Le nuove frontiere dell’anticoagulazione nel paziente con

fibrillazione atriale

14-15 Novembre 2014Gavi

Dott. Sergio AgostiCardiologo, Ospedale Novi Ligure (AL)agostisergio@virgilio.ithttp://www.arcaliguria.it/

Prevenzione dell’ictus nella fibrillazione atriale: ancora un ruolo

per ASA e VKA?

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

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

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??

Camm AJ et al. Eur Heart J

NICE 2014 Guidelines on the management of AF2

“Do not offer aspirin monotherapy solely for stroke prevention with atrial fibrillation”

2012 ESC Guidelines1

Current Guidelines do not recommend ASA for stroke prevention in most NVAF patients

1 Camm AJ et al. Eur Heart J 20122 NICE clinical Guideline. 2014. The management of AF

Limited efficacy of ASA in reducing stroke risk in patients with AF

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 dayHart RG et al. Ann Intern Med 2007;146:857–67

RRR (%)†100 –10050 0 –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 trialsRRR: 19%*

(95% CI: –1 to 35%)

Only the SPAF trial showed a benefit of ASA over placebo for reducing stroke risk

ASA was less effective than VKA in historical trials in AF

Random effects model; error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic); ASA = acetylsalicylic acidHart RG et al. Ann Intern Med 2007;146:857–67 8

RRR (%)†

100 –10050 0 –50

AFASAK I (1990)

BAFTA (2007)

EAFT (1993)

PATAF (1999)

Warfarin better ASA better

Chinese ATAFS (2006)

SPAF II (1994)Age 75 yrsAge >75 yrs

All trials (4620 pt) RRR: 38%*(95% CI: 18-52%)

Risk of major and intracranial bleeding not significantly different between ASA and OAC

*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 acidFriberg L et al. Eur Hear J 2012:33:1500-10; Pisters R et al. Chest 2010;138:1093–100

ASA (n=61

396)

Major bleeding

0

5

10

15

20

25

0 1 2 3 4 5 6 7

HAS-BLED total score*

Ble

ed

s/year

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0 1 2 3 4 5 6 7

HAS-BLED total score*

Intracranial bleeding

Ble

ed

s/year

OAC (n=48 599)Tot Pt 182,678

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

Warfarin

ESC 2012 Guideline recommendations1

1. Camm et al. Eur Heart J 2012;33:2719–2747.

*Class of recommendation; †Level of evidence; OAC, oral anticoagulant

1. Camm et al. Eur Heart J 2012;33:2719–2747.

*Class of recommendation; †Level of evidence; OAC, oral anticoagulant

ESC 2012 Guideline recommendations1

Hart RG et al. Ann Intern Med 2007;146:857–67

-60% RR

Lancet, published online December 4, 2013

STROKE OR SYSTEMIC EMBOLISM

Ruff CT,Lancet, December 4, 2013

NNT 173

MAJOR BLEEDING

Ruff CT,Lancet, December 4, 2013

EFFICACY AD SAFETYSECONDARY ENDPOINTS

ICH NNT 141

Ruff CT,Lancet, December 4, 2013

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)

Paziente con fibrillazione atriale non valvolare (FAVN)

Gruppo 1 CHA2DS2-VASC ≥1 eHAS-BLED >3

CHA2DS2-VASC ≥1 eHAS-BLED >3

CHA2DS2-VASC >3 eHAS-BLED >3

Gruppo 2 TTR negli ultimi 6 mesi <70%

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

Il trattamento anticoagulante non è attuabile per difficoltà oggettive ad eseguire i controlli INR

Il trattamento anticoagulante non è attuabile per difficoltà oggettive ad eseguire i controlli INR

Ai fini dell’eleggibilità bisogna rientrare in una delle seguenti condizioni (1 o 2 o 3)

TTR: ANALISI DI SOTTOGRUPPO TIME TO PRIMARY OUTCOME

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.

Cu

mu

lati

ve h

aza

rd r

ati

o

0.01

0.03

0.04

0.05

0.06

0

0.02

0 0.5 1.0 1.5 2.0 2.5

1497 1450 1411 1144 649 274Dabigatran 110 mg1509 1469 1427 1164 699 283Dabigatran 150 mg1504 1445 1395 1094 640 242Warfarin

Number at risk

cTTR <57.1%

0.01

0.03

0.04

0.05

0.06

0

0.02

0 0.5 1.0 1.5 2.0 2.5

1524 1477 1440 1169 783 3791526 1493 1453 1192 801 3941514 1476 1438 1175 752 351

cTTR 57.1–65.5%

Cu

mu

lati

ve h

aza

rd r

ati

o

0.01

0.03

0.04

0.05

0.06

0

0.02

0Follow-up (yrs)

0.5 1.0 1.5 2.0 2.5

1474 1456 1420 1142 760 370Dabigatran 110 mg1484 1419 1419 1153 761 369Dabigatran 150 mg1487 1458 1436 1150 755 359Warfarin

Number at risk

cTTR 65.5–72.6%

0.01

0.03

0.04

0.05

0.06

0

0.02

0 0.5 1.0 1.5 2.0 2.5

1482 1444 1405 1108 730 3471514 1487 1437 1135 750 3671509 1476 1440 1166 737 366

