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)
/ AHA / ESCof ( Fuster et al ) Circ 2006; 114: 700Prevention 8.ACC Challenge LAA VExclusion in Stroke
(3)
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 15% Other 5% Prosthetic 10% Rheumatic
50% NVAF
10% Ventricular 10% MI
MJ Schneck et al., eMedicine Neurology 2008
2) ATRIAL FIBRILLATION - RISK OF STROKE BY CHAD*SCORE CHAD Index High Risk:
Antithrombotics
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:
* RF:
0 RF
ASA 81-325 mg
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 â&#x2030;Ľ 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;376:935 HAS 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 â&#x20AC;&#x201C; 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)
/ AHA / ESCof ( Fuster et al ) Circ 2006; 114: 700Prevention 8.ACC Challenge LAA VExclusion in Stroke
(3)
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) no antithrombotics, 15%
warfarin therapeutic, 18%
dual antiplatelet therapy, 3%
single antiplatelet agent, 25% warfarin subtherapeutic, 39% REG. CANADIAN STROKE NETWORK (D Gladstone et al) Stroke 2009;40:235
• Each 10% increase in TTR associated with 1% lower annual event rate
8– 7– 6– 5– 4– 3– 2– 1– 0–
-
• Meta-analysis of 37 studies involving 34,000 patients
Outcome events rate (per 100 patient years, %)
2) Better Time in Target INR Associated with Lower Risk of Stroke and Bleeding
0
TTR = time in target range Wan Y. Circ Outcomes. 2008
40
50
60 70 TTR%
80
90
3) SCHEMATIC MODEL OF THE INTERNET-SUPERVISED PATIENT SELF-MANAGEMENT SYSTEM
Patient Information and INR Therapeutic Recommendations
Target INR and clinically stable
Minimally abnormal INR and/or symptoms
Marked abnormal INR and/or major symptoms
SYSTEM
Patient Instructed to Wait or call MD
Therapeutic Recommendations
MD Review and Assessment
PHYSICIAN
PATIENT
SI Oâ&#x20AC;&#x2122;Shea et al., J Thromb Thrombol 2008; 26:14 (Duke, Chapel Hill)
3) PERCENT TIME IN THERAPEUTIC RANGE IN ANTICOAGULATION MANAGEMENT SERVICE AMS VERSUS INTERNET-MANAGEMENT SUPERVISED OR IMS % of time in therapeutic range
100
80
60
40
20
0
AMS
p=0.00 4 IMS
Management Approach SI O’Shea et al., J Thromb Thrombol 2008; 26:14 (Duke, Chapel Hill)
ANTITHROMBOTICS AND CHALLENGES â&#x20AC;&#x201C; 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)
/ AHA / ESCof ( Fuster et al ) Circ 2006; 114: 700Prevention 8.ACC Challenge LAA VExclusion in Stroke
(3)
ESC Guidelines, EHJ 2010;31:2369 - Working Group Report, EU 2010
1) NVAF - STROKE RATES AND AGE (10% Age) 8
Stroke rate (%/year)
7 6 5 4 3 2 1 0 40-49
50-59
60-69
70-79
80-89
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) 0.15
600
0.14
550
0.13 500
0.11
450
0.10
400
0.09
350
0.08 300
0.07 0.06
250
0.05
200
0.04
Number of Patients
Predicted Bleeding Probability
0.12
150
0.03 100
0.02
50
0.01 0.00 39 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
0
Age
CHARISMA - PB Berger, DL Bhatt, V Fuster, et al., Circ 2010; 121: 2575
