• Save
Nuevos paradigmas en la prevención tromboembólica de la fibrilación auricular  - Dr. Valentin Fuster
Upcoming SlideShare
Loading in...5
×
 

Nuevos paradigmas en la prevención tromboembólica de la fibrilación auricular - Dr. Valentin Fuster

on

  • 1,701 views

Debates en Cardiología 2009

Debates en Cardiología 2009
Congreso de las enfermedades cardiovasculares
Barcelona 22/10/2009
Sociedad Española de Cardiología

Statistics

Views

Total Views
1,701
Views on SlideShare
1,593
Embed Views
108

Actions

Likes
1
Downloads
0
Comments
0

3 Embeds 108

http://profesionales.secardiologia.es 106
http://www.slideshare.net 1
http://www.secardiologia.es 1

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • A retrospective, multicentre cohort study, conducted in the US, Canada, France, Italy and Spain, randomly recruited 1511 patients from representative practices (routine medical care in the US, Canada and France and anticoagulation clinics in Italy and Spain). Medical records were used to extract data relating to their oral anticoagulant care. All patients included in this study received oral anticoagulation for at least 60 days. These data show that oral anticoagulation care varied considerably and patients spent less between 50.8% and 60.0% of their time within the target INR of 2 – 3. The percentage of time within this range varied from 58.1% to 69.5%. The mean time spent in range did not differ by age or sex. Ansell J et al . Descriptive analysis of the process and quality of oral anticoagulation management in real-life practice in patients with chronic non-valvular atrial fibrillation: the international study of anticoagulation management (ISAM). J Thromb Thrombolysis . 2007;23:83–91.
  • Source: Turpie State of the art presentation EFORT-08 (rivaroxaban, apixaban and dabigatran highlighted and all the others greyed out) Reference Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843–1853 All of the drugs in the above figure are to be found in Weitz and Bates (2005) in Figure 2, apart from: Apixaban – this was called BMS-562247 in the original figure Betrixaban and YM150 – see Graham Turpie’s review paper: Turpie AGG. New oral anticoagulants in atrial fibrillation. Eur Heart J 2008;29:155–165 Otamixaban – Guertin KR, Choi YM. The discovery of the Factor Xa inhibitor otamixaban: from lead identification to clinical development. Curr Med Chem 2007;14:2471–2481
  • Note the initial higher event rate in the device group…this was procedure-related stroke. That is, mostly air embolism during device implantation. Note that the large 12Fr sheath used to implant the device needs careful monitoring to prevent this (there were a total of 5 procedure-related strokes in the Device group).’ In the “Post-Procedure analysis” (a pre-specified analysis that looks at what happens if you ignore events on the day of the procedure), without these early peri-procedural strokes, the RR is now .45 and the Device strategy is actually superior to Warfarin
  • But there is also an important safety signal…predominantly early (most frequent complication was pericardial effusion)

Nuevos paradigmas en la prevención tromboembólica de la fibrilación auricular  - Dr. Valentin Fuster Nuevos paradigmas en la prevención tromboembólica de la fibrilación auricular - Dr. Valentin Fuster Presentation Transcript

