Top Rated Hyderabad Call Girls Erragadda ⟟ 9332606886 ⟟ Call Me For Genuine ...
Patti G. Vecchi e nuovi anticoagulanti orali a confronto. ASMaD 2013
1. Fibrillazione atriale:
dall’Epidemiologia alle nuove terapie
Roma, 16 Marzo 2013
Vecchi e nuovi anticoagulanti orali a confronto
Giuseppe Patti
Università Campus Bio-Medico di Roma
2. Why a novel anti-thrombotic Rx is needed in AF pts?
No stroke protection with aspirin (with or without clopidogrel)
Warfarin effective for stroke prevention, but
- Delayed onset/offset
- Unpredictable dose response
- Narrow therapeutic index
- Drug-drug, drug-food interactions
- Problematic monitoring and compliance
- High bleeding (especially ICH)
- Slow reversibility
5. New anticoagulants:
advantages
Short half-life:
- Immediate onset of action
- no need for bridging
Fixed doses
No lab. monitoring
A few drug-drug interactions (no food interactions)
6. New oral anticoagulants: how do they compare?
Dabigatran Rivaroxaban Apixaban Edoxaban
Action Anti-IIa Anti-Xa Anti-Xa Anti-Xa
Prodrug Yes (esterases) No No No
Bioavailability (%) 6 80-100 50-66 50
Half-life (hrs) 14-17 7-11 8-15 9-11
Protein binding (%) 35 95 87 50
Onset to peak 2-3 2-4 3 1-1.5
action (hrs)
Metabolism 80% renal CYP 3A4 CYP 3A4 CYP 3A4
20% glucur. 33% renal 22% renal 23% renal
Dose 110/150 mg BID 20 mg qD 5 mg BID 30-60 mg qD
Drug interaction P-glycoprotein CYP 3A4 CYP 3A4 CYP 3A4
P-glycoprotein P-glycoprotein P-glycoprotein
7. Questions and answers on the use of dabigatran and perpectives on the use of
other new oral anticoagulants in patients with atrial fibrillation
Pengo V., Thrombosis and Haemostasis 2011
Predictable drug interactions of the new oral anticoagulants according to the type of metabolism.
15. New oral anticoagulants: main trials’ results
Dabigatran Dabigatran Rivaroxaban Apixaban
150 mg 110 mg (N=14,264) (N=18,201)
(N=18,113) (N=18,113)
Stroke/embol. ↓ = ↓* ↓
Ischemic stroke ↓ = = =
Major bleed = ↓ = ↓
Fatal bleed ↓ ↓ ↓ ↓
(life threath.)
IC bleed ↓ ↓ ↓ ↓
Minor bleed ↓ ↓ = =
GI bleed ↑ = ↑ =
Death ↓ (P=0.05) = = ↓
16. NOACS: primary efficacy & safety outcome
ESC Working Group on Thrombosis: Task Force on anticoagulants in heart disease position paper
MT
De Caterina R. JACC 2012;59:1413
17. Ischemic Stroke
ITT : p-value
Dabigatran 110 mg 149 1.34% / yr 1.20 0.35
Dabigatran 150 mg 111 0.92% / yr 0.76 0.03
Warfarin 142 1.20% / yr RELY
Rivaroxaban 20 mg 149 1.62% / yr 0.99 0.92*
Warfarin 161 1.64% / yr
ROCKET-AF
Apixaban 5 mg 162 0.97% / yr 0.92 0.42
Warfarin 175 1.05% / yr
ARISTOTLE
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
18. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS:
STROKE AND NON-CNS EMBOLISM
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.76 P=0.072
<65 1.48 0.69 1.35
65–74 1.26 0.98 1.43
≥75 1.87 1.43 2.1
Creatinine clearance (mL/min) P=0.58 P=0.036
30–50 2.26 1.33 2.65
51–80 1.65 1.24 1.76
>80 0.92 0.72 1
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; CNS = central nervous system; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.
19. AGE AND RENAL FUNCTION SUBGROUP
ANALYSIS: MAJOR BLEEDING
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.0003 P=0.0001
<65 0.76 0.79 2.32
65–74 2.12 2.45 3.08
≥75 4.21 4.81 4.09
Creatinine clearance (mL/min) P=0.1 P=0.091
30–50 5.07 4.85 5.17
51–80 2.62 3.04 3.44
>80 1.36 1.88 2.18
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.
