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Interregionale ARCA NORD
7-8 Novembre 2014
Sirmione
NAO: ancora un ruolo per ASA e VKA
per la NAFV nel 2015?
Dott. Sergio Agosti
Cardiologo,
Ospedale Novi Ligure (AL)
www.docvadis.it/agostisergio
[email protected]
http://www.arcaliguria.it/
ASA
Introduction to ASA
• One of the most widely used drugs of the 20th century1
• Taken by millions of patients worldwide for the treatment and
prevention of CVD, and is the most widely tested antiplatelet drug1
• Has been (and is still) used for stroke prevention in AF1,2
Traditionally considered a safe, but less effective, alternative to VKAs when
anticoagulation is contraindicated, or for use in patients at low risk of stroke1,2
However, this is not consistent with the latest treatment guidelines2
ASA = acetylsalicylic acid; CVD = cardiovascular disease; VKA = vitamin K antagonist
1. Dai Y, Ge J. Thrombosis 2012;2012:245037; 2. Camm AJ et al. Eur Heart J 2012;33:2719–47
3
ASA??
Camm AJ et al. Eur Heart J
Current Guidelines do not recommend ASA for stroke
prevention in most NVAF patients
2012 ESC Guidelines1
NICE 2014 Guidelines on the management of AF2
“Do not offer aspirin monotherapy solely for stroke prevention with atrial
fibrillation”
1 Camm AJ et al. Eur Heart J 2012
2 NICE clinical Guideline. 2014. The management of AF
Limited efficacy of ASA in reducing
stroke risk in patients with AF
ASA better
Placebo better
AFASAK (1989)
Only the SPAF trial showed a
benefit of ASA over placebo
for reducing stroke risk
SPAF (1991)
EAFT (1993)
ESPS II (1997)
LASAF (1997)
125 mg/d
125 mg QOD
UK-TIA (1999)
300 mg/d
1200 mg/d
JAS (2006)T
RRR: 19%*
All trials
(95% CI: –1 to 35%)
100
50
0
RRR
(%)†
–50
–100
Random effects model; error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR) for all strokes (ischaemic and
haemorrhagic); for ischaemic stroke only, RRR was 21% (95% CI: −1 to 38%)
ASA = acetylsalicylic acid; QOD = every other day
Hart RG et al. Ann Intern Med 2007;146:857–67
ASA was less effective than VKA in historical trials in
AF
Warfarin better
ASA better
AFASAK I (1990)
BAFTA (2007)
Chinese ATAFS (2006)
EAFT (1993)
PATAF (1999)
SPAF II (1994)
Age 75 yrs
Age >75 yrs
RRR: 38%*
All trials (4620 pt)
100
(95% CI: 18-52%)
50
0
–50
–100
RRR (%)†
Random effects model; error bars = 95% CI; *P>0.2 for homogeneity;
†Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic); ASA = acetylsalicylic acid
Hart RG et al. Ann Intern Med 2007;146:857–67
8
Risk of major and intracranial bleeding not significantly
different between ASA and OAC
ASA (n=61 396)
OAC (n=48 599)
Tot Pt 182,678
Major bleeding
25
Intracranial
bleeding
2
1.8
1.6
20
15
Bleeds/year
Bleeds/year
1.4
10
1.2
1
0.8
0.6
0.4
5
0.2
0
0
0
1
2
3
4
5
HAS-BLED total score*
6
7
0
1
2
3
4
5
6
HAS-BLED total score*
*Modified HAS-BLED score used in this study: 1 point each for systolic blood pressure >160 mmHg, renal dysfunction, liver
dysfunction, stroke, bleeding, age >65 years, drugs affecting bleeding or alcohol abuse (maximum score = 7); score 0–2
indicates low bleeding risk, ≥3 indicates high bleeding risk; ASA = acetylsalicylic acid
Friberg L et al. Eur Hear J 2012:33:1500-10; Pisters R et al. Chest 2010;138:1093–100
7
ASA Conclusions
➢Antiplatelet therapy should be considered only when patients
refuse any OAC, or cannot tolerate OAC for reasons unrelated
to bleeding
➢In the real world, antiplatelet therapy is still commonly
for stroke prevention in AF
prescribed
➢Compared with ASA, NOAs (apixaban) significantly reduced the
relative risk of stroke or systemic embolism by 55% while the risk
of major bleeding was not significantly increased
➢The evidence demonstrated that oral anticoagulation should be the
preferred option in NVAF patients at risk of stroke
Warfarin
ESC 2012 Guideline recommendations1
CHA2DS2-VASc
Recommendation
0
No antithrombotic therapy
1
OAC therapy with
• Adjusted-dose VKA (INR 2–3); or
• A direct thrombin inhibitor (dabigatran); or
• An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)
…should be considered
≥2
OAC therapy with
• Adjusted-dose VKA (INR 2–3); or
• A direct thrombin inhibitor (dabigatran); or
• An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)
