la terapia anticoagulante fra warfarin e nuovi ... · la terapia anticoagulante fra warfarin e...

Data: 16 febbraio 2012

Evento: Tigullio cuore

Titolo: Nuovi anticoagulanti nel trattamento FAAutore: Stefano Savonitto

La terapia anticoagulante fra warfarin e nuovi anticoagulanti orali cosa fare?

Stefano SavonittoS.C. Cardiologia




Estimates of numbers and prevalence of patients on VKA in Italy

2005 2008

N° pts 702,052 911,269 29.8

prevalence 1.21% 1.58%

Manotti C. XXI congress FCSA, Parma 2010




66.73%

16.88%

16.39%

FA VTE PVM

Indications for VKA-treated patients in Italy

Data from quality controlOf FCSA

AF VTE PVM




AF PREVALENCE INCREASES WITH AGE

Go AS, et al. JAMA 2001;285:2370-2375

AF

prev

alen

ce (%

)9

8

7

6

5

4

3

2

1

0General population

Age≥60 yrs ≥80 yrs

9.0%

3.8%

0.95%




Conditions predisposing to AF2010 ESC Guidelines

Eur Heart J 2010;31:2369-2429

• hypertension

• heart failure NYHA II-IV

• valvular heart disease

• cardiomyopathies

• atrial septal defect and

other congenital heart defects

• coronary heart disease

• tyroid dysfunction

• obesity

• diabetes

• COPD and sleep apnea syndr

• chronic renal disease




Uomo, 58 anni, no fattori di rischio cardiovascolareImprovviso malore con shock cardiogeno




Trombosi a tappo del TCCoronarie peraltro indenni




AF SIGNIFICANTLY INCREASES THE RISK OF STROKE

• AF is associated with a pro-thrombotic state1

– ~5-fold increase in stroke risk2

• Up to 3 million people worldwide suffer strokes related to AF each year2-4

• AF-related strokes tend to be especially severe and disablingwith a 1-year mortality rate of ~50%4,5

– Cardioembolic stroke has a 30-day mortality rate of 25%4

• Risk of stroke is the same in AF patients regardless of whether they have paroxysmal or sustained AF6,7

1. Watson T, et al. Lancet 2009;373:155-166. 2. Wolf PA, et al. Stroke 1991;22:983-988. 3. Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed at http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf. 4. Lin HJ, et al. Stroke 1996;27:1760-1764. 5. Marini C, et al. Stroke 2005;36:1115-1119. 6. Rosamond W, et al. Circulation 2008;117:e25-146. 7. Hart RG, et al. J Am Coll Cardiol 2000;35:183-187.




ECONOMIC BURDEN OF STROKE

1. Rosamond W, et al. Circulation 2008;117:e25-146. 2. Kolominsky-Rabas PL, et al. Stroke 2006;37:1179-1183. 3. Stewart S, et al. Heart. 2004;90:286-292..

The American Heart Association estimates that the direct and indirect cost of stroke in the US is $65.5 billion1

A German Registry has shown that the overall first-year cost of stroke is €18,5172

A 15% reduction in hospital admissions due to AF-related strokes in the UK would save an estimated £30 million/year3




ACC/AHA/ESC 2006 GUIDELINES FOR ANTITHROMBOTIC THERAPY IN AF

Fuster V, et al. Circulation 2006;114:e257–354.

*Choice of agent should be based on consideration of bleeding risk, ability to sustain chronic anticoagulation safely and patient preference; †If mechanical valve, target INR >2.5.

Risk category CHADS2 score Recommended therapy

No risk factors 0 Aspirin 81–325 mg daily

One moderate-risk factor 1Aspirin 81–325 mg daily orwarfarin (INR 2.0–3.0, target 2.5)*

Any high-risk factor or 2 moderate-risk factors 2 Warfarin (INR 2.0–3.0, target

2.5)†

Less validated/weaker-risk factors Moderate-risk factors High-risk factors

Female genderAge 65–74 yrsCoronary artery diseaseThyrotoxicosis

Age 75 yrsHypertensionHeart failureLVEF 35%Diabetes mellitus

Previous stroke, TIA or embolismMitral stenosisProsthetic heart valve*




Mazzaglia G et al. Thromb Haemost 2010;103:968-75

Antithrombotic drug prescription per risk category according to CHADS2 score in an italian survey (y 2001-2004)





Probability of being on OAC or antiplaletet agents in AF patients Italian survey on 400 primary care physicians: years 2001-2004

