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Advanced Practice Nursing in Acute and Critical Care Environments: National ACNP Study

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Title: Advanced Practice Nursing in Acute and Critical Care Environments: National ACNP Study


1
(No Transcript)
2
New Paradigms in the Science and Medicine of
Heart Disease
Deciphering the Maze of Risk-Specific
Interventions for Stroke Prevention in Atrial
Fibrillation What Do Late-Breaking Trials Teach
Us About Optimal Alignment of New and
Established Therapies for Risk-Stratified
Subgroups with AF?  
  • Program Chairman
  • Samuel Z. Goldhaber, MD
  • Cardiovascular Division
  • Brigham and Womens Hospital
  • Professor of Medicine
  • Harvard Medical School

3
Program Faculty
Program Chairman Samuel Z. Goldhaber,
MD Cardiovascular Division Brigham and Womens
Hospital Professor of Medicine Harvard Medical
School Elaine M. Hylek, MD, MPH Associate
Professor of Medicine Department of
Medicine Boston University Medical Center Boston,
MA   David A. Garcia, MD Associate Professor,
Division of General Internal Medicine University
of New Mexico Co-Director, University of New
Mexico Anticoagulation Management
Service President, Anticoagulation Forum
Jeffrey I. Weitz, MD, FRCP, FACP Professor of
Medicine and Biochemistry McMaster
University Director, Henderson Research
Center Canada Research Chair in Thrombosis Heart
and Stroke Foundation J.F. Mustard Chair in
Cardiovascular Research Hamilton, Ontario,
Canada Jonathan L. Halperin, MD Professor of
Medicine (Cardiology) Mount Sinai School of
Medicine Director, Clinical Cardiology
Services The Zena and Michael A. Weiner
Cardiovascular Institute The Marie-Josée and
Henry R. Kravis Center for Cardiovascular
Health New York, NY
4
ATRIAL FIBRILLATION Current Dilemmas in Stroke
Prevention Challenges in Risk-Specific
Intervention for AFTaking the Pulse for Year
2010 and Beyond
New Frontiers in Atrial Fibrillation
Samuel Z. Goldhaber, MD Cardiovascular
Division Brigham and Womens Hospital Professor
of Medicine Harvard Medical School
5
Adverse Events Atrial Fibrillation
  • Death
  • Stroke
  • Hospitalizations
  • Quality of life and exercise capacity
  • Left ventricular dysfunction

European Heart Journal 2010 31 2369-2429
6
Atrial Fibrillation Twice as Common as
Previously Suspected
  • Incidence increased 13 over past 20 years
  • In USA, 12-16 million will be affected by 2050
  • Increasing obesity and increasing age are risk
    factors that help explain rise in incidence

Miyasaka Y. Circulation 2006 114 119-125
7
AF Prevalence Age and Gender
Prevalence of AF increases with age men gt
women
Prevalence, percent
Age, years
JAMA 2001 285 2370
8
The Percentage of Strokes Attributable to AF
Increases with Age
Wolf et al. Stroke 1991 22 983-988
9
Mortality Rates in AF
  • Double the overall age and gender matched
    population
  • No reduction in past two decades
  • Mortality 9-fold higher during 1st 4 months after
    diagnosis

Miyasaka Y, et al. JACC 2007 49 986-992
10
Risk Factors for Stroke
Arch Intern Med 1994 154 1449-1457
11
Atrial Fibrillation A Risk Factor for
Vascular Events
RISK FACTORS THROMBOSIS Hypertension
Hyperlipidemia Age Diabetes Mellitus
Smoking
Atherosclerosis/Atherothrombosis
Atherosclerosis/Atherothrombosis
MI
AF
CHF
MI
AF
CHF
Stroke, MI, Vascular Death
Wolf PA et al. Arch Intern Med 1987 147
1561-1564 Leckey R et al. Can J Cardiol 2000 16
481-485
12
Therapeutic Range for WarfarinINR Values at
Stroke or ICH
15.0
Stroke
Intracranial Hemorrhage
10.0
Odds Ratio
5.0
1.0
0
5.0
6.0
8.0
1.0
2.0
3.0
4.0
7.0
INR
Fuster et al. J Am Coll Cardiol.
2001381231-1266.
13
Problems with Warfarin
  • Delayed onset/offset
  • Unpredictable dose response
  • Narrow therapeutic index
  • Drug-drug, drug-food interactions
  • Problematic monitoring
  • High bleeding rate
  • Slow reversibility

14
Novel Oral Anticoagulants
The Current Landscape
15
Novel Oral Anticoagulants
  • Dabigatran An oral DTItwice daily (renal
    clearance)
  • Rivaroxaban Direct factor Xa inhibitor (renal
    clearance)once or twice daily
  • Apixaban Direct factor Xa inhibitor (hepatic
    clearance)twice daily
  • Edoxaban Direct factor Xa inhibitor (hepatic
    clearance)once daily

Circulation 2010 121 1523-1532
16
RE-LY A Non-inferiority Trial
Atrial fibrillation 1 Risk Factor Absence of
contra-indications 951 centers in 44 countries
R
Blinded Event Adjudication
Open
Blinded
Warfarin adjusted (INR 2.0-3.0) N6000
Dabigatran Etexilate 150 mg BID N6000
Dabigatran Etexilate 110 mg BID N6000
NEJM 2009 3611139-51
17
Stroke or Systemic Embolism
Warfarin better
Dabigatran better
NEJM 2009 3611139-51
18
Intracranial Bleeding
RR 0.31 (95 CI 0.200.47) plt0.001 (sup)
RR 0.40 (95 CI 0.270.60) plt0.001 (sup)
Number of events
0.74
RRR 60
RRR 69
0.30
0.23
Connolly et al., NEJM, 2009 361 1139-1151
19
Mortality Rate Dabigatran Compared To Warfarin
  • Dabigatran 15 reduction in death from
    vascular causes (p0.04)
  • 12 reduction in death from any cause (p0.05)

NEJM 2009 361 1139-1151
20
FDA Approves Dabigatran for SPAF
Dabigatran Reduces Stroke Rate Compared to
Warfarin
  • October 19, 2010
  • Dose of 75 mg BID for CrCl 15-30 ml/ min
  • Dose of 150 mg BID for CrCl gt 30 ml/ min

21
Deciphering the Maze of Risk-Specific
Interventions for SPAF
  • ROCKET-AF results just released at noon
    todayDr. Weitz will present top-line in his
    presentation and Dr. Hylek will address
    implications in her case studies
  • Will we be able to make cross-trial comparisons
    between RE-LY and ROCKET-AF? Analysis just
    beginning . . .

