antithrombotic therapy for stroke prevention in atrial fibrillation
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Antithrombotic Antithrombotic Therapy Therapy
for for
Stroke Stroke PreventionPrevention inin
Atrial Atrial FibrillationFibrillation
““To this variety of apoplexy those are To this variety of apoplexy those are most liable who lead an idle life, who most liable who lead an idle life, who are obese, whose face and hands are are obese, whose face and hands are
constantly livid and whose pulse constantly livid and whose pulse constantly unequal.”constantly unequal.”
Wepfer, 1658Wepfer, 1658
Left Atrial Appendage (LAA)Left Atrial Appendage (LAA)Left Atrial Appendage (LAA)Left Atrial Appendage (LAA)
Thromboembolic EventsThromboembolic EventsControl Patients in AF TrialsControl Patients in AF Trials
Thromboembolic EventsThromboembolic EventsControl Patients in AF TrialsControl Patients in AF Trials
Cerebral Cerebral 49 (91%)49 (91%)
Systemic Systemic 5 (9%)5 (9%)
Severity of Ischemic StrokesSeverity of Ischemic Strokes in Atrial Fibrillation in Atrial Fibrillation
Severity of Ischemic StrokesSeverity of Ischemic Strokes in Atrial Fibrillation in Atrial Fibrillation
Fatal: Fatal: 5 (10%)5 (10%)
Moderate to Moderate to severe: severe: 23 (45%)23 (45%)
Mild: Mild: 23 (45%)23 (45%)
Number of events in 1,092 control patientsNumber of events in 1,092 control patients
Age Distribution of People With AFAge Distribution of People With AFCompared With U.S. General PopulationCompared With U.S. General Population
Age Distribution of People With AFAge Distribution of People With AFCompared With U.S. General PopulationCompared With U.S. General Population
30,00030,000
20,00020,000
10,00010,000
00
Arch Int Med. Arch Int Med. 1995;155:471.1995;155:471.
5–9
5–9
5–9
5–9
Population withPopulation withAtrial FibrillationAtrial Fibrillation
U.S. PopulationU.S. Population
500500
400400
300300
200200
100100
00
Age, yearsAge, years
U.S
. Po
pu
lati
on
(x
10
00
)U
.S. P
op
ula
tio
n (
x 1
00
0)
<5<5
10–1
4
10–1
415
–19
15–1
920
–24
20–2
425
–29
25–2
930
–34
30–3
435
–39
35–3
940
–44
40–4
450
–54
50–5
460
–64
60–6
470
–74
70–7
480
–84
80–8
490
–94
90–9
4
45–4
9
45–4
955
–59
55–5
965
–69
65–6
975
–79
75–7
985
–89
85–8
9
>95
>95
AF
Po
pu
lati
on
(x
10
)A
F P
op
ula
tio
n (
x 1
0)
Efficacy of WarfarinEfficacy of WarfarinCompared with Control in Five StudiesCompared with Control in Five Studies
AFASAKAFASAK 2727 811811
BAATAFBAATAF 1515 922922
CAFACAFA 1414 478478
SPAFSPAF 2323 508508
SPINAFSPINAF 2929 972972
Combined*Combined* 108108 36913691
No. ofNo. ofEventsEvents
Patient-Patient-yearsyears
100 50100 50 0 0 -50 -50 -100 -100
Warfarin BetterWarfarin Better Warfarin WorseWarfarin Worse
Risk Reduction, %Risk Reduction, %
*Total risk reduction for all 5*Total risk reduction for all 5 studies combined is 68%studies combined is 68%
Patients Assigned toPatients Assigned to Warfarin in AF Trials Warfarin in AF Trials
Intensity of Anticoagulation When Stroke OccurredIntensity of Anticoagulation When Stroke Occurred
AFASAKAFASAK SPAF ISPAF I BAATAFBAATAF SPINAFSPINAFCAFACAFA1.01.0
2.02.0
3.03.0
4.04.01.71.7
1.61.6
1.51.51.41.41.31.31.21.21.11.11.01.0
INRINRRatioRatio
PTPTRatioRatio
(ISI 2.4)(ISI 2.4)
ACCP recommendation: INR: 2.0–3.0ACCP recommendation: INR: 2.0–3.0
1.81.8
Target range for individual studyTarget range for individual study