20. New anticoagulants and CRF
Longer half-life
Monitoring of renal function
Doses reduction?
Connolly SJ et al, NEJM 2009
21. New oral anticoagulants in pts receiving anti-PLT Rx
Triple therapy and major bleeding in RE-LY
Warfarin Dabigatran Dabigatran RR (95% RR (95%
(%) 110 mg BID 150 mg BID CI) CI)
(%) (%) Dabigatran Dabigatran
110 mg BID 150 mg BID
vs warfarin vs warfarin
ASA + 5.2 4.7 4.7 0.77 0.81
clopidogrel (0.50-1.21) (0.52-1.26)
No ASA + 3.5 2.8 3.2 0.81 0.95
clopidogrel (0.61-0.94) (0.82-1.10)
Connolly SJ et al. N Engl J Med 2009
22. New anticoagulants and
risk of CV events
MI or ACS
Issues regarding control population Stroke prevention independent of CAD
Lower protection than warfarin Ximelagatran reduced CV risk
Studies not powered for MI No dose-dependent effect
Data not corrected for beta-block., statins No correlation between CV risk and OR for MI
Uchino K et al. Arch Intern Med 2012 Hohnloser SH et al. Circulation 2012
23. Reduced LOS with dabigatran
End point Standard Dabigatran, n=18 p
anticoagulation,
n=18
Duration of in- 4.0 2.0 <0.001
hospital
anticoagulation
(median days)
Hospital length of 86 60.4 <0.05
stay (mean hours)
Hospital length of 75.5 49.4 <0.01
stay (median hours)
David A Vorchheimer, ACC Congress 2013
24. NAO e Cardioversione: raccomandazioni
Nei pazienti con FA in corso da ≥48 ore o quando la durata di FA è
sconosciuta, la terapia anticoagulante orale (es. AVK con INR 2-3 o I B
Dabigatran) è raccomandata per ≥3 settimane prima e per ≥4
settimane dopo cardioversione, indipendentemente dalla tipologia
(elettrica o farmacologica orale/endovenosa)
Non ci sono dati pubblicati relativi alla cardioversione
con Rivaroxaban o Apixaban
25. Practical issues with
new anticoagulants
Is bridging Rx needed?
Stop before surgery
Switching from warfarin
Switching from LMWH
Switching from UFH
26. How to manage a bleeding event
while on Rx with new anticoagulants?
Discontinue the anticoagulant
Investigate and treat the source of bleeding
Maintain diuresis
Blood volume replacement with/without fresh-frozen plasma
Prothrombin complex concentrates, recombinant factor VIIa
Platelet concentrates in case of Rx with long-acting
antiplatelet drugs
Use of activated charcoal Rx
Dialysis for dabigatran
27. New anticoagulants Warfarin
Economic issues Excellent efficacy
Unresolved issues Low cost
- No standardized monitoring Long track record
- Adherence to Rx Centralized anticoag. clin.
- Lack of antidote Point of care testing
- Long-term safety (real world)
- No head-to-head comparison
INR q 12 w if stable
28. New anticoagulants: Summary
Superior to aspirin
At least non-inferior to warfarin for ischemic thrombo-embolic
end-point
Significant reduction of ICH and fatal bleed
Consistent data according to history of previous stroke and CHADS
score, but dabigatran reduced ischemic stroke
Possibility to choice the dabigatran dose according to bleeding risk
Selection/prioritization of pts for these agents: pts unwilling to take
warfarin, new pts, pts with unstable INR or events while on warfarin;
pts with stable INR?
Evaluation in other settings of pts requiring anticoagulation
29.
30. D 110 R D 150
Anti-PLT Rx
CYP
CYP (high bleeding) (low bleeding)
High bleeding risk
Older
age CRF
GI bleed
GP drugs
Good INR
Valve prosthesis/
Other indication for OAC
A W
31. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS:
STROKE AND NON-CNS EMBOLISM
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.76 P=0.072
<65 1.48 0.69 1.35
65–74 1.26 0.98 1.43
≥75 1.87 1.43 2.1
Creatinine clearance (mL/min) P=0.58 P=0.036
30–50 2.26 1.33 2.65
51–80 1.65 1.24 1.76
>80 0.92 0.72 1
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; CNS = central nervous system; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.
