1. Prof Lukman.pdf

Prof .Prof .DR.drDR.dr LukmanLukman H.Makmun,SpPDH.Makmun,SpPD--KKV,KgerKKV,KgerLahat,03Lahat,03 MaretMaret 19471947

Riwayat Pendidikan:FKUI Tahun 1971Internis Tahun 1979Konsultasi Kardiologi FKUI Tahun 1984Konsultan Geriatri FKUI Tahun 2000

Jabatan:2001-2004 Ketua Devisi Geriatri FKUI RSCM2008-2011 Ketua Devisi Kardiologi Departemen Penyakit Dalam FKUI2008-2011 Ketua Departemen Pendidikan Kedokteran FKUI

Jabatan Saat ini: Guru Besar FKUI

Organisasi: Ketua Umum PB IKKI

Novel Oral Anti Coagulant forStroke Prevention in Atrial

Fibrillation Patient.

Lukman H.MakmunDiv.Kardiologi Dept.I.Peny.Dalam

FKUI/RSCM

Content review:• Epidemiology AF and Stroke• Scoring stroke risk in AF• Coagulation cascade and thrombin

formation• Effect mechanism of anti platelet and anti

thrombotic drug.• Treatment guidelines for AF.• New oral anti coagulant.• Rocket study

The number of patients with AF isanticipated to continue to increase

41. Miyasaka Y et al, 2006; 2. Go AS et al, 2001.

Year

2.08 2.442.26

5.1

5.1

0

2

4

6

8

10

12

14

16

1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050

Patie

nts

with

AF

(mill

ions

)

5.42

11.7

15.2

4.34

9.4

11.7

3.33

7.5

8.9

2.94

6.8

7.78.4

10.2

3.804.78

10.3

13.1

5.16

11.1

14.3

5.61

12.1

15.9

5.6

5.9

2.66

6.1

6.7

Olmsted County Data, 20061

(assuming a continued increase in AF incidence)

ATRIA Study Data, 20002

Olmsted County Data, 20061

(assuming no further increase in AF incidence)

Stroke is a frequent & serious complication of AF

• AF is the leading cause of embolic stroke4

• AF is associated with a 5-fold higher stroke risk overall1

• Without preventive treatment, each year approximately 1in 20 patients with AF will have a stroke3

• AF stroke is usually more severe than stroke due toother causes1

• The mortality rate for patients with AF is double that inpeople with normal heart rhythm4

1. Savelieva I et al. Ann Med 2007;39:371–91; 2. Fuster V et al. European Heart Journal 2006;27:1979–2030;3. Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449–57;4. Benjamin EJ et al. Circulation 1998;98:946–52

6

Patients with AF have an ~fivefoldincreased risk of ischaemic stroke

2-ye

ar a

ge-a

djus

ted

inci

denc

eof

str

oke/

1,00

0 in

divi

dual

s

Individualswith AF

Individualswithout AF

Risk ratio=4.8p<0.001

0

10

20

30

40

50

60

Framingham Heart Study (N=5,070)

Wolf PA et al, 1991. 6

CHADS2 risk stratification for stroke prevention inpatients with AF

• CHF +1• Hypertension +1• Age >75 years +1• Diabetes mellitus +1• Prior Stroke or TIA +2

• CHADS2 does not consider all risk factors: stroke riskmay be underestimated

Gage et al, 2001; 2004; Fuster et al, 2006; Singer et al, 2008

Risk category Score

Low 0

Intermediate 1

High 2

1.9 2.84

5.98.5

12.5

18.2

0

5

10

15

20

0 1 2 3 4 5 6

Stro

ke ra

te (%

per

yea

r)

n=120 n=463 n=523 n=337 n=220 n=65 n=5CHADS2 Score

AHA / ACC / ESC Guidelines EHJ 2006;27:1979–2030

Stroke risk in AF using the CHADS2score

C – CHF 1H – Hypertension 1A - Age > 75 1D - Diabetes mellitus 1S2 - TIA/Stroke 2

CHA2DS2-VASc score

Risk factor PointsCongestive heart failure/LV dysfunction +1Hypertension +1Age 75 years +2Diabetes mellitus +1Stroke/TIA/TE +2Vascular disease (MI, aortic plaque, PAD)* +1Age 65–74 years +1Sex category (female) +1Cumulative score Range 0 9

