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I nuovi anticoagulanti orali ed il dilemma delle copatologie. Bruno Trimarco Dipartimento di Scienze Biomediche Avanzate Università degli Studi di Napoli “Federico II”. New Oral Anticoagulants. Pathophysiology of thrombosis in heart failure. Adapted from Weitz J. J Thromb Haemost 2005. - PowerPoint PPT Presentation
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I nuovi anticoagulanti orali ed il dilemma delle copatologie
Bruno Trimarco
Dipartimento di Scienze Biomediche Avanzate
Università degli Studi di Napoli “Federico II”
Pathophysiology of thrombosis in heart failure.
Adapted from Weitz J. J Thromb Haemost 2005
New Oral Anticoagulants
DIVISION OF CARDIOLOGY - UNIVERSITY OF NAPLES
-New Oral Anticoagulants--New Oral Anticoagulants-An OverviewAn Overview
-New Oral Anticoagulants--New Oral Anticoagulants-An OverviewAn Overview
Adapted from Piccini et al. Curr Opin Cardiol 2010
-New Oral Anticoagulants--New Oral Anticoagulants-
Stroke and Systemic emboliStroke and Systemic emboli
-New Oral Anticoagulants--New Oral Anticoagulants-
Stroke and Systemic emboliStroke and Systemic emboli
-New Oral Anticoagulants--New Oral Anticoagulants-
Intracranial HemorrhageIntracranial Hemorrhage
-New Oral Anticoagulants--New Oral Anticoagulants-
Intracranial HemorrhageIntracranial Hemorrhage
Rivaroxaban Warfarin
Primary Endpoint: Stroke or non-CNS Systemic Embolism
INR target - 2.5 (2.0-3.0 inclusive)
20 mg daily15 mg for Cr Cl 30-49 ml/min
Atrial Fibrillation
RandomizedDouble Blind / Double Dummy
(n ~ 14,000)
Monthly MonitoringAdherence to standard of care guidelines
Study Design
* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%
Risk FactorsStroke, TIA or Systemic embolusOR• CHF • Hypertension • Age 75 • Diabetes
At least 2 or 3 required*
Pathophysiology of thrombosis in heart failure.
Lip G Y et al. Eur J Heart Fail 2012;14:681-695
Pathophysiology of thrombosis in heart failure
Anticoagulants in heart failure The beginning
Anticoagulants in heart failure in the New Millennium
Methods - Definitions
HF was defined as a history of HF or left ventricular ejection fraction (LVEF) <40%
Pre-specified secondary HF sub-group analyses LVEF ≥40% vs. <40% New York Heart Association (NHYA) class CHADS2 score
Implantable cardioverter defibrillator (ICD) or biventricular-ICD (BiV-ICD)
Methods - Outcomes
Efficacy endpoints (intention-to-treat population)
Primary: Stroke or systemic embolism Secondary
– All-cause death– Stroke, systemic embolism, or vascular death
Safety endpoints (safety population)
Primary : Major or non-major clinically relevant (NMCR) bleeding
Secondary– Intracranial hemorrhage (ICH)– Hemorrhagic stroke
*All outcomes reported as adjusted hazard ratios (HR) per 100 patient-years (pt-yrs)
Results – HF vs. No HF 9033 (63.7%) of patients were defined as having HF
Selected Baseline VariablesSelected Baseline VariablesPatients with HFPatients with HF
(n=9033)(n=9033)
Patients without HFPatients without HF
(n=5138)(n=5138)
Age 72 74
Female 39.1% 40.3%