2) NVAF - ODDS OF INTRACRANIAL HEMORRHAGE & AGE IN 145 CASE-PATIENTS (INR 2.0-3.0) AND 870 CONTROLS
Relative Odds
5
Subdural (>Trauma)
Intracerebral (>INR)
4 3 2 1 0
<60
60-64
65-69
70-74
75-79
80-84
≥85
Age, y
MC Fang et al., Ann Intern Med 2004; 141:745 (UCSF, Boston, Oakland)
3) NET CLINICAL BENEFITS AS WELL AS THE ANNUAL RATES OF STROKE AND INTRACRANIAL BLEEDING PER 100 PERSON YEARS WITHOUT WARFARIN THERAPY - AGE
Age, y
Net clinical benefit (95% CI)
â&#x2030;Ľ85
2.34 (1.29,3.30)
75-84
1.00 (0.44,1.40)
65-74
0.11 (-0.37,0.40)
<65
Better With Warfarin -1
-0.5
0
0.5
1
1.5
2
2.5
-0.25 (-0.65,0.08) 3
3.5
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 . DE Singer et al., Ann Int Med 2009; 151:297 - CHADS 2 On
ANTITHROMBOTICS AND CHALLENGES â&#x20AC;&#x201C; 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)
/ AHA / ESCof ( Fuster et al ) Circ 2006; 114: 700Prevention 8.ACC Challenge LAA VExclusion in Stroke
(3)
ESC Guidelines, EHJ 2010;31:2369 - Working Group Report, EU 2010
Cardiovascular & Mental Health
1). Living Beyond Our Physiological Means Small 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
148
13
146
12
144
11
142
10
140
9
138
8 Mean systolic Blood pressure (mmHg)
136
SHP-MMSE
Mean systolic blood pressure (mmHg)
1) ADVANCED AGE, HYPERTENSION AND DEMENTIA SBP AND SHORT PORTABLE MMSE SCORE BY INCREASING AGE GROUPS
7
Short portable MMSE
134
60-64
65-69
70-74 75-79 Age Group (yrs)
80-84
>84
6
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 balloonexpandable (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 â&#x20AC;&#x201C; 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) 70
TTR
65
60
55
50
MMSE:
<24 N=171
24 N=77
25 N=117
26 N=175
27 N=246
28 N=364
29 N=503
30 N=657
MMSE: Mini-Mental State Examination TTR: Time in Therapeutic Range
ACTIVE Ivn (GC Flaker et al.) Circ Cardiov. Qual Outcomes 2010; 3:277
3) THE INCIDENCE OF DEMENTIA BY THE PATIENT’S AF STATUS 3.5
p<0.0001
No Atrial Fibrillation
Incidence (%)
3
Atrial Fibrillation
2.5 2 p<0.0001
p<0.0001
1.5 p<0.0001
1 0.5 0 Nonspecific
Alzheimer’s
Senile
Vascular
Dementia Type
Thromboemboli? - Same Risks (BP)?, LA , Microvascular TJ Bunch et al., Heart Rhythm 2010; 7:433 (Murray, Utah)
ANTITHROMBOTICS AND CHALLENGES â&#x20AC;&#x201C; 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)
/ AHA / ESCof ( Fuster et al ) Circ 2006; 114: 700Prevention 8.ACC Challenge LAA VExclusion in Stroke
(3)
ESC Guidelines, EHJ 2010;31:2369 - Working Group Report, EU 2010
1) BLEEDING IN CHARISMA (CLOPIDOGREL + ASA vs ASA)
2.5
HR 1.88; p=0.001
2.0
Clopidogrel
1.5
1.0
0.5
0.0
Placebo
0
2
4
6
Month
8
10
MODERATE OR SEVERE BLEEDING AFTER THE FIRST YEAR IN PATIENTS WHO DID NOT HAVE MODERATE OR SEVERE BLEEDING DURING THE FIRST YEAR Cumulative Incidence of Moderate or Severe Bleeding (%)
Cumulative Incidence of Moderate or Severe Bleeding (%)
MODERATE OR SEVERE BLEEDING IN THE FIRST YEAR
12
2.5
HR 1.18; p=0.197 2.0
1.5
Clopidogrel 1.0
Placebo
0.5
0.0
12
14
16
18
20
22
24
26
28
30
Month
CHARISMA - PB Berger, DL Bhatt, V Fuster, et al., Circ 2010; 121: 2575
