• No mass effects

• No hydrocephalus


CXR

• Pacemaker in-situ

• Cardiomegaly

• No obvious congestion


ECG

• Paced rhythm

• No acute ischaemia

Progress

• Started stroke rehabilitation

• Added simvastatin 5mg daily for hyperlipidaemia

• Continued warfarin therapy with drug titration

(2mg daily → 1mg → 1.5mg daily)

Date INR Warfarin dosage

15/6/2012 3.3 1mg daily

18/6/2012 1.3 1.5mg daily

19/6/2012 1.2 1.5mg daily

21/6/2012 1.6 1.5mg daily

22/6/2012 1.9 1.5mg daily

Progress

• Transferred to Tai Po Hospital (TPH) for

further rehabilitation on 21/6/2012

• Right power improved to 4/5

• Walked with frame with standby assistance

• Slurring improved

• Tolerated minced diet , oral intake good

• Discharged on 12/7/2012 , referred to AHNH

GDH for further stroke rehabilitation

• Further improved in mobility and ADL seen

History Clarification

• Lived with the family of youngest daughter

• Both daughter and son-in-law available at home

(just retired)

• Caring training provided before TPH discharge

back to home

• Will consider hiring a domestic helper to assist

caring tasks at home

Compliance Checking

• Used to take drugs by herself

• Told good drug compliance all along

• Premorbid meals prepared by patient at home ,

dined out sometimes on weekends

• ? Change in vegetable intake

• No acute illnesses before this stroke episode

• No over-the-counter drugs / herbs intake

Anti-coagulation Issue

• Patient did not strongly object regular blood-

taking for INR monitoring

• Children eagerly asked about alternative options

– Avoid too frequent blood-taking on patient

– Avoid the need of strict diet compliance

• Pros and cons of continuing warfarin versus

switching to self-paid dabigatran proposed

• Patient and relatives agreed SFI dabigatran ,

understood the importance of compliance

(started on 22/6/2012)

Topic Discussion:

Atrial Fibrillation –

Updates on Options of

Thromboembolism Prophylaxis

Contents

• Atrial Fibrillation – Overview

• Anti-platelet therapy

• Oral anti-coagulant therapy

– Traditional agent – warfarin

– Newer agents

Atrial Fibrillation – Epidemiology

• The commonest pathological arrhythmia

• Overall prevalence ~1% (all ages)

– ~2.3 % (age ≥ 40Y)

– ~6.0 % (age ≥ 60Y)

– 10+ % (age ≥ 80Y)

Fuster V, Rydén LE, Cannom DS et al. (2006). "ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial

Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and

the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for

the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association

and the Heart Rhythm Society". Circulation 114 (7): e257–354.

Hobbs FD et al. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total

population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The

SAFE study. Health Technol Assess. 2005 Oct;9(40):iii-iv, ix-x, 1-74 [ Note : A UK Study ]


Renate B Schnabel, et. al. Atrial Fibrillation: Its Prevalence and Risk Factor Profile in the German

General Population. Dtsch Arztebl Int. 2012 April; 109(16): 293–299. [ Note: A German Study ]


• Increasing over years

– 2.8% (year 1985)

– 5.1% (year 1995)

– 6.9% (year 1999)

– 10.9% (year 2004)

Reardon G , et al. Prevalence of atrial fibrillation in US nursing homes: results from the National Nursing

Home Survey, 1985-2004. J Am Med Dir Assoc. 2012 Jul;13(6):529-34. [ Note : A US Study ]


Among all people with AF

• ≥ 50 % at age ≥ 75 Y

Overall in-hospital prevalence (all ages)

• 7.5% – 17%Rich MW. Atrial Fibrillation in Long-Term Care. J Am Med Dir Assoc. 2012 Aug 11.

Atrial Fibrillation – Types

• First-episode AF

– Only 1 diagnosed episode , terminated in 7 days

• Paroxysmal AF

– Repeated diagnosed episodes within and terminated in 7 days

• Persistent AF

– AF lasting for more than 7 days , can still be cardioverted

back to sinus rhythm

• Permanent AF

– Persistent AF that cardioversion fails / is not attemptedFuster V, Rydén LE, Cannom DS et al. (2006). "ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial

Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and

the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for

the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association

and the Heart Rhythm Society". Circulation 114 (7): e257–354.