32. AGE AND RENAL FUNCTION SUBGROUP
ANALYSIS: MAJOR BLEEDING
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.0003 P=0.0001
<65 0.76 0.79 2.32
65–74 2.12 2.45 3.08
≥75 4.21 4.81 4.09
Creatinine clearance (mL/min) P=0.1 P=0.091
30–50 5.07 4.85 5.17
51–80 2.62 3.04 3.44
>80 1.36 1.88 2.18
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.
33. Study design
AF on Electrical
N = 21,107 Recording < 12 mo
Intended oral A/C
CHADS2 > 2
R
Low Exposure High Exposure Active Control
Strategy Strategy Warfarin
Edoxaban 30 mg QD Edoxaban 60 mg QD (INR 2.0 – 3.0)
Median duration of follow up 24-months
Primary Objective
Edoxaban: Therapeutically as good as Warfarin
1º EP = Stroke or SEE (Non inferiority Boundary HR 1.38)
2º EP = Stroke or SEE or All-Cause Mortality
Safety EPs = Major Bleeding, Hepatic Function
SEE=systemic embolic event
Ruff CT et al. Am Heart J. 2010;160:635-41
34. Other issues regarding
new anticoagulants
Results of these drugs in pts with older age?
Compliance?
Need for monitoring?
Anti-thrombotic Rx in pts with AF receiving coronary stents?
35. CTRs vs. real world observations
CRTs Real world
Age 30% 65%
CRF 20% 58%
Low body weight 30% 50%
Harper P et al. N Engl J Med 2012
36. Effects of Apixaban vs Warfarin Among Patients
Using and Not Using Aspirin in ARISTOTLE
HR ASA HR No ASA
Stroke or 0.55 0.80
embolism
Major bleeding 0.77 0.65
Hemorrhagic 0.40 0.51
stroke
Granger CB et al. N Engl J Med 2011
37. Messages from trials
according to patients age and renal function
Reduction of the benefit on the efficacy endpoint with 150 mg Dabigatran over
the spectrum of ages. Maintained improvement on the efficacy endpoint with
150 mg Dabigatran in pts with CRF (real world?)
Trend towards increase in major bleeding in older pts with 150 mg Dabigatran.
No reduction of bleeding in older pts and in pts with CRF with 110 mg
Dabigatran
Consistent reduction in the efficacy endpoint with Apixaban and Rivaroxaban
over the spectrum of ages (possibly higher in older pts) and of renal function
Monitoring of renal function?
Dose modification? 15-30 ml/min Dabi 75 mg x 2; 30-50 ml/min Riva 15 mg;
creat. >1.5 mg/dl Api 2.5 mg x 2
45. Messages from trials
according to patients age
Consistent reduction of the efficacy endpoint with 150
mg Dabigatran over the spectrum of ages
Trend towards reduction of major bleeding with 110 mg
Dabigatran confined to younger pts (no reduction of
bleeding in older pts); trend towards increase in bleeding
with 150 mg Dabigatran in older pts
Consistent (and possibly higher in older pts) reduction in
the efficacy endpoint with Apixaban and Rivaroxaban
46. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS:
STROKE AND NON-CNS EMBOLISM
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.76 P=0.072
<65 1.48 0.69 1.35
65–74 1.26 0.98 1.43
≥75 1.87 1.43 2.1
Creatinine clearance (mL/min) P=0.58 P=0.036
30–50 2.26 1.33 2.65
51–80 1.65 1.24 1.76
>80 0.92 0.72 1
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.
47. AGE AND RENAL FUNCTION SUBGROUP
ANALYSIS: MAJOR BLEEDING
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.0003 P=0.0001
<65 0.76 0.79 2.32
65–74 2.12 2.45 3.08
≥75 4.21 4.81 4.09
Creatinine clearance (mL/min) P=0.1 P=0.091
30–50 5.07 4.85 5.17
51–80 2.62 3.04 3.44
>80 1.36 1.88 2.18
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.