…is recommended
Class*
Level†
I
B
IIa
A
I
A
*Class of recommendation; †Level of evidence; OAC, oral anticoagulant
1. Camm et al. Eur Heart J 2012;33:2719–2747.
ESC 2012 Guideline recommendations1
Recommendations for prevention of thromboembolism
in NVAF—NOACs
Class*
Level†
IIa
A
Where OAC is recommended, one of the NOACs, either:
• A direct thrombin inhibitor (dabigatran); or
• An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)
…should be considered rather than adjusted-dose VKA
(INR 2–3) for most patients with NVAF, based on their net clinical benefit
*Class of recommendation; †Level of evidence; OAC, oral anticoagulant
1. Camm et al. Eur Heart J 2012;33:2719–2747.
Lancet, published online December 4, 2013
STROKE OR SYSTEMIC EMBOLISM
NNT 173
Ruff CT,Lancet, December 4, 2013
MAJOR BLEEDING
Ruff CT,Lancet, December 4, 2013
EFFICACY AD SAFETY
SECONDARY ENDPOINTS
ICH NNT 141
Ruff CT,Lancet, December 4, 2013
1
TTR: ANALISI DI SOTTOGRUPPO
TIME TO PRIMARY OUTCOME
Cumulative hazard ratio
Dabigatran 150 mg
0.06
Cumulative hazard ratio
0.06
cTTR <57.1%
0.05
0.04
0.04
0.03
0.03
0.02
0.02
0.01
0.01
0
0.5
1.0
1.5
2.0
2.5
1497
1509
1504
1450
1469
1445
1411
1427
1395
1144
1164
1094
649
699
640
274
283
242
0.06
0
0.5
1.0
1.5
2.0
2.5
1524
1526
1514
1477
1493
1476
1440
1453
1438
1169
1192
1175
783
801
752
379
394
351
2.0
2.5
730
750
737
347
367
366
0.06
cTTR 65.5–72.6%
0.05
0.04
0.04
0.03
0.03
0.02
0.02
0.01
0.01
0
0.5
1474
1484
1487
1456
1419
1458
1.0
1.5
Follow-up (yrs)
1420
1419
1436
cTTR 57.1–65.5%
0
0.05
0
Number at risk
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
Warfarin
0.05
0
Number at risk
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
Dabigatran 110 mg
1142
1153
1150
2.0
2.5
760
761
755
370
369
359
0
cTTR >72.6%
0
0.5
1482
1514
1509
1444
1487
1476
1.0
1.5
Follow-up (yrs)
1405
1437
1440
1108
1135
1166
TTR = time in therapeutic range; cTTR = centre mean TTR.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Wallentin L, et al. Lancet 2010;376:975-983.
TTR: ANALISI DI SOTTOGRUPPO
TIME TO MAJOR BLEEDING
Cumulative hazard ratio
Dabigatran 150 mg
Dabigatran 110 mg
0.12
0.12
cTTR <57.1%
cTTR 57.1–65.5%
0.10
0.10
0.08
0.08
0.06
0.06
0.04
0.04
0.02
0.02
0
Number at risk
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
0
0
0.5
1.0
1.5
2.0
2.5
0
0.5
1.0
1.5
2.0
2.5
1497
1509
1504
1443
1448
1430
1398
1399
1371
1135
1135
1065
647
680
614
274
276
231
1524
1526
1514
1465
1467
1460
1416
1416
1403
1139
1160
1140
753
774
729
362
377
333
2.0
2.5
706
716
714
336
350
354
Cumulative hazard ratio
0.12
0.12
cTTR 65.5–72.6%
0.10
cTTR >72.6%
0.10
0.08
0.08
0.06
0.06
0.04
0.04
0.02
0.02
0
Number at risk
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
Warfarin
0
0
0.5
1474
1484
1487
1445
1415
1445
1.0
1.5
Follow-up (yrs)
1392
1372
1398
1108
1105
1121
2.0
2.5
0
0.5
736
715
725
364
343
344
1482
1514
1509
1438
1455
1452
1.0
1.5
Follow-up (yrs)
1385
1399
1411
1087
1109
1129
TTR = time in therapeutic range; cTTR = centre mean TTR; HR = hazard ratio; CI = confidence interval.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Wallentin L, et al. Lancet 2010;376:975-983.