Atrial Fibrillation – Brief Pathology

• Progressive fibrosis of atria (structural change

to atrium , inflammation , ? genetics)

• Excitation of multiple (abnormal) foci in atria

and near pulmonary veins

• Repetitive spatial ‘break-up and fragmentation’

leading to fibrillatory conduction

Atrial Fibrillation – Causes

• Probably chronic

– Hypertension (29%)

– Valvular heart diseases (25%)

– Chronic rheumatic heart diseases (18%)

– Chronic lung diseases (19%)

• Probably reversible

– Thyrotoxicosis (6.2%)

– Sepsis (e.g. pneumonia)

Lok NS, Lau CP. Presentation and management of patients admitted with atrial fibrillation: a

review of 291 cases in a regional hospital. Int J Cardiol. 1995;48:271–278.

Prevalence of hypertension and co-morbidities in AF patients in surveys and trials.

Hypertension is the most common cardiovascular risk factor in AF patients

Chern-en Chiang et. al. Atrial fibrillation management in Asia: From the Asian expert forum on

atrial fibrillation. Int. J Cardio 2010 Jan.

Atrial Fibrillation – Burden

• Higher risks for many vascular diseases

– Heart failure

– Coronary heart diseases

– Ischaemic stroke (OR 4.3)

• More elderly patients involved

– Dilemma in management of the AF itself and the

associated diseases

– Benefits and risks in the use of traditional oral

anti-coagulants


Management Issues

1. Looking for (and treat) reversible causes

2. Rate control vs. rhythm control

3. Prophylaxis against thromboembolism

– Anti-platelet agents

– Oral anti-coagulants

• Traditional agent – warfarin

• Newer agents


Rate versus Rhythm Control

Guidelines for the Management of Atrial

Fibrillation – The Task Force for the

Management of Atrial Fibrillation of the

European Society of Cardiology (ESC)

European Heart Journal 2010 31 ; 2369-

2429



Guidelines for the Management of Atrial Fibrillation – The Task Force for the Management of Atrial Fibrillation of

the European Society of Cardiology (ESC) European Heart Journal 2010 31 ; 2369-2429



General Recommendations

• Rate control as initial approach on elderly patients

• Rate control is usually more effective than rhythm

control in permanent AF

• Rhythm control may be needed in those remaining

symptomatic despite rate control

• Rhythm control may be considered in younger patients

with higher activity levels , or those with reversible

factors corrected

Guidelines for the Management of Atrial Fibrillation – The Task Force for the Management of Atrial Fibrillation of

the European Society of Cardiology (ESC) European Heart Journal 2010 31 ; 2369-2429


Prophylaxis against Thromboembolism

A) Anti-platelet Drugs

B) Oral anti-coagulants

Anti-platelet Drugs

Anti-platelet Agents – Overview

• Minimize the platelet aggregates / thrombi

formation within blood vessels

• Minimize chances of blood flow reduction in

small vessels to critical organs (e.g. brain /

heart / limbs)

Anti-platelet Agents – Examples

• NSAID derivative (e.g. aspirin)

• Thromboxane synthase inhibition

(e.g. dipyridamole [Persantin® ])

• Glycoprotein IIb/IIIa inhibition (e.g.

clopidogrel [Plavix® ])

Anti-platelet Agents – aspirin

Mechanism

• Irreversible cyclo-oxygenase (COX-1 + partly COX-2) inhibitor

• Inhibits thromboxane (TXA) formation

• Inhibits platelet aggregation

Anti-platelet Agents – dipyridamole

Mechanism

• Thromboxane synthase inhibitor

• Lowers TXA levels

• Stops TXA effects (platelet aggregation , vasoconstriction)

• Inhibits phosphodiesterase enzymes → increases cAMP levels

→ further inhibits platelet response to ADP

Anti-platelet Agents – clopidogrel

Mechanism

• Binds to an ADP receptor on platelet molecule

• Inhibits platelet activation and subsequent cross-link fibrin

formation

• More deployed in use of ischaemic cardiovascular diseases

than ischaemic stroke nowadays

Pereillo JM, Maftouh M, Andrieu A, Uzabiaga MF, Fedeli O, Savi P, Pascal M, Herbert JM,

Maffrand JP, Picard C (2002). "Structure and stereochemistry of the active metabolite of

clopidogrel". Drug Metab. Dispos. 30 (11): 1288–95.

