NEWER ANTICOAGULANTS -Dr.Deep Chandh Raja (as on Feb’2013)

SYNOPSIS

• OVERVIEW OF COAGULATION CASCADE• CONTEMPORARY ANTICOAGULANTS & THEIR

DISADVANTAGES• “IDEAL” ANTICOAGULANT• SPECTRUM OF NEWER ANTICOAGULANTS• PRESENT INDICATIONS OF NEWER

ANTICOAGULANTS• FUTURE OF ANTICOAGULATION

• COAGULATION- “A DEFENCE MECHANISM of the body”

ANTI-COAGULANTS

COAGULANTS

VIRCHOW’S TRIAD

CLINICAL EXAMPLES OF DISTURBANCES IN VIRCHOW’S TRIAD

• HYPERTENSION • ENDOTOXINS• ULCERATED ATHEROSCLEROTIC PLAQUES• ANEURYSMS• PROSTHESIS• DILATED LEFT ATRIUM• FACTOR V MUTATIONS• APLS SYNDROME• HIT SYNDROME

FORMATION OF “BLOOD CLOT”• Platelet adhesion • Platelet aggregation

• “Trap” of coagulation factors

• Clot formation

• Clot stabilisation (Fibrin formation)• Clot resolution

ANTIPLATELETS

ANTICOAGULANTS

THROMBOLYTICS

THROMBIN- The ANCHOR !

The Common Pathway

xx

ANTICOAGULANTS- “Blood Thinners”

• ‘Fixed’ ‘oral’ dose• No need for dose adjustment• Wide therapeutic range• Acceptable bleeding risks• No need for monitoring

AN “IDEAL” ANTI COAGULANT

Indications of Anticoagulant Therapy

• Prevention and Treatment of Deep Venous Thrombosis

• Treatment of Pulmonary Emboli• Prevention of stroke in patients with atrial

fibrillation, artificial heart valves, established thrombosis (DVT, Cardiac)

• Ischaemic heart disease• During procedures such as cardiac catheterisation

EVIDENCE BASED MEDICINE

CONTEMPORARY ANTICOAGULANTS

PARENTERAL• UNFRACTIONATED HEPARIN

(HMWH)• LOW MOLECULAR WEIGHT

HEPARIN (LMWX)

ORAL• WARFARIN

NEWER ANTICOAGULANTS

PARENTERAL• FONDAPARINUX• INDRAPARINUX• LEPIRUDIN• ARGATROBAN• BIVALURIDIN

ORAL• RIVAROXABAN• APIXABAN• XIMELAGATRAN• DABIGATRAN

CLASSIFICATION BASED ON MECHANISM OF ACTION

THROMBIN INHIBITORS

CONTEMPORARY

• HMWH• LMWH

NEWER

-NONE- • LEPIRUDIN• ARGATROBAN• BIVALURIDIN

• XIMELAGATRAN• DABIGATRAN

PARENTERAL ORAL

INDIRECT THROMBIN INHIBITORS DIRECT THROMBIN INHIBITORS

FACTOR Xa INHIBITORS

LMWHHMWH •

FONDAPARINUX• INDRAPARINUX

• RIVAROXABAN• APIXABAN

INDIRECT DIRECT

CONTEMPORARY NEWER ANTICOAGULANTS

VITAMIN K ANTAGONIST

• Only one drug which has a rich history and the center of many controversies !

• But still the only dispensable option all over the years !• WARFARIN

CLASSIFICATION BASED ON MODE OF ADMINISTRATION

PARENTERAL ANTICOAGULANTS

CONTEMPORARY• UNFRACTIONATED HEPARIN

(HMWH)• LOW MOLECULAR WEIGHT

HEPARIN (LMWX)

NEWER• FONDAPARINUX• INDRAPARINUX• LEPIRUDIN• ARGATROBAN• BIVALURIDIN

NO ONE PREFERS AN INJECTION !!!