Persistent AF 83.0% 77.6%
Previous embolic event 3.8% 4.0%
CHADS2 score 3.7 3.1
LVEF <40% 33.9% Excluded
Hypertension 93.0% 86.1%
Diabetes mellitus 42.4% 35.4%
Previous and concurrent medications
Concurrent ASA use 31.0% 25.2%
Beta-blocker 69.6% 56.4%
Digitalis 44.9% 27.2%
ACE inhibitor 60.9% 42.0%
Diuretics 70.9% 39.6%
OutcomesHF
No HF
HF vs. No HFHR (95% CI)
p value
Efficacy Outcomes Stroke or systemic embolization 1.99 2.32 0.94 (0.78, 1.13) 0.51
Stroke, systemic embolization, or vascular death
5.00 3.50 1.28 (1.11, 1.47) <0.01
Stroke 1.84 2.16 0.95 (0.78, 1.15) 0.57Systemic embolization 0.17 0.17 0.93 (0.48, 1.82) 0.84
All-cause death 5.26 3.37 1.34 (1.17, 1.55) <0.01Vascular death 3.53 1.75 1.65 (1.37, 1.98) <0.01
Myocardial infarction 1.15 0.71 1.20 (0.89, 1.63) 0.23
Results - HF vs. No HF
Safety Outcomes Major or NMCR bleeding 14.12 15.73 1.00 (0.92, 1.08) 0.99
Hemorrhagic stroke 0.29 0.45 0.73 (0.45, 1.20) 0.22Intracranial hemorrhage 0.53 0.77 0.84 (0.58, 1.22) 0.36
Results – HF Status and Treatment Assignment
Selected Variables
Heart Failure No Heart Failure
Rivaroxaban(N=4530)
Warfarin(N=4503)
Rivaroxaban(N=2551)
Warfarin(N=2587)
Age 72 72 74 74
Female 39.1% 39.1% 40.3% 40.3%
Persistent AF 83.6% 82.3% 77.0% 78.2%
Previous embolic event 3.7% 4.0% 4.1% 3.8%
CHADS2 score 3.7 3.7 3.2 3.1
LVEF <40% 33.3% 34.5% N/A N/A
NYHA Class III/IV 30.0% 29.9% N/A N/A
ICD or BiV-ICD 3.6% 3.7% 0.4% 0.3%
Hypertension 92.8% 93.3% 85.7% 86.4%
Diabetes mellitus 42.3% 42.5% 36.7% 34.2%
Previous and concurrent medications
Concurrent ASA use 30.3% 31.7% 25.8% 24.7%
Beta-blocker 68.7% 70.5% 56.8% 56.0%
Digitalis 44.7% 45.2% 27.4% 27.1%
ACE inhibitor 61.6% 60.1% 41.5% 42.5%
Diuretics 71.4% 70.4% 39.4% 39.9%
Results – HF Subgroups
HF Subgroup
Stroke or non-CNS embolism
Rivaroxaban WarfarinRivaroxaban vs. Warfarin
HR (95% CI)p-value
LVEF
≥40% 2.00 2.06 0.98 (0.74, 1.31) 0.38
<40% 1.34 1.87 0.72 (0.46, 1.12)
NYHA Class
I or II 1.90 2.02 0.94 (0.73, 1.22) 0.68
III or IV 1.88 2.10 0.90 (0.61, 1.32)
Device Therapy
No Device 1.96 2.08 0.94 (0.75, 1.18) 0.11
ICD or BiV-ICD 0.33 1.96 0.17 (0.02, 1.39)
CHADS2 Score
2 1.30 1.16 1.09 (0.44, 2.69) 0.48
≥3 1.96 2.18 0.90 (0.72, 1.12)
Results – Heart Failure Subgroups
Heart Failure Subgroup
Major or Non-Major Clinically Relevant Bleeding
Rivaroxaban WarfarinRivaroxaban vs. Warfarin
HR (95% CI) p-value
Ejection Fraction
≥ 40% 14.18 14.81 1.00 (0.88, 1.13) 0.051
< 40% 15.34 14.10 1.15 (0.96, 1.36)
NYHA Class
I or II 14.83 14.15 1.08 (0.97, 1.21) 0.19
III or IV 12.45 13.54 0.96 (0.80, 1.15)
Device therapy
No Device 13.08 13.72 0.99 (0.89, 1.09) 0.002
ICD or BiV-ICD 32.43 16.37 2.00 (1.31, 3.05)
CHADS2 score
2 15.96 10.02 1.54 (1.10, 2.16) 0.15
≥3 14.06 14.42 1.02 (0.92, 1.12)
Available now online from European Heart Journal
http://eurheartj.oxfordjournals.org/cgi/content/full/ehr342
ASA, acetylsalicylic acid; IQR, interquartile range; VKA, vitamin K antagonistSafety population (minus 9 pts in warfarin arm with no CrCl data)
Baseline demographics
Characteristic
CrCl 30–49 ml/min CrCl ≥50 ml/min
