debates en cardiología: implicaciones clínicas de la anticoagulación en las nuevas guías

ANTITHROMBOTICS AND CHALLENGES – 2010 -2020

1. Challenge by ESC of ACC / AHA Guidelines in AF (3)

2. Challenge of INR - TE / Bleeding (3)

3. Challenge of Age - TE / Bleeding (3)

4. Challenge of Brain - Microvascular Disease (3)

5. Challenge of Multiple Antithrombotics (3)

6. Challenge of Novel Platelet Inhibitors (3)

7. Challenge of Nobel Anticoagulants (3)

8. Challenge of LAA Exclusion in Stroke Prevention (3)

ACC / AHA / ESC ( Fuster V et al ) Circ 2006; 114: 700 ESC Guidelines, EHJ 2010;31:2369 - Working Group Report, EU 2010

1) STROKE: A SIGNIFICANT CAUSE OF POOR HEALTH AND DEATH

• Stroke accounts for nearly 10% of all deaths worldwide.

• The number of strokes per year is predicted to rise dramatically as the population ages.

• About 20-30% strokes are cardioembolic and 15% relate to AF

• Strokes in patients with AF are more severe and have worse outcomes than strokes in people without AF.

• AF almost doubles the death rate from stroke. AF increases the risk of remaining disabled following stroke by almost 50%.

ESC Guidelines EHJ 2010;31:2369 - Working Group Report, EU 2010

1) SOURCES OF CARDIOEMBOLIC STROKE

50%NVAF

10%MI

10%Ventricular

10%Rheumatic

5%Prosthetic

15%Other

MJ Schneck et al., eMedicine Neurology 2008

2) ATRIAL FIBRILLATION - RISK OF STROKE BY CHAD*SCORE

CHAD Index Antithrombotics High Risk: TE, MS, PHV Warfarin INR 2.0-3.5 2 RF Warfarin INR 2-3 Moderate Risk: 1 RF ASA 81-325mg Warfarin INR 2-3 (<EF)

Low Risk: 0 RF ASA 81-325 mg

* RF: C.Fail./ EF <35% 1, Hypert. 1, Age >75 1, Diabetes 1, ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700

2) STROKE RISK ASSESSMENT IN AF: CHA2DS2-VASc Stroke Risk Factors Score

Congestive heart failure/LV dysfunction 1

Hypertension 1

Age ≥ 75 yrs 2

Diabetes melitus 1

Stroke/TIA/TE 2

Vascular disease (prior MI, PAD, or aortic plaque) 1

Age 65-74 years 1 ?

Sex category (i.e., female sex) 1 ? GY Lip et al. Chest 2010;137:263 - ESC Guidelines EHJ 2010;31:2369

2) AF -Assessment of Bleeding Risk

R Pisters et. al. Chest 2010 (March 18) - DA Lane et. al. Lancet. 2010;376:935HAS BLEED Score =3 > 3 Risk Bleed

3) EHRA Score of AF-related symptoms

ESC (AJ Camm et. al.) Eur Heart J 2010;31:2369 – ANSD !!!.






5 Challenge of Multiple Antithrombotics (3)





1) PREADMISSION MEDICATIONS IN PATIENTS WITH KNOWN AF AND PREVIOUS ISCHEMIC STROKE/TIA ADMITTED WITH ACUTE ISCHEMIC

STROKE (HIGH-RISK, N=323)

warfarintherapeutic,

18%

warfarinsubtherapeutic,

39%

singleantiplateletagent, 25%

dual antiplatelettherapy, 3%

noantithrombotics,

15%

REG. CANADIAN STROKE NETWORK(D Gladstone et al) Stroke 2009;40:235

2) Better Time in Target INR Associated with Lower Risk of Stroke and Bleeding

TTR = time in target rangeWan Y. Circ Outcomes. 2008

• Meta-analysis of 37 studies involving

34,000 patients

• Each 10% increase in TTR associated with 1% lower annual event rate

8 –7 –6 –5 –4 –3 –2 –1 –0 –

Out

com

e ev

ents

rate

(per

100

pat

ient

yea

rs, %

)

