1. Le nuove frontiere dell’anticoagulazione nel paziente con
fibrillazione atriale
14-15 Novembre 2014
Gavi
Prevenzione dell’ictus nella fibrillazione atriale: ancora un ruolo per ASA e VKA?
Risposta a BMJ: capire se monitoraggio possa migliorare i dati di outcome, intanto accontentiamoci del fatto che con due dosaggi fissi somministrati in fx dell fx renale i risultati sono stati superiori in termini di efficacia e sicurezza al warfarin.
I risultati attuali non dimostrano ancora come modulare la posologia di pradaxa in base ai valori ematici si rifletta su un miglioramento di outcome clinici forti… quindi nao sebbene perfettibile sia attualmente il gold standard… noi non usiamo ancora i nao che già vorremmo avere qualcosa che funziona meglio…
Dott. Sergio Agosti
Cardiologo,
Ospedale Novi Ligure (AL)

2. ASA

3. However, this is not consistent with the latest treatment guidelines2
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

5. ASA??
Camm AJ et al. Eur Heart J

6. 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 The management of AF

7. Limited efficacy of ASA in reducing stroke risk in patients with AF
RRR (%)†
100
–100 50
–50
AFASAK (1989)
SPAF (1991)
EAFT (1993)
ESPS II (1997)
ASA better
Placebo better
LASAF (1997)
125 mg/d
125 mg QOD
UK-TIA (1999)
300 mg/d
1200 mg/d
JAS (2006)T
All trials
Only the SPAF trial showed a benefit of ASA over placebo for reducing stroke risk
A meta-analysis of study data showed that ASA had a limited and non-significant effect on stroke risk in patients with AF.
Analysis of data from 7 trials involving 3990 patients that compared ASA alone with placebo or no treatment showed that ASA was associated with a 19% (95% CI, –1% to 35%) reduction in the incidence of stroke.
When only strokes classified as ischaemic were considered (5 trials), ASA treatment resulted in a 21% (CI, –1% to 38%) reduction in strokes.
Only one study, the SPAF trial, showed a significant benefit of ASA over placebo in reducing stroke risk, with a 44% risk reduction.
Hart RG et al. Ann Intern Med 2007;146:857–67
RRR: 19%* (95% CI: –1 to 35%)
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

8. ASA was less effective than VKA in historical trials in AF
RRR (%)†
100
–100 50
–50
AFASAK I (1990)
BAFTA (2007)
EAFT (1993)
PATAF (1999)
Warfarin better
ASA better
Chinese ATAFS (2006)
SPAF II (1994)
Age 75 yrs
Age >75 yrs
All trials (4620 pt)
Meta-analysis of data from 8 studies comparing ASA with adjusted-dose warfarin (n=3647) showed that warfarin provided a 38% (95% CI, 18 to 52%) reduction in stroke risk.
Thus, ASA was shown to be statistically inferior to warfarin for stroke prevention in AF.
Hart RG et al. Ann Intern Med 2007;146:857–67
RRR: 38%* (95% CI: 18-52%)
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

10. Intracranial bleeding
Risk of major and intracranial bleeding not significantly different between ASA and OAC
Tot Pt 182,678
ASA (n=61 396)
OAC (n=48 599)
0.2
0.4
0.6
0.8 1
1.2
1.4
1.6
1.8 2 3 4 5 6 7
HAS-BLED total score*
Intracranial bleeding
Bleeds/year
Major bleeding 5 10 15 20 25 1 2 3 4 6 7
HAS-BLED total score*
Bleeds/year
The risk of major and intracranial bleeding does not differ significantly between treatment with ASA and OACs.
This study stratified 182,678 patients by their modified HAS-BLED score, which assesses their risk of bleeding from the number of risk factors present (hypertension, renal dysfunction, stroke, bleeding, age >65 years, drugs affecting bleeding or alcohol abuse).1,2
The rates of major and intracranial bleeding were similar for patients using ASA or OACs.2
Bleeding risk increased with increasing HAS-BLED scores, irrespective of whether the patient was taking ASA, OAC, OAC plus ASA, or no antithrombotic therapy.2
Pisters R et al. Chest 2010;138:1093–100
Friberg L et al. Eur Hear J 2012:33: ;
*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: ; Pisters R et al. Chest 2010;138:1093–100

11. Quando pubblicato…??

22. 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 prescribed for stroke prevention in AF
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

23. Warfarin

25. ESC 2012 Guideline recommendations1
CHA2DS2-VASc
Recommendation
Class*
Level†
No antithrombotic therapy I B 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
IIa A ≥2
An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)
…is recommended
*Class of recommendation; †Level of evidence; OAC, oral anticoagulant
1. Camm et al. Eur Heart J 2012;33:2719–2747.

26. ESC 2012 Guideline recommendations1
Recommendations for prevention of thromboembolism in NVAF—NOACs
Class*
Level†
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
IIa A
*Class of recommendation; †Level of evidence; OAC, oral anticoagulant
1. Camm et al. Eur Heart J 2012;33:2719–2747.