22
Deciphering the Maze of Risk-Specific
Interventions for SPAF
  • Pivotal SPAF trials (AVERROES, RE-LY, and ROCKET
    AF) focus on different subsets of patients with
    AF How will this affect risk- specific alignment
    of therapy for
  • Patients intolerant of, or unwilling to take
    wafarin? (AVERROES, apixaban)
  • Patients stratified to higher CHADS2 risk
    scores? (ROCKET-AF, rivaroxaban)
  • Patients stratified across multiple CHADS2
    risk profiles (RE-LY, dabigatran)

23
Deciphering the Maze of Risk-Specific
Interventions for SPAF
  • This Science-to-Strategy Summit will focus on
    how best to translate landmark trials for SPAF
    into the front lines of cardiovascular practice
  • Are cross trial comparisons possible? And what
    are the implications for selecting new agents
    across the risk spectrum of AF?
  • How do we use CHADS2 risk scores, alone, or in
    combination with other risk assessment tools? Is
    CHADS2 enough?
  • Should goal be optimizing use of warfarin, using
    pharmacogenetic and point-of-care
    approaches, or should it be risk-specific
    alignment of new agents with carefully selected
    patient subsets requiring SPAF?
  • How will cost figure in to our decision-making?

24
New Paradigms in the Science and Medicine of
Heart Disease
Deciphering the Maze of Risk-Specific
Interventions for Stroke Prevention in Atrial
Fibrillation Aligning Therapy with Stroke Risk
Jonathan L. Halperin, MD Professor of Medicine
(Cardiology) Mount Sinai School of
Medicine Director, Clinical Cardiology
Services The Zena and Michael A. Weiner
Cardiovascular Institute The Marie-Josée and
Henry R. Kravis Center for Cardiovascular Health
25
Atrial FibrillationA Substantial Threat to the
Brain
  • Affects
  • 4 of people aged gt60 years
  • 9 of those aged gt80 years
  • 5/year stroke rate
  • 12/year for those with prior stroke
  • billions annual cost for stroke care
  • AF-related strokes have worse outcomes

AF identifies millions of people with a five-fold
increased risk of stroke
26
Atrial FibrillationAn Opportunity for Stroke
Prevention
Affects 1 of the population, 10 of
elderly The number is rising 5/year stroke
rate Is the rate falling? 12/year for those
with prior stroke An opportunity for stroke
prevention! AF-related strokes have worse
outcomes Always costly, often
horrible / billions annual cost for stroke
care Prevention means savings.
27
Anticoagulation in Atrial FibrillationStroke
Risk Reductions
Warfarin Better
Control Better
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
Aggregate
-100
50
100
-50
0
Hart R, et al. Ann Intern Med 2007146857.
28
Anticoagulation in Atrial FibrillationThe
Standard of Care for Stroke Prevention
Warfarin Better
Control Better
AFASAK
Unblinded
SPAF
Unblinded
BAATAF
Unblinded
CAFA
Terminated early
SPINAF
Double-blind Men only
EAFT
2o prevention Unblinded
Aggregate
-100
50
100
-50
0
Hart R, et al. Ann Intern Med 2007146857.
29
Efficacy of Warfarin in Trials vs.
PracticeStroke Risk Reductions
Treatment Better
Treatment Worse
6 Trials n 2,900
Warfarin vs. Placebo/Control
Warfarin vs. No anticoagulation
Medicare cohort n 23,657
50
100
-50
0
Hart R, et al. Ann Intern Med 2007146857 Birman-
Deych E. Stroke 2006 37 10701074
30
Aspirin for Atrial FibrillationStroke Risk
Reductions
AFASAK I
SPAF I
EAFT
ESPS II
LASAF
UK-TIA
Aggregate
-100
50
100
-50
0
Aspirin Worse
Aspirin Better
Hart RG, et al. Ann Intern Med 2007 147590.
31
Aspirin for Atrial FibrillationStroke Risk
Reductions
AFASAK I
SPAF I
EAFT
ESPS II
LASAF
UK-TIA
Aggregate
-100
50
100
-50
0
Aspirin Worse
Aspirin Better
Hart RG, et al. Ann Intern Med 2007 147590.
32
Rates of Stroke or Systemic Embolismin
Anticoagulation Candidates
Warfarin or Aspirin
Placebo
Risk reduction 82
Event Rate (/y)
Months
N Engl J Med 1990 322 863.
33
Stroke Risk in Atrial FibrillationUntreated
Control Groups of Randomized Trials
Stroke Rate ( per year)
Age (years)
Atrial Fibrillation Investigators. Arch Intern
Med 19941541449.
34
Aspirin Effect Related to AgeSPAF-I Study
gt 75 years
lt 75 years
150
- 150
0
Aspirin Better
Aspirin Worse
35
SPAF-IIRates of Disabling Stroke
6
Ischemic
Hemorrhagic
4
Event Rate (/year)
2
0
Aspirin
Warfarin
Aspirin
Warfarin
lt 75 years
gt 75 years
SPAF Investigators. Lancet 1994 343 687.
36
Rates of Disabling Stroke on WarfarinPatients
gt75 Years Old
2006
1992
SPAF Investigators. Lancet 1994 343 687. Mant
J, et al. Lancet 2007 370 493.
37
Intracerebral Hemorrhage
The Most Feared Complication of Antithrombotic
Therapy
  • gt10 of intracerebral hemorrhages (ICH) occur in
    patients on antithrombotic therapy
  • Aspirin increases the risk by 40
  • Warfarin (INR 23) doubles the risk to
    0.30.6/year
  • ICH during anticoagulation is catastrophic

Hart RG, et al. Stroke 2005361588
38
Risk Stratification in AFStroke Risk Factors
  • High-Risk Factors
  • Mitral stenosis
  • Prosthetic heart valve
  • History of stroke or TIA