0 40 50 60 70 80 90 TTR%

- - - - - -

3) SCHEMATIC MODEL OF THE INTERNET-SUPERVISED PATIENT SELF-MANAGEMENT SYSTEM

SI O’Shea et al., J Thromb Thrombol 2008; 26:14 (Duke, Chapel Hill)

Patient Informationand INR

TherapeuticRecommendations

Patient Instructed toWait or call MD

TherapeuticRecommendations

MD Review andAssessment

Marked abnormal INRand/or major symptoms

Target INR andclinically stable

Minimally abnormalINR and/or symptoms

SYSTEM

PATIENTPHYSICIAN

3) PERCENT TIME IN THERAPEUTIC RANGE IN ANTICOAGULATION MANAGEMENT SERVICE AMS VERSUS INTERNET-MANAGEMENT SUPERVISED OR IMS

SI O’Shea et al., J Thromb Thrombol 2008; 26:14 (Duke, Chapel Hill)

% o

f tim

e in

ther

apeu

tic ra

nge

100

80

60

40

20

0AMS IMS

Management Approach

p=0.004

40-49 50-59 60-69 70-79 80-890

1

2

3

4

5

6

7

8

Stro

ke ra

te (%

/yea

r) 1) NVAF - STROKE RATES AND AGE (10% Age)

Framingham - PA Wolf et al., Ann Int Med 1987;147:1561 Unrelated to Left Atrium (CVD, other Cardiac, aorta) 25% (Plat. Inhib ?) Bogousslavsky J et al & Miller VT et al Neurol 1990;40:1046 & 1993;43:32

2) RELATIONSHIP BETWEEN AGE AND FREQUENCY OF BLEEDING (95% CI) IN CHARISMA PATIENTS RECEIVING PLACEBO (ASA)

CHARISMA - PB Berger, DL Bhatt, V Fuster, et al., Circ 2010; 121: 2575

0.15

0.14

0.13

0.12

0.11

0.10

0.09

0.08

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0.0039 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75 77 79 81 83 85 87 89 91 93 95

600

550

500

450

350

250

150

50

400

300

200

100

0

Num

ber of PatientsPr

edic

ted

Ble

edin

g Pr

obab

ility

Age

0

1

2

3

4

5

<60 60-64 65-69 70-74 75-79 80-84 85

Age, y

Rel

ativ

e O

dds

Intracerebral (>INR)

2) NVAF - ODDS OF INTRACRANIAL HEMORRHAGE & AGEIN 145 CASE-PATIENTS (INR 2.0-3.0) AND 870 CONTROLS

MC Fang et al., Ann Intern Med 2004; 141:745 (UCSF, Boston, Oakland)

Subdural (>Trauma)

3) NET CLINICAL BENEFITS AS WELL AS THE ANNUAL RATES OF STROKE AND INTRACRANIAL BLEEDING PER 100 PERSON YEARS

WITHOUT WARFARIN THERAPY - AGE

DE Singer et al., Ann Int Med 2009; 151:297 - CHADS 2 On

-1 -0.5 0 0.5 1 1.5 2 2.5 3 3.5

≥85

75-84

65-74

<65 Better With Warfarin

Age

, y

Net clinical benefit was defined as the adjusted difference between the annual rate of stroke or peripheral embolism and the annual rate of intracranial hemorrhage attributable to warfarin.