Lip et al, 2010

Score: 0 = low risk; 1 = intermediate risk; 2 = high risk

Left: MS, AF, LA enlargement; Right: Sludge in LAA that can form thrombus.(Siglow et al. TEE. Thieme Verlag. 1993)

Multiple small thrombusSiglow et al. TEE. Thieme Verlag. 1993)

Fuster V et al. Circulation 2006;114:e257–354

Treatment goals of atrial fibrillation

• Key goals of AF management :1.Prevention of thromboembolism and stroke2.Restoration & maintenance of sinus rhythm3.Control of heart rate

• Anticoagulant therapy is recommendedfor all patients regardless of the level ofstroke risk, other than those with lone AFor contra-indications to anticoagulanttherapy

AggregationAggregationof platelets intoof platelets into

a thrombusa thrombus

PlateletsPlatelets

Endothelial cellsEndothelial cells

Subendothelial spaceSubendothelial space

Platelets adheringPlatelets adheringto subendothelialto subendothelialspacespace

PlateletPlateletthrombusthrombus

Platelet Adhesion andActivation

Normal plateletsNormal plateletsin flowing bloodin flowing blood

Platelets adhering toPlatelets adhering todamaged endotheliumdamaged endothelium

and undergoingand undergoingactivationactivation

7

Platelets in Initiation of Thrombus Formation

Von Willebrand factorVon Willebrand factor

Gp IIb/IIIa complexGp IIb/IIIa complex

PlateletPlateletFibrinogenFibrinogen

FibrinogenFibrinogen

SD3321 03/12/98

SlideE972095A 15

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SlideE972095A 16

SD33157/15/98

LMWH

LMWH

Antiplatelet Agents

• Thromboxane A2 inhibitor– Acetylsalicylic acid (ASA)

• Phosphodiesterase inhibitor– Dipyridamole

• Glycoprotein (GP) IIb/IIIa blockers– Parenteral: abciximab, eptifibatide, tirofiban

• ADP-receptor antagonists– Clopidogrel– Ticlopidine

Cilostazol

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Platelets and Prevention ofPlatelets and Prevention ofAtherothrombosisAtherothrombosis

Platelets play a central role in thrombusPlatelets play a central role in thrombusformationformation

Initiate thrombus formation on atheroscleroticInitiate thrombus formation on atheroscleroticplaqueplaque

Platelet aggregation inhibitors inhibit formationPlatelet aggregation inhibitors inhibit formationof plateletof platelet--rich thrombi on disrupted plaquerich thrombi on disrupted plaque

Prevention of thrombus formation can preventPrevention of thrombus formation can preventacute cardiovascular ischemic events: e.g.,acute cardiovascular ischemic events: e.g.,myocardial infarction,myocardial infarction, ischemic strokeischemic stroke, and, andvascular deathvascular death

Current antithrombotic agentsCurrent antithrombotic agents

1. Rosenberg RD, Aird WC. N Engl J Med 1999;340:1555–64.2. Hirsh J, et al. Chest 1995;108 Suppl:258–75S.

3. Samama CM et al. Thromb Haemost July 2001;ISTH Abstract OC2343.4. Hirsh J, Fuster V. Circulation 1994 ;89:1469–80.5. Hirsh J, Fuster V. Circulation 1994 ;89:1449–68.

TF: tissue factorPL: phospholipidTFPI: tissue factor pathway inhibitorPS: protein SPC: protein CPCa: activated protein CTM: thrombomodulinATIII: antithrombin III

Clot

Intrinsic Pathway Extrinsic Pathway

TF

Ca2+

Xa X

II

IX

XI

XII XIIa

FibrinFibrinogen

XaVa

PLCa2+

IIa

VII

Heparin

Vitamin Kantagonists

XIa VIIa

VIIIaCa2+

PL

IXa

Fondaparinux

Direct thrombininhibitron

Key Steps in Coagulation PathwayKey Steps in Coagulation Pathway

Inhibition of one moleculeof factor Xa can inhibit thegeneration of 50 moleculesof thrombin2

Intrinsic pathway Extrinsic pathway

1. Rosenberg RD, Aird WC. N Engl J Med 1999;340(20):1555–64.2. Wessler S, Yin ET. Thrombo Diath Haemorrh 1974;32(1):71–8.