Follow-up (yrs)

cTTR >72.6%

WarfarinDabigatran 150 mg Dabigatran 110 mg

TTR: ANALISI DI SOTTOGRUPPO TIME TO MAJOR BLEEDING

WarfarinDabigatran 150 mg Dabigatran 110 mgC

um

ula

tive h

aza

rd r

ati

o

0 0.5 1.0 1.5 2.0 2.5

Dabigatran 110 mgDabigatran 150 mgWarfarin

Number at risk

cTTR <57.1%

0

0.02

0.06

0.08

0.10

0.12

0.04

149715091504

144314481430

139813991371

113511351065

647680614

274276231

0 0.5 1.0 1.5 2.0 2.5

cTTR 57.1–65.5%

0

0.02

0.06

0.08

0.10

0.12

0.04

152415261514

146514671460

141614161403

113911601140

753774729

362377333

Cu

mu

lati

ve h

aza

rd r

ati

o

0Follow-up (yrs)

0.5 1.0 1.5 2.0 2.5

Dabigatran 110 mgDabigatran 150 mgWarfarin

Number at risk

cTTR 65.5–72.6%

0

0.02

0.06

0.08

0.10

0.12

0.04

1474 1445 1392 1108 736 3641484 1415 1372 1105 715 3431487 1445 1398 1121 725 344

0 0.5 1.0 1.5 2.0 2.5Follow-up (yrs)

cTTR >72.6%

0

0.02

0.06

0.08

0.10

0.12

0.04

1482 1438 1385 1087 706 3361514 1455 1399 1109 716 3501509 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;376:975-983.

Wallentin et al. Circulation 2013; 127: 2166-76

TTR subgroup analysis: intracranial bleeding

cTTR

Dabigatran

110 mg

Dabigatran

150 mgWarfarin

Dabigatran 110 mgvs warfarin

Dabigatran 150 mgvs warfarin

Rate per100

person-yrs

Rate per100

person-yrs

Rate per100

person-yrs

HR(95% CI)

P value*(interactio

n)

HR (95% CI)

P value*(interaction

)

<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)

0.71 0.39(0.18–0.84)

0.89

*Interaction P value evaluated by a multivariate approach with centre-based TTR as a continuous variablecTTR = centre mean TTR; HR = hazard ratio; INR = international normalized ratio; TTR = time in therapeutic range Wallentin L et al. Lancet 2010;376:975–83

Reduced risk of intracranial bleeding with both doses vs warfarin, irrespective of centre-based INR control

VALVULAR HEART DISEASE and PROSTHETIC VALVE

NOACs

Non valvular atrial fibrillation

PATIENTS EXCLUDED

ARISTOTELE: moderate or severe mitral stenosis

ENGAGE TIMI 38: moderate or severe mitral stenosis

RE-LY: mitral stenosishemodynamically 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

Valvular heart disease patients in NOACs trials

VHD in ARISTOTLE4808 (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

VHD in RE-LY3950 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 2014 63 SA 325 Michael D. Ezekowitz Poster Contribution

NEJM, 2013 Sep, 26; 369:1206-14

NEJM, 2013 Sep, 26; 369:1206-14

NEJM, 2013 Sep, 26; 369:1206-14

NEJM, 2013 Sep, 26; 369:1206-14

RE-ALIGN

ATLANTIS trial: Apixaban in patients who underwent a clinically successful TAVI procedure

* 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)

1509 patients after successful TAVI procedure Stratum 2

No indication for anticoagulation

Stratum 1Indication for anticoagulatio

n

R 1:1

R 1:1

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

6 m

on

ths o

f fo

llow

-u

p

Apixaban 5mg twice daily

2.5 mg twice daily in select patients**

SOC*-VKA

SOC-DAPT/ SAPT

Design and execution of this trial is not yet finalized and may be subject to further changes

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

NOACs in RENAL FAILURE

DABIGATRAN RIVAROXABAN

ClCr <15 ml/min non raccomandato 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 15 mg/die

ClCr >50ml/min 150 mg BID 20 mg/die

NOACs in RENAL FAILURE

Pengo V. et al. Thromb Haemost 2012; 10:1979-87

Clearance cratinineNumber of patients included in NOACs Trials

DRUG INTERACTIONS

Possible drug-drug interactions – Effect on NOAC plasma levels part 1

Dabigatran Apixaban Edoxaban Rivaroxaban

Atorvastatin P-gp/ CYP3A4 +18%no data

yetno effect no effect

Digoxin P-gp no effectno data

yetno effect no effect

Verapamil P-gp/ wk CYP3A4+12–180% no data

yet

+ 53% (slow release) minor effect

Diltiazem P-gp/ wk CYP3A4 no effect +40% No data minor effect

Quinidine P-gp +50%no data

yet+80% +50%

Amiodarone P-gp +12–60%no data

yetno 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 Dabigatran Apixaban Edoxaban Rivaroxaban

Fluconazole CYP3A4 no data no data no data +42%

Cyclosporin; tacrolimus

P-gp no data no data no data +50%

Clarithromycin; erythromycin

P-gp/ CYP3A4 +15–20% no data no data +30–54%

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?

GRAZIE PER L’ATTENZIONE

www.docvadis.it/agostisergio