Efficacy of Aspirin Compared with Efficacy of Aspirin Compared with ControlControl
AFASAKAFASAK 3535 807807
SPAFSPAF 6565 14571457
EAFTEAFT 130130 838838
CombinedCombined** 230230 31023102
No. ofNo. ofEventsEvents
Patient-Patient-yearsyears
100 50 0 -50100 50 0 -50 -100 -100
Aspirin BetterAspirin Better Aspirin WorseAspirin Worse
Risk Reduction (%)Risk Reduction (%)
*Total risk reduction for all 3 studies combined is 21%*Total risk reduction for all 3 studies combined is 21%
SPAF III StudySPAF III Study
Atrial FibrillationAtrial Fibrillation
Clinical Assessment Clinical Assessment Echocardiography (TTE)Echocardiography (TTE)
Female > 75 yearsFemale > 75 years Systolic hypertensionSystolic hypertension Impaired LV functionImpaired LV function Prior thromboembolismPrior thromboembolism
Low Risk CohortLow Risk Cohort
AspirinAspirin 325 mg/day 325 mg/day
High Risk CohortHigh Risk Cohort
WarfarinWarfarinCombinationCombination
INR 2–3INR 2–3 1–3 mg 1–3 mg Warfarin +Warfarin +Monthly INR toMonthly INR to 325 mg 325 mg AspirinAspirinadjust doseadjust dose fixed fixed
dosedose
– +
SPAF III ResultsSPAF III ResultsHigh Risk CohortHigh Risk Cohort
SPAF III ResultsSPAF III ResultsHigh Risk CohortHigh Risk Cohort
Lancet 1996; 348; 633-638.Lancet 1996; 348; 633-638.
00
11
22
33
44
55
66
77
88
Stroke orStroke orSystemic EmbolismSystemic Embolism
Major BleedingMajor Bleeding IntracranialIntracranialHemorrhageHemorrhage
Aspirin Plus Fixed-Dose WarfarinAspirin Plus Fixed-Dose WarfarinAdjusted-Dose Warfarin (INR 2-3)Adjusted-Dose Warfarin (INR 2-3)
Even
t Rat
e, %
per
Pat
ient
-yea
rEv
ent R
ate,
% p
er P
atie
nt-y
ear
SPAF III StudySPAF III Study
Atrial FibrillationAtrial Fibrillation
Clinical Assessment Clinical Assessment Echocardiography (TTE)Echocardiography (TTE)
Female > 75 yearsFemale > 75 years Systolic hypertensionSystolic hypertension Impaired LV functionImpaired LV function Prior thromboembolismPrior thromboembolism
Low Risk CohortLow Risk Cohort
AspirinAspirin 325 mg/day 325 mg/day
High Risk CohortHigh Risk Cohort
WarfarinWarfarinCombinationCombination
INR 2–3INR 2–3 1–3 mg 1–3 mg Warfarin +Warfarin +Monthly INR toMonthly INR to 325 mg 325 mg AspirinAspirinadjust doseadjust dose fixed fixed
dosedose
– +
SPAF III Non-RandomizedSPAF III Non-Randomized Aspirin-Only Arm Aspirin-Only Arm
Low Stroke Risk CohortLow Stroke Risk Cohort**
SPAF III Non-RandomizedSPAF III Non-Randomized Aspirin-Only Arm Aspirin-Only Arm
Low Stroke Risk CohortLow Stroke Risk Cohort**
% per year% per year 95% CI95% CI % per year% per year 95% CI95% CI
Stroke or syst.Stroke or syst. 1.1%1.1% (0.6%–2.0%)(0.6%–2.0%) 3.6%3.6% (2.5%–5.2%)(2.5%–5.2%) embolismembolism
No History of Hypertension History of HypertensionNo History of Hypertension History of Hypertension
*Patients enrolled had none of these high risk features: female >75 *Patients enrolled had none of these high risk features: female >75 years, impaired LV function, current SBP >160 mm Hg, years, impaired LV function, current SBP >160 mm Hg,
prior thromboembolismprior thromboembolism
Risk Factors for Stroke and Risk Factors for Stroke and Efficacy of Efficacy of
Antithrombotic Therapy Antithrombotic Therapy in Atrial Fibrillationin Atrial Fibrillation
Archives of Internal MedicineArchives of Internal MedicineJuly 11, 1994July 11, 1994
Predicting Stroke Risk in AF—Who Predicting Stroke Risk in AF—Who Benefits Most?Benefits Most?