Net clinical benefit(95% CI)

2.34 (1.29,3.30)

1.00 (0.44,1.40)

0.11 (-0.37,0.40)

-0.25 (-0.65,0.08)

Cardiovascular & Mental Health

1). Living Beyond Our Physiological MeansSmall Vessel Disease of the Brain Is an Expression of a Systemic

Failure in Arteriolar Function: A Unifying Hypothesis

CS Thompson, AM Hakim. Stroke 2009; 40:e322

1). Highlight Dementia Risk to Reduce CVD

BM Mearns, V Fuster. Nature Rev Card 2010; 7:237

1) ADVANCED AGE, HYPERTENSION AND DEMENTIA SBP AND SHORT PORTABLE MMSE SCORE BY INCREASING

AGE GROUPS148

146

144

142

140

138

136

134

13

12

11

10

9

8

7

6

SHP-

MM

SE

Mea

n sy

stol

ic b

lood

pre

ssur

e (m

mH

g)

60-64 65-69 75-7970-74 80-84 >84Age Group (yrs)

Mean systolicBlood pressure(mmHg)Short portableMMSE

TO Obisecon. Clin Ger. Med 2009; 25:259 (NIH) – 5 Longitudinal Studies, Last 5 yrs

1) Mechanisms of Disease: Alzheimer’s Disease

C. Iadecola et. al. Stroke 2009;40[suppl 1]:S40.HW Querfurth, FM LaFerla. NEJM 2010; 362:329 - 60 to 90%D L. Dickstein et al Mt Sinai J of Med 2010; 77:82-102 – All RF

2) Transcatheter Aortic-Valve Implantation for Aortic Stenosis in Patients Who Cannot Undergo Surgery

PARTNER (MB Leon et. al.) N Engl J Med. 2010. Sept 22 – Stroke 5% (30 days), 7.8% (1 year)R Gurvitch, JG Webb et al Circulation 2010;122:1 319 – Stroke 8.6% (2/3 >6 months)

2) Silent Cerebral Ischemia After TAVI (n=32)

Diffusion-Weighted Magnetic Resonance Imaging Study

The risk of stroke after TAVI due to dislodgement from aortic arch atheroma or from the calcified valve itself ranges between 2% and 10%. The rate of clinically silent cerebral ischemia is unknown. Thirty-two patients who underwent TAVI with the use of a balloon-expandable (n=22) or self-expandable (n=10) stent valve prosthesis were included and compared with a historical control group of 21 patients undergoing open surgical AVR. Early clinically silent new foci of restricted diffusion on cerebral MRI were detected in almost all or 84% of patients undergoing TAVI. Although typically multiple, these foci were not associated with apparent neurological events measurable deterioration of neurocognitive function at 3-mo. FU

P Kahlert, R Erbel, H Eggebrecht, et al., Circ 2010; 121:878 (Essen, Germ) A Ghanem et al JACC 2010; 55:1427 - 72% (22 pts) J Osorio, V Fuster Nature Rev. Card. 2010;7: 355 – TAVI, A Word of Caution

2) Clinically Silent New Foci of Restricted Diffusion on Cerebral MRI Detected in Patients Undergoing TAVI

P Kahlert, R Erbel, H Eggebrecht. Circ 2010;121:870 (Essen, Germ)

3) COGNITIVE FUNCTION & ORAL ANTICOAGULATION IN ATRIAL FIBRILLATION (N=2510, AGE 71 ± 9.5 Y)

<24N=171

24N=77

25N=117

26N=175

27N=246

28N=364

29N=503

30N=657

50

55

60

65

70

TTR

MMSE: Mini-Mental State ExaminationTTR: Time in Therapeutic Range

ACTIVE Ivn (GC Flaker et al.) Circ Cardiov. Qual Outcomes 2010; 3:277

MMSE:

3) THE INCIDENCE OF DEMENTIA BY THE PATIENT’S AF STATUS

3.5

3

2.5

2

1.5

1

0.5

0 Nonspecific

Alzheimer’s Senile Vascular

Dementia Type

No Atrial Fibrillation

Atrial FibrillationIn

cide

nce

(%)

p<0.0001

p<0.0001 p<0.0001

p<0.0001

Thromboemboli? - Same Risks (BP)?, LA , Microvascular TJ Bunch et al., Heart Rhythm 2010; 7:433 (Murray, Utah)