Wallentin et al. Circulation 2013; 127: 2166-76
TTR subgroup analysis: intracranial bleeding
Reduced risk of intracranial bleeding with both doses vs warfarin, irrespective of
centre-based INR control
Dabigatran
110 mg
Dabigatran
150 mg
Warfarin
Rate per
100
person-yrs
Rate per
100
person-yrs
Rate per
100
person-yrs
<57.1%
0.28
0.34
0.64
0.43
(0.19–1.00)
0.53
(0.25–1.15)
57.1–
65.5%
0.30
0.42
0.93
0.31
(0.15–0.66)
0.45
(0.24–0.88)
65.5–
72.6%
0.13
0.24
0.67
0.20
(0.07–0.58)
0.35
(0.15–0.82)
>72.6%
0.21
0.30
0.77
0.27
(0.11–0.66)
cTTR
Dabigatran 110 mg
vs warfarin
HR
(95% CI)
P value*
(interaction)
0.71
Dabigatran 150 mg
vs warfarin
HR
(95% CI)
0.39
(0.18–0.84)
*Interaction P value evaluated by a multivariate approach with centre-based TTR as a continuous variable
cTTR = centre mean TTR; HR = hazard ratio; INR = international normalized ratio; TTR = time in therapeutic range
Wallentin L et al. Lancet 2010;376:975–83
P value*
(interaction)
0.89
VALVULAR HEART DISEASE and PROSTHETIC VALVE
NOACs
Non valvular atrial fibrillation
Valvular heart disease patients in NOACs trials
PATIENTS EXCLUDED
ARISTOTELE: moderate or severe mitral stenosis
ENGAGE TIMI 38: moderate or severe mitral stenosis
RE-LY: mitral stenosis
hemodynamically relevant valve disease that is expected to
require surgical intervention during the course of the study
ROCKET AF: Hemodynamically significant mitral valve stenosis
VHD PATIENTS
ARISTOTELE: 4808 (26,4%) patients had a history of VHD at baseline
RE-LY: 21,8% dei pz con VHD
ROCKET AF: 14,1% had severe valvular disease
ENGAGE TIMI 38: mancanza di dati pubblicati
VHD in RE-LY
3950 VHD (21.8% of 18113 pz)
Any VHD
3950
Any mitral valve disease
100.0%
83,4
Mitral regurgitation
3.101
78,5
Mitral stenosis
193
4,9
Any aortic valve disease
32,6
Aortic stenosis
471
11,9
Aortic regurgitation
817
20,7
Tricuspidal regurgitation
1179
29,8
JACC 2014 63 SA 325 Michael D. Ezekowitz Poster Contribution
VHD in ARISTOTLE
4808 (26,4%) patients had a history of VHD at baseline
Any VHD*
4.808
100.0%
Any mitral valve
disease
3.578
74.4
Mitral regurgitation
3.526
73.3
Mitral stenosis
131
2.7
Any aortic valve disease 1.150
23.9
Aortic stenosis
887
18.4
Aortic regurgitation
384
8.0
Tricuspidal
regurgitation
2.124
44.2
2013, Dr Alvaro Avezum, Duke
Prior valve surgeryESC Congress251
5.2Clinical Research Institute
NEJM, 2013 Sep, 26; 369:1206-14
NEJM, 2013 Sep, 26; 369:1206-14
NEJM, 2013 Sep, 26; 369:1206-14
RE-ALIGN
NEJM, 2013 Sep, 26; 369:1206-14
SOC*-VKA
Stratum 1
1509 patients after
successful TAVI
procedure
Indication for
anticoagulation
Stratum 2
No indication for
anticoagulation
R
1:1
Apixaban 5mg
twice daily
2.5 mg twice daily
in select patients**
R
1:1
SOC-DAPT/ SAPT
Primary endpoint
composite of death, myocardial Infarction, stroke/TIA/systemic emboli, intracardiac or
bioprosthesis thrombus, episode of deep vein thrombosis or pulmonary embolism, major
bleedings over 6 months of follow-up
* Standard of Care
** 2.5mg bid if creatinine clearance 15-29mL/min or if two of the following criteria: age ≥80 years, weight ≤ 60kg or
creatinine ≥1,5mg/dL (133µMol)
Design and execution of this trial is not yet finalized and may be subject to
further changes