Multivariate Analysis of Pooled DataMultivariate Analysis of Pooled Data
Clinical risk factorsClinical risk factors Relative riskRelative risk
Previous stroke or TIAPrevious stroke or TIA 2.5 x2.5 x
History of hypertensionHistory of hypertension 1.6 x1.6 x
DiabetesDiabetes 1.7 x1.7 x
Increasing age (per decade)Increasing age (per decade)1.4 x1.4 x
Transthoracic Echocardiographic Transthoracic Echocardiographic Predictors of Stroke in Patients with AFPredictors of Stroke in Patients with AF
Transthoracic Echocardiographic Transthoracic Echocardiographic Predictors of Stroke in Patients with AFPredictors of Stroke in Patients with AF
Atrial Fibrillation InvestigatorsAtrial Fibrillation Investigators
Combined databases from 3 randomized trials Combined databases from 3 randomized trials (N=1,066)(N=1,066)
Moderate to severe LV dysfunction was the only Moderate to severe LV dysfunction was the only independent predictor of stroke (RR 2.5, p<0.001)independent predictor of stroke (RR 2.5, p<0.001)
Left atrial size did not predict stroke riskLeft atrial size did not predict stroke risk
Atrial Fibrillation Follow-up Atrial Fibrillation Follow-up Investigation of Rhythm ManagementInvestigation of Rhythm Management
AFFIRMAFFIRM
Atrial Fibrillation Follow-up Atrial Fibrillation Follow-up Investigation of Rhythm ManagementInvestigation of Rhythm Management
AFFIRMAFFIRM
Multicenter, randomized clinical trialMulticenter, randomized clinical trial
NHLBI-NIH supportedNHLBI-NIH supported
Patients with AF at high risk of stroke Patients with AF at high risk of stroke or deathor death
Randomized to either rate-control or rhythm-Randomized to either rate-control or rhythm-control strategycontrol strategy
Primary endpoint: all-cause mortalityPrimary endpoint: all-cause mortality
The AFFIRM Investigators. The AFFIRM Investigators. N Engl J MedN Engl J Med. 2002;347:1825-1833.. 2002;347:1825-1833.
AFFIRMAFFIRM Stroke EventsStroke Events
AFFIRMAFFIRM Stroke EventsStroke Events
0
1
2
3
4
5
6
7
8
9
Ischemicstroke
ICH SDH/SAH All stroke
Rate Rhythm
5.55.5
7.17.1
1.11.1 1.31.30.80.8 0.80.8
7.47.4
8.98.9PP=.79=.79
PP=.73=.73PP=.68=.68
PP=.93=.93
The AFFIRM Investigators. The AFFIRM Investigators. N Engl J MedN Engl J Med. 2002;347:1825-1833.. 2002;347:1825-1833.