2) META-ANALYSIS OF OBSERVATIONAL STUDIES REPORTING 30DAY BLEEDING RATES IN PATIENTS RECEIVING “TRIPLE THERAPY”(TT) Study Days, %
Dual Antiplatelets + Warfarin Pts on TT, n Stent, n ACS, n
Bleed. AF, n
at 30
Orford et al. 65 65 26 25 3.1 Konstatino et al. 76 76 76 N/A 2.6 Porter et al. 180 180 150 67 1.1 Lip et al. 6 6 6 6 0.0 Khurram et al. 107 107 n/a 86 0.0 Rubboli et al. 20 20 N/A 8 15.0 Nguyen et al. 580 580 580 267 5.9 Nguyen et al. 86 N/A 86 N/A 1.2 Rogacka et al. 127 127 127 75 3.2 Rossini et al. 102 102 102 68 1.0 Total 1349 1263 1153 602 Pooled rate JS Paikin et al., Circ 2010; 121:2067 (McMaster Univ) 2.2 (0.7-3.7)
2) MAJOR BLEEDING IN MATCHED COHORT TRIALS OF STENTING Study
Warf+Asp+Clop n/N
Asp+Clop n/N
De Eugenio et al.
14/97
3/97
Kanaiginen et al.
18/239
4/239
Khurram et al.
7/107
9/107
443
443
Total 95% CI
0.01
RR (fixed) 95% CI
0.1
Favours Triple Therapy
A Sourgounis et al., Circ 2009; 119:1682
1
10
100
Favours DoubleTherapy
Risk of ST within 4 years (%)
3) DES-T (N=6816): CHANGE IN THE RISK OF STENT THROMBOSIS IN RELATION TO CLOPIDOGREL TREATMENT DURATION
0.4 0.10
0.3
0.075
0.05
0.2
0.025
0.0
0.1
0
50
100 days
150
200
0 0
6
12
18
24
30
36
42
Clopidogrel treatment duration (months)
S Schultz et al., EHJ 2010 (In Press) (Munich)
48
ANTITHROMBOTICS AND CHALLENGES â&#x20AC;&#x201C; 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)
/ AHA / ESCof ( Fuster et al ) Circ 2006; 114: 700Prevention 8.ACC Challenge LAA VExclusion in Stroke
(3)
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 OUTCOMES Trial
CT-C
PCI
ACS
AF
Clinical Impact
Cardiovasc Outcome (%) (+) variant allele
(-) variant allele
Stent Thromb Risk (%) (+) (-) variant variant 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 Primary Outcome
Stroke
0.4
P<0.001
0.3 0.2
Aspirin
Clopidogrel + aspirin
0.1 0.0
0
1
2
3 Years
4
Cumulative incidence
Cumulative incidence
0.4
0.3
P<0.0001
0.2
Aspirin Clopidogrel + aspirin
0.1 0.0
0
1
2
3
4
Years
Major bleeding: 2.0% per year clopidogrel and 1.3% per year placebo(p<0.001).
The Active A Invest. N Engl J Med 2010; 360 (In Press)
2) ACS (N=18624) - TICAGRELOR (180LD-90mgx2d ) VS CLOPIDOGREL (300/600LD-75mgx2d)
12
15
Clopidogrel
10 Ticagrelor
8
Cumulative Kaplan–Meier Estimates of the Time to the First Major Bleeding End Point, According to Study Criteria
6 4 2 0
Cumulative Incidence of Major Bleeding (%)
Cumulative Incidence of Primary End Point (%)
Cumulative Kaplan–Meier Estimates of the Time to the First Adjudicated Occurrence of Primary Efficacy End Point
Ticagrelor 10
Clopidogrel
5
0 0
2
4
6 Months
8
10
12
0
2
4
6 Months
8
10
12
End Point: Death (Vascular), MI, Stroke – Ticagrelor: Early reversibility (CABG etc)
PLATO (Lars Wallentin et al.,) N Engl J Med 2009; 361:1
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
3) Design of the TRA 2◦P-TIMI 50 trial
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
S Leonardi et. al. Drugs 2010;70:1771. DA Morrow et. al. Am Heart J. 2009;158:335..