Anti-platelet Agents – Comparison

ESPRIT Study

• RCT (sample size 2739)

• Compare between aspirin + dipyridamole (A+D) and

aspirin-alone (A) groups in the prevention of

thrombotic events after first ischaemic stroke

• Primary outcome: vascular events

• Results

– A+D : 173 / 1363 (13%)

– A : 216 / 1376 (16% , p < 0.01)Halkes PH et al. Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT):

a randomised controlled trial. Lancet Neurol. 2007 Feb;6(2):115-24

Anti-platelet Agents – Comparison

ACTIVE-A Study

• RCT (sample size 7554)

• Compare between aspirin + clopidogrel (A+C) and

aspirin-alone (A) groups in the prevention of non-fatal

ischaemic stroke in AF patients unsuitable for warfarin

• Outcomes: non-fatal strokes / non-fatal bleeding

• Results

– Stroke: A+C : 226 / 3772 (6.0%) ; A : 315 / 3782 (8.3%)

– Bleeding: A+C : 167 / 3772 (4.4%) ; A : 112 / 3782 (3.0%)

Oral Anti-coagulants

A) Traditional agent – warfarin

B) Newer agents

Oral Anti-coagulants –

Warfarin

Warfarin – Brief History

• Related chemical dicoumarol isolated and

confirmed in 1940 , which leads to lack of

functioning prothrombin , when investigating for

mysterious death of cattle of bleeding in 1920s

• Initially as pesticides to rodents in 1948

• Found also effective and safe to prevent

thromboembolism in 1950s

• Marketed in 1954 as an oral anti-coagulant

Warfarin – Mechanism

As ‘vitamin-K antagonists’

• Inhibits vitamin K epoxide reductase

• Inhibits the recovery of oxidized form of vitamin K

(vitamin K epoxide) to its original reduced form , after

carboxylation of several calcium-dependent coagulation

proteins (e.g. factors X , IX , VII , prothrombin) and

regulatory proteins (proteins C and S)

• Certain clotting factors cannot be activated

Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E (2004). "The pharmacology and management of

the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy".

Chest 126 (3 Suppl): 204S–233S

Warfarin – Thromboembolic Prevention

Action

• Danish Atrial Fibrillation , Aspirin and

Anti-coagulation Trial (AFASAK , 1989)

• European Atrial Fibrillation Trial

(EAFT , 1993)

• Stroke Prevention in Atrial Fibrillation

(SPAF , 1994)

All showed warfarin superior than aspirin in

reducing thromboembolic events in AF

Anti-platelet Agents versus Warfarin in

Atrial Fibrillation

c.f. warfarin , anti-platelet agents provide :

a) Inferior thromboembolic prevention actions

(50+ % higher)

b) Lower bleeding risks (30-50% lower)

c) Existence of other side effects / risks , e.g.

– Peptic ulcer

– Renal failure

– Allergy susceptibility

→ used in ‘low-risk’ AF patients

Risk Stratification

• CHADS2 score

– Congestive heart failure [1]

– Hypertension [1]

– Age ≥ 75 years [1]

– Diabetes mellitus [1]

– Stroke / TIA / thrombosis [2]

Interpretation:

0-1 : low risk , 2 : moderate risk , ≥ 3 : high risk

CHADS2 Stroke Risk

0 1.9%

1 2.8%

2 4.0%

3 5.9%

4 8.5%

5 12.5%

6 18.2%

Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ (2001). "Validation of clinical classification schemes

for predicting stroke: results from the National Registry of Atrial Fibrillation". JAMA 285 (22): 2864–70. 2001 June

Risk Stratification

• CHA2DS2-VASc score

– CHF [1]

– HT [1]

– Age ≥ 75 Y [2]

– DM [1]

– Stroke / TIA / thrombosis [2]

– Vascular diseases [1]

(peripheral vascular diseases , MI , aortic plaques)

– Age 65 – 74Y [1]

– Female Sex [1]Atrial Fibrillation (Management of) 2010 and Focused Update (2012)

ESC Clinical Practice Guidelines

CHA2DS2-VASc Stroke Risk

0 0%

1 1.3%

2 2.2%

3 3.2%

4 4.0%

5 6.7%

6 9.8%

7 9.6%

8 6.7%

9 15.2%

Risk Stratification

• CHA2DS2-VASc score

Atrial Fibrillation (Management of) 2010 and Focused Update (2012)

ESC Clinical Practice Guidelines

Choice of Anti-platelet versus

Anti-coagulants in Elderly

• Risks

– Inclusion (CHA2DS2-VASc score)

– Exclusion (e.g. bleeding risks , fall risks)

• Patients’ / relatives’ preference

– More frequent follow-ups

– Regular blood-taking

– Lifestyle modification (drug / food restriction)

Warfarin – Discussion Issues

When choosing warfarin as anti-coagulant on

your patients , …

a) Why warfarin ? (i.e. indications)

b) Is the target INR achieved ?

c) If b) is not achieved , why ?