ORAL ANTICOAGULANTS

CONTEMPORARY• WARFARIN

NEWER• RIVAROXABAN• APIXABAN• XIMELAGATRAN• DABIGATRAN ….a lot more..

New and Emerging Anticoagulants

• Anti – Xa : direct– Rivaroxaban (oral)– Apixaban (oral)– Betrixiban (oral)– Edoxaban (oral)– Otamixaban (parenteral)– LY – 517717 (oral)– DU – 176B (oral)– DX – 9065a (parenteral)– PRT054021 (oral)

• Anti – Xa : indirect– Idraparinux biotinylated

(parenteral)

• Anti – IIa– Dabigatran (oral)– Odiparcil (oral)– Flovagatran (parenteral)– Pegmusirudin (parenteral)– Peg Hirudin– Desiruidin– Ximelgatran

THE INDIVIDUAL DRUGS !!!

1. WHY LMWH OVER HMWH ???2. WHY NOT WARFARIN ???

THE HEPARINS

Heparin mechanism of action

Heparin

Antithrombin III

Thrombin

THE HEPARINS !!!

• HMWH- long chains• LMWH- short chains• ‘PARINUX’-very short

specific sequences

HMWH

LMWH PARINUX

HMWH vs LMWHHMWH

• Dose dependent clearance

• Low bioavailability• Short t 1/2 • Unpredictable response• Close monitoring• H.I.T• Bleeding• Osteoporosis• Extrarenal clearance

LMWH

x

WARFARIN & ITS PROBLEMS !

WarfarinWarfarin

Synthesis of Non Synthesis of Non Functional Functional

Coagulation Coagulation FactorsFactors

Antagonismof

Vitamin K

Warfarin Mechanism of Action

Vitamin KVitamin K

VIIVII

IXIX

XX

IIII

DISADVANTAGES • RESISTANCE (Cyt 2C9 & VKOR C1 enzymes)• Diet interference• Disease states• Drug interactions• Narrow therapeutic window• Slow onset of action• Skin necrosis• Bleeding• Pregnancy• APLS syndrome

Warfarin-induced Skin Necrosis

THE NEWER ANTICOAGULANTS !!!

FONDAPARINUX

Properties

• Complete bioavailability• Plasma t 1/2- 17 hours• Subcutaneous once daily dosing• Renal clearance• Prophylactic dosing- 2.5 mg once daily• Therapeutic dosing- 7.5 mg once daily• H.I.T does not occur• Bleeding risks equal to LMWH

Idraparinux• Once weekly SC injection• 100% SC bioavailability• Half-life ~ 96-130 hours• Renal elimination• No monitoring required• FAILED APPROVAL BY THE US FDA

LEPIRUDIN, ARGATROBAN

• Parenteral Direct Thrombin Inhibitors• Lepirudin- i.v infusion, t ½ of 60 minutes, renal clearance• Argatroban- i.v infusion, t ½ of 45 minutes, hepatic clearance

BIVALURIDIN

• Divalent thrombin inhibitor• Shortest half life of all DTIs- 20 minutes• Degraded by peptidases• i.v infusions• Significantly less bleeding

Rivaroxaban

• Oral tablet• Factor Xa inhibitor• High oral bioavailability

(>80%)• Onset of action 2-4 hours• Half-life 9-12 hours• No observed effects on

agonist-induced platelet aggregation

• Primarily renal elimination• No laboratory monitoring

required• No dosage adjustment for

gender, age, extreme body weight

• Approved by Europe and Canadian agencies, and FDA

Rivaroxaban in VTE Prevention:RECORD 3 - TKA

02468

101214161820

Rivarox 10Qday x 14 d

Enox 40 Qdayx 14 days

Composite Major VTE

0

1

2

3

4

5

6

Rivarox 10Qday

Enox 40 Qday

Major Bleed Any Bleed

%

RRR 49%

RRR 62%

%No Difference

2531 patients

Rivaroxaban in VTE Prevention:RECORD 4 - TKA

3034 patients

0

2

4

6

8

10

Rivarox 10 mgQday

Enox 30 mg BID

Composite

Symptomatic VTE and all-cause mortality

0

0.5

1

1.5

2

2.5

3

3.5

Rivarox 10 mgQday

Enox 30 mg BID

Major Bleed Any Bleed

%%

Turpie, et al. Lancet 2009;373:1673 – 80.