Rivaroxaban 15 mg od(N=1474)
Warfarin(N=1476)
Rivaroxaban 20 mg od(N=5637)
Warfarin(N=5640)
Age, median (IQR), yrs 79 (75–82) 79 (75–83) 71 (63–76) 71 (63–76)
Female (%) 55.0 55.9 35.6 35.4
BMI, median (IQR),kg/m2 25.1 (22.7–28.0) 25.2 (22.8–27.9) 29.2 (26.1–33.0) 28.9 (26.0–32.7)
SBP, median (IQR),mm Hg 130 (120–140) 130 (120–140) 130 (120–140) 130 (120–140)
Paroxysmal AF (%) 16.6 14.6 17.7 18.7
Prior ASA use (%) 35.9 37.4 36.4 36.5
Prior VKA use (%) 62.7 61.3 62.2 62.9
Baseline demographics (continued)
Characteristic
CrCl 30–49 ml/min CrCl ≥50 ml/min
Rivaroxaban 15 mg od(N=1474)
Warfarin(N=1476)
Rivaroxaban 20 mg od(N=5637)
Warfarin(N=5640)
CHADS2 score(mean ± SD) 3.68 ± 1.00 3.67 ± 1.01 3.42 ± 0.91 3.41 ± 0.92
Prior stroke/TIA orsystemic embolism (%) 50.1 49.1 56.2 56.0
Congestive heart failure (%) 66.0 65.3 61.8 61.5
Hypertension (%) 91.7 92.1 89.9 90.4
Diabetes mellitus (%) 31.8 33.3 42.6 41.1
Prior myocardialinfarction (%) 18.7 20.5 16.0 17.3
SD, standard deviation; TIA, transient ischaemic attackSafety population (minus 9 pts in warfarin arm with no CrCl data)
ROCKET AF: stroke or non-CNS embolism among patients with CrCl 30–49 ml/min
0
1
2
3
4
5
6
7
8
0 120 240 360 480 600 720 840
Cu
mu
lati
ve e
ven
t ra
te (
%)
Warfarin
Rivaroxaban
HR (95% CI): 0.84 (0.57, 1.23)
Days since randomizationNo. at risk:Rivaroxaban 1,434 1,226 1,103 1,027 806 621 442 275Warfarin 1,439 1,261 1,140 1,052 832 656 455 272
Event rates are % per year; Based on Protocol Compliant on Treatment Population
Fox KA et al. Eur Heart J 2011; 32 (19): 2387-2394
ROCKET AF: Primary efficacy endpoint: stroke or non-CNS embolism patients with CrCl 30–49 ml/min vs. ROCKET AF overall
1 Fox KA et al. Eur Heart J 2011; 32 (19): 2387-2394; 2 Patel MR et al. N Engl J Med 2011;365:883–8911 Fox KA et al. Eur Heart J 2011; 32 (19): 2387-2394; 2 Patel MR et al. N Engl J Med 2011;365:883–891
Days since randomization
0 120 240 480 600 7200
1
2
3
4
5
6
840360
Cu
mu
lati
ve e
ven
t ra
te (
%)
* among patients with CrCl 30-49 ml/min:HR 0.84 (95% CI: 0.57-1.23)
** HR 0.79 (95% CI: 0.66-0.96) p<0.001 (non-inferiority)
Warfarin, overall**,2Warfarin, overall**,2
Warfarin, renally impaired*,1Warfarin, renally impaired*,1
Rivaroxaban overall**,2Rivaroxaban overall**,2
Rivaroxaban renally impaired*,1Rivaroxaban renally impaired*,1
Per-protocol population on-treatment
Safety outcomes
Clinical endpoint(% per year)
Rivaroxaban(N=7111)
Warfarin(N=7116)
HR (95% CI)Rivaroxabanvs warfarin
P(interaction)
Principal safety outcome*
14.2417.82
13.6718.28
1.04 (0.96–1.13)0.98 (0.84–1.14)
0.45
Major bleeding3.394.49
3.174.70
1.07 (0.91–1.26)0.95 (0.72–1.26)
0.48
Hct or Hb drop2.543.76
2.033.28
1.25 (1.03–1.52)1.14 (0.83–1.58)
0.65
Transfusion1.492.34
1.162.00
1.28 (0.99–1.65)1.17 (0.77–1.76)
0.71
Critical organ0.830.76
1.131.39
0.74 (0.55–0.99)0.55 (0.30–1.00)
0.39
Fatal bleeding0.230.28
0.430.74
0.55 (0.32–0.93)0.39 (0.15–0.99)
0.53
Intracranial haemorrhage
0.440.71
0.710.88
0.62 (0.42–0.92)0.81 (0.41–1.60)
0.51