Singer DE, et al. Chest 2004126429S. Fang MC,
et al. Circulation 2005 112 1687.
39
Risk Stratification in AFStroke Risk Factors
  • Moderate-Risk Factors
  • Age gt75 years
  • Hypertension
  • Diabetes mellitus
  • Heart failure or ? LV function
  • High-Risk Factors
  • Mitral stenosis
  • Prosthetic heart valve
  • History of stroke or TIA

Singer DE, et al. Chest 2008133546S. Fang MC,
et al. Circulation 2005 112 1687.
40
The CHADS2 Index Stroke Risk Score for Atrial
Fibrillation
Prevalence ()
Score (points)
Congestive Heart failure 1
32 Hypertension 1
65 Age gt75 years 1
28 Diabetes mellitus 1
18 Stroke or
TIA 2 10 Moderate-High risk gt2
50-60 Low risk 0-1
40-50
VanWalraven C, et al. Arch Intern Med 2003
163936. Nieuwlaat R, et al. (EuroHeart survey)
Eur Heart J 2006 (E-published).
41
Nonvalvular Atrial Fibrillation
Stroke Rates Without Anticoagulation According to
Isolated Risk Factors
Stroke Rate (/year)
Heart Failure ? LVEF
Female
Diabetes
Prior Stroke/TIA
Hypertension
Age gt 75 years
Hart RG et al. Neurology 2007 69 546.
42
CV Event Rates in Patients with AF Related to
CHADS2 Score
REACH Registry
Goto S, et al. Am Heart J 2008 156 855.
43
Risk Stratification in AFStroke Risk Factors
  • Moderate-Risk Factors
  • Age gt75 years
  • Hypertension
  • Diabetes mellitus
  • Heart failure or ? LV function
  • High-Risk Factors
  • Mitral stenosis
  • Prosthetic heart valve
  • History of stroke or TIA

Singer DE, et al. Chest 2004126429S. Fang MC,
et al. Circulation 2005 112 1687.
44
Risk Stratification in AFStroke Risk Factors
  • Moderate-Risk Factors
  • Age gt75 years
  • Hypertension
  • Diabetes mellitus
  • Heart failure or ? LV function
  • High-Risk Factors
  • Mitral stenosis
  • Prosthetic heart valve
  • History of stroke or TIA

Less Validated Risk Factors
Dubious Factors
  • Age 6575 years
  • Coronary artery disease
  • Female gender
  • Thyrotoxicosis
  • Duration of AF
  • Pattern of AF
  • - (persistent vs. paroxysmal)
  • Left atrial diameter

Singer DE, et al. Chest 2004126429S. Fang MC,
et al. Circulation 2005 112 1687.
45
The CHA2DS2VASc Index Stroke Risk Score for
Atrial Fibrillation
Weight (points)
Congestive heart failure or LVEF lt 35
1
Hypertension 1
Age gt75 years
2
Diabetes mellitus 1
Stroke/TIA/systemic
embolism 2 Vascular Disease
(MI/PAD/Aortic plaque) 1 Age 65-74 years
1 Sex category (female)
1 Moderate-High risk gt 2 Low
risk 0-1
Lip GYH, Halperin JL. Am J Med 2010 123 484.
46
Risk Stratification and Anticoagulation Stroke
Reduction with Warfarin Instead of Aspirin
Number of patients Needed-to-treat with Warfarin
vs. Aspirin to prevent 1 stroke/year
gt250
100
50
Event Rate (/year)
CHADS2 Score
AFASAK I, AFASAK II, ATHENS, BAFTA, EAFT,
NASPEAF, PATAF, SIFA, SPAF II, SPAF III, WASPO
47
The CHADS2 Index Stroke Risk in Patients with
Atrial Fibrillation
Score (points)
Risk of Stroke (/year)
0 1.9 1 2.8 2 4.0 3 5.
9 4 8.5 5 12.5 6
18.2
Approximate Risk threshold for Anticoagulation
3/year
Van Walraven C, et al. Arch Intern Med 2003
163936. Go A, et al. JAMA 2003 290 2685. Gage
BF, et al. Circulation 2004 110 2287.
48
Antithrombotic Therapy for Atrial
FibrillationACC/AHA/ESC Guidelines 2006
Fuster V, et al. Eur Heart J 2006271979.
49
Patient Selection for AnticoagulationAdditional
Considerations
  • Risk of bleeding
  • Newly anticoagulated vs. established therapy
  • Availability of high-quality anticoagulation
    management program
  • Patient preferences

50
Warfarin vs. Aspirin Excess Major Bleeding
Excess bleeds (per 100 patients/year)
11 trials, mean follow-up 1.8 years
51
The HAS-BLED Score
Risk Score for Predicting Bleeding
in Anticoagulated Patients with Atrial
Fibrillation
Weight (points)

