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
-New Oral AnticoagulantsAn Overview
Adapted from Piccini et al. Curr Opin Cardiol
2010
DIVISION OF CARDIOLOGY - UNIVERSITY OF NAPLES
-New Oral AnticoagulantsStroke and Systemic emboli
-New Oral AnticoagulantsIntracranial Hemorrhage
Risk Factors
Stroke, TIA or
Systemic embolus
OR
Study Design
Atrial Fibrillation
Rivaroxaban
20 mg daily
15 mg for Cr Cl 30-49 ml/min
Randomized
Double Blind /
Double Dummy
(n ~ 14,000)
• CHF
• Hypertension
• Age  75
• Diabetes
Warfarin
INR target - 2.5
(2.0-3.0 inclusive)
Monthly Monitoring
Adherence to standard of care guidelines
Primary Endpoint: Stroke or non-CNS Systemic Embolism
* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%
At least 2 or
3 required*
Pathophysiology of thrombosis in heart
failure
Pathophysiology of thrombosis in heart failure.
Lip G Y et al. Eur J Heart Fail
2012;14:681-695
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 (BiVICD)
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
Patients with HF
Patients without HF
(n=9033)
(n=5138)
72
74
Female
39.1%
40.3%
Persistent AF
83.0%
77.6%
Previous embolic event
3.8%
4.0%
3.7
3.1
LVEF <40%
33.9%
Excluded
Hypertension
93.0%
86.1%
Diabetes mellitus
42.4%
35.4%
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%
Selected Baseline Variables
Age
CHADS2 score
Previous and concurrent medications
Results - HF vs. No HF
Outcomes
Efficacy Outcomes
Stroke or systemic embolization
Stroke, systemic embolization, or
vascular death
Stroke
Systemic embolization
All-cause death
Vascular death
Myocardial infarction
Safety Outcomes
Major or NMCR bleeding
Hemorrhagic stroke
Intracranial hemorrhage
HF
No HF
HF vs. No HF
HR (95% CI)
p value
1.99
5.00
2.32
3.50
0.94 (0.78, 1.13)
1.28 (1.11, 1.47)
0.51
<0.01
1.84
0.17
5.26
3.53
1.15
2.16
0.17
3.37
1.75
0.71
0.95 (0.78, 1.15)
0.93 (0.48, 1.82)
1.34 (1.17, 1.55)
1.65 (1.37, 1.98)
1.20 (0.89, 1.63)
0.57
0.84
<0.01
<0.01
0.23
14.12
0.29
0.53
15.73
0.45
0.77
1.00 (0.92, 1.08)
0.73 (0.45, 1.20)
0.84 (0.58, 1.22)
0.99
0.22
0.36
Results – HF Status and Treatment Assignment
Heart Failure
Selected Variables
Age
Female
Persistent AF
Previous embolic event
CHADS2 score
LVEF <40%
NYHA Class III/IV
ICD or BiV-ICD
Hypertension
Diabetes mellitus
Previous and concurrent medications
Concurrent ASA use
Beta-blocker
Digitalis
ACE inhibitor
Diuretics
No Heart Failure
Rivaroxaban
(N=4530)
Warfarin
(N=4503)
Rivaroxaban
(N=2551)
Warfarin
(N=2587)
72
39.1%
83.6%
3.7%
3.7
33.3%
30.0%
3.6%
92.8%
42.3%
72
39.1%
82.3%
4.0%
3.7
34.5%
29.9%
3.7%
93.3%
42.5%
74
40.3%
77.0%
4.1%
3.2
N/A
N/A
0.4%
85.7%
36.7%
74
40.3%
78.2%
3.8%
3.1
N/A
N/A
0.3%
86.4%
34.2%
30.3%
68.7%
44.7%
61.6%
71.4%
31.7%
70.5%
45.2%
60.1%
70.4%
25.8%
56.8%
27.4%
41.5%
39.4%
24.7%
56.0%
27.1%