Based on safety population on treatment*Composite of major plus non-major clinically relevant bleeding. †Rivaroxaban 20 mg od. ‡Rivaroxaban 15 mg od
0.01 0.1 1 10
CrCl ≥50 ml/min†
CrCl 30–49 ml/min‡
Bleeding sites
Major bleeding(% per year)
CrCl 30–49 ml/min CrCl ≥50 ml/min
Rivaroxaban15 mg
(N = 1474)
Warfarin(N=1476)
Rivaroxaban20 mg
(N=5637)
Warfarin(N=5640)
GI (upper, lower, and rectal)† 2.88 1.77 1.79 1.12
Intracranial haemorrhage‡ 0.71 0.88 0.44 0.71
Macroscopic haematuria 0.05 0.18 0.28 0.19
Bleeding associated with non-cardiac surgery 0.24 0.42 0.15 0.19
Intra-articular 0.00 0.23 0.18 0.17
Epistaxis 0.19 0.09 0.10 0.13
† p=0.02 (riva vs. warf in CrCl 30–49 ml/min); p=0.0002 (riva vs. warf in CrCl ≥50 ml/min)‡ p=0.02 (riva vs. warf in CrCl ≥50 ml/min)
Secondary prevention cohortkey demographics
Rivaroxaban Warfarin
With prior stroke* (N=3,754)
Without prior stroke* (N=3,377)
With prior stroke* (N=3,714)
Without prior stroke* (N=3,419)
Age (years)# 69.7±9.46 72.9±9.15 69.7±9.33 72.8±9.20
TTR Median (IQR) 57.1 (42.6–70.1) 58.6 (43.6–71.0)
CHADS2 score# 3.93±0.91 2.97±0.66 3.93±0.93 2.96±0.67
Prior medications
ASA 37.5% 34.9% 37.7% 35.7%
Vitamin K antagonists 59.2% 65.8% 59.4% 65.9%
Clinical risk factors
Hypertension 84.8% 96.3% 85.1% 97.0%
Congestive heart failure 50.7% 75.9% 50.6% 74.9%
Diabetes 24.6% 57.9% 23.8% 56.5%
Myocardial infarction 14.3% 19.1% 16.0% 20.2%
*‘Prior stroke’ includes TIA, ischaemic stroke, stroke of unknown type, and haemorrhagic stroke. #Mean±SD. IQR, interquartile range; TTR, time in therapeutic INR range *‘Prior stroke’ includes TIA, ischaemic stroke, stroke of unknown type, and haemorrhagic stroke. #Mean±SD. IQR, interquartile range; TTR, time in therapeutic INR range
Results: Primary efficacy endpoint
Per protocol population, on-treatment
Kaplan–Meier survival curve showing time to the primary endpoint (stroke or systemic embolism)
Months from randomizationMonths from randomization
Cu
mu
lati
ve e
ven
t ra
te –
str
oke
or
syst
emic
em
bo
lism
(%
)C
um
ula
tive
eve
nt
rate
– s
tro
ke o
r sy
stem
ic e
mb
olis
m (
%)
00
11
22
33
00
44
55
66
77
No prior stroke/TIA, warfarinNo prior stroke/TIA, warfarin
3030
Prior stroke/TIA, warfarinPrior stroke/TIA, warfarin
66 1212 1818 2424
No prior stroke/TIA, rivaroxabanNo prior stroke/TIA, rivaroxaban
Prior stroke/TIA, rivaroxabanPrior stroke/TIA, rivaroxaban
Rivaroxaban
Events/100 pt-yrs
Warfarin
Events/100 pt-yrsInteraction p-
value
Stroke or systemic embolism
1.09
2.26
1.69
2.600.15
Any stroke1.06
2.21
1.53
2.370.16
Haemorrhagic stroke0.17
0.35
0.41
0.470.22
Ischaemic or unknown stroke
0.89
1.86
1.11
1.920.41
Disabling or fatal stroke0.45
1.15
0.88
1.310.07
Non-CNS systemic embolism
0.04
0.05
0.16
0.230.99
Any cause death2.00
1.74
2.35
2.070.94
Vascular death1.61
1.44
1.70
1.710.60
Results: Efficacy analysis
Per protocol population, on-treatmentNo prior stroke or TIAPrior stroke or TIA
Rivaroxaban
Events/100 pt-yrs
Warfarin
Events/100 pt-yrsInteraction p-
value
Major and non-major clinically relevant bleeding†
16.6913.31
15.1913.87
0.0800
Major bleeding4.103.13
3.693.22
0.3598