Intrinsic pathway

1

50

Xa X

II

FibrinFibrinogen

Clot

XaVa

PLCa2+

IIa

VIIIaCa2+

PL

IXa

SlideE972095A 22

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Unfractionated heparin:

- campuran molekul glycosaminoglycan- 40.000 dalton- mekanisme kerja: mengkatalysis AT III untuk

menghambat factor IIa (thrombin), F.IXa,Xa,Xia,XIIa

- mengikat sel endotel- adsorbsi s.c. kurang baik.

SlideE972095A 23

SD33157/15/98

LMWH:

- 4500 Dalton- depolymerisasi molekul unfractionated heparinMekanisme kerja: sama seperti UH- inhibisi trombin lebih lemah- anti Xa- Dual action: - inhibisi prothrombinase (F.Xa-Ca-

phospholipidV)- inaktivasi trombin langsung.

- Tidak berefek pada fungsi platelet- Afinitas lemah terhadap sel endotel- Efek hemoragik lebih sedikit- Availabilitas dengan s.c. tinggi

Anticoagulants in development havesingle targets

Adapted from Spyropoulos AC et al. Expert Opin Investig Drugs 2007;16:431–440

Clot formation

Initiation

Propagation

X

IXa

IIaThrombin

Xa

Fibrinogen Fibrin

Prothrombin

VIIa

IX

II

TF

AT

IndirectFondaparinux

DirectRivaroxaban

ApixabanEdoxabanBetrixabanDarexaban

DirectLepirudin

BivalirudinArgatrobanDabigatranTGN-167

Inactive factor

Active factor

Transformation

Catalysis

25

IIa ThrombinII

Fibrinogen Fibrin clot

FXa

Direct and indirect factor Xa (FXa) inhibition

Adapted from Turpie AG et al. N Engl J Med 2001;344:619–25

ATAT AT

Indirect factor Xainhibitor

FXa

Direct factorXa inhibitor

INDIRECTBinds to antithrombin (AT)and potentiates the activity of ATagainst FXa(e.g. idraparinux, SSR 126517)

DIRECTBinds directly to the active site of FXa,blocking substrate interactions(e.g. apixaban, rivaroxaban,edoxaban, betrixaban)

Treatment guidelines for SPAF

evidence and recommendations

Guideline recommendations ESC 2010

• Major risk factors:– Previous stroke, TIA or systemic

embolism– Age 75 years

• Clinically relevent non-major riskfactors:

– Heart failure or moderate tosevere LV systolic dysfunction(e.g. LV EF < 40%)

– Hypertension– Diabetes mellitus– Female sex– Age 65–74 years– Vascular disease

Camm et al, 2010

OAC is the preferred treatment for all patients with at leastone CHA2DS2-VASc risk factor

ACC/AHA/ESC risk stratification

• Low risk‘Lone’ AF (no other risk factors)

• Moderate riskOnly one of: age 75 years, hypertension, heart failure, LVEF 35%or diabetes mellitus

• High riskPrior thromboembolism (stroke, TIA, systemic embolism) orRheumatic mitral stenosis orProsthetic heart valve or2 of the following: age 75 years, hypertension, heart failure,

LVEF 35% or diabetes mellitus

Fuster et al. Circulation 2006

Guidelines: stroke prevention in AF

Riskcategory

Guideline recommendationsACC/AHA/ESC1 ACCP2

Low ASA (81–325 mg/day) ASA (75–325 mg/day)Moderate Oral VKA

target INR 2.5 (range 2–3)or

ASA (81–325 mg/day)

Oral VKAtarget INR 2.5 (range 2–3)

orASA (75–325 mg/day)

High risk Oral VKAtarget INR 2.5 (range 2–3)*

Oral VKAtarget INR 2.5 (range 2–3)

Fuster et al. Circulation 2006; 2. Singer et al. Chest 2008*If mechanical valve, target INR 2.5

30Error bars = 95% CI; *Relative risk reduction for all strokes (ischaemic and haemorrhagic)

Warfarin reduces the risk of stroke in patients with AF

Relative risk reduction (%)*100 –10050 0 –50

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

All trials

Warfarin better Placebo better

RRR = 64%95% CI: 49 to 74%

Hart RG et al. Ann Intern Med 2007;146:857–67

Warfarin vs Placebo

BMJ 2002;325:1022-5

22% (2% to 38%)