Probability of being on OAC

Probability of being on antiplatelet agents

0.5 1 2 3 4

Age %30-64 2865-74 4075-84 33>85 15

0.5 1 2 3 4

Age %30-64 2465-74 3475-84 40>85 52

N p1140 <0.00116981946636

N p1140 <0.00116981946636




1. Connolly S for the ACTIVE Investigators. Lancet 2006;367:1903-1912. 2. Mant J, et al. Lancet 2007;370:493-503.

SIMILAR RATES OF MAJOR BLEEDING FOR ORAL ANTICOAGULATION VS. ANTIPLATELET THERAPY

Rat

e of

all

maj

or b

leed

ing

(%)

Rat

e of

maj

or b

leed

ing

(% p

er y

ear) 4

3

0

2

Oral anticoagulationN=3,371

Clopidogrel + AspirinN=3,335

Warfarin Aspirin

4

3

0

2

In ACTIVE-W trial1 In BAFTA trial2 patients ≥75 yrs of age(N=973)

P=0.53 P=0.9

42% risk of stroke with oral anticoagulation

vs. clopidogrel + Aspirin

52% risk of stroke, intracranialhaemorrhage, systemic embolism

with warfarin vs. Aspirin

1 1

Superior strokeprevention withanticoagulation




MANAGEMENT OF AF IN CLINICAL PRACTICE: PRESCRIPTION OF VKAs in AF patients

N=11,409ATRIA cohort

(managed care system,California, USA)

Go AS, et al.JAMA 2003;290:2685-2692

N=5,333EuroHeart survey

Nieuwlaat R, et al.Eur Heart J 2005;26:2422-2434

N=23,657Medicare cohort, USA

Birman-Deych E, et al.Stroke 2006;37:1070-1074

64% 67% 55%

No anticoagulation VKAs





One and two-year persistence on OAC in AF patients italian survey on 400 primary care physicians: years 2001-2004




Limitations of VKA therapy

Unpredictable response

Need for routine monitoring of INR

Slow onset/offset of action Warfarin resistance

VKA therapy has

limitations that render their use

difficult in clinical practice

Numerous drug-drug interactions

Numerous food-drug interactions

Need for frequent dose adjustments

Narrow therapeutic window

(INR range 2-3)




Gersh B. Rev Esp Card 2011;64;260-8

The narrow therapeutic window of VKA




TIME-IN-THERAPEUTIC-RANGE WITH WARFARIN USE IN CLINICAL PRACTICE

1. Baker WL, et al. J Manag Care Pharm 2009;15:244-252. 2. Samsa GP, et al. Arch Intern Med 2000;160:967-973. 3. McCormick D, et al. Arch Intern Med 2001;161:2458-2463. 4. Matchar DB. Card Electrophysiol Rev 2003;7:379-381. 5. Go AS, et al. JAMA2003;290:2685-2692. 6. Shen AY, et al. J Am Coll Cardiol 2007;50:309-315. 7. Nichol MB, et al. Ann Pharmacother 2008;42:62-70.

Tim

e in

ther

apeu

tic ra

nge

(%)

100

80

60

40

20

0Samsa20002

N=61

Samsa20002

N=125

McCormick20013

N=174

Matchar20034*

N=363

Matchar20034*

N=317

Matchar20034*

N=317

Go20035

N=7,445

Shen20076

N=11,016

Nichol20087*

N=756

Average1†

5542

514736

51 5649 52

63




Gersh B. Rev Esp Card 2011;64;260-8

Established and new Anticoagulants

a. Bypasses the CYP450 pathway. b: withdrawan due to hepatotoxcicity




Comparison of the pharmacological characteristics of warfarin and newer antithrombotic agents in atrial fibrillation.

Granger CB , Armaganijan LV. Circulation 2012;125:159-164




Phase III AF Trials

Re-LY ROCKET-AF ARISTOTLE ENGAGE AF-TIMI 48

Drug Dabigatran Rivaroxaban Apixaban Edoxaban

Dose (mg)Freq

150, 110BID

20 (15*)QD

5 (2.5*)BID

60*, 30*QD

N 18,113 14,266 18,206 >21,000

Design PROBE 2x blind 2x blind 2x blind

AF criteria AF x 1< 6 mths

AF x 2(>1 in <30d)

AF or AFl x 2<12 mths

AF x 1 < 12 mths

% VKA naive 50% 38% 43% 40% goal

*Dose adjusted in patients with ↓drug clearance. **Max of 10% with CHADS-2 score = 2 and no stroke/TIA/SEEPROBE = prospective, randomized, open-label, blinded end point evaluation VKA = Vitamin K antagonist