Not Significant

Rivarox: RRR 31%; ARR 3.2%

ROCKET-AF TRIAL

Rivaroxaban Ongoing Clinical Trials

DVTEinstein-DVT

Rivarox 15mg BID x 3 wks then 20mg

Qday vs Enox/VKA

PEEinstein-PE

Rivarox 15mg BID x 3 wks then 20mg

Qday vs Enox/VKA

Medically IllRivarox 10mg Qday x 35

days vs Enox 40mg Qday

x 10 days

DVT/PEEinstein-Extension

Rivarox 20mg Qday vs

Placebo

Apixaban

• Oral tablet• Bioavailability: 50%• Peak Plasma Levels = 3 hrs• Half-life ~ 12 hours • Metabolized in liver via

CYP3A4 and CYP independent mechanisms

• Eliminated via multiple pathways

• No laboratory monitoring required

• Has been submitted for approval by the US FDA

Apixaban Efficacy Outcomes in TKR

0

5

10

15

20

25

30

35

40

5

QDay

10

QDay

20

QDay

Enox 30mg BID

(n=152)

Warf

(n=153)

2.5

BID5

BID10

BID

Apixaban (mg) (n = 933)

Incidence of VTE and all-cause death (%)

Duration = 10 -14 days

Lassen MR, et al. J Thromb Haemost. 2007;5:2368 – 2375.

Apixaban Safety Outcomes in TKR

0

2

4

6

8

10

12

14

16

18

5

QDay

10

QDay

20

QDay

Enox 30mg BID

(n=152)

2.5

BID5

BID10

BID

Apixaban (mg) (n = 933)

Warf

(n=153)

Incidence of bleeding events (%)

Summary of ADVANCE – 2 TRIAL

• Apixaban 2.5mg BID vs. Enoxaparin 40mg QD• Superior for:

– Primary endpoint of ANY DVT/PE/All-Cause Death– Secondary endpoint for Major VTE

• Lower observed bleeding rates – Major – Clinically relevant non-major

• Similar overall safety profile

Ximelagatran• First target-specific oral anticoagulant in trials• Ximelagatran is the oral prodrug of Melagatran• Hepatatoxicity

– Did not receive FDA approval in 2004– On the market in Europe but pulled in 2006

• ‘proof of principle’– “efficacious” as warfarin– Wider therapeutic index– Little dosage adjustment/ no monitoring

Dabigatran Etexilate• Potent and reversible oral Direct Thrombin Inhibitor • Inhibiting both clot bound and free thrombin• Predictable and consistent PK profile -Rapid onset/offset of

action (Peak plasma levels within 2 hours)• Anticoagulation monitoring—Not required• Half-life 12–17 hours (twice-daily dosing)• Low drug–drug interactions (not metabolised by CYP450

enzymes) However, P glycoprotein inhibitors Amiodarone, verapamil and quinidine may increase its plasma level

• No food–drug interactions reported• Dosing independent of meals or dietary restrictions• 65% bioavailability, ~80% renal excretion

TRIALS IN PREVENTION OF DVT

• RE-MOBILISE• RE-NOVATE• RE-MODEL“Dabigatran was non inferior to enoxaparin in

terms of efficacy and bleeding risks”

Dabigatran:

Acute VTE TreatmentRE-COVER

AF and Stroke

Prevention

RE-LY

Secondary VTE PreventionRE-MEDY

# Patients# Patients 25542554 1800018000 20042004

Study ArmsStudy Arms

Dabigatran Dabigatran 150 mg BID 150 mg BID

vsvs

warfarinwarfarin

Dabigatran Dabigatran 100 mg BID 100 mg BID and 150 mg and 150 mg

BIDBID

vsvs

warfarinwarfarin

Dabigatran Dabigatran

150 mg BID 150 mg BID

vs vs

warfarinwarfarin

What about RE-LY?