42.5%
39.9%
Results – HF Subgroups
Stroke or non-CNS embolism
HF Subgroup
Rivaroxaban
Warfarin
Rivaroxaban vs. Warfarin
HR (95% CI)
p-value
≥40%
2.00
2.06
0.98 (0.74, 1.31)
0.38
<40%
1.34
1.87
0.72 (0.46, 1.12)
I or II
1.90
2.02
0.94 (0.73, 1.22)
III or IV
1.88
2.10
0.90 (0.61, 1.32)
No Device
1.96
2.08
0.94 (0.75, 1.18)
ICD or BiV-ICD
0.33
1.96
0.17 (0.02, 1.39)
2
1.30
1.16
1.09 (0.44, 2.69)
≥3
1.96
2.18
0.90 (0.72, 1.12)
LVEF
NYHA Class
0.68
Device Therapy
0.11
CHADS2 Score
0.48
Results – Heart Failure Subgroups
Major or Non-Major Clinically Relevant Bleeding
Heart Failure
Subgroup
Rivaroxaban
Warfarin
Rivaroxaban vs. Warfarin
HR (95% CI)
p-value
≥ 40%
14.18
14.81
1.00 (0.88, 1.13)
0.051
< 40%
15.34
14.10
1.15 (0.96, 1.36)
I or II
14.83
14.15
1.08 (0.97, 1.21)
III or IV
12.45
13.54
0.96 (0.80, 1.15)
No Device
13.08
13.72
0.99 (0.89, 1.09)
ICD or BiV-ICD
32.43
16.37
2.00 (1.31, 3.05)
2
15.96
10.02
1.54 (1.10, 2.16)
≥3
14.06
14.42
1.02 (0.92, 1.12)
Ejection Fraction
NYHA Class
0.19
Device therapy
0.002
CHADS2 score
0.15
Available now online from
European Heart Journal
http://eurheartj.oxfordjournals.org/cgi/content/full/ehr342
Baseline demographics
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)
79 (75–82)
79 (75–83)
71 (63–76)
71 (63–76)
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
Characteristic
Age, median (IQR), yrs
Female (%)
ASA, acetylsalicylic acid; IQR, interquartile range; VKA, vitamin K antagonist
Safety population (minus 9 pts in warfarin arm with no CrCl data)
Baseline demographics (continued)
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)
3.68 ± 1.00
3.67 ± 1.01
3.42 ± 0.91
3.41 ± 0.92
Prior stroke/TIA or
systemic 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 myocardial
infarction (%)
18.7
20.5
16.0
17.3
Characteristic
CHADS2 score
(mean ± SD)
SD, standard deviation; TIA, transient ischaemic attack
Safety 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
8
Cumulative event rate (%)
7
6
Warfarin
5
Rivaroxaban
4
3
HR (95% CI): 0.84 (0.57, 1.23)
2
1
0
No. at risk:
Rivaroxaban
Warfarin
0
120
240
360
480
600
1,434
1,439
1,226
1,261
1,103
1,140
1,027
1,052
806
832
621
656
Days since randomization
Event rates are % per year; Based on Protocol Compliant on Treatment Population
Fox KA et al. Eur Heart J 2011; 32 (19): 2387-2394
720
442
455
840
275
272
ROCKET AF: Primary efficacy endpoint: stroke or
non-CNS embolism patients with CrCl 30–49 ml/min
vs. ROCKET AF overall
Warfarin, renally impaired*,1
Cumulative event rate (%)
6
Rivaroxaban renally impaired*,1
5
Warfarin, overall**,2
4
Rivaroxaban overall**,2
3
* among patients with CrCl 30-49 ml/min:
HR 0.84 (95% CI: 0.57-1.23)
2
** HR 0.79 (95% CI: 0.66-0.96) p<0.001 (noninferiority)
1
0
0
120
240
480
600
360
Days since randomization