1) BLEEDING IN CHARISMA (CLOPIDOGREL + ASA vs ASA)

2.5

2.0

1.5

1.0

0.5

0.00 2 4 6 8 10 12

Month

Placebo

Clopidogrel

Cum

ulat

ive

Inci

denc

e of

Mod

erat

e or

Sev

ere

Ble

edin

g (%

)

HR 1.88; p=0.001 2.5

2.0

1.5

1.0

0.5

0.012 14 16 18 20 22 24

Month

Placebo

Clopidogrel

Cum

ulat

ive

Inci

denc

e of

Mod

erat

e or

Sev

ere

Ble

edin

g (%

)

HR 1.18; p=0.197

26 28 30

MODERATE OR SEVERE BLEEDING IN THE FIRST YEAR

MODERATE OR SEVERE BLEEDING AFTER THE FIRST YEAR IN PATIENTS WHO DID

NOT HAVE MODERATE OR SEVERE BLEEDING DURING THE FIRST YEAR

CHARISMA - PB Berger, DL Bhatt, V Fuster, et al., Circ 2010; 121: 2575

2) META-ANALYSIS OF OBSERVATIONAL STUDIES REPORTING 30-DAY BLEEDING RATES IN PATIENTS RECEIVING “TRIPLE

THERAPY”(TT) Dual Antiplatelets + Warfarin Bleed.Study Pts on TT, n Stent, n ACS, n AF, n at 30 Days, %

Orford et al. 65 65 26 25 3.1Konstatino et al. 76 76 76 N/A 2.6Porter et al. 180 180 150 67 1.1Lip et al. 6 6 6 6 0.0Khurram et al. 107 107 n/a 86 0.0Rubboli et al. 20 20 N/A 8 15.0Nguyen et al. 580 580 580 267 5.9Nguyen et al. 86 N/A 86 N/A 1.2Rogacka et al. 127 127 127 75 3.2Rossini et al. 102 102 102 68 1.0Total 1349 1263 1153 602Pooled rate 2.2 (0.7-3.7) JS Paikin et al., Circ 2010; 121:2067 (McMaster Univ)

2) MAJOR BLEEDING IN MATCHED COHORT TRIALS OF STENTING

Study Warf+Asp+Clop Asp+Clop RR (fixed)n/N n/N 95% CI

De Eugenio et al. 14/97 3/97

Kanaiginen et al. 18/239 4/239

Khurram et al. 7/107 9/107

Total 95% CI 443 443

0.01 0.1 1 10 100

Favours Triple Therapy

Favours DoubleTherapy

A Sourgounis et al., Circ 2009; 119:1682

3) DES-T (N=6816): CHANGE IN THE RISK OF STENT THROMBOSIS IN RELATION TO CLOPIDOGREL TREATMENT DURATION

S Schultz et al., EHJ 2010 (In Press) (Munich)

0 6 12 18 24 30 36 42 48

Clopidogrel treatment duration (months)

0

0.1

0.2

0.3

0.4

Ris

k of

ST

with

in 4

yea

rs (%

)

0 50 100 150 200days

0.0

0.025

0.05

0.075

0.10

Sites of Action of Current and Emerging Antithrombotic Drugs and Antiplatelet Agents

DJ Angiolillo EHJ 2010;31:17- TA Meadows Circ Res. 2007;100:1261.