50. Messages from trials
according to renal function
Consistent (and possibly higher in pts with CRF)
reduction of the efficacy endpoint with 150 mg
Dabigatran over the spectrum of renal function
Trend towards lower reduction of major bleeding
with 110 mg Dabigatran in pts with CRF
Consistent reduction in the efficacy endpoint with
Apixaban and Rivaroxaban over the spectrum of
renal function
Monitoring of renal function?
Dose modification? Dabigatran 15-30 ml/min 75 mg
x 2; Riva 30-50 ml/min 15 mg
51. CHADS2 subgroup analysis:
stroke and systemic embolism
Effect of dabigatran 150 mg was consistent
Dabigatran 110 mg BID Dabigatran 150 mg BID
vs. warfarin vs. warfarin
Annual rate (%)
D 110 D 150 P=0.37 P=0.84
CHADS2 mg mg
core BID BID Warf.
0–1 1.06 0.65 1.08
2 1.45 0.84 1.38
3–6 2.12 1.88 2.73
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction
Oldgren J et al. Ann Int Med 2011;155:660−9
52. History of stroke, TIA or non-CNS SE
OR
≥2* of the following:
CHF
Hypertension
Age ≥75 years
Diabetes
Effect of Rivaroxaban was consistent
53. Apixaban vs warfarin in
ARISTOTLE
Effect of Apixaban was consistent
Granger NEJM 2011
54. Prior stroke subgroup analysis: major clinical outcomes in
patients with or without previous stroke or TIA
Rate (% per year)
Dabigatran
110 mg 150 mg Warfarin Interaction P Interaction P
Stroke
Previous stroke or TIA 2.23 1.91 2.53
0.85 0.28
No previous stroke or TIA 1.24 0.78 1.34
chaemic or unknown stroke
Previous stroke or TIA 2.19 1.75 1.75
0.46 0.12
No previous stroke or TIA 1.12 0.71 1.08
Death from any cause
Previous stroke or TIA 3.24 4.39 4.58
0.06 0.50
No previous stroke or TIA 3.87 3.45 4.02
Haemorrhagic stroke
Previous stroke or TIA 0.08 0.20 0.77
0.09 0.97
No previous stroke or TIA 0.13 0.07 0.29
0.5 1.0 1.5 0.5 1.0 1.5
Favours Favours Favours Favours
110 mg warfarin 150 mg warfarin
dabigatran dabigatran
Effect of dabigatran was consistent with regard to reduction of the efficacy
endpoint (150 mg) as well as to reduction of ICH (both doses)
Diener HC et al. Lancet Neurol 2010;9:1157–63
55. Apixaban vs Warfarin in ARISTOTLE (Eastone et al. Lancet Neurology 2011)
Effect of Apixaban was consistent (and possibly higher) for reduction of the safety endpoints in pts with previous stroke
Eastone et al. Lancet Neurology 2011
56. Nuovi Anticoagulanti Orali non VK Antagonisti
Vantaggi
Dose – risposta prevedibile : dose fissa giornaliera
Non necessità di monitoraggio dell’anticoagulazione
Elevata efficacia e sicurezza
Significativa riduzione del rischio emorragico
Inizio e termine d’azione rapidi: non necessità di bridge con
eparina
Minime interazioni farmacologiche
Assenza di interazioni alimentari
Di Pasquale G, Riva L, G Ital Cardiol 2011; 12: 556-65
57. Nuovi Anticoagulanti Orali non VK Antagonisti
Svantaggi
Aggiustamento empirico del dosaggio
Necessità di nuovi test laboratoristici da eseguire in caso di
eventi emorragici o trombotici
Difficoltà di valutare l’aderenza del paziente alla terapia
Mancanza di antidoto in caso di sovradosaggio o emorragie
Inizio e termine d’azione rapidi: potenziale svantaggio nei
pazienti con bassa aderenza terapeutica
Possibile ridotta consapevolezza della terapia da parte del
paziente
Costo elevato
Di Pasquale G, Riva L, G Ital Cardiol 2011; 12: 556-65
58. Nuovi farmaci anticoagulanti
Problemi Aperti
Aderenza/persistenza
Come monitorare
Range terapeutico
Antidoto
Gestione dell’emorragia
Safety a lungo termine
59. Possible reasons to AF keep pts on warfarin (1)
GOOD LEVEL OF CONTROL - Because of the
twice daily dosing (D, A) and greater risk of
nonhemorrhagic side effects (D) patients already
taking warfarin with excellent INR control may have
little to gain by switching to dabigatran. Patient values
and preferences should influence the decision to initiate
dabigatran.