Compliance

Drug interactions

? Diet influence

Warfarin – Indications

• Non-valvular AF + moderate to high risk of stroke /

TIA / thromboembolism

• Mechanical prosthetic heart valves

• Cardioversion

• Venous thromboembolism (e.g. DVT)

• Pulmonary embolism

• Anti-phospholipid syndrome

Warfarin – Target INR

British Society for Haematology (2011)http://www.bcshguidelines.com/documents/warfarin_4th_ed.pdf

• Non-valvular AF for thromboembolic prophylaxis : 2.5

• Mechanical prosthetic heart valves : 2.5 – 3.5

(depending on valve thrombogenicity + patient’s risk

factors)

• Cardioversion : 2.5

• Venous thromboembolism: 2.5 (first) , 3.5 (recurrent)

• Anti-phospholipid syndrome: 2.5

http://www.bcshguidelines.com/documents/warfarin_4th_ed.pdf

Warfarin – ↑ INR : Suspected Causes

Subjects : ~500 patients with INR ≥ 6.0 at least once

Jon J. Glover et al. Conservative Treatment of Over-anti-coagulated Patients. Chest 1995 ; 108: 987-90

Warfarin – Drug Interactions

Metabolism

• The cytochrome P450 enzyme system

(CYP2C8/9 , CYP2C18/19 , CYP3A4 , CYP1A2)

• Largely affected by drugs that :

– Increase / induce the isoenzyme of another drug

(enzyme inducers)

– Decrease / inhibit the isoenzyme of another drug

(enzyme inhibitors)

Warfarin – Drug Interactions

Warfarin – Diet Influence

Warfarin – Non-compliance

• Forms

– Incorrect dosage

– Missed doses

– Extra doses

• Reasons for non-compliance

– Medical reasons

– Social reasons

Warfarin – Non-compliance (medical)

• Complicated / unfriendly warfarin regime

(alternate-day dosing , half-tablet dosing)

• Combination of different warfarin tablets

(1mg – brown / 3mg – blue / 5mg – pink)

• Frequently changing dosages

• Duplicated warfarin prescription

• Drugs prescribed by multiple parties / clinics

• Too many drugs (poly-pharmacy)

Warfarin – Non-compliance (social)

• Do not aware the importance of drug compliance

• Do not aware of diet compliance

• Misunderstanding correct dosage

• Misunderstanding drug intake

• Access to drugs

– Personal

– Carers

Warfarin – Improving INR Stability

• Always check correct drug dosage in each

follow-up

– the correct dosage

– the correct pills to take

• Clear explanation to any modification of drug

dosage

• Refer to pharmacist for compliance education

in problematic cases

1mg

5mg

3mg

Warfarin – Improving INR Stability

• Avoid alternate-day regime if possible

• Avoid halving-tablet regime if possible

• Avoid poly-pharmacy

• Avoid drugs that strongly interact with warfarin

• Educate patients ± care-givers to indicate

warfarin usage when attending other clinics ;

avoid self-taking OTC drugs / herbs

• Emphasize the importance of diet compliance

Warfarin – Extreme Over-dosage

Source: Hospital Authority COC (Medicine)

Handbook of Internal Medicine 6th Edition

2011

Warfarin – Extreme Under-dosage

• Increase warfarin dose (for most patients)

• Co-committing heparin (for patients having

high risk of thromboembolism , e.g. patients

with mechanical prosthetic heart valves)

Warfarin – Other Side-effects

• Osteoporosis

– ‘Risk of Osteoporotic Fracture in Elderly Patients

Taking Warfarin’

• A retrospective cohort in 2006 (sample size 14564)

• Compare the occurrence of osteoporotic fractures between

those on warfarin ≥ 1 year and those not on warfarin , in AF

• Results: warfarin group – adjusted odds ratio 1.25 , more

significant in male group (OR 1.63) than female (OR 1.05)

• ? ↓ vitamin K-mediated carboxylation of few bone proteins

• Limitations: unmeasured factors like BMD / obesity ;

failure of verifying ‘osteoporosis’ as cause of fractures

Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF (2006). "Risk of osteoporotic fracture in elderly

patients taking warfarin: results from the National Registry of Atrial Fibrillation 2". Arch. Intern. Med. 166 (2): 241–6.