3) Design of the TRAâ&#x2014;ŚCER trial Primary endpoint: CV death/MI/stroke/hospitalization for RI/urgent coronary revascularization Key secondary endpoint: CV death/MI/stroke
S Leonardi et. al. Drugs 2010;70:1771. The Tracer Executive and Steering Committee. Am Heart J. 2009;158;327.
ANTITHROMBOTICS AND CHALLENGES â&#x20AC;&#x201C; 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)
/ AHA / ESCof ( Fuster et al ) Circ 2006; 114: 700Prevention 8.ACC Challenge LAA VExclusion in Stroke
(3)
ESC Guidelines, EHJ 2010;31:2369 - Working Group Report, EU 2010
1 ) Investigational Anticoagulant Targets ORAL
PARENTERAL TF/VIIa TF/VIIa
TTP889
TFPI (tifacogin)
X
Rivaroxaban Apixaban LY517717 YM150 DU-176b, Edoxaban Betrixaban TAK 42
Dabigatran
IX VIIIa
Va Xa Xa
APC (drotrecogin alfa) sTM (ART-123)
IXa AT
II (thrombin)
Idraparinux
DX-9065a Otamixaban
IIa IIa Fibrinogen
Fibrin
APC AT sTM TF FPI
activated protein C antithrombin soluble thrombomodulin tissue factor tissue factor pathway inhibitor
Adapted from Weitz JI. Thromb Haemost 2007; 5 Suppl 1:65-7.
1 ) PHASE III STUDIES OF NEW PHARMACEUTICAL AGENTS FOR STROKE PREVENTION IN ATRIAL FIBRILLATION (AF) Drug or intervention
Oral direct thrombin inhibitor Dabigatran etexilate Direct factor Xa inhibitors Apixiban Rivaroxaban Edoxaban (DU-176b) Indirect factor Xa inhibitor Biotinylated Idraparinux
Study acronym
RE-LY
Estimated completion
Completed
ARISTOTLE AVERROES J-ROCKET ROCKET-AF ENGAGE-AF TIMI 48
November 2010 April 2010 December 2009 June 2010 March 2011
BOREALIS-AF
March 2011
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) RE-LY速 Trial
Randomized Evaluation of Long-term
Anticoagulant Therapy with Dabigatran Etexilate
Non-valvular AF + >1 stroke risk factor Open-label
Warfarin (INR 2.0-3.0) n = 6,022
N = 18,113
Blinded
Dabigatran 110 mg bid n = 6,015
Dabigatran 150 mg bid n = 6,076
Primary objective: noninferiority vs. warfarin Observation period: minimum 1, mean 2, maximum 3 years Primary endpoint: all stroke + systemic embolism Safety measure: bleeding during treatment Connolly SJ, Ezekowitz MD et al. N Engl J Med 2009; 361, 1139,
2) RE-LY速 Trial Net Clinical Benefit
Net Benefit (Adverse Events Avoided)
Nonhemorrhagic strokes + Life-threatening bleeds + Deaths
Dabigatran Compared to Warfarin
Connolly SJ, Ezekowitz MD et al. N Engl J Med 2009; 361, 1139
2) Distribution of Mean Time in Therapeutic Range Dabigatran: Total Events related to cTTR site Warfarin: Total Events lowest at cTTR > 72.6% Dabigatran 150mg: Major bleed related to cTTR site
RE-LY Investigators (L Wallentin et. al.) Lancet. 2010;376:975.