Dabigatran versus Warfarin in Patients with Atrial Fibrillation

• Non-inferiority trial • Over 18,000 patients• Followup = 2 years

Dabigatran 110 mg and 150mg Dabigatran 110 mg and 150mg vs.vs.

Adjusted dose warfarinAdjusted dose warfarin

Incidence of Stroke or Systemic Embolism

RR 0.65 (95% CI: 0.52–0.81)

Str

oke

/syst

em

ic e

mbolis

m (

%/y

r)

Events/n:

BID, twice daily; NI, non-inferiority; RR, relative risk; RRR , relative risk reduction; Sup, superiority

Connolly SJ, et al. N Engl J Med. 2010;363:1875–1876.

183/6015 134/6076 202/6022

Dabigatran110 mg BID

Dabigatran150 mg BID

Warfarin0.0

0.3

0.6

0.9

1.2

1.5

1.8

1.54

1.11

1.71P<.001 (Sup)

P<.001 (NI)

RR 0.90 (95% CI: 0.74–1.10)

RRR35%

Events/n:BID, twice daily; RR, relative risk; RRR, relative risk reduction; Sup, superiorityConnolly SJ et al. NEJM 2009; 361 (12): 1139-1151.

27/6015 36/6076 87/6022

Dabigatran110 mg BID

Dabigatran150 mg BID

Warfarin0

0.6

0.9

Intr

acr

ania

l ble

edin

g (

%/y

r)

0.8

0.7

0.5

0.4

0.3

0.2

0.1

0.230.30

0.74

RR 0.31(95% CI: 0.20–0.47)

P<.001 (Sup)RR 0.40 (95% CI: 0.27–0.60)

P<.001 (Sup)

RRR69%

RRR60%

Significantly Lower Intracranial Bleeding with Dabigatran

Most Common Adverse EventsAdverse event (%)

Dabigatran110 mg BID

Dabigatran150 mg BID

Warfarin

Dyspepsia* 11.8 11.3 5.8

Dyspnoea 9.3 9.5 9.7

Dizziness 8.1 8.3 9.4

Peripheral oedema 7.9 7.9 7.8

Fatigue 6.6 6.6 6.2

Cough 5.7 5.7 6.0

Chest pain 5.2 6.2 5.9

Arthralgia 4.5 5.5 5.7

Back pain 5.3 5.2 5.6

Nasopharyngitis 5.6 5.4 5.6

Diarrhoea 6.3 6.5 5.7

Urinary tract infection 4.5 4.8 5.6

Upper respiratory tract infection

4.8 4.7 5.2

Adverse events occurring in >5% of patients in any treatment group; *Occurred more commonly with dabigatran, P<.001;BID, twice daily

Tab

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20

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Mass

ach

use

tts

Med

ical S

oci

ety

PropertyProperty RivaroxabanRivaroxaban ApixabanApixaban IdraparinuxIdraparinux DabigatranDabigatran

TargetTarget Factor XaFactor Xa Factor XaFactor Xa Factor Xa Factor Xa (indirect)(indirect)

ThrombinThrombin

ROAROA OralOral OralOral SubcutaneousSubcutaneous OralOral

ProdrugProdrug No No NoNo YesYes YesYes

BioavailabilityBioavailability > 80%> 80% > 50%> 50% 100%100% 6%6%

Time to peak Time to peak 33 33 ______ 22

Half-life Half-life 9 hrs9 hrs 9 – 14 hrs9 – 14 hrs 80 hrs80 hrs 14 – 17 hrs14 – 17 hrs

Frequency of Frequency of AdministrationAdministration

QdayQday BIDBID Q WeekQ Week Qday or BIDQday or BID

Drug Drug InteractionsInteractions

Potent CYP3A4 & Potent CYP3A4 & P-glycoprotein P-glycoprotein

inhibitorsinhibitors

Potent CYP3A4 & Potent CYP3A4 & P-glycoprotein P-glycoprotein

inhibitorsinhibitors

______ P-glycoprotein P-glycoprotein inhibitorsinhibitors

Renal excretion Renal excretion 66%66% 25%25% YesYes 80%80%

Safe in Safe in pregnancypregnancy

NoNo NoNo UnknownUnknown NoNo

AntidoteAntidote NoNo NoNo NoNo NoNoAdapted from: Gross, PL. Arterioscler Thromb Vasc Biol. 2008; 28:380-386.