Reduction of Risk of Thromboembolism in Atrial Fibrillation

Aspirin vs Placebo

100 –10050 0 –50Aspirin better Aspirin worse

AFASAK I

SPAF I

EAFT

ESPS II

LASAF

UK-TIA

All trials (n=6)

Aspirin vs Clopidogrel + Aspirin

ACTIVE-A STUDY

N Engl J Med 2009;360;2066-78

0.4

0.3

0.2

0.1

00 1 2 3 4

Aspirin

Clopidogrel + AspirinCum

ulat

ive

Inci

denc

e

Years

0.4

0.3

0.2

0.1

00 1 2 3 4

Aspirin

Clopidogrel + AspirinCum

ulat

ive

Inci

denc

e

Years

STROKEPRIMARY OUTCOME

RR=0.72, p<0.001RR=0.89, p=0.01

Primary outcome : Stroke, MI, Non-CNS SystemicEmbolism or Death from Vascular Causes

Lancet 2006;367:1903-12

Years

STROKE

0.05

0.04

0.03

0.02

0.01

0

0 0.5 1.0 1.5

Clopidogrel+Aspirin

Warfarin

RR=1.72 (1.24-2.37), p=0.001

Cum

ulat

ive

haza

rd ra

tes

Years

Clopidogrel + Aspirin vs Warfarin

ACTIVE-W STUDY

0.10

0.8

0.6

0.4

0.2

0

0 0.5 1.0 1.5

Clopidogrel+Aspirin

Warfarin

RR=1.44 (1.18-1.76), p=0.0003

Cum

ulat

ive

haza

rd ra

tes

PRIMARY OUTCOME

34

Limitations of current Anticoagulants

• Vitamin K antagonists (VKAs) have greater efficacy butthe range of limitations make them challenging agents touse:1,2

– Narrow therapeutic window– Variable and unpredictable pharmacokinetics and pharma-

codynamics– Wide variety of drug–drug and drug–food interactions– Need for regular anticoagulation monitoring and dose

adjustments– Slow onset and offset of action

1. Turpie AG. Eur Heart J 2008;29:155–65;2. Khoo CW et al. Int J Clin Pract 2009;63:630–41

VKAs have a narrow therapeutic window

Fuster V et al. Circulation 2006;114:e257–e354

1International Normalized Ratio (INR)

Odd

s ra

tio

2

15

8

10

5

01

3 4 5 6 7

Therapeuticrange

20

Ischaemic strokeIschaemic stroke

Intracranial bleedingIntracranial bleeding

36

In the small proportion of patientswith AF receiving warfarin, the INR isoften outside the therapeutic range

No warfarin65%

INR above target6%

INR on target15%INR below target

13%

Samsa GP et al. Arch Intern Med 2000;160:967–73

Contraindications to VKA treatment

Coumadin: SmPC, 2009

Bleeding tendencies associated with active ulceration or overt bleeding:– Gastrointestinal, genitourinary or respiratory tracts– Cerebrovascular haemorrhage– Pericarditis and pericardial effusions– Cerebral aneurysms, dissecting aorta– Bacterial endocarditis

Haemorrhagic tendencies or blood dyscrasias– Thrombocytopaenia– Coagulation factor abnormalities

Recent or contemplated surgery of:– Central nervous system– Eye– Traumatic surgery resulting in large open surfaces

Severe hepatic or renal diseaseDiastolic blood pressure >110 mmHgPregnancyThreatened abortion

– Eclampsia– Preeclampsia

New oral anticoagulant agents• A number of novel anticoagulant agents have been developed,

targeting different components of the coagulation cascade

• Factor Xa inhibitors:– Direct: Rivaroxaban (phase III completed), Apixaban (phase III

completed), Edoxaban (phase III in development)– Indirect: idraparinux (Phase III trial terminated)

• Direct thrombin inhibitors– Ximelagatran: provided proof-of-concept but withdrawn from the

market in 2006 due to liver toxicity– AZD0837: Phase II completed– Dabigatran etexilate: Phase III completed

Rivaroxaban• Selective, direct Factor Xa

inhibitor1

• High oral bioavailability2

• Rapid onset of action3

• Half-life:2–4

– 7 – 11 hours• Dual mode of elimination:5

– 1/3 of active drug excretedunchanged by the kidneys

– 2/3 of drug metabolized by the liver;half of which is excreted renally,half excreted via thehepatobiliary route