2) The RE-LY速 Trial Clinical Implications Exclusion criteria Patients with severe renal impairment (ClCr <30 ml/min) Patients with liver disease
Questions of Dose 150 mg vs 110 mg bid Patients at higher risk of thromboembolism or lower risk of bleeding Questions for further exploration AF - Elderly (age >75 years) AF - Lower thromboembolic risk (CHADS2 score =1) Mechanical Heart Valves
3a) AF – UNSUITABLE FOR ANTICOAGULATION APIXABAN, 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 Bleeding
0.5
0.4
1.09
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 â&#x20AC;&#x201C; 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 â&#x20AC;&#x201C; Am Heart J 2010; 159:340
ANTITHROMBOTICS AND CHALLENGES â&#x20AC;&#x201C; 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)
/ AHA / ESC V et al and ) Circ 2006; 700 8.ACC Challenge of( Fuster Ablation LAA114: Exclusion in AF
(3)
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
Cumulative Incidence (%)
5
HR (95% CI) â&#x20AC;&#x201C; 0.66 (0.46-0.96) P value = 0.027
4
Placebo (n=70, annual rate = 1.8%)
3 Dionedarone (n=46, annual rate = 1.2%)
2 1 0
0
6
12
18
24
30 Months
ATHENA (SJ Connolly et al.) Circ 2009; 120; 1174
1) RANDOMIZED TRIALS COMPARING EFFICACY OF ABLATION AND ANTI-ARRHYTHMIC DRUGS FOR THE TREATMENT OF AF Study
N (Ablation/AAD)
AF type
Ablation strategy
Efficacy Ablation
Efficacy AAD
Krittayaphong et al.
15/15
Persist. AF
PVI+linear abl.
78%
40%
Waznie et al.
33/37
PAF, 4%
PVI Persist. AF
85%
21%
Pappone et al.
99/99
PAF
CPVA+CTI +mitral line
85%
35%
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 (Ablation/AAD)
AF type
Ablation strategy
Efficacy Ablation
Efficacy AAD
Oral et al.
77/69
Persistent
CPVA+roof and mitral line
74%
58%
Stabile et al.
68/69
PAF, 33% Persistent
CPVA+CTI+mitral line
65%
9%
Jais et al.
53/59
PAF
PVI+extra PV ablation
89%
23%
Forleo et al.
35/35
Persistent AF, PVI+CTI+roof and 41% PAF mitral line
80%
43%
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 Off-OAT Group (n=2692) On-OAT Group (n=663)
1.00
0.99
CHADS2
0.98
1
0.97
=>2
Off-OAT 27% 13%1 0.96
ON-OAT 39%
0.95
37%
Log-rank p-value = 0.003
0.94 0
6
12
18
24
30
36
42
48
54
60
Months
No Strokes S Themistoclakis, A Natale, et al., JACC 2010; 55:735 1
3) LAA Closure: Clinical Outcomes PROTECT-AF Trial Barbs Engage LAA Wall
Non-Valvular AF CHADs ≥ 1
160 µ PET fabric
Randomization (1:2)
Warfarin
Watchman
Watchman Device
Follow-Up
LA
LV
Holmes, Reddy, et al. Lancet 2009; 374:534.
3)Intent-to-Treat: Primary Efficacy Results WATCHMAN
Cohort 1050 Pt-Yrs
Control
Rate
Rate
(Events/100 Pt-Yrs)
(Events/100 Pt-Yrs)
Relative Risk
95% CI
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
* Using Cox Proportional Model
0
365
730
Time (Days)
1095
0.20 0.15
CHADS 2 = 1 or 2
0.00
0.05
0.10
0.15 0.10 0.05 0.00
0.00
0.05
0.10
0.15
CHADS 2 = 1
0.20
0.20
All Patients
Control Device
0
365
730
Time (Days)
1095
Learning Curve â&#x20AC;&#x201C; Air Embolism ?
0
365
730
Time (Days)
1095
ANTITHROMBOTICS AND CHALLENGES â&#x20AC;&#x201C; 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)
/ AHA / ESC V et al and ) Circ 2006; 700 8.ACC Challenge of( Fuster Ablation LAA114: Exclusion in AF
(3)
ESC Guidelines, EHJ 2010;31:2369 - Working Group Report, EU 2010