Warfarin – Other (Rarer) Side-effects

• Purple toe syndrome (< 1 %)

– Blood clots removed from atherosclerotic

plaques

→ Cholesterol embolism

• Warfarin necrosis (0.01 – 0.1 %)

– Paradoxical massive thromboembolism →

skin necrosis and limb gangrene

– Commoner in patients with protein C /

protein S deficiency

Chan YC, Valenti D, Mansfield AO, Stansby G (2000). "Warfarin induced skin necrosis".

Br J Surg 87 (3): 266–72

Talmadge DB, Spyropoulos AC (2003). "Purple toes syndrome associated with

warfarin therapy in a patient with antiphospholipid syndrome". Pharmacotherapy

23 (5): 674–7

Oral Anti-coagulants –

Besides Warfarin ?

Newer agents

• Factor Xa inhibitors (e.g. -xabans)

• Direct thrombin inhibitors (e.g. dabigatran)

Xabans – Brief History

• Xa (factor Xa) + ban (stop → inhibit)

• Natural Xa-inhibitors in late 1980s

– Antistasin (isolated from a Mexican leech

Haementeria officinalis)

– Tick anticoagulant peptide (isolated from the tick

Ornithodoros moubata)

• Synthetic Xa-inhibitors began in 1990s

– e.g. fondaparinux , given daily in subcutaneous route

Xabans – Brief History

• Oral Xa-inhibitors had been paid more attention

since 2000s

– Rivaroxaban (~2005 , Germany ; approved in 2008 ,

the first approved oral xaban drug)

– Apixaban (~2007 , USA ; approved in 2012)

– Edoxaban (~1994 , Japan ; approved in 2011)

– Otamixaban (~2007 , France)

– Betrixaban (~2009 , USA)

Xabans – Mechanism

• Highly selective factor Xa inhibition

• Interrupts both intrinsic and extrinsic pathways

• Reduced thrombin formation and thrombi

development

• No direct effect on thrombin , anti-thrombin III

and platelet functions

rivaroxaban apixaban

Xabans – Efficacy Results

AVERROES Study (3/2011)[AVERROES : Apixaban vs. Acetylsalicylic Acid to Prevent Stroke]

http://www.nejm.org/doi/full/10.1056/NEJMoa1007432#t=article

• RCT in 2007-2009 (sample size 5599)

• Compare between apixaban 5mg BD (Ap) and aspirin

80-300mg daily (A) in the ability to prevent stroke /

systemic embolism , in AF unsuitable for warfarin

• Primary outcomes: stroke (any) , systemic embolism

• Results: (% primary outcome per year)

– Ap : 1.6% (51/2808)

– A : 3.7% (113/2791) , p < 0.001Connolly, Stuart J.; Eikelboom, John; Joyner, Campbell; Diener, Hans-Christoph; Hart, Robert; Golitsyn, Sergey; Flaker, Greg;

Avezum, Alvaro et al. (2011). "Apixaban in Patients with Atrial Fibrillation". New England Journal of Medicine 364 (9): 806–17.

http://www.nejm.org/doi/full/10.1056/NEJMoa1007432

Connolly, Stuart J.; Eikelboom, John; Joyner, Campbell;

Diener, Hans-Christoph; Hart, Robert; Golitsyn, Sergey;

Flaker, Greg; Avezum, Alvaro et al. (2011). "Apixaban

in Patients with Atrial Fibrillation". New England

Journal of Medicine 364 (9): 806–17.


ARISTOTLE Study (9/2011)[ARISTOTLE : Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation]



• Compare between apixaban 5mg BD (Ap) and

adjusted-dose warfarin (W) in the ability to prevent

stroke / systemic embolism in AF


• Results: (% primary outcome per year)

– Ap : 1.27% (212/9120)

– W : 1.60% (265/9081) , p < 0.001Granger, Christopher B.; Alexander, John H.; McMurray, John J.V.; Lopes, Renato D.; Hylek, Elaine M.; Hanna, Michael; Al-Khalidi, Hussein R.;

Ansell, Jack et al. (2011). "Apixaban versus Warfarin in Patients with Atrial Fibrillation". New England Journal of Medicine 365 (11): 981–92.