1. Perzborn et al, 2005; 2. Kubitza et al, 2005a; 3. Kubitza et al, 2005b;4. Kubitza et al, 2008; 5. Weinz et al, 2009

Rivaroxaban

Xa

IIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

Adapted fromWeitz et al, 2005; 2008

TF/VIIa

The promise of novel OACs

40

Improvedcompliance

Improvedefficacy

and safety

Less impact onpatient’s daily

life

ImprovedQoL

Less labour-intensive

Reducedadministrative

costs

Reduced potentialfor food and drug

interactions

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.

Simplified dosing regimen, no dietaryrestrictions, predictable anticoagulation

and no need for routine coagulationmonitoring.

Can be given at fixed doses

Rivaroxaban Once-daily oral direct factor Xa inhibition

Compared with vitamin K antagonism for prevention

of stroke and Embolism Trial in Atrial Fibrillation

42

Rivaroxaban Warfarin

Primary endpoint: stroke or non-CNS systemic embolism

INR target: 2.5(2.0–3.0 inclusive)

20 mg once daily(15 mg once daily

for CrCl 30–49 ml/min)

Atrial fibrillation

Randomizeddouble blind /

double dummy

Monthly monitoringAdherence to standard-of-care guidelines

ROCKET AF – study design

*Enrolment of patients without prior stroke, TIA or SE and only two factors capped at 10%

Risk factors• Stroke, TIA orsystemic embolus

OR• CHF• Hypertension• Age 75• Diabetes

At least 2or 3required*

Patel MR et al, 2010;

43

ROCKET AF – study endpointsPrimary efficacy endpoint• Composite of stroke and sytemic embolism (SE)

Secondary efficacy endpoints• Composite of stroke, SE and cardiovascular death• Composite of stroke, SE, cardiovascular death and MI• Individual components of the above endpoints

Principal safety endpoint• Composite of major and non-major clinically

relevant bleeding

Patel MR et al, 2011.

44

ROCKET AF – baseline characteristics (2)

CharacteristicRivaroxaban

(N=7,131)Warfarin(N=7,133)

CHADS2 score, mean ± SD 3.48±0.94 3.46±0.952, n (%) 925 (13.0) 934 (13.1)3, n (%) 3,058 (42.9) 3,158 (44.3)4, n (%) 2,092 (29.3) 1,999 (28.0)5, n (%) 932 (13.1) 881 (12.4)6, n (%) 123 (1.7) 159 (2.2)

Co-existing conditions, n (%)Previous stroke/TIA or SE 3,916 (54.9) 3,895 (54.6)Congestive heart failure 4,467 (62.6) 4,441 (62.3)Hypertension 6,436 (90.3) 6,474 (90.8)Diabetes mellitus 2,878 (40.4) 2,817 (39.5)Previous MI 1,182 (16.6) 1,286 (18.0)Peripheral vascular disease 401 (5.6) 438 (6.1)Chronic obstructive pulmonary disease 754 (10.6) 743 (10.4)

CrCl, median (25th, 75th), ml/min 67 (52, 88) 67 (52, 86)

ITT populationPatel MR et al, 2011.

45

Number of subjects at riskRivaroxaban 6,958 6,211 5,786 5,468 4,406 3,407 2,472 1,496Warfarin 7,004 6,327 5,911 5,542 4,461 3,478 2,539 1,538

ROCKET AF – primary efficacyendpoint

Per-protocol population – as treated

Warfarin

Rivaroxaban

Days since randomization

HR=0.79 (0.66, 0.96)p<0.001 (non-inferiority)

0 120 240 480 600 7200

1

2

3

4

5

6

840360

Cum

ulat

ive

even

t rat

e (%

)Stroke or systemic embolism


46

ROCKET AF – primary efficacyendpoint components

Safety population – on-treatment analysis*Statistically significant

Favoursrivaroxaban

Favourswarfarin

Hazard ratioand 95% CIs

0.2 0.5 1 2 5

Endpoints

Rivaroxaban(N=7,061)

Warfarin(N=7,082)

Hazard ratio(95% CI)

n(% per year)

n(% per year)

