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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 !!!.
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) 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
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
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)
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
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)
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) 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
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
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.
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 ) 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
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 Ablation and LAA Exclusion in AF (3)
ACC / AHA / ESC ( Fuster V et al ) Circ 2006; 114: 700 ESC Guidelines, EHJ 2010;31:2369 - Working Group Report, EU 2010
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 ?
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 Ablation and LAA Exclusion in AF (3)
ACC / AHA / ESC ( Fuster V et al ) Circ 2006; 114: 700 ESC Guidelines, EHJ 2010;31:2369 - Working Group Report, EU 2010