6 months of follow-up
ATLANTIS trial: Apixaban in patients who underwent a
clinically successful TAVI procedure
NOACs in RENAL FAILURE
NOACs in RENAL FAILURE
DABIGATRAN
ClCr <15 ml/min
non raccomandato
ClCr 15-30 ml/min
non raccomandato
(75 mg BID in USA)
ClCr 30-50 ml/min
110 mg BID
ClCr 15-50 ml/min
ClCr >50ml/min
RIVAROXABAN
non raccomandato
15 mg/die
150 mg BID
20 mg/die
NOACs in RENAL FAILURE
APIXABAN
Se due di tre:
• età >80 anni
• Creatinina > 1,5 mg/dl
• peso <60 Kg
Utilizzare 2,5 mg BID
Altrimenti 5 mg BID
ClCr 15-29 ml/min
Utilizzare 2,5 BID
Pengo V. et al. Thromb Haemost 2012; 10:1979-87
Clearance cratinine
Number of patients included in NOACs Trials
DRUG INTERACTIONS
Possible drug-drug interactions –
Effect on NOAC plasma levels part 1
Atorvastatin
P-gp/ CYP3A4
Digoxin
P-gp
Verapamil
P-gp/ wk CYP3A4
Diltiazem
P-gp/ wk CYP3A4
Quinidine
Dabigatran
Apixaban
Edoxaban
Rivaroxaban
+18%
no data yet
no effect
no effect
no effect
no data yet
no effect
no effect
+12–180%
no data yet
+ 53% (slow release)
minor effect
no effect
+40%
No data
minor effect
P-gp
+50%
no data yet
+80%
+50%
Amiodarone
P-gp
+12–60%
no data yet
no effect
minor effect
Dronedarone
P-gp/CYP3A4
+70–100%
no data yet
+85%
no data yet
Ketoconazole;
itraconazole;
voriconazole;
posaconazole;
P-gp and BCRP/
CYP3A4
+140–150%
+100%
no data yet
up to +160%
Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present;
hatching – no data available; recommendation made from pharmacokinetic considerations
EHRA GL 2013
Possible drug-drug interactions –
Effect on NOAC plasma levels part 2
Interaction
Fluconazole
Cyclosporin;
tacrolimus
Clarithromycin;
erythromycin
Dabigatran
Apixaban
Edoxaban
Rivaroxaban
CYP3A4
no data
no data
no data
+42%
P-gp
no data
no data
no data
+50%
+15–20%
no data
no data
+30–54%
P-gp/ CYP3A4
HIV protease
inhibitors
P-gp and BCRP/
CYP3A4
no data
strong increase
no data
up to +153%
Rifampicin;
St John’s wort;
carbamezepine;
phenytoin;
phenobarbital
P-gp and BCRP/
CYP3A4/CYP2J2
-66%
-54%
-35%
up to -50%
Antacids
GI absorption
-12-30%
no data
no effect
no effect
Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present;
hatching – no data available; recommendation made from pharmacokinetic considerations
EHRA GL 2013
Warfarin Conclusions
➢Warfarin will continue to be used in patients with mecanical prosthetic
heart valve and patients with rheumatic valve disease
➢Warfarin will continue to be used in patients with severe renal failure
➢Warfarin will continue to be used in patients with drug-drug
interactions
➢NOAs should be considered rather than adjusted-dose VKA for most
patietns with NVAF, based on their net clinical benefit
Assume that NAOs have been on the market for 5 year
➢A new drug comes to the market. Compared to NAOs, the new drug
has:
- cheaper
- antidote
- requirement for monthly monitoring to adjust dose
- many food and drug interactions
- 25% increased relative risk of stroke/systemic embolism
- nearly 50% increased relative risk of major bleeding
- approx. 2.5 times the rate of ICH
- 10% increased relative risk of mortality
➢Would Warfarin be approved by regulatory authorities now?
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