Pe
rce
nt
Pe
rce
nt
7th ACCP 7th ACCP Consensus Consensus
Conference on Conference on Antithrombotic Antithrombotic
TherapyTherapyCHEST Supplement: 2004CHEST Supplement: 2004
ACCP Recommendations 2004ACCP Recommendations 2004Risk Factors for StrokeRisk Factors for Stroke
ACCP Recommendations 2004ACCP Recommendations 2004Risk Factors for StrokeRisk Factors for Stroke
Prior stroke, TIA, systemic embolismPrior stroke, TIA, systemic embolism
HypertensionHypertension
Moderate or severely impaired LV Moderate or severely impaired LV systolic function and / or CHFsystolic function and / or CHF
Age >75 yearsAge >75 years
Rheumatic mitral valve diseaseRheumatic mitral valve disease
Prosthetic heart valvesProsthetic heart valves
Diabetes mellitusDiabetes mellitus
Age 65-75Age 65-75Moderate RiskModerate Risk
High RiskHigh Risk
ACCP 2004 Recommendations for ACCP 2004 Recommendations for Stroke Prevention in Atrial Fibrillation*Stroke Prevention in Atrial Fibrillation*
ACCP 2004 Recommendations for ACCP 2004 Recommendations for Stroke Prevention in Atrial Fibrillation*Stroke Prevention in Atrial Fibrillation*
Risk FactorsRisk Factors Recommended TherapyRecommended Therapy
Any High Risk Factor WarfarinAny High Risk Factor Warfarin (target INR 2.5, range 2.0-3.0)**(target INR 2.5, range 2.0-3.0)**
Age 65-75 years and Aspirin 325 mg qdAge 65-75 years and Aspirin 325 mg qd No high risk factors or WarfarinNo high risk factors or Warfarin
(target INR 2.5, range 2.0-3.0)**(target INR 2.5, range 2.0-3.0)**
No Risk Factors and age < 65 Aspirin 325 mg qdNo Risk Factors and age < 65 Aspirin 325 mg qd
*Applies to persistent (sustained or permanent) and paroxysmal (intermittent) AF*Applies to persistent (sustained or permanent) and paroxysmal (intermittent) AF
**target INR > 2.5 for patients with mechanical heart valves**target INR > 2.5 for patients with mechanical heart valves
ACCP Recommendations 2004ACCP Recommendations 2004
CardioversionCardioversion
ACCP Recommendations 2004ACCP Recommendations 2004
CardioversionCardioversion
Continuation of anticoagulation beyond 4 Continuation of anticoagulation beyond 4 weeks after successful pharmacological or weeks after successful pharmacological or electrical cardioversion is based on whether electrical cardioversion is based on whether the patient has experienced more than 1 the patient has experienced more than 1 episode of AF and on their risk factor status.episode of AF and on their risk factor status.
Patients experiencing more than 1 episode of Patients experiencing more than 1 episode of AF should be considered as having AF should be considered as having paroxysmal AF paroxysmal AF
0
20
40
60
80
Warfarin for Atrial FibrillationWarfarin for Atrial FibrillationLimitations Lead to Under-treatmentLimitations Lead to Under-treatmentWarfarin for Atrial FibrillationWarfarin for Atrial FibrillationLimitations Lead to Under-treatmentLimitations Lead to Under-treatment
<55<55 55-6455-64 65-7465-74 75-8475-84 8585
44%44%
58%58%61%61%
57%57%
35%35%
Age (years)Age (years)
Wa
rfa
rin
Us
e in
Wa
rfa
rin
Us
e in
Elig
ible
Pat
ien
ts (
%)
Elig
ible
Pat
ien
ts (
%) 55% 55%
Overall Overall UseUse
Go A et al. Go A et al. Ann Intern MedAnn Intern Med 1999;131:927. 1999;131:927.
Warfarin for Atrial FibrillationWarfarin for Atrial Fibrillation Limitations Lead to Inadequate TreatmentLimitations Lead to Inadequate Treatment
Warfarin for Atrial FibrillationWarfarin for Atrial Fibrillation Limitations Lead to Inadequate TreatmentLimitations Lead to Inadequate Treatment
Samsa GP, et al. Arch Intern Med 2000;160:967.
INR above targetINR above target6%6%
Subtherapeutic INR Subtherapeutic INR 13%13%
INR inINR intarget rangetarget range
15%15%
No No warfarinwarfarin
65%65%
Adequacy of Anticoagulation inAdequacy of Anticoagulation inPatients with AF in Primary Care PracticePatients with AF in Primary Care Practice
XimelagatranXimelagatranOral Direct Thrombin InhibitorOral Direct Thrombin Inhibitor
XimelagatranXimelagatranOral Direct Thrombin InhibitorOral Direct Thrombin Inhibitor
Prompt onset and offset of anticoagulationPrompt onset and offset of anticoagulation
Wider Wider therapeutic margin than warfarintherapeutic margin than warfarin
Predictable pharmacokineticsPredictable pharmacokinetics
Low potential for food and drug interactionsLow potential for food and drug interactions
No dose adjustmentNo dose adjustment
No coagulation monitoringNo coagulation monitoring
Sarich TC, et al. Sarich TC, et al. J Am Coll CardiolJ Am Coll Cardiol 2003;41:557. 2003;41:557.Eriksson H, et al. Eriksson H, et al. Drug Metab DispDrug Metab Disp 2003;31:294. 2003;31:294.