RENAL FAILURE - Warfarin remains the treatment
of choice for patients with a calculated creatinine
clearance close to or less than 30 mL/min.
MECHANICAL HEART VALVE
REPLACEMENT Schulman and Crowther 2012
60. Possible reasons to keep AF patients on warfarin (2)
GI DISEASE AND ELDERLY - When extracranial
bleeding is of particular concern, for example in patients over
75 yrs with a history of recurrent extracranial bleeding or
with preexisting coagulopathy, warfarin may be preferable vs D
because this drug is rapidly reversible. This concern may not be
true for the factor Xa inhibitors (?)
Patients with intestinal angiodysplasia, IBD, or diverticulosis, or
those with a history of other forms of GI bleeding may experience
a deterioration on treatment with D or R
Discontinuation of D was more frequent as a result of GI
distress, and over 11% of pts complained of dyspepsia
(attributed to both tartaric acid contained in the capsule and to a
high concentration of active drug in the colon).
Schulman and Crowther 2012
61. Possible reasons to keep AF patients on warfarin (3)
POOR COMPLIANCE (?) – However, with novel
agents, the first marker of noncompliance is probably
stroke or other thrombotic complications.
COSTS (?) - Many patients who do not have drug
coverage will probably remain on warfarin, despite
evidence that from a broader perspective novel agents
are cost-neutral or cost-effective in many settings
Schulman and Crowther 2012
62. Possible reasons to keep AF patients on NOAs
UNEXPLAINED POOR WARFARIN CONTROL - Warfarin-experienced
patients who continue to have variable INR results, corresponding to a TTR of
less than 65%, have lower rates of stroke and other complications when treated
with D 150 mg twice daily
POOR LEVEL OF CONTROL BECAUSE OF UNAVOIDABLE DRUG-
DRUG INTERACTION – frequent need for antibiotic treatment,
chemotherapy, amiodarone, frequent use of acetaminophen, azathioprine, or a
large number of concomitant medications, particularly if the exposure to these
medications varies
HISTORY OF INTRACRANIAL BLEEDING
NEW PATIENTS ON AF OR PATIENTS NEVER PRESCRIBED AVK
LOGISTIC PROBLEMS
PTS WILLING TO RECEIVE NOA
Modified from Schulman and Crowther 2012
63. ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran) JACC 2011
64. stroke risk reduction with antithrombotic therapy in AF
MT
Granger CB, Circulation 2012
66. Apixaban vs Warfarin in ARISTOTLE
Effect of Apixaban was consistent with regard to reduction of the safety endpoint
Granger NEJM 2011
67. CHADS2 subgroup analysis:
intracranial bleeding
Effect of dabigatran was consistent (no significant interaction with treatment)
Dabigatran 110 mg BID Dabigatran 150 mg BID
vs. warfarin vs. warfarin
Annual rate (%)
D 110 D 150 P=0.70 P=0.82
CHADS2 mg mg Warfari
score BID BID n
0-1 0.20 0.20 0–1
2 0.22 0.26 0.69
3–6 0.26 0.52 1.07
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction
Oldgren J et al. Ann Int Med 2011;155:660−9
68. New anticoagulants and CRF
Longer half-life
Monitoring of renal function
Doses reduction?
Drug interaction?