  • Presenter Disclosure Information Valentin Fuster, M.D., Ph.D. Category Company Level Chair HRP BG Medicine Significant
  • ATHERO-THROMBOSIS- 2009 NOVEL ANTITHROMBOTIC RX - AF AS A MODEL 1. Basic Framework – Virchow’s Triad 2. Vascular Compartment – Platelets vs Fibrin 3. Antithrombotics – The Bleeding Problem 4. Antithrombotic Approaches – The Six Steps 5. New Directions – Non Pharmacological ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700 AHA Guidelines Handbook – Ed. V Fuster 2009
  • THROMBO-EMBOLIC DISEASE
    • Virchow’s Triad
    • Thrombus Composition
    • Compartment High Shear Low Shear
    • Disease Platelets 1 /Fibrin 2 Fibrin 2 Platelets 1 /Fibrin 2
    • Arterial
    • CAD, CVD, PVD + – +/–
    • Chamber
    • AF, DCM – + +/–
    • Venous
    • DVT – + +/–
    • Drugs: 1 Platelet Inhibitors, 2 Anticoagulants
    • Approach: 1ary prevention, Acute, 2ary Prev.
    • Outcome : Non Inferiority, Superior (ie  10%) Superior
    • Timing : Phase 3, Phase 2, Phase 1
    Other
  • ATHERO-THROMBOSIS- 2009 NOVEL ANTITHROMBOTIC RX - AF AS A MODEL 1. Basic Framework – Virchow’s Triad 2. Vascular Compartment - Platelet vs Coagulation 3. Antithrombotics – The Bleeding Problem 4. Antithrombotic Approaches – The Six Steps 5. New Directions – Non Pharmacological ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700 AHA Guidelines Handbook – Ed. V Fuster 2009
  • THROMBO-EMBOLIC DISEASE
    • Virchow’s Triad
    • Thrombus Composition
    • Compartment High Shear Low Shear
    • Disease Platelets 1 /Fibrin 2 Fibrin 2 Platelets 1 /Fibrin 2
    • Arterial
    • CAD, CVD, PVD + – +/–
    • Chamber
    • AF, DCM – + +/–
    • Venous
    • DVT – + +/–
    • Drugs: 1 Platelet Inhibitors, 2 Anticoagulants
    • Approach: 1ary prevention, Acute, 2ary Prev.
    • Outcome : Non Inferiority, Superior (ie  10%) Superior
    • Timing : Phase 3, Phase 2, Phase 1
    Other
  • ARTERIAL COMPARTEMENT Iba ñez B, et al. Eur Heart J 2006 ; 8 (suppl): G3-G9
  • CHAMBER & VENOUS COMPARTMENTS T Watson et. al. Lancet 2009 ;373:155. SPAF Investigators 1. JL Blackshear et. al. Stroke 1999 ;30:834. 2. Ann Intern Med. 1998 ;128:639.
  • WASHED RED BLOOD CELLS (HEMATOCRIT = 58%) AND FIBRINOGEN = 493MG/DL R A Merino et al JACC 1992 ;20:1661 R Rastegar et al., JACC 2003 ;41:603 STASIS – SEC – ACTIVATION OF THE COAGULATION SYSTEM
  • ATHERO-THROMBOSIS- 2009 NOVEL ANTITHROMBOTIC RX - AF AS A MODEL 1. Basic Framework – Virchow’s Triad 2. Vascular Compartment - Platelet vs Coagulation 3. Antithrombotics – The Bleeding Problem 4. Antithrombotic Approaches – The Six Steps 5. New Directions – Non Pharmacological ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700 AHA Guidelines Handbook – Ed. V Fuster 2009
  • 1) RISK FACTORS FOR MAJOR BLEEDING IN PATIENTS WITH ACUTE CORONARY SYNDROME Eikelboom et al. Kinnaird et al. Morcucci et al. Rao et al. Manoukian et al. Risk factor 2006 (N=34,126) 2003 (N=10,974) 2003 (N=24,045) 2005 (N=26,452) 2007 (N=13,819) Older age √ √ √ √ √ Diabetes mellitus √ √ √ √ √ Renal dysfunction √ √ √ √ √ Female sex √ √ √ √ History of hypert. √ √ √ √ SBP or MAP √ √ History of stroke √ √ M Cohen. Mayo Clin Proc 2009 ; 84:149