1a) Hepatic Cytochrome 2C19 Enzyme (CYP2C19) is in Part Responsible For The Bioactivation of Clopidogrel

V Fuster, JM Sweeny, JAMA 2010 (In Press)

1a) CLOPIDOGREL TREATMENT (CT) vs. CONTROL (C) EFFECTS OF CYP2C19 GENOTYPE ON CARDIOVASCULAR

OUTCOMESTrial CT-C PCI ACS AF Clinical Cardiovasc Stent

Impact Outcome Thromb Risk(%) (%)

(+) (-) (+) (-)variant variant variant variantallele allele allele allele

CURE + - + - No 8.0 9.5 n/a n/a

ACTIVE A + - - + No 21.5 17.1 n/a n/a

PLATO + + + - Yes 5.7 3.8 2.2 1.5

TRITON-TIMI 38 + + + - Yes 12.1 8.0 2.6 0.8

Mega et al - + + + Yes 10 8 1.9 0.1

V Fuster, JM Sweeny. JAMA 2010 (In Press)

1b) Recommended Therapy in Suspected ACS

V Fuster. N Engl J Med. 2010;363:976.

1c) Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation

0 1 2 3 40.0

0.1

0.2

0.3

0.4

Aspirin Clopidogrel + aspirin

Years

Cum

ulat

ive

inci

denc

e

0 1 2 3 40.0

0.1

0.2

0.3

0.4

Aspirin Clopidogrel + aspirin

YearsC

umul

ativ

e in

cide

nce

Primary Outcome Stroke

The Active A Invest. N Engl J Med 2010; 360 (In Press)

P<0.001P<0.0001

Major bleeding: 2.0% per year clopidogrel and 1.3% per year placebo(p<0.001).

0 2 4 6 8 10 120

2

46

8

10

12

0 2 4 6 8 10 120

5

10

15Ticagrelor

Clopidogrel

Clopidogrel

Ticagrelor

Months Months

Cum

ulat

ive

Inci

denc

eof

Prim

ary

End

Poin

t (%

)

Cum

ulat

ive

Inci

denc

eof

Maj

or B

leed

ing

(%)

Cumulative Kaplan–Meier Estimates of the Time to the First Major Bleeding End

Point, According to Study Criteria

Cumulative Kaplan–Meier Estimates of the Time to the First Adjudicated Occurrence of

Primary Efficacy End Point

PLATO (Lars Wallentin et al.,) N Engl J Med 2009; 361:1

2) ACS (N=18624) - TICAGRELOR (180LD-90mgx2d )VS CLOPIDOGREL (300/600LD-75mgx2d)

End Point: Death (Vascular), MI, Stroke – Ticagrelor: Early reversibility (CABG etc)

3) Platelet Activation & Current Antiplatelet Agents

S Leonardi et. al. Drugs 2010;70:1771.

3) Thrombin Receptor Antagonists Therapeutic Potential of Vorapaxar and E-5555

The major pathway involved in platelet activation is triggered by thrombin. Thrombin receptor antagonists are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preliminary data indicate that these compounds may have the potential to improve ischaemic outcomes without significantly increasing the bleeding liability. Currently, two agents of this class are under clinical development: vorapaxar (previously known as SCH 530348) and E-5555.

S Leonardi, P Tricoci, RC Becker. Drugs 2010; 70:1771

Primary endpoint:CV death, MI, stroke, urgent coronary revascularization

Major secondary endpoint:CV death, nonfatal MI, nonfatal stroke

Additional endpoints:Hospitalization for vascular cause, any revascularization

3) Design of the TRA 2◦P-TIMI 50 trial

S Leonardi et. al. Drugs 2010;70:1771.DA Morrow et. al. Am Heart J. 2009;158:335..

Primary endpoint:CV death/MI/stroke/hospitalization for RI/urgent coronary revascularization

Key secondary endpoint:CV death/MI/stroke

3) Design of the TRA◦CER trial

S Leonardi et. al. Drugs 2010;70:1771.The Tracer Executive and Steering Committee. Am Heart J. 2009;158;327.