Granger, Christopher B.; Alexander, John H.; McMurray, John J.V.;

Lopes, Renato D.; Hylek, Elaine M.; Hanna, Michael; Al-Khalidi,

Hussein R.; Ansell, Jack et al. (2011). "Apixaban versus Warfarin in

Patients with Atrial Fibrillation". New England Journal of Medicine

365 (11): 981–92.


ROCKET-AF Study (9/2011)[ROCKET-AF : Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonist for

Prevention of Stroke and Embolism Trial in Atrial Fibrillation]



• Compare between rivaroxaban 20mg daily (R) and

adjusted-dose warfarin (W) in preventing stroke and

systemic embolism in AF at high-risk of stroke

• Primary outcomes: stroke , systemic embolism

• Results:

– R to W hazard ratio 0.88 (CI 0.74-1.03) → non-inferiorityManesh R. Patel, et al (2011). "Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation".

New England Journal of Medicine 365 (10): 883–91.


Manesh R. Patel, et al (2011). "Rivaroxaban versus Warfarin in

Nonvalvular Atrial Fibrillation". New England Journal of Medicine

365 (10): 883–91.

DTIs – Mechanism

• Direct inhibition of thrombin (a serine protease

enzyme) → limits the conversion of fibrinogen

to fibrin , the final path of coagulation cascade

• Two types

– Bivalent inhibition : act on both active and exosite

sites of thrombin (e.g. hirudin analogues , parenteral

administration)

– Univalent inhibition : act on active site of thrombin

only (e.g. dabigatran)

DTIs – Brief History

The first DTI – ximelagatran

• The ‘SPORTIF III , V’ Study in 2003 , 2005[SPORTIF : Stroke Prevention Using an Oral Thrombin Inhibitor in Patients with AF]

– RCT in North America (sample size 3922)

– Comparison between ximelagatran and warfarin in preventing

stroke and systemic embolism in non-valvular AF

– Primary outcome: stroke , systemic embolism

– Conclusion: ximelagatran was non-inferior to warfarin in

preventing primary outcome

• Drug withdrawn in 2006 due to concern of liver toxicity

– ~ 5% patients developed persistently ↑ ALT , some even after

stopping the drug for 1 year

DTIs – Brief History

Dabigatran

• Discovered as similar structure to benzamidine-based

thrombin inhibitor α-NAPAP (N-alpha-(2-

naphthylsulfonylglycyl)-4-amidinophenylalanine

piperidide) in 2000s

• Developed by Boehringer Ingelheim , a German

pharmaceutical company

• Licensed for use in Europe and US in 2008

Dabigatran – Efficacy Results

The RE-LY Study (2009)[ RE-LY : Randomized Evaluation of Long-term Anti-coagulation Therapy]



• Compare between dose-adjusted warfarin (W),

dabigatran 110mg BD (D-110) and dabigatran 150mg

BD (D-150) in the ability of preventing stroke in AF


• Results (in % primary outcome per year)

– W : 1.69%

– D-110 : 1.53%

– D-150 : 1.11% (p < 0.001)


Newer Anti-coagulants - Discussion

When choosing these newer oral anti-coagulants

on your patients , …

a) Safety Profile , Precautions ?

b) Drug interactions ?

c) If overdose , how to check and how to treat ?

Newer Oral Anti-coagulants –

A) Safety Profile

Newer Anti-coagulants – Safety

• Geriatric Patients

• Bleeding Risks

• Renal Impairment

• Liver Impairment


Geriatric Patients• Xabans

– As indicated in the presence of other risk factors

– Usual dosing for AF : rivaroxaban 20mg daily , apixaban 5mg BD

• Dabigatran

– Drug concentration higher than in younger subjects

– Correlated with creatinine clearance (CrCl)

– Still save at 150mg BD dosage for AF

– A lower dose (e.g. 110mg BD) may be considered in

• Age ≥ 80 Y

• Age ≥ 75 Y + at least one other risk factors (e.g. GI bleeding ,

moderately severe renal failure)

European Medicines Agency. Pradaxa® Drug Information (2008)


Bleeding Risks (All major bleeding)

• AVERROES : Ap 1.4% vs. A 1.2% (p = 0.57)