Hypertension (gt160 mmHg systolic) 1
Abnormal renal or
hepatic function 1-2
Stroke 1 Bleeding history or
anemia 1 Labile INR (TTR lt60) 1 Elderly (age gt75
years) 1 Drugs (antiplatelet, NSAID) or alcohol
1-2 High risk (gt4/year) gt 4 Moderate risk
(2-4/year) 2-3 Low risk (lt2.year) 0-1
Pisters R, et al Chest 2010 (online)
http//chestjournal.chestpubs.org/content/early/20
10/03/18/chest.10-0134
52
The ACTIVE TrialClopidogrel Aspirin
Atrial Fibrillation Risk Factors
ACTIVE - W
ACTIVE - A
OAC Contraindications or Unwilling
Anticoagulation-eligible
Open-label Non-inferiority n 6,706
Double-blind Superiority n 7,554
Irbesartan, 300 mg/d vs. Placebo n 9,016
ACTIVE - I
Risk Factors Age ?75, hypertension, prior
stroke/TIA, LVEFlt45, PAD, age 55-74 CAD or
diabetes
Primary outcome Stroke, systemic embolism, MI
or cardiovascular death
53
The ACTIVE TrialClopidogrel Aspirin
Atrial Fibrillation Risk Factors
ACTIVE - A
OAC Contraindications or Unwilling
Anticoagulation-eligible
Open-label Non-inferiority n 6,706
Double-blind Superiority n 7,554
Irbesartan, 300 mg/d vs. Placebo n 9,016
ACTIVE - I
54
Antithrombotic Therapy for Atrial
FibrillationStroke Risk Reductions
Warfarin Better
Antiplatelet Rx Better
ACTIVE-W Anticoagulation vs. Aspirin Clopidogrel
n 6,706
Anticoagulation vs. Antiplatelet drugs
7 Trials n 4,232
50
100
-50
0
Connolly S, et al. Lancet 2006 3671903. Hart R,
et al. Ann Intern Med 2007146857.
55
Antithrombotic Therapy for Atrial
FibrillationStroke Risk Reductions
Warfarin Better
Antiplatelet Rx Better
All patients
Warfarin vs. Aspirin Clopidogrel
Prior OAC
VKA-naïve
50
100
-50
0
Connolly S, et al. Lancet 2006 3671903.
56
Major Hemorrhage in Relation toPrior
Anticoagulant TherapyACTIVE-W
Starters
Switchers
Interaction p0.028
Yes
No
Anticoagulant Therapy at Entry
Connolly S, et al. Lancet 2006 3671903.
57
The ACTIVE TrialClopidogrel Aspirin
Atrial Fibrillation Risk Factors
ACTIVE - A
OAC Contraindications or Unwilling
Anticoagulation-eligible
Open-label Non-inferiority n 6,706
Double-blind Superiority n 7,554
Irbesartan, 300 mg/d vs. Placebo n 9,016
ACTIVE - I
Connolly SJ, et al. N Engl J Med 2009 3602066.
58
ACTIVE-A Reasons for Exclusion from
Anticoagulation
  • Inability to comply with INR monitoring
  • Predisposition to falling or head trauma
  • Persistent hypertension gt160/100 mmHg
  • Previous serious bleeding on VKA
  • Severe alcohol abuse within 2 years
  • Peptic ulcer disease
  • Thrombocytopenia
  • Chronic need for NSAID

Connolly SJ, et al. N Engl J Med 2009 3602066.
59
ACTIVE-ATotal Stroke Rates
28 RRR HR 0.72 (95 CI, 0.620.83) p lt0.001
0.15
408 (3.3/year)
Aspirin

0.10
296 (2.4/year)
Cumulative Incidence
0.05
Clopidogrel Aspirin
0.0
0
1
2

3
4














Years
Connolly SJ, et al. N Engl J Med 2009 3602066.
60
The ACTIVE TrialsStroke Rates and Risk Reductions
VKA oral anticoagulant CA clopidogrel
aspirin
Connolly SJ, et al. Lancet 2006
3671903. Connolly SJ, et al. N Engl J Med 2009
3602066.
61
Apixaban vs. Aspirin The AVERROES Trial Primary
and Secondary Endpoints
Connolly S. European Society of Cardiology,
Stockholm, August 31, 2010
62
Apixaban vs. Aspirin The AVERROES Trial Bleeding
Events
Connolly S. European Society of Cardiology,
Stockholm, August 31, 2010
63
RE-LY TrialPrimary Events
All Strokes and Systemic Embolic Events
p lt0.001 (Superiority)
p lt0.001 (Noninferiority)
Event Rate (/year)
Connolly SJ et al. N Engl J Med 2009 361 1139.
64
RE-LY TrialHemorrhagic Stroke Events
Intracerebral Hemorrhages
p lt0.001
p lt0.001
Event Rate (/year)
Connolly SJ et al. N Engl J Med 2009 361 1139.
65
Quality of Warfarin ControlInternational
Normalized Ratio
SPORTIF-V
SPORTIF-III
ACTIVE-W
RE-LY
Warfarin control necessary For efficacy
noninferior to Dabigatran 150 mg bid
Gage BF. N Engl J Med 2009 361, 1200.
66
Oral Factor Xa Inhibitors
Ongoing Phase III Trials for Prevention of
Strokeand Systemic Embolism in Patients with AF
Adjusted based on renal function
67
Antithrombotic Therapy for Atrial
FibrillationThe Future of Risk-Stratified
Treatment?
Fuster V, et al. Eur Heart J 2006271979.
68
Alternatives to AnticoagulationAtrial
Fibrillation
Current approaches
  • Restoration and maintenance of sinus rhythm
  • Antiarrhythmic drug therapy
  • Catheter ablation
  • Maze operation

Emerging (investigational) approaches
  • Obliteration of the left atrial appendage
  • Trans-catheter occluding devices
  • Thoracoscopic epicardial plication
  • Amputation

69
Strokes after Conversion to NSRRate vs. Rhythm
Control Trials
Verheugt F, et al. J Am Coll Cardiol
200341(suppl)130A.
70
AFFIRM TrialStroke Rates
  • 74 of all strokes were proven ischemic
  • 44 occurred after stopping warfarin
  • 28 in patients taking warfarin with INR lt2.0
  • 42 occurred during documented AF

Wyse AG, et al. N Engl J Med 2002 347 1825.
71
ATHENA TrialDronedarone vs. Placebo in Patients
with AFStroke Rates (Secondary Analysis)
Connolly S, et al Circulation 2009 1201174.
72
Cardiovascular Outcomes in the ATHENA Trial
Rates of Stroke, ACS or Cardiovascular Death
p lt 0.001
p 0.538
73
Percutaneous LAA OcclusionThe WATCHMAN Device
Syed T, Halperin JL. Nature Clin Prac Cardiovasc
Med 2007 4428 Holmes DR, et al. Lancet 2009
374 534
74
PROTECT-AF TrialAll Strokes (ITT Analysis)
Posterior probabilities
Device
Control
Event-free probability
Days
Holmes D, et al. ACC i2 Summit, Orlando, FL,
March 28, 2009
75
Atrial Fibrillation and ThromboembolismThe Next
Challenges
  • Better risk-stratification that balances stroke
    and bleeding
  • Noninvasive methods to predict events and guide
    therapy
  • Safe treatments for the highest risk patients
  • Achieving and confirming successful rhythm
    control over time
  • Targeted AF prevention

76
From Fermented Sweet Cloverto Molecular
Targeting of CoagulationThe Promise of New
Approaches
The Goal
To bring effective therapy to many more patients
and prevent thousands of strokes.
77
Thank you !
78