720
840
Per-protocol population on-treatment
1
Fox KA et al. Eur Heart J 2011; 32 (19): 2387-2394; 2 Patel MR et al. N Engl J Med 2011;365:883–891
Safety outcomes
Clinical endpoint
(% per year)
CrCl ≥50 ml/min†
CrCl 30–49 ml/min‡
Rivaroxaban
(N=7111)
Warfarin
(N=7116)
Principal safety
outcome*
14.24
17.82
13.67
18.28
1.04 (0.96–1.13)
0.98 (0.84–1.14)
0.45
Major bleeding
3.39
4.49
3.17
4.70
1.07 (0.91–1.26)
0.95 (0.72–1.26)
0.48
Hct or Hb drop
2.54
3.76
2.03
3.28
1.25 (1.03–1.52)
1.14 (0.83–1.58)
0.65
Transfusion
1.49
2.34
1.16
2.00
1.28 (0.99–1.65)
1.17 (0.77–1.76)
0.71
Critical organ
0.83
0.76
1.13
1.39
0.74 (0.55–0.99)
0.55 (0.30–1.00)
0.39
Fatal bleeding
0.23
0.28
0.43
0.74
0.55 (0.32–0.93)
0.39 (0.15–0.99)
0.53
0.44
0.71
0.71
0.88
0.62 (0.42–0.92)
0.81 (0.41–1.60)
0.51
Intracranial
haemorrhage
0.01
Based on safety population on treatment
*Composite of major plus non-major clinically relevant bleeding.
†Rivaroxaban 20 mg od. ‡Rivaroxaban 15 mg od
0.1
1
HR (95% CI)
Rivaroxaban
vs warfarin
10
P
(interaction)
Bleeding sites
CrCl 30–49 ml/min
Major bleeding
(% per year)
CrCl ≥50 ml/min
Rivaroxaban
15 mg
(N = 1474)
Warfarin
(N=1476)
Rivaroxaban
20 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)
ROCKET AF –
PREVENZIONE SECONDARIA
28
Secondary prevention cohort
key demographics
Warfarin
Rivaroxaban
Age (years)#
With prior stroke*
(N=3,754)
Without prior stroke*
(N=3,377)
With prior stroke*
(N=3,714)
Without prior stroke*
(N=3,419)
69.7±9.46
72.9±9.15
69.7±9.33
72.8±9.20
57.1 (42.6–70.1)
58.6 (43.6–71.0)
TTR Median (IQR)
CHADS2 score#
3.93±0.91
2.97±0.66
3.93±0.93
2.96±0.67
ASA
37.5%
34.9%
37.7%
35.7%
Vitamin K antagonists
59.2%
65.8%
59.4%
65.9%
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 medications
Clinical risk factors
*‘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
Kaplan–Meier survival curve showing time to the primary endpoint (stroke or systemic embolism)
Cumulative event rate – stroke or
systemic embolism (%)
7
6
Prior stroke/TIA,
warfarin
5
Prior stroke/TIA,
rivaroxaban
4
No prior stroke/TIA,
warfarin
3
No prior stroke/TIA,
rivaroxaban
2
1
0
0
6
12
18
Months from randomization
Per protocol population, on-treatment
24
30
Results:
Efficacy analysis
Rivaroxaban
Events/100 pt-yrs
Warfarin
Events/100 pt-yrs
Interaction pvalue
Stroke or systemic
embolism
1.09
2.26
1.69
2.60
0.15
Any stroke
1.06
2.21
1.53
2.37
0.16
Haemorrhagic stroke
0.17
0.35
0.41
0.47
0.22
Ischaemic or
unknown stroke
0.89
1.86
1.11
1.92
0.41
Disabling or fatal stroke
0.45
1.15
0.88
1.31
0.07
Non-CNS systemic
embolism
0.04
0.05
0.16
0.23
0.99
Any cause death
2.00
1.74
2.35
2.07
0.94
Vascular death
1.61
1.44
1.70
1.71
0.60
Per protocol population, on-treatment
No prior stroke or TIA
Prior stroke or TIA
Results:
Principal safety outcome