Connolly SJ et al, NEJM 2009
69. Age and bleeding subgroup analysis: intracranial and
extracranial bleeding
Annual rate (%) D110 vs. warfarin D150 vs. warfarin
Warfari P P
D110 D150 RR (95% CI) RR (95% CI)
n value* value*
Intracranial bleeding
0.22 (0.11– 0.43 (0.25–
<75 yrs 0.14 0.26 0.61
0.45) 0.74)
0.37 (0.21– 0.42 (0.25–
≥75 yrs 0.37 0.41 1.00 0.28 0.91
0.64) 0.70)
Extracranial bleeding
0.72 (0.57– 0.78 (0.63–
<75 yrs 1.76 1.91 2.44
0.90) 0.98)
1.20 (0.97– 1.39 (1.13–
≥75 yrs 4.10 4.68 3.44 0.001 <0.001
1.48) 1.70)
*P value for interaction; CI = confidence interval; D110 = dabigatran 110 mg twice daily;
D150 = dabigatran 150 mg twice daily; RR = relative risk
Eikelboom JW et al. Circulation 2011;123:2362–72
Dec 2011
70. Indirect Comparisons of New Oral Anticoagulant Drugs for Efficacy and Safety
When Used for Stroke Prevention in Atrial Fibrillation
Lip GYH, JACC 2012
71. Prior stroke subgroup analysis: major clinical outcomes
in patients with or without previous stroke or TIA
Rate (% per year)
Dabigatran
110 mg 150 mg
Warfarin Interaction P Interaction P
Total bleeding
Previous stroke or TIA 14.49 16.90 18.53
0.57 0.65
No previous stroke or TIA 14.71 16.33 18.15
Major bleeding
Previous stroke or TIA 2.74 4.15 4.15
0.15 0.51
No previous stroke or TIA 2.91 3.10 3.43
Intracranial bleeding
Previous stroke or TIA 0.25 0.53 1.28
0.26 0.91
No previous stroke or TIA 0.22 0.27 0.63
Gastrointestinal major bleed
Previous stroke or TIA 1.39 2.32 1.41
0.68 0.53
No previous stroke or TIA 1.35 1.73 1.23
0.5 1.0 1.5 0.5 1.0 1.5
Favours Favours Favours Favours
110 mg warfarin 150 mg warfarin
dabigatran dabigatran
No significant interactions between primary and secondary outcomes in
patients with and without a history of prior stroke
TIA = transient ischaemic attack
Diener HC et al. Lancet Neurol 2010;9:1157–63 Dec 2011
72. SUBGROUP ANALYSIS:
HAEMORRHAGIC STROKE
Annual rate (%)
D 110 D 150 D 110 mg BID D 150 mg BID
Warfarin vs. warfarin vs. warfarin
mg BID mg BID
Age (yrs) P=0.51 P=0.75
<65 0.05 0.05 0.38
65–74 0.08 0.08 0.31
≥75 0.2 0.15 0.47
Creatinine clearance (mL/min) P=0.67 P=0.4
30–50 0.26 0.12 0.58
51–80 0.12 0.09 0.47
>80 0.03 0.08 0.13
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0
Dabigatran Warfarin Dabigatran Warfarin
better better better better
BID = twice daily; D = dabigatran; P values for interaction.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Healey JS, et al. ACC 2010; abstr 1078-120.
73. Stroke prevention: Anticoagulant effect
Meta-analysis of stroke or systemic embolism
ICH
Relative Hazard Ratio
(95% CI) W vs Dabiga 110
W vs Placebo W vs Rivaroxa
W vs W low dose W vs Dabiga 150
W vs Aspirin W vs Apixaban 5
W vs Aspirin+Clop
W vs Ximelagatran
W vs Dabiga 110
Major bleeding
W vs Rivaroxa
W vs Dabiga 150 W vs Dabiga 110
W vs Apixaban 5 W vs Rivaroxa
W vs Dabiga 150
Favours Warfarin Favours other RX W vs Apixaban 5
Favours Warfarin Favours other RX
74. Age and bleeding subgroup analysis:
major bleeding