New Paradigms in the Science and Medicine of
Heart Disease
FROM RISK TO REMEDY Role of Thrombin and
Factor Xa Inhibitors for Stroke Prevention in AF
  • Jeffrey I. Weitz, MD, FRCP(C), FACP
  • Professor of Medicine and Biochemistry
  • McMaster University
  • Canada Research Chair in Thrombosis
  • Heart Stroke Foundation/ J.F. Mustard Chair
  • in Cardiovascular Research

79
Overview
  • Risk of stroke in AF
  • Choice of antithrombotic drugs
  • Which drug for which patient

80
Atrial FibrillationMajor Risk Factor for Stroke
  • Independent risk factor for stroke - increases
    risk of stroke 5-fold
  • Accounts for 15-20 of all strokes
  • Patients with paroxysmal and sustained AF have
    same risk of stroke

AFatrial fibrillation
Wolf PA, et al. Stroke 1991 Savelieva I, et al.
Ann Med 2007 Singer DE, et al. Chest 2008
81
Antithrombotic Drug Choices for Stroke Prevention
  • Antiplatelet agents
  • ASA
  • ASA plus clopidogrel
  • Anticoagulants

82
Which Drug for Which Patient?
ACCP 2008
83
Are Patients With CHADS2 of 0-1 Really Low Risk?
Role of CHADS2-Vasc Score
Pamukcu et al. Age and ageing 2010
84
CHADS2-Vasc Score and Antithrombotic Therapy
ESC guidelines 2010
85
Anticoagulant Choices for Stroke Prevention
  • Warfarin
  • New oral anticoagulants
  • Dabigatran
  • Rivaroxaban
  • Apixaban
  • Edoxaban

86
Limitations of Warfarin
87
Comparison of Features of New Anticoagulants
with Those of Warfarin
88
How Do the New Oral Anticoagulants Compare with
Warfarin?
The Current Landscape
89
Stroke or Systemic Embolism
Warfarin better
Dabigatran better
Connolly et al., NEJM, 2009
90
Annual Rates of Bleeding
Connolly et al., NEJM, 2009
91
Intracranial Bleeding Rates
RR 0.31 (95 CI 0.200.47) plt0.001 (sup)
RR 0.40 (95 CI 0.270.60) plt0.001 (sup)
Number of events
0,74
RRR 60
RRR 69
0,30
0,23
Connolly et al., NEJM, 2009
92
Which Patients are Candidatesfor Dabigatran?
  • Higher dose dabigatran regimen more effective
    than warfarin in all CHADS2 categories

93
Stroke and Systemic Embolism
D150 vs. warfarin
Annual rate,
D110
D150
WARFARIN
CHADS2
0-1
1.06
0.65
1.05
2
1.43
0.84
1.38
3-6
2.12
1.88
2.68
Oldgren et al., JACC, 2010
94
What Have We Learned About Dabigatran Versus
Warfarin?
  • Benefits of dabigatran over warfarin apparent at
    all levels of TTR
  • Benefits of dabigatran greatest in centers with
    lowest TTR

95
RRR in Stroke or Systemic Embolism with
Dabigatran Versus Warfarin by TTR by Center
Wallentin et al, Lancet, 2010
96
What About Dabigatran inthe Elderly?
  • Lower risk of stroke and intracranial bleeding
  • Higher risk of extracranial (mostly GI) bleeding

97
Stroke or Systemic Embolism
Healey et al., JACC, 2010
98
Hemorrhagic Stroke
Healey et al., JACC, 2010
99
Major Bleeding
Healey et al., JACC, 2010
100
Which Dabigatran Dose forWhich Patient?
101
What About The Elderly?
  • Health Canada approved the 110 mg
  • dose for patients gt 80 years of age

102
Who is Not a Candidate for Dabigatran?
  • Stable on warfarin?
  • CrCl less than 15 ml/min
  • Severe hepatic dysfunction
  • High risk of GI bleeding?
  • Mechanical valve

103
Practical Issues in Dabigatran Management
The Current Landscape
104
Switching from Warfarinto Dabigatran
  • Start dabigatran when INR 2.0

105
Assessment of DabigatranActivity
  • Normal aPTT and/or thrombin time indicates absent
    activity
  • Dabigatran calibrators will be available

106
Unanswered QuestionsWith Dabigatran
  • Will dyspepsia lead to discontinuation?
  • How will we manage patients with a history of GI
    bleeding?
  • Will short half-life obviate need for an
    antidote?

107
What About Other Agents?
108
ROCKET-AF LATE-BREAKING
Placeholder for ROCKET-AF Trial Results
109
Opportunities for Oral Factor Xa Inhibitors
  • Once daily dosing
  • No dyspepsia
  • No excess GI bleeding
  • Better benefit-to-risk profile in elderly?

110
Challenges for New Oral Anticoagulants?
  • Costs will be high who will pay?
  • How will we assess compliance?
  • How will we treat bleeds?

111
Conclusions
  • New oral anticoagulants are poised to replace
    warfarin for stroke prevention in AF
  • Dabigatran is the first, but others will soon
    follow
  • How the new agents compare with each other
    remains to be determined

112
The Evolving Paradigm of Warfarin-Based Therapy
Still Relevant? And for How Long?
New Paradigms in the Science and Medicine of
Heart Disease
  • David A. Garcia, MD
  • Associate Professor, Division of General Internal
    Medicine
  • University of New Mexico
  • Co-Director, University of New Mexico
  • Anticoagulation Management Service
  • President, Anticoagulation Forum