  • 1) RELATIONSHIP BETWEEN AGE AND FREQUENCY OF BLEEDING (95% CI) IN CHARISMA PATIENTS RECEIVING PLACEBO CHARISMA (PB Berger, DL Bhatt, V Fuster et al.,) 2009 (Subm) 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 0.00 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 95 600 550 500 450 350 250 150 50 400 300 200 100 0 Number of Patients Predicted Bleeding Probability Age
  • Cardiovascular Events Hazard Ratio No Bleed Bleed HR (95% CI) p-value n (%) n (%) CV death/MI/stroke 949 (6.3) 59 (15.2) 2.518 (1.936, 3.276) <0.001 CV death 384 (2.5) 74 (15.5) 6.588 (5.136, 8.449) <0.001 Non-fatal MI 271 (1.8) 15 (3.9) 2.259 (1.343, 3.800) 0.002 Non-fatal stroke 294 (1.9) 3 (0.8) 0.412 (0.132, 1.286) 0.115 All-cause death 630 (4.2) 106 (22.2) 5.791 (4.714, 7.115) <0.001 CV death/MI/stroke/hosp 2464 (16.3) 61 (19.3) 1.183 (0.918, 1.525) 0.194 Hospitalization 1707 (11.3) 21 (6.6) 0.592 (0.385, 0.910) 0.016 2) CHRONIC EVENT RATES OF PATIENTS WHO SUFFERED A MODERATE OR SEVERE BLEED vs THOSE WHO DID NOT 0 1 2 3 4 5 6 7 8 9 CHARISMA (PB Berger, DL Bhatt, V Fuster et al.,) 2009 (Subm)
  • Linking Post-PCI Bleeding With Increased Mortality BJ Doyle et. al., J Am Coll Cardiol . 2009 ;53:2019 .
  • Impact of Storage on RBCs & Tissue Oxygen Delivery BJ Doyle et. al., J Am Coll Cardiol . 2009 ;53:2019
  • Kaplan-Meier Estimates of Survival and Death After Transfusion of Older or Newer Blood DH Adams et. al. JACC 2009 ;53:2389. CG Koch et. al. N Engl J Med . 2008 ;358:1229 .
  • 3) 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
  • 3a) Efficacy and Safety of Drug-Eluting Stent Use in Patients With Atrial Fibrillation We reviewed 604 patients with AF who had undergone percutaneous coronary intervention with stent over a period of 7 years (January 2001 - January 2008). On the basis of this study, the routine use of DES in patients with AF does not seem to be justified. A higher risk of major bleeding with DES in comparison with BMS raises the possibility that DES should be limited to lesions or patients with a high risk of restenosis. JM Ruiz-Nodar et al., Eur Heart J 2009 ; 30:932
  • 3b) TRIPLE THERAPY WITHIN TARGETED INR VALUES 2.0 TO 2.5 AND THOSE WHO WERE NOT (>2.5) CUMULATIVE EVENT-FREE SURVIVAL FROM OVERALL BLEEDING 0 200 300 450 600 Days 100 90 90 90 90 90 Bleeding event free survival (%) Dual therapy (n=102) Triple therapy (INR: 2.0-2.5) (n=81) Triple therapy (INR > 2.5) (n=21) 66.7% 95.1% 95.1% R Rossini, DJ Angiolillo et al., AJC 2008; 102:1618 (non-randomized)
  • 3c) DES-T (N=6816): CHANGE IN THE RISK OF STENT THROMBOSIS IN RELATION TO CLOPIDOGREL TREATMENT DURATION S Schultz et al., EHJ 2009 (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 Risk of ST within 4 years (%) 0 50 100 150 200 days 0.0 0.025 0.05 0.075 0.10
  • ATHERO-THROMBOSIS- 2009 NOVEL ANTITHROMBOTIC RX - AF AS A MODEL 1. Basic Framework – Virchow’s Triad 2. Vascular Compartment - Platelet vs Coagulation 3. Antithrombotics – The Bleeding Problem 4. Antithrombotic Approaches – The Six Steps 5. New Directions – Non Pharmacological ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700 AHA Guidelines Handbook – Ed. V Fuster 2009
  • 1) PREVALENCE / INCIDENCE OF ADULTS WITH AF IN THE US 1995 AND 2050 1990 1995 2000 2005 2050 2010 2045 2015 2020 2025 2030 2035 2040 Year Adults with Atrial Fibrillation in millions 0 1 2 3 4 5 6 7 2.08 2.26 2.44 2.68 2.94 3.33 3.50 4.34 4.78 5.16 5.42 6.07 ATRIA (AS Go et al.) JAMA 2001 ; 285: 2370 (Kaiser Permanente, North Ca) Age -1% at 60 y….+ 5% decade- , Cardiac Failure (1-25%) etc