INDICATIONS OF NEWER ANTICOAGULANTS

PREVENTION OF DVT

Principles of treatment

• HMWH• LMWH• Warfarin

NEWER• Fondaparinux• Dabigatran 220 mg bd (Post THR, TKR)• Rivaroxaban 10 mg qd (Post THR, TKR)

• In critically ill patients

• Post THR, TKR• Orthopedic &

other surgeries• Medical

conditions like post MI, Stroke

CONTEMPORARY

TREATMENT OF DVT

Principles of treatment

• HMWH80 U/kg STAT f/b

18 U/kg/hr infusion

• LMWH

NEWER• Fondaparinux• Dabigatran awaits

approval by US FDA

• Anti thrombotics- a must• Decision to be

taken reg. IVC filters

• 2nd VTE, unprovoked VTE & cancer associated VTE-indefinite duration

• Else- 3-6 months duration

CONTEMPORARY

TREATMENT OF PULMONARY EMBOLISM

Principles of treatment• HMWH80 U/kg stat f/b

18 U/kg/hr infusion

• LMWH

NEWER• Fondaparinux• Other trials are

ongoing….

• Presence of RV dysfunction / hemodynamic instability

Thrombolysis• Small to

moderate PE-antithrombotics

• Well’s criteria> 3- antithrombotics

CONTEMPORARY

PREVENTION OF STROKE IN AF

Why do we need long term anticoagulation ?

• Atrial fibrillation (AF) is responsible for one-third of all strokes and is the leading cause of embolic stroke

• Stroke is the most serious complication of AF• There is 5 fold and 17 fold increase in the risk of stroke due to

non-valvular AF (NVAF) and valvular AF respectively• About one in four people at age 55 years will go on to develop

AF (24% of men and 22% of women)• 1 in 20 (5%) AF patients can have a stroke if not prevented• In excess of 7% per year can be attributed to rate of brain

ischemia due to transient ischemic attacks and clinically ‘silent’ strokes, associated with Non valvular Atrial Fibrillation

PREVENTION OF STROKE IN ATRIAL FIBRILLATION

• CLASS 1 INDICATIONS:1.Presence of cardiac thrombus / DVT2.In AF due to valvular causes3.In AF due to non valvular causes (as per CHADS2 score)

Choice In AF due to non valvular causes (as per CHADS2 score)

• 1= aspirin / anticoagulant

• >1=anticoagulant

PREVENTION OF STROKE

Principles of treatment

• HMWH• LMWH

NEWER• FONDAPARINUX• DABIGATRAN

110/150 mg BD• RIVAROXABAN 20 mg QD• APIXABAN awaits

approval by US FDA

• In AF• Mechanical heart

valves• In

cardiomyopathies• Inherited

coagulopathies• DVT

CONTEMPORARY

150 mg OR 110 mg DABIGATRAN ?

150 mg 110 mg

< 75 years1, 2 ≥ 75 years1, 2 with risk factors:(i) Higher risk for bleed*(ii)Pharmacodynamic interactions**(iii)Factors increasing dabigatran plasma levels***1, 2

Superior vs warfarin for stroke1, 2 Noninferior vs warfarin for stroke1, 2

Noninferior vs warfarin for risk of major bleed1, 2 –

Superior vs warfarin for ICH

Superior vs warfarin for risk of major bleed1, 2 Superior vs warfarin for ICH

*1. Congenital or acquired coagulation disorders, 2.Thrombocytopenia or functional platelet defects, 3.Active ulcerative gastrointestinal (GI) disease, 4.Recent GI bleeding, 5.Recent biopsy or major trauma, 6.Recent intracranial hemorrhage, 7.Brain, spinal or ophthalmic surgery, 8.Bacterial endocarditis**Acetylsalicylic acid, NSAID, Clopidogrel***Moderate renal impairment (30-50ml/min CrCL), P- glycoprotein-inhibitor comedication