Rivaroxaban
Events/100 pt-yrs
Warfarin
Events/100 pt-yrs
Interaction pvalue
Major and non-major clinically
relevant bleeding†
16.69
13.31
15.19
13.87
0.0800
Major bleeding
4.10
3.13
3.69
3.22
0.3598
Haemoglobin/ Haematocrit drop
3.42
2.16
2.53
2.00
0.1924
Transfusion
2.28
1.06
1.53
1.12
0.0488
Gastrointestinal major bleeding
0.69
0.21
0.39
0.17
0.4600
Critical organ
bleeding
0.61
1.01
1.19
1.17
0.0625
ICH
0.39
0.59
0.68
0.80
0.4656
Fatal bleeding
0.22
0.26
0.48
0.49
0.7419
Non-major clinically relevant
bleeding
12.93
10.78
11.78
10.98
0.1995
Safety population, on-treatment
†Principal
safety outcome
No prior stroke or TIA
Prior stroke or TIA
ROCKET AF – subanalysis elderly patients Rationale
 To determine the efficacy and safety of rivaroxaban
compared with warfarin among elderly patients (>75 years
old) with AF compared with patients <75 years
 6,229 patients were ≥75 years
 Mean CHADS2 3.7 vs 3.3
 Female 46% vs. 35%
 Prior stroke/TIA 42% vs 65%
Halperin JL et al. presented at AHA 2012
ROCKET AF - subanalysis elderly patients Results
Age (Years)
Stroke/SE
(n=14.171)
Major Bleeding
(n=14.236)
<75
HR 0.95 (0.76-1.19)
HR 0.96 (0.78-1.19)
≥75
HR 0.80 (0.63-1.02)
HR 1.11 (0.92-1.34)
p*=0.31
p*=0.34
Rivaroxaban
better
* p-value for interaction
Halperin JL et al. presented at AHA 2012
Warfarin
better
Rivaroxaban
better
Warfarin
better
ROCKET AF - subanalysis elderly patients Results
Age ≥ 75 years
R
N=3082
W
N=3082
Stroke/SE1
2.29
Fatal/disabling
stroke1
Age < 75 years
HR (95% CI)
R
N=3999
W
N=4088
HR (95% CI)
pvalue*
2.85
0.80 (0.63-1.02)
2.00
2.10
0.95 (0.76-1.19)
0.31
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 (0.781.19)
0.34
0.66
0.83
0.80 (0.4991.282)
0.37
0.68
0.54 (0.33-0.89)
0.27
15.61
13.54
1.15 (1.03-1.23)
9.22
9.87
0.94 (0.83-1.05)
0.01
%/year
ICH3
CRNMB3
R=rivaroxaban; W=warfarin; *p-value for interaction; ICH=intracerebral haemorrhage;
CRNMB=clinically relevant non-major bleeding
1ITT population, 2 safety population excluding a GCP violating site, 3safety population
Halperin JL et al. presented at AHA 2012
ROCKET AF - subanalysis elderly patients Results
Age ≥ 75 years
R
N=3082
W
N=3082
Stroke/SE1
2.29
Fatal/disabling
stroke1
Age < 75 years
HR (95% CI)
R
N=3999
W
N=4088
HR (95% CI)
pvalue*
2.85
0.80 (0.63-1.02)
2.00
2.10
0.95 (0.76-1.19)
0.31
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 (0.781.19)
0.34
0.66
0.83
0.80 (0.4991.282)
0.37
0.68
0.54 (0.33-0.89)
0.27
15.61
13.54
1.15 (1.03-1.23)
9.22
9.87
0.94 (0.83-1.05)
0.01
%/year
ICH3
CRNMB3
R=rivaroxaban; W=warfarin; *p-value for interaction; ICH=intracerebral haemorrhage;
CRNMB=clinically relevant non-major bleeding
1ITT population, 2 safety population excluding a GCP violating site, 3safety population
Halperin JL et al. presented at AHA 2012