  • 40-49 5 0-59 6 0-69 7 0-79 8 0-89 0 1 2 3 4 5 6 7 8 Stroke rate (%/year) 1) STROKE RATES IN RELATION TO AGE AMONG PATIENTS WITH ATRIAL FIBRILLATION Framingham - PA Wolf et al., Ann Int Med 1987;147:1561 – 10% Age Unrelated to Left Atrium (CVD, other Cardiac, aorta) 25% Bogousslavsky J et al & Miller VT et al Neurol 1990 ;40:1046 & 1993;43:32
  • 2) Meta-analysis - Antithrombotic Therapy in Atrial Fibrillation (AF) Thirteen new trials are available since a 1999 meta-analysis of antithrombotic agents for stroke prevention in patients with AF. This updated meta-analysis shows that adjusted-dose warfarin reduces stroke risk by 64% (6 trials) and antiplatelet agents reduce stroke risk by 22% (8 trials). Meta-analysis of 12 trials shows that adjusted-dose warfarin is more effective than antiplatelet therapy, but it doubles the risk for major extracranial and intracranial hemorrhage. But, these adverse events were only 0.2% per year. Additional trials are unlikely to change current estimates of the effectiveness of vitamin K antagonists and antiplatelet agents RG Hart et al., Ann Int Med 2007; 146:857 (San Antonio, Tx)
  • 3) 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
  • 4a) USE OF ORAL ANTICOAGULANT THERAPY TO PREVENT STROKE ATRIAL FIBRILLATION - RESULTS OF RECENT SURVEYS ATRIA: Anticoagulation and Risk Factors in Atrial Fibrillation; NABOR: National Anticoagulation Benchmark and Outcomes Report. SJ Connolly, S Yusuf et al.Circ 2007 ; 116:450 Year Treated w/ Warfarin, % Published Survey Population (Patient Status) 1999 ATRIA Study 11,082 US patients large HMO - No 60 2005 NAROR Study 945 US patients from teaching, 55 community, and VA hospital 2006 Euro Heart Survey 2706 outpatients in 35 European 64 countries 2006 Hylek et al. 402 US patients,  55 years old, 51 learning hospital 2006 Birman-Deych et al. 16,007 US Medicare patients 49
  • 4a) Management of AF in Clinical Practice Prescription of vitamin K antagonists n = 11,379 ATRIA cohort (managed care system, California, U.S.A.) Go AS, et al. JAMA 2003; 290: 2685 n = 5,333 EuroHeart survey Nieuwlaat R, et al. Eur Heart J 2005; 29: 1181 n = 23,657 Medicare cohort, U.S.A. Birman-Deych E, et al. Stroke 2006; 37: 1070 vitamin K antagonists no anticoagulation
  • 4b) EURO HEART SURVEY ON AF ANTITHROMBOTIC Rx AT DISCHARGE 1 (2003-2004) 0 20 40 60 80 100 % Patients OAC OAC + antiplatelet Antiplatelet Other antithrombotic No antithrombotic 1 35 Countries,182 Hosp, 5333 pts - R Nieuwlaat et al.EHJ 2007 ; 26:2422 US - SB Rowan et al., JACC 2007 ; 49:1561 Ineligible (n=517) Eligible (n=517)
  • 4c) PROPORTION OF PATIENTS PERSISTING WITH WARFARIN TREATMENT OVER TIME STRATIFIED BY AGE AND CHADS 2 SCORE 100 80 60 40 20 0 % Warfarin by age 0 2 4 6 Time (years after diagnosis) 100 80 60 40 20 0 % Warfarin by CHADS2 score 0 2 4 6 Time (years after diagnosis) Age 40-64 Age 65-69 Age 70-74 Age 75-79 Age 80-84 Age 85+ CHADS2=0 CHADS2=3 CHADS2=6 CHADS2=1 CHADS2=4 CHADS2=2 CHADS2=5 UK-GPs: n=41910 pts with chronic AF AM Gallagher et al., J Thromb Hemost 2008 ; 6:1500