Prevention of Atrial Fibrillation-Related Stroke

76

The Newer Anticoagulants on the Horizon

Trial Drug Dose Comparator NCHADS2 score

RE-LY Dabigatran150 mg and

110 mg*BID

Warfarin(INR 2.0–3.0)

18,113 >0

ROCKET-AF5,6 Rivaroxaban20 mg*

ODWarfarin

(INR 2.0–3.0)14,264 ≥2

AVERROES3,4 Apixaban5 mgBID

Aspirin (81–324 mg OD)

6000 ≥1

ARISTOTLE1,2 Apixaban5 mgBID

Warfarin(INR 2.0–3.0)

18,201 ≥1

ENGAGE-AF TIMI 487 Edoxaban

30 mg OD60 mg OD

Warfarin(INR 2.0–3.0)

>20,000 ≥2

*Adjusted based on renal function. BID, twice daily; INR, international normalised ratio; OD, once daily

PREVENTION OF STROKE IN NON CARDIOEMBOLIC EVENTS

“No evidence that warfarin is superior to aspirin in stroke prevention”Evidence based on the following landmark trials-•WATCH- low ef CHF•APASS- APLS syndrome pts.•PICSS- Patent foramen ovale pts.•WARSS trials

IN H.I.T Syndromes

Withdraw heparin and initiate one of the following:•Lepirudin – preferred over Argatroban in hepatic diseases•Argatroban- preferred over lepirudin and fondaparinux in renal diseases•Fondaparinux “Warfarin NOT TO BE USED IMMEDIATELY post HMWH/LMWH”

Pre Cardiac catherisation (PCI)

• LMWH / Bivaluridin preferred post MI

Potential Limitations of New Anticoagulants

• Antidotes– None of the newer agents has a specific antidote

• Monitoring• Adverse Drug Events• Compliance• Cost• Clinical Trials vs. Actual Clinical Practice• Patient populations not even studied (i.e. Cancer)

FUTURE OF ANTI COAGULATION

Summary

Dabigatran

Rivaroxaban

Apixaban

Time to Market for New Anti-Thrombotic Agents

2010

2011 2012

2013

Otomaxiban

AnticoagulantsAnticoagulants• CURRENT DRUGS

– Unfractionated Heparin______________– Low Molecular Weight Heparin________– Lepirudin (DTI)____________________– Bivalirudin (DTI) ___________________– Argatroban(DTI)____________________– Danaparoid_______________________– Drotrecogin Alfa____________________– Vitamin K antagonists (Warfarin)_______

• NEW/ in DEVELOPMENT DRUGS– Fondaparinux_____________________– Idraparinux_______________________– SSR 126517______________________– Rivaroxaban______________________– Apixaban_________________________– LY517717________________________– YM150__________________________– DU-176b_________________________– Betrixaban________________________– Ximelagatran*_____________________– Dabigatran etexilate________________

*taken off the market Italics are Oral Drugs

TARGETED FACTORAntithrombin (indirectly Xa and IIa)Antithrombin (indirectly Xa and IIa)Thrombin (IIa)Thrombin (IIa)Thrombin (IIa)AntithrombinVa, VIIIaProthrombin (II), VII, IX, X

XaXaXaXaXaXaXaXaXaThrombin (IIa)Thrombin (IIa)

• “HAD WARFARIN INTRODUCED INTO THE MARKET TODAY, THE US FDA WOULD HAVE

REJECTED”-A FAMOUS CARDIOLOGIST DURING THE ESC

“BUT STILL, WARFARIN REMAINS OUR POOR MAN’S CHOICE”

THANK YOU !!!