• ARISTOTLE : Ap 2.13% vs. W 3.09% (p = 0.047)

• ROCKET-AF : R 3.6% vs. W 3.4% (p = 0.58)

• RE-LY : D-150 3.16% , D-110 2.71% vs. W 3.11%

(p = 0.003)

[Key: Ap – apixaban , R – rivaroxaban , D – dabigatran ,

A – aspirin , W – warfarin]


Bleeding Risks (Intra-cerebral bleeding)

• AVERROES : Ap 11 cases vs. A 13 cases

• ARISTOTLE : Ap 0.24% vs. W 0.47% (p < 0.001)

• ROCKET-AF : R 0.5% vs. W 0.7% (p = 0.02)

• RE-LY : D-150 0.10% , D-110 0.12% vs. W 0.38%

(p < 0.001)

[Key: Ap – apixaban , R – rivaroxaban , D – dabigatran ,

A – aspirin , W – warfarin]


Bleeding Risks – conclusion

• No significant increase in bleeding risk overall when

compared with aspirin / warfarin

• Safe if used in therapeutic doses

• Contraindicated in cases of :

– Active clinically significant bleeding

– Lesions at high risk of bleeding

– Clotting impairment



Peri-operative management

Before major surgeries

• Rivaroxaban , dabigatran

– Short half lives (~12 hours)

– Stop drug 1-2 days (2-5 days in renal / liver impairment)

• c.f. warfarin : stop 5 days before surgery ± heparin ;

aspirin : stop 7 days before surgery


Renal Impairment• Rivaroxaban

– Dual excretion : both by liver (60-75%) and kidneys (25-40%)

– Normal drug half-life (T½ ) : 7-14 hours

– If CrCl 50-80 ml/min , CAUC ~1.4 x higher than normal subjects

– If CrCl 15-50 ml/min , CAUC ~1.5 – 1.6 x higher

→ Modest increase in concentration in patients with renal failure

– Recommended dose adjustment for AF :

• CrCl >50 ml/min : 20mg daily (normal dose)

• CrCl 15-50 ml/min : 15mg daily

• CrCl <15 ml/min : contraindicated

Dagmar Kubitza et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of

rivaroxaban, an oral, direct Factor Xa inhibitor. British J of Clinical Pharmacology Volume 70 (5) , 703-12


Renal Impairment• Dabigatran

– Excreted mainly as unchanged form by kidneys

– Normal drug half-life (T½ ) : 12-14 hours

– Normal dosage for AF : 150mg BD

– If CrCl 30-50 ml/min , CAUC ~2.7 x higher than normal subjects

– If CrCl 10-30 ml/min , CAUC ~6.0 x higher and T½ ~2x longer

– Recommended dose adjustment for AF

• CrCl >50 ml/min : 150mg BD (normal dose)

• CrCl 30-50 ml/min : 150mg daily

• CrCl <30 ml/min : contraindicated



Liver Impairment• Rivaroxaban

– Metabolized by oxidative degradation catalyzed by CYP3A4/5 and CYP2J2

– T½ significantly ↑ in case of moderate or severe liver failure

→ contraindicated in these patients

• Dabigatran

– Drug remains largely unchanged before excretion

– No specific change in concentration of drug in moderately severe liver

failure patients

– Patients with significant liver failure were excluded in trials

→ not recommended in patient with significant liver failure





B) Drug Interactions

Newer Anti-coagulants –

Drug Interactions

Rivaroxaban

• No serious or critical interaction reported so far

• Significant interaction needing caution , e.g. :

– Drugs altering coagulation (e.g. anti-platelets , NSAIDs , heparin ,

thrombolytics , warfarin , DTI ; all ↑)

– Anti-arrhythmics (e.g. verapamil ↑ , diltiazem ↑ , amiodarone ↑)

– Anti-convulsants (e.g. phenytoin ↑↓ , carbamazepine ↑)

– Antibiotics (macrolides like clarithromycin ↑ ; rifampicin ↓)

– Antifungals (e.g. ketoconazole ↑)

– Miscellaneous (allopurinol ↑ , steroids ↑ , tamoxifen ↑ , etc.)