SStroke troke PPrevention Using anrevention Using anORORal Direct al Direct TThrombin hrombin IInhibitor in nhibitor in AAtrial trial
FFibrillationibrillationThe SPORTIF III and V TrialsThe SPORTIF III and V Trials
SStroke troke PPrevention Using anrevention Using anORORal Direct al Direct TThrombin hrombin IInhibitor in nhibitor in AAtrial trial
FFibrillationibrillationThe SPORTIF III and V TrialsThe SPORTIF III and V Trials
Fixed-doseFixed-doseXimelagatranXimelagatran(36 mg bid)(36 mg bid)
Adjusted-doseAdjusted-doseWarfarinWarfarin(INR 2-3)(INR 2-3)
Patients with Nonvalvular AFPatients with Nonvalvular AFand Risk Factors for Strokeand Risk Factors for Stroke
n=7,320 n=7,320
SPORTIF IIISPORTIF III 23 nations23 nations open-label open-label ((nn=3,407)=3,407)
SPORTIF VSPORTIF V US, CanadaUS, Canada double-blinddouble-blind ((nn=3,913)=3,913)
SPORTIF ProgramSPORTIF ProgramPrimary AnalysesPrimary Analyses
Intention-to-treat AnalysisIntention-to-treat Analysis
SPORTIF ProgramSPORTIF ProgramPrimary AnalysesPrimary Analyses
Intention-to-treat AnalysisIntention-to-treat Analysis
Difference in Absolute Event Rates(Ximelagatran – Warfarin)
Ximelagatran Better Warfarin Better
-1-1 00 11 22
SPORTIF IIISPORTIF IIISPORTIF IIISPORTIF III
SPORTIF VSPORTIF VSPORTIF VSPORTIF V
-0.66-0.66
+0.45+0.45
pp=0.10=0.10
pp=0.13=0.13
PooledPooledPooledPooled-0.03-0.03
pp=0.94=0.94
33 44-2-2-3-3-4-4
SPORTIF VSPORTIF VHemorrhageHemorrhage
SPORTIF VSPORTIF VHemorrhageHemorrhage
3.1%
47%
0.1% 0.1% 2.4%
37%
0
10
20
30
40
50
ICH Major Bleeding Major + MinorBleeding
Warfarin
Ximelagatran
Ev
ent
Ra
te (
% /y
ea
r)E
ven
t R
ate
(%
/ye
ar)
pp<0.0001 <0.0001
p=p=0.160.16p=p=NSNS
SPORTIF VSPORTIF VLiver Enzyme ElevationLiver Enzyme Elevation
ALT >3 x ULNALT >3 x ULN
SPORTIF VSPORTIF VLiver Enzyme ElevationLiver Enzyme Elevation
ALT >3 x ULNALT >3 x ULN
0
10
20
30
40
50
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
MonthsMonths
Nu
mb
er o
f P
atie
nts
Ximelagatran
Warfarin
Inci
den
ce (
%)
Inci
den
ce (
%)
ALT >3x ALT >3x ULNULN
pp<0.001<0.001
0.8%
6.0%
0
2
4
6
8
10
12
14 Warfarin
Ximelagatran
ConclusionsConclusionsConclusionsConclusions
Fixed oral dosing without coagulation monitoringFixed oral dosing without coagulation monitoring
Effectiveness non-inferior to well-controlled warfarin in Effectiveness non-inferior to well-controlled warfarin in preventing stroke and systemic embolic eventspreventing stroke and systemic embolic events
Less bleeding than warfarinLess bleeding than warfarin
Elevated liver enzymes in ~6% of patientsElevated liver enzymes in ~6% of patients
A promising treatment option for prevention of A promising treatment option for prevention of thromboembolismthromboembolism
In high-risk patients with atrial fibrillation, In high-risk patients with atrial fibrillation, ximelagatran offers:ximelagatran offers:
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