113
Long-Term Oral AnticoagulationThe State of the
Art
114
Warfarin Protects Against StrokeAdjusted-Dose
Warfarin Compared With Placebo
Hart, et al. Ann Intern Med. 2007 Jun
19146(12)857-67.
115
AC management clinics become increasingly
prevalent
Warfarin first used
POC testing, PST, dosing algorithms, software
programs, better understanding of genetics and
drug interactions
WHO endorses INR
1950s
1991
1999
1983
Efficacy of VKA to prevent AF-related
stroke demonstrated
116
WarfarinMechanism of Action
Vitamin K
VII
Vitamin K Utilization Impaired
IX
Synthesis of Dysfunctional Coagulation Factors
X
CYP450
II
Warfarin
Slight genetic variation can produce significant
differences in dose-response relationship
117
WarfarinMechanism of Action
Carboxylated zymogen
Decarboxylated zymogen
Vitamin K Epoxide
Vitamin KH2
X
Vitamin K reductase
Vitamin K
Vitamin K epoxide reductase
Slight genetic variation can produce significant
differences in dose-response relationship
NADPH
118
Coagulation Pathway
Initiation
Vlla/TF
X
IX
Propagation
IXa
VllIa
Xa
Va
II
IIa (Thrombin)
Fibrin Formation
119
Limitations of Warfarin (VKA)
Requires frequent Monitoring ? Genotype testing
Narrow Therapeutic Index Drug/Diet Interactions
  • Complicates Management
  • Of
  • Bleeding patient
  • Patient with High INR

Long Half-Life
Slow Onset of Action
Heparin overlap often necessary
Periprocedural Anticoagulation Difficult
120
Is VKA (Warfarin) Therapy Getting Safer and more
User-friendly?
  • Widespread use of the INR
  • Anticoagulation management services
  • Patient self-testing
  • Pharmacogenomics
  • Reversal strategies

121
Does time in therapeutic range matter?
Is VKA (Warfarin) Therapy Getting Safer and more
User-friendly?
122
Events per 100 Patient-Years According to
International Normalized Ratio Control
White H et al. Arch Intern Med. 2007.167239-245
123
Increased Time-in-Range Better Outcomes
Witt et al. Blood 2009. 114 952-956.
124
Dabigatran vs. Warfarin, Stratified by
Center-Based Time-in-Range
Time to stroke or systemic embolism
Wallentin et al. Lancet 2010. 376975-83
125
Anticoagulation Management Service Can Increase
Time-in-Range
of patients
Clinical Pharmacy AMS Control (Usual Care)
time in range
Witt et al. Chest 2005.
126
Anticoagulation Management Services
  • PROS
  • Increase TTR
  • Probably improve outcomes
  • CONS
  • Resource-intensive
  • Only available to a minority of patients in many
    countries (including the United States)

127
Patient self-testing may reduce risk of
thromboembolic events
Heneghan et al. Lancet. 2006 Feb
4367(9508)404-11.
128
Self-testing vs. Clinic TestingA Randomized
Trial
Time to stroke, major bleed or death
Matchar et al. NEJM 2010 3631608-1620
129
Patient Self-testing
  • Not feasible for all warfarin-treated patients
  • Uptake in U.S. also limited by low CMS
    reimbursement for physician oversight
  • Recently published RCT suggests no better than
    high-quality AC-clinic based management

130
Knowledge of Genotype Allows Better Dose
Prediction
Gage B. NEJM 2005.
131
Anderson et al RCT (n200)
  • Only published high-quality RCT
  • Incorporated both CYP2C9 and VKORC1 genotypes

Anderson et al, Circulation, 2007 116 2563-70.
132
Meta-analysis Time Therapeutic
Kangelaris, JGIM, 2009 24(5) 656-64.
133
Pharmacogenetic Testing
  • Promising science but
  • Clinical benefit still unproven

134
Reversal Strategies
4-factor prothrombin complex concentrate
administered
Preston et al. British Journal of Haematology
2002. 116 619624
135
Warfarin Reversal
  • PO/IV vitamin K
  • Effective but INR decrease not immediate
  • Fresh frozen plasma
  • Each unit contains limited amount of vitamin-K
    dependent clotting proteins
  • Significant volume challenge infection risk
  • 4-factor PCC
  • Not available in U.S.
  • ? Cost
  • ? Risk of thrombosis

136
Conclusions
  • Although warfarin treatment is safer and more
    practical than it was 10-15 years ago, there is
    certainly room for further improvement.
  • The new agents in development may
  • Eliminate some of the challenges unique to
    warfarin
  • Allow patients for whom warfarin is not feasible
    to receive highly effective anti-thrombotic
    therapy

137
Questions Regarding the New Oral Anticoagulants
  • Do they represent a significant improvement for
    patients who have been taking warfarin with
    consistently therapeutic INR values for
    months/years?
  • Will the elimination of regular INR measurement
    reduce compliance?
  • How will their cost compare to current costs
    (including INR monitoring, dose adjustment,
    etc.)?
  • Which (if any) will be available to patients with
    significantly impaired renal function?

138
How do I Convert a Patient from Warfarin to
Dabigatran and Vice Versa?
  • Warfarin to dabigatran discontinue warfarin and
    start dabigatran when the international
    normalized ratio (INR) is below 2.0.
  • Dabigatran to warfarin
  • CrCl gt50 mL/min, start warfarin 3 days before
    discontinuing dabigatran.
  • CrCl 31-50 mL/min, start warfarin 2 days before
    discontinuing dabigatran.
  • CrCl 15-30 mL/min, start warfarin 1 day before
    discontinuing dabigatran.
  • CrCl lt15 mL/min, no recommendations can be made.
  • Because dabigatran can contribute to an elevated
    INR, the INR will better reflect warfarins
    effect after dabigatran has been stopped for at
    least 2 days.

Dabigatran prescribing information 2010.
139
What should I do if my patient has an ischemic
stroke on dabigatran?
  • Consider
  • Is the patient compliant with dabigatran? Check
    aPTT if dose taken within past 12 hours, it
    should be prolonged.
  • If the stroke is not cardiogenic, consider
    adding anti-platelet therapy.
  • Convert dabigatran to warfarin (target INR 2-3 or
    higher?).