Primary efficacy endpoint 189 (1.7) 243 (2.2) 0.79 (0.65, 0.95)*

All-cause stroke 184 (1.7) 221 (2.0) 0.85 (0.70,1.03)

Haemorrhagic stroke 29 (0.3) 50 (0.4) 0.59 (0.37,0.93)*

Ischaemic stroke 149 (1.3) 161 (1.4) 0.94 (0.75,1.17)

Unknown stroke type 7 (0.1) 11 (0.1) 0.65 (0.25,1.67)

Non-CNS SE 5 (0.04) 22 (0.2) 0.23 (0.09, 0.61)*


Parameter

Rivaroxaban(N=7111)

Warfarin(N=7125) Hazard ratio

(95% CI)n (% per year) n (% per year)Principal safetyendpoint

1475 (14.9) 1449 (14.5) 1.03 (0.96,1.11)

Major bleeding 395 (3.6) 386 (3.4) 1.04 (0.90,1.20)

Hemoglobin drop2 g/dl)

305 (2.8) 254 (2.3) 1.22 (1.03,1.44)*

Transfusion 183 (1.6) 149 (1.3) 1.25 (1.01,1.55)*

Critical organbleeding

91 (0.8) 133 (1.2) 0.69 (0.53,0.91)*

Intracranialhemorrhage

55 (0.5) 84 (0.7) 0.67 (0.47,0.93)*

Fatal bleeding 27 (0.2) 55 (0.5) 0.50 (0.31,0.79)*

Non-major clinicallyrelevant bleeding

1185 (11.8) 1151 (11.4) 1.04 (0.96,1.13)

Safety population – as-treated analysis; *statistically significant

ROCKET AF – Bleeding Analysis

Major bleeding from gastrointestinal site (upper, lower and rectal):rivaroxaban = 224 events (3.2%); warfarin = 154 events (2.2%); p<0.001*


0.2 0.5 1 2 5

Favorsrivaroxaban Favors

warfarinPatel et al. NEJM 2011, August 10th epub ahead of print

48

ROCKET AF – most frequenttreatment-emergent adverse events

Adverse event, no. (%)Rivaroxaban

(N=7,111)Warfarin(N=7,125)

Total patients with treatment-emergent AEs# 5,791 (81.4) 5,810 (81.5)Epistaxis* 721 (10.1) 609 (8.6)Peripheral oedema 435 (6.1) 444 (6.2)Dizziness 433 (6.1) 449 (6.3)Nasopharyngitis 421 (5.9) 455 (6.4)Cardiac failure 397 (5.6) 420 (5.9)Bronchitis 396 (5.6) 417 (5.9)Dyspnoea 380 (5.3) 394 (5.5)Diarrhoea 379 (5.3) 397 (5.6)Cough 343 (4.8) 353 (5.0)Back pain 338 (4.8) 347 (4.9)Upper respiratory tract infection 336 (4.7) 325 (4.6)Headache 324 (4.6) 363 (5.1)Arthralgia 301 (4.2) 331 (4.7)Haematuria* 296 (4.2) 242 (3.4)Urinary tract infection 293 (4.1) 321 (4.5)ALT >3× ULN and bilirubin >2× ULNeither on same day or within following 30 days

33 (0.5) 35 (0.5)

Safety population; *p<0.05. 15 most frequent based on rivaroxaban treatment arm.#Events that started on or after the first dose and up to 2 days after the last dose of study medication.

Patel MR et al, 2011. Slide notes contain data on file

49

ROCKET AF – all-cause mortality

Safety population – on-treatment analysis


0.2 0.5 1 2 5Favours

rivaroxabanFavourswarfarin

Endpoints


Warfarin(N=7,082)


n(% per year)

n(% per year)

All-cause mortality 208 (1.9) 250 (2.2) 0.85 (0.70,1.02)

Vascular death 170 (1.5) 193 (1.7) 0.89 (0.73, 1.10)

Non-vascular death 21 (0.2) 34 (0.3) 0.63 (0.36, 1.08)

Unknown cause 17 (0.2) 23 (0.2) 0.75 (0.40, 1.41)


50

ROCKET AF – conclusions• Based on the prespecified primary efficacy outcome:

– A once-daily fixed dose regimen of rivaroxaban was non-inferior towarfarin for prevention of stroke or non-CNS systemic embolism

• Safety:– Similar overall incidence of bleeding and adverse events– Increase in gastrointestinal bleeds but importantly fewer intracranial

haemorrhages and less fatal bleeding with rivaroxaban• Implication:

– Rivaroxaban, once approved in the indication, is a once-daily, provenalternative to warfarin with superior efficacy ‘on treatment’, similar overallbleeding and fewer intracranial haemorrhages

Conclusion:

• AF is a serious risk factor for Stroke• AF must be treated with anti platelet,

antithrombotic drug regardless to therisk level

• Currently some new oral antithromboticdrug are available.