Annual rate (%) D110 vs. warfarin D150 vs. warfarin
RR P RR P
D110 D150 Warfarin
(95% CI) value* (95% CI) value*
0.62 0.70
<75 yrs 1.89 2.12 3.04
(0.50–0.77) (0.57–0.86)
<0.001 <0.001
1.01 1.18
≥75 yrs 4.43 5.10 4.37
(0.83–1.23) (0.98–1.42)
*P value for interaction; CI = confidence interval; D110 = dabigatran 110 mg twice daily;
D150 = dabigatran 150 mg twice daily; RR = relative risk
Eikelboom JW et al. Circulation 2011;123:2362–72
Dec 2011
75. New Anticoagulants
ORAL PARENTERAL
TF/VIIa TFPI (tifacogin)
TTP889
X IX
IXa APC (drotrecogin alfa)
VIIIa sTM (ART-123)
Va
Rivaroxaban AT Fondaparinux
Apixaban Xa
Idraparinux
Edoxaban
II
DX-9065a
Dabigatran IIa
THROMBIN
Fibrinogen Fibrin
Weitz & Bates, J Thromb Haemost 2005
77. Dabigatran versus Warfarin in Patients with Atrial Fibrillation:
RE-LY trial
Dabigatran 110
mg BID
(N=6013)
Blinded
Patients with Primary study outcome:
Dabigatran 150 stroke or systemic
NVAF and ≥ 1
mg BID
F.U. embolism
risk factors R
(N=6075) 2 years Primary safety outcome:
(N=18113)
major bleeding
Open
Warfarin adjusted
(N=6013)
Connolly SJ et al, NEJM 2009
78. Rivaroxaban versus Warfarin in Nonvalvular atrial
fibrillation: ROCKET AF trial
Rivaroxaban 20
mg/die (or 15
mg/die if Cr Cl Primary study outcome:
Patients with 30-49 ml/min) stroke or systemic
NVAF at F.U. embolism
moderate-to-high R (N=7131)
risk of stroke Primary safety outcome:
Warfarin adjusted major and nonmajor
(N=14.264)
(N=7133) clinically relevant bleeding
Patel MR et al, NEJM 2011
79. Apixaban versus Warfarin in Patients with Atrial
Fibrillation: ARISTOTLE trial
Apixaban 5 mg BID
(2.5 mg BID if age≥80
ys, body weight<60 Kg,
Patients with AF Crea>1.5 mg/dl)
Primary study outcome:
and ≥ 1 risk
(N=9120)
F.U. stroke or systemic
factors R embolism
(N=18.201) Primary safety outcome:
Warfarin adjusted major bleeding according to
the ISTH criteria
(N=9081)
Granger CB et al, NEJM 2011
80. Bleeding
P<0.001
%
20 P=0.002
15
10
P=0.03
P<0.01 P=0.43
P=0.31
5
P=0.04 P<0.001
0
g g g g
in in in in
eed e ed e ed ed
bl bl bl le
al or g a lb
t aj in in
To M en t
t t es
ea in
hr ro
fe
-T a st
Li G
Dabigatran 110 mg Dabigatran 150 mg Warfarin
Connolly SJ et al, NEJM 2009
82. Study design
AF on Electrical
N = 21,107 Recording < 12 mo
Intended oral A/C
CHADS2 > 2
R
Low Exposure High Exposure Active Control
Strategy Strategy Warfarin
Edoxaban 30 mg QD Edoxaban 60 mg QD (INR 2.0 – 3.0)
Median duration of follow up 24-months
Primary Objective
Edoxaban: Therapeutically as good as Warfarin
1º EP = Stroke or SEE (Non inferiority Boundary HR 1.38)
2º EP = Stroke or SEE or All-Cause Mortality
Safety EPs = Major Bleeding, Hepatic Function
SEE=systemic embolic event
Ruff CT et al. Am Heart J. 2010;160:635-41
Notas do Editor
G02-536 w_script.ppt 03/20/13 10:47 AM
G02-536 w_script.ppt 03/20/13 10:47 AM * In an on treatment analysis in Rocket AF Ischemic Stoke rates were 1.34% / yr for rivaroxaban and 1.42% / yr for warfarin, p=0.58. No on treatment analysis is available from RE-LY.