  • 4d) Anticoagulation with Warfarin Intensity Often Outside the Target Range Ansell J, et al . J Thromb Thrombolysis 2007; 23: 83 International Study of Anticoagulation Management % Time in Target Range 0 20 40 60 80 100 U.S. Canada France Italy Spain INR <2 INR 2–3 INR >3
  • 4d) AF - RELATIONSHIP BETWEEN THE OR (RELATIVE TO C+A) OF STROKE, MI, SYSTEMIC EMBOLISM, VASCULAR DEATH, OR MAJOR HEMORRHAGE AND TTR ACTIVE W (SJ Connolly et al.) Circ 2008 ; 118:2029 – Dot = Country 4.0 3.5 2.0 2.5 2.0 1.5 1.0 0.5 0.0 40 50 60 70 80 Not TTR (%) OR for Primary + Major Bleed OAC
  • Thrombin SCH 530348 AZD0837 ADP ATP P2X 1 P2Y 1 Aspirin P2Y 12 Abciximab Eptifibatide Tirofiban Stable/sustained platelet aggregation Initiation of transient platelet aggregation Stable/sustained platelet aggregation Cross-linking of adjacent platelets TXA 2 and prothrombotic (ADP) molecules Shape change PAR-1 Gq Gr shape change granule release fibrinogen “ GPIIb/IIIa receptor activation” PLC [Ca++] PKC augmented granule release and TXA 2 production Adenyl cyclase downregulation /↓ camp Gi-coupled signaling pathways Gi-coupled signaling pathway Gq and Gi-coupled signaling pathways Ca++ flux COX-1 TXA 2 Shape change Gq G 12 ← Ticlopidine ← Clopidogrel ← Prasugrel Active metabolite Ticagrelor Cangrelor IV hepatic biotransformation Gi 5)
  • The ACTIVE Trial Clopidogrel + Aspirin Atrial Fibrillation + Risk Factors X Double-blind Superiority n~7,500 Open-label Non-inferiority n=6,500 Anticoagulation-eligible OAC Contraindications or Unwilling Irbesartan, 300 mg/d vs. Placebo n ~9,000 Primary outcome : Stroke, systemic embolism, MI or cardiovascular death ACTIVE - W ACTIVE - A ACTIVE - I Risk Factors : Age  75, hypertension, prior stroke/TIA, LVEF<45%, PAD, age 55-74 + CAD or diabetes VKA (INR 2-3) Clopidogrel + Aspirin Aspirin + Placebo Clopidogrel + Aspirin
  • Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation 0 1 2 3 4 0.0 0.1 0.2 0.3 0.4 Aspirin Clopidogrel + aspirin Years Cumulative incidence 0 1 2 3 4 0.0 0.1 0.2 0.3 0.4 Aspirin Clopidogrel + aspirin Years Cumulative incidence Primary Outcome Stroke The Active A Invest . N Engl J Med 2009 ; 360 (In Press) P<0.001 P<0.0001 Major bleeding : 2.0% per year clopidogrel and 1.3% per year placebo (p<0.001).
  • 0 2 4 6 8 10 12 0 2 4 6 8 10 12 0 2 4 6 8 10 12 0 5 10 15 Ticagrelor Clopidogrel Clopidogrel Ticagrelor Months Months Cumulative Incidence of Primary End Point (%) Cumulative Incidence of Major Bleeding (%) 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 ACS (N=18624) - TICAGRELOR (180LD-90mgx2d ) VS CLOPIDOGREL (300/600LD-75mgx2d ) End Point: Death (Vascular), MI, Stroke – Ticagrelor: Early reversibility (CABG etc)
  • 6) Investigational Anticoagulant Targets TFPI (tifacogin) Idraparinux Rivaroxaban Apixaban LY517717 YM150 DU-176b Betrixaban TAK 42 Dabigatran ORAL PARENTERAL DX-9065a Otamixaban Xa IIa TF/VIIa X IX IXa VIIIa Va II (thrombin) Fibrin Fibrinogen AT APC (drotrecogin alfa) sTM (ART-123) Adapted from Weitz JI. Thromb Haemost 2007 ; 5 Suppl 1:65-7. TTP889 APC activated protein C AT antithrombin sTM soluble thrombomodulin TF tissue factor FPI tissue factor pathway inhibitor