140
What should I do if my patient on dabigatran is
bleeding?
  • Volume support maintain good renal function.
  • Anatomic interventions
  • Direct compression
  • Arterial embolization
  • Animal models
  • Prothrombin complex concentrate (e.g.
    F.E.I.B.A.)?
  • Recombinant factor VIIa?
  • Hemodialysis

Wienen W, J Thromb Haemost 2008 3(Suppl. 1)
P1703.
141
How do I Prepare a Patient on Dabigatran for
Elective Surgery?
  • If possible, discontinue dabigatran 1 to 2 days
    (CrCl 50 mL/min) prior
  • or 3 to 5 days (CrCl lt50 mL/min)
  • Consider longer times for patients undergoing
    major surgery, spinal puncture, or placement of a
    spinal or epidural catheter or port, in whom
    complete hemostasis may be required

Dabigatran prescribing information 2010.
142
New Paradigms in the Science and Medicine of
Heart Disease
So What Now? Applying Remedies to Risk Groups
in the Real World Setting for SPAF   Case Study
Analysis with Audience Response System (ARS)
Focus on Risk-Specific Alignment of
Thromboprotective in Patients with AF    
  • Elaine M. Hylek, MD, MPH
  • Associate Professor of Medicine
  • Department of Medicine
  • Boston University Medical Center
  • Boston, MA

143
Atrial Fibrillation Case Study
144
Atrial Fibrillation Case Study
  • An 82-year-old man with hypertension and diabetes
    has permanent atrial fibrillation
  • He has a history of spinal stenosis and walks
    with a walker

145
Atrial Fibrillation Case Study
Question 1 Which regimen would you prescribe
for prophylaxis against thromboembolism?
  • Warfarin (INR 2.0-3.0)
  • Warfarin (INR 1.5-2.0)
  • Aspirin, 81 mg daily
  • Aspirin, 81 mg clopidogrel, 75 mg daily
  • An oral Factor Xa or direct thrombin inhibitor

146
Atrial Fibrillation Case StudyAssessment of
Thromboembolic Risk
Score (points)
Risk of Stroke (/year)
0 1.9 1 2.8 2 4.0 3 5.9
4 8.5 5 12.5 6
18.2
Van Walraven C, et al. Arch Intern Med 2003 163
936. Go A, et al. JAMA 2003 290 2685. Gage BF,
et al. Circulation 2004 110 2287.
147
Atrial Fibrillation Case Study
Question 2 What if you learn that he has tripped
and fallen twice in the past two years?
  • Warfarin (INR 2.0-3.0)
  • Warfarin (INR 1.5-2.0)
  • Aspirin, 81 mg daily
  • Aspirin, 81 mg clopidogrel, 75 mg daily
  • An oral Factor Xa or direct thrombin inhibitor

148
Atrial Fibrillation Case Study
Question 3 In this patient with a history of
tripping you would treat with
  • Warfarin (INR 2.0-3.0)
  • Warfarin (INR 1.5-2.0)
  • Dabigatran 150 mg P.O. B.I.D.
  • Aspirin, 81 mg clopidogrel, 75 mg daily
  • Rivaroxaban 20 mg PO once-daily

149
Atrial Fibrillation Case StudyAnticoagulation in
Patients at Risk of Falls
150
Atrial Fibrillation Case StudyAnticoagulation in
Patients at Risk of Falls
persons taking warfarin must fall about 295
(535/1.81) times in 1 year for warfarin not to be
the optimal therapy
151
Atrial Fibrillation Case StudyICH in Patients
with AF Prone to Falls
Hazard ratios of independent predictors of
intracranial hemorrhage
  • The risk of ICH was 2.8/year in patients at
    high risk of falls and 1.1 in other patients.
  • Warfarin was associated with an increased risk
    of mortality among those with ICH (30 day
    mortality 52 vs. 34, p 0.007).

Gage BF, et al. Am J Med 2005 118612.
152
Atrial Fibrillation Case StudyOutcomes in
Patients with AF Prone to Falls
Hazard ratio of warfarin for composite
outcomeout-of-hospital death or hospitalization
for stroke, MI, or hemorrhagein 1245 patients at
high risk for falls
Gage BF, et al. Am J Med 2005 118612.
153
Summary of Case Study
  • The risk of intracranial hemorrhage is increased
    in patients who fall.
  • The use of oral anticoagulation does not predict
    ICH, but mortality is higher among patients on
    anticoagulants who develop ICH.
  • The risk of mortality due to ICH is offset by the
    reduction in ischemic events achieved with
    anticoagulation in elderly patients with AF at
    high risk of thromboembolism.
  • Better risk-stratification instruments are needed.

154
Atrial Fibrillation Case Study
155
Atrial Fibrillation Patient Case Study
  • 85-year-old female with AF, HTN, HF, prior TIA,
    osteoarthritis and prior diverticular GIB six
    months ago, on warfarin, who presents to the ED
    with complaints of SOB for several days and black
    stools.
  • Medications atenolol, lisinopril, lasix,
    warfarin, ASA
  • Most recent INR 3 weeks ago 3.1

156
Atrial Fibrillation Case Study
  • Question 1 This patients estimated stroke
    risk per year without warfarin is
  • 5
  • 12
  • 20
  • None of the above

157
Physical Exam and Pertinent Data
Exam Afebrile, HR 110-130, BP 154/90
Lungs-bibasilar rales COR-irreg
irreg ABD-nontender Guaiac ECG AF with
rapid VR CXR Mild pulmonary edema Labs Hct21,
INR8.0, Troponin -
158
Atrial Fibrillation Case Study
  • Question 2 The most appropriate management
    strategy for this patient would be to
  • Stop both aspirin and warfarin Resume aspirin
    only in one week
  • Stop both aspirin and warfarin Resume warfain
  • Stop both aspirin and warfarin Resume both
    warfarin and aspirin in one week
  • Stop both aspirin and warfarin permanently

159
Atrial Fibrillation Case Study
  • Question 3 The patients bleeding episode
    resolves, she is started back on warfarin, and
    she returns six months later with an hematocrit
    of 35 (her baseline). Her INR is 3.7. At this
    point you would
  • Stop warfarin and put the patient on clopidogrel
    and aspirin
  • Adjust the warfarin to achieve an INR of 2.0 -
    3.0
  • Transition patient to dabigatran 150 mg PO BID
  • Transition patient to rivaroxaban 20 mg PO QD
  • Start aspirin only
  • Stop all anticoagulation

160
Atrial Fibrillation Case Study
161
Atrial Fibrillation Case Study
  • Mrs. A. is a 78-year-old woman who is taking
    warfarin for stroke prevention on the background
    of atrial fibrillation. She also takes ASA 81 mg
    daily.
  • Her risk factors for stroke include hypertension
    and type II diabetes mellitus. Her INR control
    has been erratic with values ranging from 1.5 to
    6.8.
  • For the past two weeks, she has had intermittent
    nosebleeds lasting 5 to 20 minutes. She is
    anxious to stop warfarin.