RE-LY ® – Age and renal function subgroup analysis: Stroke and non-CNS embolism There was no significant interaction between either patient age or renal function subgroup and the rate of stroke and non-CNS embolism with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
RE-LY ® – Age and renal function subgroup analysis: Major bleeding There was a significant interaction between patient age and the rate of major bleeding with both doses of dabigatran versus warfarin. 1 For dabigatran 150 mg BID and 110 mg, major bleeding rates were significantly lower compared with warfarin in patients aged <65 years and 65-74 years, whereas in patients aged ≥75 years, major bleeding rates were similar with dabigatran and warfarin. 1 There was no significant interaction between renal function and the rate of major bleeding with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
RE-LY ® – Age and renal function subgroup analysis: Stroke and non-CNS embolism There was no significant interaction between either patient age or renal function subgroup and the rate of stroke and non-CNS embolism with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
RE-LY ® – Age and renal function subgroup analysis: Major bleeding There was a significant interaction between patient age and the rate of major bleeding with both doses of dabigatran versus warfarin. 1 For dabigatran 150 mg BID and 110 mg, major bleeding rates were significantly lower compared with warfarin in patients aged <65 years and 65-74 years, whereas in patients aged ≥75 years, major bleeding rates were similar with dabigatran and warfarin. 1 There was no significant interaction between renal function and the rate of major bleeding with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
Patients with atrial fibrillation ( paroxysmal, persistent, or permanent) AF and a CHADS2 score of 2 or greater are eligible for the study, and both patients with or without previous Vitamin K antagonist experience can be included in the trial. Patients will be randomized to one of two dosing regimens of Edoxaban or to the Vitamin K antagonist Warfarin in a 1:1:1 matter. In addition, dose reductions for certain patient groups will apply similarly in both Edoxaban regimens. The primary objective of the study is to demonstrate non-inferiority of either Edoxaban arm versus Warfarin with regard to the primary endpoint, the incidence of stroke and systemic embolic events. The non-inferiority margin for this study for the risk ratio is set at 1.38. The mean follow up of this event driven study is not fixed as ENGAGE AF-TIMI 48 is an event-driven study, but it is expected to be 2 years.
Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638).
RE-LY ® – Age and renal function subgroup analysis: Stroke and non-CNS embolism There was no significant interaction between either patient age or renal function subgroup and the rate of stroke and non-CNS embolism with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
RE-LY ® – Age and renal function subgroup analysis: Major bleeding There was a significant interaction between patient age and the rate of major bleeding with both doses of dabigatran versus warfarin. 1 For dabigatran 150 mg BID and 110 mg, major bleeding rates were significantly lower compared with warfarin in patients aged <65 years and 65-74 years, whereas in patients aged ≥75 years, major bleeding rates were similar with dabigatran and warfarin. 1 There was no significant interaction between renal function and the rate of major bleeding with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638).
RE-LY ® – Age and renal function subgroup analysis: Stroke and non-CNS embolism There was no significant interaction between either patient age or renal function subgroup and the rate of stroke and non-CNS embolism with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
RE-LY ® – Age and renal function subgroup analysis: Major bleeding There was a significant interaction between patient age and the rate of major bleeding with both doses of dabigatran versus warfarin. 1 For dabigatran 150 mg BID and 110 mg, major bleeding rates were significantly lower compared with warfarin in patients aged <65 years and 65-74 years, whereas in patients aged ≥75 years, major bleeding rates were similar with dabigatran and warfarin. 1 There was no significant interaction between renal function and the rate of major bleeding with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638).
Interaction with age was evident for extracranial bleeding, but not for intracranial bleeding
RE-LY ® – Age and renal function subgroup analysis: Haemorrhagic stroke There was no significant interaction between either patient age or renal function and the rate of haemorrhagic stroke with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
Compared with warfarin, both doses of dabigatran were associated with lower risks of major bleeding in patients aged <75 years and with similar or higher risks for those aged ≥75 years
ISTH criteria: clinically overt bleeding accompanied by a decrease in the hemoglobin level of at least 2 g per deciliter or transfusion of at least 2 units of packed red cells, occurring at a critical site, or resulting in death.
Patients with atrial fibrillation ( paroxysmal, persistent, or permanent) AF and a CHADS2 score of 2 or greater are eligible for the study, and both patients with or without previous Vitamin K antagonist experience can be included in the trial. Patients will be randomized to one of two dosing regimens of Edoxaban or to the Vitamin K antagonist Warfarin in a 1:1:1 matter. In addition, dose reductions for certain patient groups will apply similarly in both Edoxaban regimens. The primary objective of the study is to demonstrate non-inferiority of either Edoxaban arm versus Warfarin with regard to the primary endpoint, the incidence of stroke and systemic embolic events. The non-inferiority margin for this study for the risk ratio is set at 1.38. The mean follow up of this event driven study is not fixed as ENGAGE AF-TIMI 48 is an event-driven study, but it is expected to be 2 years.