1 ) Investigational Anticoagulant Targets

TFPI (tifacogin)

Idraparinux

RivaroxabanApixabanLY517717YM150DU-176b, EdoxabanBetrixabanTAK 42

Dabigatran

ORALORAL PARENTERALPARENTERAL

DX-9065aOtamixaban

Xa

IIa

TF/VIIa

XX IXIX

IXaIXaVIIIaVIIIa

VaVa

II (thrombin)II (thrombin)

FibrinFibrinFibrinogenFibrinogen

ATAT

APC (drotrecogin alfa)sTM (ART-123)

Adapted from Weitz JI. Thromb Haemost 2007; 5 Suppl 1:65-7.

TTP889

APC activated protein CAPC activated protein CAT antithrombinAT antithrombinsTM soluble thrombomodulinsTM soluble thrombomodulinTF tissue factorTF tissue factorFPI tissue factor pathway inhibitorFPI tissue factor pathway inhibitor

1 ) PHASE III STUDIES OF NEW PHARMACEUTICAL AGENTS FOR STROKE PREVENTION IN ATRIAL FIBRILLATION (AF)

Drug or Study Estimatedintervention acronym completion

Oral direct thrombin inhibitorDabigatran RE-LY Completedetexilate

Direct factor Xa inhibitorsApixiban ARISTOTLE November 2010

AVERROES April 2010Rivaroxaban J-ROCKET December 2009

ROCKET-AF June 2010Edoxaban ENGAGE-AF March 2011(DU-176b) TIMI 48

Indirect factor Xa inhibitorBiotinylated BOREALIS-AF March 2011Idraparinux

2) Dabigatran: An Oral Novel Potent Reversible Nonpeptide Inhibitor of Thrombin

Dabigatran is a highly selective, reversible, and potent thrombin inhibitor and is orally available as the prodrug, dabigatran etexilate. Peak plasma concentrations occur 1 to 2 hours after ingestion. The half-life is 12 to 14 hours. Dabigatran is not metabolized by cytochrome P450 isoenzymes and does not interact with food, has a low potential for drug-drug interactions and is predominantly renally excreted. Dabigatran etexilate as chronic therapy effectively prevents the recurrence of venous thromboembolism and cardioembolic stroke. For the first time, it has been demonstrated clinically that there may be an effective and safe alternative to warfarin.

WG Eisert et al., ATVB 2010; 30:1885

2)2) RE-LYRE-LY®® Trial TrialRRandomizedandomized EEvaluation of valuation of LLong-termong-term

Anticoagulant TherapAnticoagulant Therapyy with Dabigatran Etexilatewith Dabigatran Etexilate

Primary objective: noninferiority vs. warfarinPrimary objective: noninferiority vs. warfarin Observation period: minimum 1, mean 2, maximum 3 yearsObservation period: minimum 1, mean 2, maximum 3 years Primary endpoint: all stroke + systemic embolismPrimary endpoint: all stroke + systemic embolism Safety measure: bleeding during treatmentSafety measure: bleeding during treatment

Connolly SJ, Ezekowitz MD et al. Connolly SJ, Ezekowitz MD et al. N Engl J MedN Engl J Med 2009;2009; 361, 1139, 361, 1139,

Non-valvular AF +Non-valvular AF +>>1 1 stroke risk factorstroke risk factor

WarfarinWarfarin(INR 2.0-3.0)(INR 2.0-3.0)

n = 6,022n = 6,022

DabigatranDabigatran110 mg bid110 mg bidn = 6,015n = 6,015

DabigatranDabigatran150 mg bid150 mg bidn = 6,076n = 6,076

BlindedBlindedOpen-labelOpen-label

N = 18,113N = 18,113

2) RE-LY2) RE-LY®® Trial Trial Net Clinical BenefitNet Clinical Benefit

Net

Ben

efit

(A

dver

se E

vent

s A

void

ed)

Connolly SJ, Ezekowitz MD et al. Connolly SJ, Ezekowitz MD et al. N Engl J MedN Engl J Med 20092009; 361, 1139; 361, 1139

Nonhemorrhagic strokes + Life-threatening bleeds + DeathsNonhemorrhagic strokes + Life-threatening bleeds + Deaths

Dabigatran Compared to Warfarin

2) Distribution of Mean Time in Therapeutic Range

Warfarin: Total Events lowest at cTTR > 72.6% Dabigatran: Total Events related to cTTR site Dabigatran 150mg: Major bleed related to cTTR site

RE-LY Investigators (L Wallentin et. al.) Lancet. 2010;376:975.