  • 5B)ANTITHROMBOTIC REGIMENS UNDER INVESTIGATION FOR CHRONIC TREATMENT OF PATIENTS WITH ATRIAL FIBRILLATION Phase 3 trial in AF Drug Class Phase 2 trial in AF Non-inf trial vs OAC Sup trial vs aspirin Dabigatran Dir thromb. inhib Done NCT00262600 (RE-LV) Not done Results 2009 AZD0837 Plat.-thromb. inhib Not done Planned Rivaroxaban Oral Xa inhib Not done NCT00403767 Not done Results 2010 Apixaban Oral Xa inhib Not done NCT00412984 NCT00496769 (AVERROES) (ARISTOTLE) Results 2010 Results 2010 Betrixoban Oral Xa inhib Plan 10/2008 ‒ Not done Du-176b Oral Xa inhib Done NCT00504556 Not done Biotimyl. Idrap. Parent Xa inhib Not done NCT00580216 ( BOREALIS) Not done Results 2010? R Nicuwlaat, SJ Connolly, Heart 2009; 95:95
  • RE-LY ® Trial R andomized E valuation of L ong-term Anticoagulant Therap y with Dabigatran Etexilate 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, August 30, Open-label n = 18,113 Non-valvular AF + > 1 stroke risk factor Warfarin (INR 2.0-3.0) n = 6,022 Dabigatran 110 mg bid n = 6,015 Dabigatran 150 mg bid n = 6,076 Blinded
  • RE-LY ® Trial Primary Events Event Rate (%/year) p <0.001 (Noninferiority) p <0.001 (Superiority) All Strokes and Systemic Embolic Events Connolly SJ, Ezekowitz MD et al. N Engl J Med 2009; 361, August 30,
  • RE-LY ® Trial All-Cause Mortality Event Rate (%/year) p = NS p = 0.051 Connolly SJ, Ezekowitz MD et al. N Engl J Med 2009; 361, August 30, 2009
  • RE-LY ® Trial Hemorrhagic Stroke Events Event Rate (%/year) p <0.001 p <0.001 Connolly SJ, Ezekowitz MD et al. N Engl J Med 2009 ; 361, August 30
  • RE-LY ® Trial All Major Bleeding Event Rate (%/year ) p = 0.003 p = NS Hgb  > 2 g/dl or Transfusion > 2 units or Critical Site Connolly SJ, Ezekowitz MD et al. N Engl J Med 2009 ; 361, August 30 p = 0.04
  • The RE-LY ® Trial Clinical Implications
    • Exclusion criteria
      • Patients with severe renal impairment (Cl Cr <30 ml/min)
      • Patients with liver disease
      • Noncompliant patients
    • Questions for further exploration
      • Patients well controlled on warfarin
      • Warfarin-naïve vs. experienced patients
      • Elderly patients (age >75 years)
      • Patients at lower thromboembolic risk (CHADS 2 score = 1)
  • 5B)ANTITHROMBOTIC REGIMENS UNDER INVESTIGATION FOR CHRONIC TREATMENT OF PATIENTS WITH ATRIAL FIBRILLATION Phase 3 trial in AF Drug Class Phase 2 trial in AF Non-inf trial vs OAC Sup trial vs aspirin Dabigatran Dir thromb. inhib Done NCT00262600 (RE-LV) Not done Results 2009- AZD0837 Plat.-thromb. inhib Not done Planned Rivaroxaban Oral Xa inhib Not done NCT00403767 Not done Results 2010 Apixaban Oral Xa inhib Not done NCT00412984 NCT00496769 (AVERROES) (ARISTOTLE) Results 2010 Results 2010 Betrixoban Oral Xa inhib Plan 10/2008 ‒ Not done Du-176b Oral Xa inhib Done NCT00504556 Not done Biotimyl. Idrap. Parent Xa inhib Not done NCT00580216 ( BOREALIS) Not done Results 2010? R Nicuwlaat, SJ Connolly, Heart 2009; 95:95
  • APIXABAN AND ACUTE CORONARY SYNDROME Composite of CV Death, MI, Severe Rec. Ischemia , and Ischemic Stroke Composite of Major and Clinically Relevant Nonmajor Bleeding APPRAISE Steering Committee and Invest. – Circ 2009; 119:2877 0 4 8 12 16 20 24 28 0 0.02 0.04 0.06 0.08 0.1 Weeks from Randomization Proportion with ISTH Major or CRNM Bleeding Apix 10 mg OD Apix 2.5 mg BID Placebo 0 4 8 12 16 20 24 28 0 0.02 0.04 0.06 0.08 0.1 Weeks from Randomization Proportion with CV Death, MI, SRI, or Stroke Apix 10 mg OD Apix 2.5 mg BID Placebo