Haemoglobin/ Haematocrit drop3.422.16
2.532.00
0.1924
Transfusion2.281.06
1.531.12
0.0488
Gastrointestinal major bleeding0.690.21
0.390.17
0.4600
Critical organbleeding
0.611.01
1.191.17
0.0625
ICH 0.390.59
0.680.80
0.4656
Fatal bleeding 0.220.26
0.480.49
0.7419
Non-major clinically relevant bleeding
12.9310.78
11.7810.98
0.1995
Results: Principal safety outcome
Safety population, on-treatment†Principal safety outcome
No prior stroke or TIAPrior stroke or TIA
ROCKET AF – subanalysis elderly patients - Rationale To determine the efficacy and safety of rivaroxaban To determine the efficacy and safety of rivaroxaban
compared with warfarin among elderly patients (compared with warfarin among elderly patients (>>75 years 75 years old) with AF old) with AF compared with patients <75 years
6,229 patients were ≥75 years6,229 patients were ≥75 years Mean CHADSMean CHADS22 3.7 vs 3.3 3.7 vs 3.3
Female 46% vs. 35%Female 46% vs. 35%
Prior stroke/TIA 42% vs 65%Prior stroke/TIA 42% vs 65%
Halperin JL et al. presented at AHA 2012
Rivaroxaban better
Warfarin better
<75
≥75
Stroke/SE(n=14.171)
Rivaroxaban better
Warfarin better
Major Bleeding(n=14.236)
ROCKET AF - subanalysis elderly patients - Results
HR 0.95 (0.76-1.19)
HR 0.80 (0.63-1.02)p*=0.31
HR 0.96 (0.78-1.19)
HR 1.11 (0.92-1.34)p*=0.34
* p-value for interaction
Halperin JL et al. presented at AHA 2012
ROCKET AF - subanalysis elderly patients - Results
%/year
Age ≥ 75 years Age < 75 years
p-value*
RN=3082
WN=3082 HR (95% CI)
RN=3999
WN=4088 HR (95% CI)
Stroke/SE1 2.29 2.85 0.80 (0.63-1.02) 2.00 2.10 0.95 (0.76-1.19) 0.31
Fatal/disabling stroke1
1.14 1.50 0.76 (0.55-1.06) 0.90 1.09 0.83 (0.60-1.15) 0.72
Mortality2 2.08 2.49 0.84 (0.64-1.07) 1.71 2.01 0.85 (0.66-1.09) 0.93
Major bleeding3
4.86 4.40 1.11 (0.92-1.34) 2.69 2.79 0.964 (0.78-1.19)
0.34
ICH3 0.66 0.83 0.80 (0.499-1.282)
0.37 0.68 0.54 (0.33-0.89) 0.27
CRNMB3 15.61 13.54 1.15 (1.03-1.23) 9.22 9.87 0.94 (0.83-1.05) 0.01
Halperin JL et al. presented at AHA 2012
R=rivaroxaban; W=warfarin; *p-value for interaction; ICH=intracerebral haemorrhage; CRNMB=clinically relevant non-major bleeding1ITT population, 2 safety population excluding a GCP violating site, 3safety population
ROCKET AF - subanalysis elderly patients - Results
%/year
Age ≥ 75 years Age < 75 years
p-value*
RN=3082
WN=3082 HR (95% CI)
RN=3999
WN=4088 HR (95% CI)
Stroke/SE1 2.29 2.85 0.80 (0.63-1.02) 2.00 2.10 0.95 (0.76-1.19) 0.31
Fatal/disabling stroke1
1.14 1.50 0.76 (0.55-1.06) 0.90 1.09 0.83 (0.60-1.15) 0.72
Mortality2 2.08 2.49 0.84 (0.64-1.07) 1.71 2.01 0.85 (0.66-1.09) 0.93
Major bleeding3
4.86 4.40 1.11 (0.92-1.34) 2.69 2.79 0.964 (0.78-1.19)
0.34
ICH3 0.66 0.83 0.80 (0.499-1.282)
0.37 0.68 0.54 (0.33-0.89) 0.27
CRNMB3 15.61 13.54 1.15 (1.03-1.23) 9.22 9.87 0.94 (0.83-1.05) 0.01
Halperin JL et al. presented at AHA 2012
R=rivaroxaban; W=warfarin; *p-value for interaction; ICH=intracerebral haemorrhage; CRNMB=clinically relevant non-major bleeding1ITT population, 2 safety population excluding a GCP violating site, 3safety population