27. -60% RR
Hart RG et al. Ann Intern Med 2007;146:857–67

28. Lancet, published online December 4, 2013

29. STROKE OR SYSTEMIC EMBOLISM
NNT 173
Ruff CT,Lancet, December 4, 2013

30. MAJOR BLEEDING
Ruff CT,Lancet, December 4, 2013

31. EFFICACY AD SAFETY SECONDARY ENDPOINTS
NNT PER ICH è 140
ICH NNT 141
Ruff CT,Lancet, December 4, 2013

32. Condizioni di ingresso
Eliquis
Pradaxa
Xarelto
Condizioni di ingresso
Paziente con fibrillazione atriale non valvolare (FAVN) cronica o parossistica (>65 anni)
Paziente con fibrillazione atriale non valvolare (FAVN)
Ai fini dell’eleggibilità bisogna rientrare in una delle seguenti condizioni (1 o 2 o 3)
Gruppo 1
CHA2DS2-VASC ≥1 e
HAS-BLED >3
CHA2DS2-VASC >3
Gruppo 2
TTR negli ultimi 6 mesi <70%
TTR negli ultimi 6 mesi <60%
Gruppo 3
Il trattamento anticoagulante non è attuabile per difficoltà oggettive ad eseguire i controlli INR

33. TTR: ANALISI DI SOTTOGRUPPO TIME TO PRIMARY OUTCOME
Dabigatran 150 mg
Dabigatran 110 mg
Warfarin
0.06
0.06
cTTR <57.1%
cTTR 57.1–65.5%
0.05
0.05
0.04
0.04
Cumulative hazard ratio
0.03
0.03
0.02
0.02
0.01
0.01
Number at risk
0.5
1.0
1.5
2.0
2.5
0.5
1.0
1.5
2.0
2.5
Dabigatran 110 mg
1497
1450
1411
1144
649
274
1524
1477
1440
1169
783
379
Dabigatran 150 mg
1509
1469
1427
1164
699
283
1526
1493
1453
1192
801
394
Warfarin
1504
1445
1395
1094
640
242
1514
1476
1438
1175
752
351
0.06
0.06
cTTR 65.5–72.6%
cTTR >72.6%
0.05
0.05
0.04
0.04
Cumulative hazard ratio
0.03
0.03
0.02
0.02
0.01
0.01
0.5
1.0
1.5
2.0
2.5
0.5
1.0
1.5
2.0
2.5
Number at risk
Follow-up (yrs)
Follow-up (yrs)
Dabigatran 110 mg
1474
1456
1420
1142
760
370
1482
1444
1405
1108
730
347
Dabigatran 150 mg
1484
1419
1419
1153
761
369
1514
1487
1437
1135
750
367
Warfarin
1487
1458
1436
1150
755
359
1509
1476
1440
1166
737
366
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:

34. TTR: ANALISI DI SOTTOGRUPPO TIME TO MAJOR BLEEDING
Dabigatran 150 mg
Dabigatran 110 mg
Warfarin
Cumulative hazard ratio
0.5
1.0
1.5
2.0
2.5
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
Number at risk
cTTR <57.1%
0.02
0.06
0.08
0.10
0.12
0.04
1497
1509
1504
1443
1448
1430
1398
1399
1371
1135
1065
647
680
614
274
276
231
0.5
1.0
1.5
2.0
2.5
cTTR 57.1–65.5%
0.02
0.06
0.08
0.10
0.12
0.04
1524
1526
1514
1465
1467
1460
1416
1403
1139
1160
1140
753
774
729
362
377
333
Cumulative hazard ratio
Follow-up (yrs)
0.5
1.0
1.5
2.0
2.5
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
Number at risk
cTTR 65.5–72.6%
0.02
0.06
0.08
0.10
0.12
0.04
1474
1445
1392
1108
736
364
1484
1415
1372
1105
715
343
1487
1398
1121
725
344
0.5
1.0
1.5
2.0
2.5
Follow-up (yrs)
cTTR >72.6%
0.02
0.06
0.08
0.10
0.12
0.04
1482
1438
1385
1087
706
336
1514
1455
1399
1109
716
350
1509
1452
1411
1129
714
354
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:

35. Wallentin et al. Circulation 2013; 127: 2166-76
Nell’ir nao utili in tutti i gradi di ir - sottopopolazioni, no in ir avanzata…
Wallentin et al. Circulation 2013; 127:

36. TTR subgroup analysis: intracranial bleeding
Reduced risk of intracranial bleeding with both doses vs warfarin, irrespective of centre-based INR control
cTTR
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
Dabigatran 110 mg vs warfarin
Dabigatran 150 mg vs warfarin
Rate per 100 person-yrs
HR (95% CI)
P value* (interaction)
HR (95% CI)
<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
0.77
0.27
(0.11–0.66)
0.71
0.39
(0.18–0.84)
0.89
Non è stato ristretta indicazione perché su emorragia intracranica non c’è differenza per TTR. Mi serve diapo dove ci sia rappresentazione grafica intuitiva dell’HR delle sottopopolazioni TTR per l’emorragia intracranica.
Vorrei far passare il concetto che anche se il beneficio in termini di endpoint primario si riduce al confronto con un Coumadin con TTR molto alto, il sanguinamento intracranico risulta progressivamente più a favore di dabigatran anche nella sottopolazione con TTR più elevato.
*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

37. Interazioni farmacologiche

38. VALVULAR HEART DISEASE and PROSTHETIC VALVE

39. Non valvular atrial fibrillation
NOACs
Non valvular atrial fibrillation

40. 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

41. ESC Congress 2013, Dr Alvaro Avezum, Duke Clinical Research Institute
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
Prior valve surgery
251
5.2
ESC Congress 2013, Dr Alvaro Avezum, Duke Clinical Research Institute

42. VHD in RE-LY 3950 VHD (21.8% of 18113 pz)
Any VHD
3950
100.0%
Any mitral valve disease
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 SA 325 Michael D. Ezekowitz Poster Contribution

43. Studio di fase II. Tre dosaggi in base a cl cr 150x2, 220x2, 300x2 fino a raggiungere dosaggio ematico di dabigatran pari a 50 ng (dosaggio efficace nel rely). Due gruppi: popolazione A ha iniziato D entro una sett dall’intervento, popol B ha iniziato D a 3 mesi dall’intervento. Gli eventi ischemici cerebrali e le emorragie maggiori (emopericardio) sono stati nella popolaz A. Anche se TIA e sanguinam minori sono stati maggiori nella popolaz B vs Warfarin
NEJM, 2013 Sep, 26; 369:

44. NEJM, 2013 Sep, 26; 369:

45. NEJM, 2013 Sep, 26; 369:

46. RE-ALIGN
NEJM, 2013 Sep, 26; 369:

47. 1509 patients after successful TAVI procedure
ATLANTIS trial: Apixaban in patients who underwent a clinically successful TAVI procedure
SOC*-VKA
Stratum 1
Indication for anticoagulation R
1:1
Apixaban 5mg twice daily 2.5 mg twice daily in select patients**
1509 patients after successful TAVI procedure
6 months of follow-up
Stratum 2
No indication for anticoagulation R
1:1
SOC-DAPT/ SAPT
Phase 4, randomised, open label, parallel group (N-1500)
To asses whether anticoagulation with apixaban is not less safe than standard of care therapy in patients with valvular heart disease
following transcatheter aortic valve implantation (TAVI)
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

49. NOACs in RENAL FAILURE

50. NOACs in RENAL FAILURE Se due di tre: età >80 anni
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 ml/min Utilizzare 2,5 BID

51. NOACs in RENAL FAILURE DABIGATRAN RIVAROXABAN ClCr <15 ml/min
non raccomandato
ClCr ml/min
(75 mg BID in USA)
ClCr ml/min
110 mg BID
ClCr ml/min
15 mg/die
ClCr >50ml/min
150 mg BID
20 mg/die

52. Scala di jadad 3 per rely e 4 per aristotele e rocket… valutazione della qualità dei trials… (da 1 a 5)
Pengo V. et al. Thromb Haemost 2012; 10:

53. Number of patients included in NOACs Trials
Clearance cratinine
Number of patients included in NOACs Trials

54. DRUG INTERACTIONS

55. Possible drug-drug interactions – Effect on NOAC plasma levels part 1
Dabigatran
Apixaban
Edoxaban
Rivaroxaban
Atorvastatin
P-gp/ CYP3A4
+18%
no data yet
no effect
Digoxin
P-gp
Verapamil
P-gp/ wk CYP3A4
+12–180%
+ 53% (slow release)
minor effect
Diltiazem
+40%
No data
Quinidine
+50%
+80%
Amiodarone
+12–60%
Dronedarone
P-gp/CYP3A4
+70–100%
+85%
Ketoconazole; itraconazole; voriconazole; posaconazole;
P-gp and BCRP/ CYP3A4
+140–150%
+100%
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

56. Possible drug-drug interactions – Effect on NOAC plasma levels part 2
Dabigatran
Apixaban
Edoxaban
Rivaroxaban
Fluconazole
CYP3A4
no data
+42%
Cyclosporin; tacrolimus
P-gp
+50%
Clarithromycin; erythromycin
P-gp/ CYP3A4
+15–20%
+30–54%
HIV protease inhibitors
P-gp and BCRP/ CYP3A4
strong increase
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 effect
Non dimentichiamo che apixaban e rivarox hanno un metabolismo da parte del citocromo P 450
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

57. 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

58. 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?

59. GRAZIE PER L’ATTENZIONE