2)2) The RE-LYThe RE-LY® ® TrialTrial Clinical ImplicationsClinical Implications

Exclusion criteriaExclusion criteria Patients with severe renal impairment (ClPatients with severe renal impairment (ClCr Cr <30 ml/min)<30 ml/min) Patients with liver diseasePatients with liver diseaseQuestions of Dose 150 mg vs 110 mg bidQuestions of Dose 150 mg vs 110 mg bidPatients at higher risk of thromboembolism or lower Patients at higher risk of thromboembolism or lower

risk of bleedingrisk of bleeding Questions for further explorationQuestions for further exploration

AF - AF - Elderly (age >75 years)Elderly (age >75 years) AFAF - Lower thromboembolic risk (CHADS - Lower thromboembolic risk (CHADS2 2 score =1)score =1) Mechanical Heart ValvesMechanical Heart Valves

3a) AF – UNSUITABLE FOR ANTICOAGULATIONAPIXABAN, STROKE AND BLEEDING (FU 36 MO)

Apixaban (n=2809) ASA (n=2791) Relative Risk

Stroke or System. Emboli 1.8 3.6 0.46

+ MI, Vascular Death 4.1 6.2 0.66

Major Bleeding 1.4 1.2 1.14

Fatal or Extracranial 0.5 0.4 1.09 Bleeding

CHADS 0-1: 36% - CHADS 2: 37% - CHADS ≥ 3: 27%

1.Apixaban vs A/C? - 2. Apixaban vs Dabigatran? (ARISTOTLE)

AVERROES (S Connolly et al.): ESC – Stockholm 2010

3b) AF – Rivaroxaban, Once Daily, Oral, Direct Fr Xa Inhibition vs Warfarin For Prevention of Stroke & Emboli

ROCKET AF aims to establish the noninferiority of rivaroxaban compared with warfarin in patients with nonvalvular AF who have a history of stroke or at least 2 additional independent risk factors for future stroke. Patients are randomly assigned to receive rivaroxaban, 20 mg once daily (od), or dose-adjusted warfarin. The primary efficacy end point is a composite of all-cause stroke and noncentral nervous system embolism. Over 14,000 patients have been randomized at 1,100 sites across 45 countries, and will be followed until 405 primary outcome events are observed.

ROCKET AF – Am Heart J 2010; 159:340









8. Challenge of Ablation and LAA Exclusion in AF (3)


1) DRONEDARONE AND CUMULATIVE RISK OF STROKE

The stroke prevention in AF comes from a secondary analysis of the

ATHENA, a placebo-controlled, double-blind, parallel-arm Trial to

assess the efficacy of dronedarone 400 mg BID for the prevention

of cardiovascular hospitalization or death from any cause in

patients with Atrial fibrillation/atrial flutter. In ATHENA, there were

70 strokes with placebo (1.8% per year) compared with 46 strokes

with dronedarone (1.2% per year), yielding a HR of 0.66 (95% CI:

0.46 to 0.96) and p=0.027. The Kaplan-Meier curves were noted to

separate early and remain that way throughout the study.

