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Transcript of Newer anticoagulants
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
le r
ep
rod
uce
d w
ith
perm
issi
on
: ©
20
09
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 !!!