  • APIXABAN AND CLOPIDOGREL CV Death, MI, Severe Ischemia And Ischemic Stroke Major or Clinically Relevant Nonmajor Bleeding APPRAISE Steering Committee and Invest. – Circ 2009 ; 119:2877 0.1 0.08 0.06 0.04 0.02 0 Clopidogrel No Clopidogrel 0.03 0.04 0.02 0.03 0.07 0.09 Placebo Apixaban 2.5 mg BID Apixaban 10 mg OD N 453 230 241 146 85 74 0.16 0.12 0.08 0.04 0 Clopidogrel No Clopidogrel 0.07 0.09 0.13 0.15 0.06 0.05 N 462 232 243 149 85 75
  • ATHERO-THROMBOSIS- 2009 NOVEL ANTITHROMBOTIC RX - AF AS A MODEL 1. Basic Framework – Virchow’s Triad 2. Vascular Compartment - Platelet vs Coagulation 3. Antithrombotics – The Bleeding Problem 4. Antithrombotic Approaches – The Six Steps 5. New Directions – Non Pharmacological ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700 AHA Guidelines Handbook – Ed. V Fuster 2009
  • 1) LAA Closure: Clinical Outcomes Holmes, Reddy, et al. Lancet 2009 ; 374:534. PROTECT-AF Trial LA LV Watchman Device Follow-Up Non-Valvular AF CHADs ≥ 1 Randomization (1:2) Warfarin Watchman Barbs Engage LAA Wall 160 µ PET fabric
  • PROTECT-AF: Primary Efficacy Results Intention-to-Treat * Using Cox Proportional Model Post-Procedure
    • Composite Endpoint :
      • Stroke
      • CV death
      • Systemic embolism
    DR Holmes, VY Reddy et al.) Lancet 2009 ; 374:534 Cohort 1050 Pt-Yrs WATCHMAN Control Relative Risk 95% CI Rate (Events/Pt-Yrs) Rate (Events/Pt-Yrs) Intention-to-Treat 3.0 21/694.1 4.9 18/370.8 0.62 0.33, 1.17* Post-Procedure 2.2 15/684.0 4.9 17/370.8 0.45 0.23, 0.90*
  • PROTECT-AF: Primary Safety Results 900 patient-year Analysis - - - - Watchman _____ Control / Warfarin Primary Safety All-Cause Mortality DR Holmes, VY Reddy et al.) Lancet 2009 ; 374:534 Cohort 1050 Pt-Yrs WATCHMAN Control Relative Risk 95% CI Rate (Events/Pt-Yrs) Rate (Events/Pt-Yrs) Primary Endpoint 7.4 49/658.8 4.4 16/364.2 1.69 0.96, 2.97 All-Cause Mortality 3.0 20/658.8 4.8 /364.2 0.62 0.34, 1.24
  • LAA Closure: Pericardial Suture Ligation V Reddy et al 2009 Pre-Ligation LAA Mitral Valve Post-Ligation Mitral Valve Sternum Needle Liver RV LV Provided by: E Sosa, M Scanavacca, A d’Avila
  • 2) D Display and Integration of Scar Within the Electroanatomic Map FM Bogun et. al. J Am Coll Cardiol . 2009 ;53:1138.
  • AF - CORRELATION BETWEEN ENHANCEMENT ON DE-MRI AND LOW-VOLTAGE REGIONS ON ELECTROANATOMIC (EA) MAP 40 30 20 10 0 0 5 10 15 20 25 30 35 40 45 Extent of Delayed Enhancement (MRI) Low Voltage Tissue (EA Map) R 2 =0.67 P<0.05 95% CI (0.81-1.30) RS Oakes et al., Circulation 2009; 119:1758 (Utah)
  • AF - PATIENTS IN NSR AFTER LA ABLATION. COX REGRESSION CURVES FOR PATIENTS WITH DIFFERENT DEGREES OF DE-MRI RS Oakes et al., Circulation 2009 ; 119:1758 (Utah) 100 200 300 400 500 Time since ablation (days) Proportion of Patients in Sinus Rhythm 0.00 0.25 0.50 0.75 1.00 Mild Moderate Extensive Enhancement
  • ATHERO-THROMBOSIS- 2009 NOVEL ANTITHROMBOTIC RX - AF AS A MODEL 1. Basic Framework – Virchow’s Triad 2. Vascular Compartment - Platelet vs Coagulation 3. Antithrombotics – The Bleeding Problem 4. Antithrombotic Approaches – The Six Steps 5. New Directions – Non Pharmacological ACC/AHA/ESC (Fuster V et al) Circ 2006; 114:700 AHA Guidelines Handbook – Ed. V Fuster 2009