ATHENA (SJ Connolly et al.) Circ 2009; 120; 1174

1) DRONEDARONE AND CUMULATIVE RISK OF STROKE

ATHENA (SJ Connolly et al.) Circ 2009; 120; 1174

5

4

3

2

1

00 6 12 18 24 30 Months

Cum

ulat

ive

Inci

denc

e (%

)

HR (95% CI) – 0.66 (0.46-0.96)P value = 0.027

Placebo(n=70, annual rate = 1.8%)

Dionedarone(n=46, annual rate = 1.2%)

1) RANDOMIZED TRIALS COMPARING EFFICACY OF ABLATION AND ANTI-ARRHYTHMIC DRUGS FOR THE TREATMENT OF AF

Study N AF type Ablation strategy Efficacy Efficacy(Ablation/AAD) Ablation AAD

Krittayaphong 15/15 Persist. AF PVI+linear abl. 78% 40%et al.

Waznie et al. 33/37 PAF, 4% PVI 85% 21% Persist. AF

Pappone et al. 99/99 PAF CPVA+CTI 85% 35% +mitral line

PVI: Pulmonary Vein Isolation CPVI: Circumferential Pulmonary Vein Ablation

I Nault, M Haissaguerre et al., EHJ 2010; 31:1046

1) RANDOMIZED TRIALS COMPARING EFFICACY OF ABLATION AND ANTI-ARRHYTHMIC DRUGS FOR THE TREATMENT OF AF

Study N AF type Ablation strategy Efficacy Efficacy(Ablation/AAD) Ablation AAD

Oral et al. 77/69 Persistent CPVA+roof and 74% 58%mitral line

Stabile et al. 68/69 PAF, 33% CPVA+CTI+mitral 65% 9%Persistent line

Jais et al. 53/59 PAF PVI+extra PV 89% 23%ablation

Forleo et al. 35/35 Persistent AF, PVI+CTI+roof and 80% 43%41% PAF mitral line

PVI: Pulmonary Vein Isolation CPVI: Circumferential Pulmonary Vein Ablation

I Nault, M Haissaguerre et al., EHJ 2010; 31:1046

2) POST-ABLATION THROMBOEMBOLIC AND HEMORRHAGIC STROKE IN THE OFF- AND ON-OAT GROUPS(5 CENTERS) - RETROSPECTIVE

0 6 12 18 24 30 36 42 48 54 600.94

0.95

0.96

0.97

0.98

0.99

1.00

Log-rank p-value = 0.003

Months

CHADS2

1 =>2

Off-OAT 27% 13%1

ON-OAT 39% 37%

Off-OAT Group (n=2692) On-OAT Group (n=663)

1No StrokesS Themistoclakis, A Natale, et al., JACC 2010; 55:735

LA

LV

Watchman Device

3) LAA Closure: Clinical Outcomes

Follow-Up

Non-Valvular AFCHADs ≥ 1

Randomization (1:2)

Warfarin Watchman

Holmes, Reddy, et al. Lancet 2009; 374:534.

PROTECT-AF Trial

Barbs Engage LAA Wall

160 µ PET fabric

3)Intent-to-Treat: Primary Efficacy Results

Cohort

1050 Pt-Yrs

WATCHMAN ControlRelative

Risk 95% CIRate (Events/100 Pt-Yrs)

Rate (Events/100 Pt-Yrs)

All Patients 3.0 21/694.1 4.9 18/370.8 0.62 0.33, 1.17*

Only CHADS2 = 1 1.3 3/225.7 2.8 3/107.3 0.50 0.10, 2.51

Only CHADS2 = 1, 2 1.5 7/481.7 3.7 9/244.0 0.40 0.15, 1.06

All Patients CHADS2 = 1 CHADS2 = 1 or 2

Time (Days)

0 365 730 1095

0.00

0.05

0.10

0.15

0.20

ControlDevice

Time (Days)

0 365 730 1095

0.00

0.05

0.10

0.15

0.20

Time (Days)

0 365 730 1095

0.00

0.05

0.10

0.15

0.20

* Using Cox Proportional Model

Learning Curve – Air Embolism ?









8. Challenge of Ablation and LAA Exclusion in AF (3)


debates en cardiología: implicaciones clínicas de la anticoagulación en las nuevas guías

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