162
Atrial Fibrillation Case Study
  • Question 1 What is the best approach for this
    patient?
  • Stop the warfarin and the ASA
  • Stop the ASA, but continue warfarin
  • Perform CYP2C9 and VKORC1 genotyping to better
    identify an appropriate warfarin dose
  • Stop the warfarin and add clopidogrel 75 mg daily
  • Continue warfarin and ASA, but monitor the INR
    more frequently

163
Atrial Fibrillation Case Study
  • The ASA was stopped, but Mrs. A. still complains
    of nosebleeds.
  • Despite weekly monitoring, her INR continues to
    range from 1.8 to 4.8.
  • A calculated creatinine clearance is 45 ml/min.

164
Atrial Fibrillation Case Study
  • Question 2 What would you likely do at this
    point?
  • Continue on warfarin
  • Continue on warfarin, but add low-dose vitamin K
  • Switch from warfarin to dabigatran 150 mg BID
  • Switch from warfarin to dabigatran 75 mg BID
  • Switch from warfarin to ASA and clopidogrel
  • Switch from warfarin to rivaroxaban 20 mg QD
  • Switch from warfarin to rivaroxaban 15 mg QD

165
ATRIAL FIBRILLATION Deciphering the Maze
What Have the Trials Told Us? What Will SPAF
Look Like for Cardiologists at the Front Lines of
Clinical Practice?
New Frontiers in Atrial Fibrillation
Samuel Z. Goldhaber, MD Cardiovascular
Division Brigham and Womens Hospital Professor
of Medicine Harvard Medical School
166
Deciphering the Maze Anticoagulation Efficacy
and Safety
  • Efficacy Dabigatran, the first approved novel
    oral anticoagulant, is superior to warfarin for
    SPAF 34 reduction in stroke
  • Safety Dabigatran causes less intracerebral
    hemorrhage than warfarin 60 reduction in ICH

167
Efficacy A Driving Force for FDA Approval
  • The 150-mg dose of dabigatran was superior to
    warfarin (relative risk, 0.66 95 confidence
    interval CI, 0.53 to 0.82 Plt0.001)
  • But the 110-mg dose was not (relative risk, 0.91
    95 CI, 0.74 to 1.11 P 0.34).

168
Safety A Driving Force for FDA Approval
  • Warfarin versus dabigatran 150 mg rates of
  • Life-threatening bleeding (1.8 vs. 1.2)
  • Intracranial bleeding (0.7 vs. 0.2)
  • Major or minor bleeding (18.2 vs. 16.4)

169
Deciphering the Maze Cost-effectiveness
  • Cost Must take into account the costs of
    caring long-term for debilitated thromboembolic
    stroke patients and the costs of caring for
    intracranial hemorrhage when doing a
    cost-effectiveness analysis of dabigatran
    versus warfarin.
  • However, we continue to have mostly silo
    budgeting.

170
Drug Costs per Day Dabigatran versus Warfarin
  • Dabigatran 6.75 per day
  • Warfarin 0.75 per day (average)
  • Warfarin INR Testing 3.00 per day
  • Warfarin PharmD/RN 1.00 per day
  • Difference in Cost 2.00 per day

171
Incremental Effectiveness Dabigatran versus
Warfarin
  • Dabigatran
  • 0.5 lower annual mortality (p0.051)
  • 0.6 lower annual stroke (plt0.001)
  • 0.4 lower annual ICH (plt0.001)
  • Versus 730/year additional drug cost

172
What Happens When You Account for Cost Of
Complications (Stroke, Major Bleeding and MI)
  • Treating 200 patients with dabigatran for a year
    costs an additional 186,00 over warfarin
  • Among 200 treated patients, there is a cost
    reduction of 112,000 due to 1.12 fewer stroke
    cases with dabigatran
  • Among 200 treated patients, there is a cost
    reduction of 4,800 due to 0.6 fewer major bleeds
  • Among 200 treated patients, there is a cost
    increase of 2,800 due to 0.4 MI cases
  • The total additional cost of dabigatran
    treatment inclusive of complications in 200
    patients is 81,600
  • The cost per year of life saved assuming 6.75
    years of survival is 12,089
  • Freeman, JV et. Al., AIM, 2010, Nov 3,
    Cost-effectiveness of dabigatran vs warfarin for
    SPAF

173
What About Warfarin Compared to New Oral
Anticoagulants?
  • Warfarin Reinventing itself with rapid
    turnaround genetic testing, point of care
    testing, specialized and centralized clinics.
  • The net result is more effective and safer
    therapy. How or whether these improvements will
    change approach to new agents remains to be seen.

174
ESC AF Guidelines September, 2010
175
ESC AF Guidelines September, 2010
  • New ESC Guidelines for AF
  • OACs, such as a VKA, should be adjusted to an
    intensity range of INR 2.03.0 (target 2.5).
  • New OAC drugs DTIs and factor Xa inhibitors
    which may be viable alternatives to a VKA, may
    ultimately be considered.
  • Where oral anticoagulation is appropriate
    therapy, dabigatran may be considered, as an
    alternative to adjusted dose VKA therapy . . .
    dabigatran 150 mg b.i.d. may be considered, in
    view of the improved efficacy in the prevention
    of stroke and systemic embolism (but lower rates
    of intracranial haemorrhage and similar rates of
    major bleeding events, when compared with
    warfarin)
  • Europace (2010) 12, 13601420
    doi10.1093/europace/euq350, p. 16

176
Next Steps Information to Application
  • Hospital formulary committee evaluations
  • Reevaluate whether established AF patients meet
    the current guidelines for anticoagulation
  • Reevaluate rate vs. rhythm control
  • Determine whether to transition to dabigatran or
    continue warfarin and analyze new trials and
    data being aware of pitfalls of cross-trial
    comparisons
  • Address risk factors that predispose to AF,
    thereby preventing AF if possible
  • Deciphering the maze of risk-specific
    interventions for SPAF will challenge us for
    years to come
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