• Rivaroxaban give a good promising inthe treatment of AF to prevent stroke.

Thank U

Atrial fibrillation is a commondisorder

• Approximately 1% of all people are affected by AF1

• Estimated prevalence rates for paroxysmal or persistent AF:2– Europe : 4.5 million USA : 2 million

• The lifetime risk of AF is almost one in four3

• The overall prevalence of AF is increasing, driven by:– Ageing of populations worldwide– Rising prevalence of chronic heart disease– Rising prevalence of AF risk factors, e.g. diabetes mellitus

• Hospital admissions for AF have increased by 60% over thepast 20 years4

1. Go AS et al. JAMA 2001;285:2370–5; 2. Fuster V et al. Circulation 2006;114:e257–354;3. Heeringa J et al. Eur Heart J 2006;27:949–53 4. Friberg J et al. Epidemiology 2003;14:666-72

Risk of major bleeding increases with theHAS-BLED score (p=0.007)

54

0

2

4

6

8

10

12

14

0 1 2 3 4 5 6 7 8 9

Ble

eds

per 1

00 p

atie

nt-y

ears

AF cohort of theEuro Heart Survey

HAS-BLED score

Pisters R et al, 2010.

Number ofpatients 798 1,286 744 187 46 8 2 0 0 0

Number ofbleeding events 9 13 14 7 4 1 0 0 0 0

Clinicalcharacteristic Points

Hypertension (SBP>160 mmHg) 1

Abnormal renal orliver function 1 + 1

Stroke 1Bleeding 1Labile INRs 1Elderly (age>65 years) 1

Drugs or alcohol 1 + 1Cumulative score Range 0 9

55

ROCKET AF – stroke outcomes

Endpoints


Warfarin(N=7,082)


n(% per year)

n(% per year)

Stroke 184 (1.7) 221 (2.0) 0.85 (0.70–1.03)

Stroke leadingto death*

47 (0.4) 67 (0.6) 0.71 (0.49–1.03)

Disabling* 43 (0.4) 57 (0.5) 0.77 (0.52–1.14)

Non-disabling* 88 (0.8) 87 (0.8) 1.03 (0.76–1.38)

Unknown 7 (0.1) 12 (0.1) 0.59 (0.23–1.50)

Safety population – on-treatment analysis*Based on investigator’s assessment of modified Rankin scale score:0–2=non-disabling, 3–5=disabling, and 6=death

Favoursrivaroxaban

Favourswarfarin


0.2 0.5 1 2 5


56

ROCKET AF – major bleeding by siteSite*


Warfarin(N=7,125)

Major bleeding, n (%) 395 (5.6) 386 (5.4)Gastrointestinal (upper, lower, rectal)# 224 (3.2) 154 (2.2)Intracranial‡ 55 (0.8) 84 (1.2)

Intraparenchymal‡ 37 (0.5) 56 (0.8)Non-traumatic‡ 33 (0.5) 54 (1.8)Traumatic 4 (0.1) 2 (0.03)

Intraventricular 2 (0.03) 4 (0.1)Subdural haematoma 12 (0.2) 22 (0.3)Subarachnoid 4 (0.1) 1 (0.01)Epidural haematoma 0 1 (0.01)

Macroscopic haematuria 26 (0.4) 21 (0.3)Bleeding associated with non-cardiac surgery 19 (0.3) 26 (0.4)Intraocular/retinal 17 (0.2) 24 (0.3)Intraarticular 16 (0.2) 21 (0.3)Epistaxis 13 (0.2) 14 (0.2)

*Site based on blinded adjudication.#Combined gastrointestinal bleed rate p<0.001; ‡p<0.05Patel MR et al, 2011.

1. Prof Lukman.pdf

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