[Key: ↑ – rivaroxaban effect potentiation , ↓ – effect reduction ]




Drug Interactions

Dabigatran

• As drug is generally not metabolized in liver , theoretically much

less drug interactions anticipated

• P-glycoprotein as transporter , which interacts with some drugs :

– Quinidine (↑↑) – contraindicated , amiodarone (↑)

– Antibiotics , e.g. clarithromycin (↑) ; rifampicin (↓)

– Antifungals (↑) , e.g. ketaconazole , itraconazole

– Colchicine (↑)

– Cyclosporin A (↑)

– Proton-pump inhibitors (PPI) , e.g. pantoprazole (↓)

[Key: ↑ – dabigatran effect potentiation , ↓ – effect reduction ]



C) Activity Checking


Checking for Overdose

• Xabans

– Factor X as merging point of both intrinsic

(activated by factor IXa) and extrinsic pathways

(activated by factor VIIa) to the common pathway

– Both pathways affected

– Both PT and APTT prolonged

– Future direction: ? Anti-Factor Xa assay that uses

rivaroxaban-containing plasma calibratorsLindhoff-Last E. et al. Assays for measuring rivaroxaban: their suitability and limitations.

Ther Drug Monit. 2010 Dec ; 32 (6): 673-9



• DTI

– PT / INR (extrinsic pathway)

• Mildly ↑ or even normal INR may already indicate a

significant overdose

• A large overdose may show a significant ↑ INR

– APTT (intrinsic pathway)

• Normal APTT specifically exclude DTI overdose , but

• Mildly ↑ APTT may already indicate a significant overdose

• Significantly ↑ APTT highly suggestive of a large overdose

→ may be deployed as ‘preliminary screening’

Douxfils J et al. Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory

recommendations for monitoring of dabigatran etexilate. Thromb Haemost. 2012 May 2;107(5):985-97. Epub 2012 Mar 22



• DTI

– Ecarin clotting time (ECT)

• Ecarin – A reagent isolated from

the venom of the saw-scaled

viper Echis carinatus

• Prothrombin meizo-

thrombin , also inhibited by DTI

• By adding a known fixed amount

of ecarin and comparing the

clotting time , a prolonged ECT

indicates DTI overdose

Götz Nowak. The Ecarin Clotting Time: A Universal Method to Quantify Direct Thrombin Inhibitors.

Pathophysiol Haemost Thromb 2003/04 ; 33 : 173-83

ecarin



• DTI

– Hemoclot® Thrombin Inhibitor Assay (HTI)

• Adding a constant and excess amount of highly purified

human α-thrombin , then compare the clotting time

Douxfils J et al. Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory

recommendations for monitoring of dabigatran etexilate. Thromb Haemost. 2012 May 2;107(5):985-97. Epub 2012 Mar 22


Treatment for Overdose

• Both rivaroxaban and dabigatran

– No specific antidote → compliance equally important

– Supportive treatment in the event of bleeding

• Stop the drug

• Investigate the source of bleeding

• ± Fresh frozen plasma

• ± Surgery

• ? Activated charcoal (if ingestion within a couple of hours)

• ? Haemodialysis (for dabigatran)

– Future direction: ? ecarin-derived antagonist for DTIs

Kaatz S et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012 May;87 Suppl 1:S141-5

Newer Anti-coagulants – Prescription

• Dabigatran (Pradaxa® )

– ~ $13 per capsule (both 110mg &

150mg)

→ $780 monthly

– Samples in certain HA hospitals

– Not to be crushed

HA Drug Formulary

Version 8.1 (14 July 2012)

Newer Anti-coagulants – Prescription

• Rivaroxaban (Xarelto® , by Bayer) and

Apixaban (Eliquis® , by Pfizer and Bristol-Myers Squibb)

– Both already registered in Hong Kong

– Not yet under HA formulary to date

– Can be crushed

Take-home Messages

Anti-platelets

a) Inferior anti-thromboembolic action when compared

with anti-coagulants in AF

b) Less bleeding risks than warfarin , but seemingly

comparable with newer anti-coagulants

c) Existence of other side effects / risks , e.g.

– Peptic ulcer

– Renal failure

– Allergy susceptibility

Take-home Messages

Oral anti-coagulants

a) Good anti-thromboembolic action in AF

b) Always verify the indications and check compliance

c) For those using warfarin , be prepared to see patients

with INR beyond targets

– Try to elicit the causes AND to correct it

d) Newer agents emerging with comparable with warfarin

– As SFI

– Unanswered areas remain

inter-hospital geriatric meeting emerging drugs for …hkgs.org/ihgm/ihgm_ks_lai_28sept2012.pdf ·...

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