Indirect comparisons of the relative effects of placebo or no therapy, antiplatelet regiments, and anticoagulant regimens vs

warfarin in reducing the risk of stroke and systemic embolism

Hankey G J , Eikelboom J W Circulation 2011;123:1436-1450




RELY Dabigatran 110 mg Dabigatran 150 mg Warfarin

CHADS2 Mean0-1 (%)2 (%)3+ (%)

2.132.634.732.7

2.232.235.232.6

2.130.937.032.1

C. Michael Gibson, M.S., M.D.

ROCKET AF Rivaroxaban Warfarin

CHADS2 Mean2 (%)3 (%)4 (%)5 (%)6 (%)

3.5134329132

3.5134428122

ARISTOTLE Rivaroxaban Warfarin

CHADS2 Mean0-1 (%)2 (%)3+ (%)

2.134

35.830.2

2.134

35.830.2

3+87%

Comparison of Trial Metrics




RE-LY ROCKET AF

ARISTOTLE

Time in Therapeutic Range (TTR)

64%67% warfarin-

experienced61% warfarin-

naïve

Mean 55%Median

58%

62%

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


Comparison of Trial Metrics




RE-LYDabigatran 110 mg 1.53% per yearDabigatran 150 mg 1.11% per yearWarfarin 1.69% per year

ROCKET AFRivaroxaban 20mg 1.7% per yearWarfarin 2.2% per year

ARISTOTLEApixaban 5 mg 1.27% per yearWarfarin 1.60% per year

Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis

p<0.001

p<0.001p<0.001

Non Inferiorirtyp vs warfarin

ITT Analysis

Modified ITT

No ITT analysis is available for non-inferiority in Rocket AF. An on treatment or per-protocol analysis is generally performed in the assessment of non-inferiority. If numerous patients come off of study drug, this biases the trial towards a non-inferior result in an ITT analysis. This is the basis for performing a per-protocol analysis in a non-inferiority assessment.


p<0.001ITT Analysis


HR = 0.79

HR = 0.79

HR = 0.91HR = 0.66




All Cause Mortality

Dabigatran 110 mg 3.75% / yr 0.91 0.35Dabigatran 150 mg 3.64% / yr 0.88 0.051 Warfarin 4.13% / yr

HRITT

p-value

Rivaroxaban 20 mg 4.52% / yr 0.92 0.152*Warfarin 4.91% / yr

ROCKET

RELY


*In an on treatment analysis in Rocket AF mortality rates were 1.87% / yr for rivaroxaban and 2.21% / yr for warfarin, p=0.073. No on treatment analysis is available from RE-LY.

Apixaban 5 mg 3.52% / yr 0.89 0.01Warfarin 3.94% / yr

ARISTOTLE





Ischemic Stroke

Dabigatran 110 mg 1.34% / yr 1.20 0.35Dabigatran 150 mg 0.92% / yr 0.76 0.03 Warfarin 1.20% / yr

HRITT

P-value


ROCKET

RELY

*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.

Apixaban 5 mg 0.97% / yr 0.92 0.42Warfarin 1.05% / yr

ARISTOTLE





Hemorrhagic Stroke

Dabigatran 110 mg 0.12% / yr 0.31 <0.001Dabigatran 150 mg 0.10% / yr 0.26 <0.001Warfarin 0.38% / yr

HRITT

P-value


ROCKET

RELY

*In an on treatment analysis in Rocket AF Hemorrhagic Stoke rates were 0.26% / yr for rivaroxaban and 0.44% / yr for warfarin, p=0.024. No on treatment analysis is available from RE-LY.

Apixaban 5 mg 0.24% / yr 0.51 <0.001Warfarin 0.47% / yr

ARISTOTLE





Dabigatran 110 mg 2.71% / yr 0.8 0.003Dabigatran 150 mg 3.11% / yr 0.93 0.31Warfarin 3.36150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052

Major Bleeding

HRITT

P-valueRE-LY


ROCKET

*There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY.

On TreatmentP-value

P-value

Apixaban 5 mg 2.13% / yr 0.69 <0.001Warfarin 3.09% / yr

ARISTOTLE





Conclusions

Class Effects:• All three novel anticoagulants are non-inferior to warfarin in reducing the risk of stroke and systemic embolization.• All three agents reduce the risk of bleeding and intracranial hemorrhage. • The directionality and magnitude of the mortality reduction is consistent and approximates a RRR of 10% / year

Differentiators:• Dabigatran at a dose of 150 mg was associated with a reduction in ischemic stroke• Rivaroxaban is a once a day drug associated with a lower rate of fatal bleeding• Apixaban was associated with a reduction in all cause but not CV mortality





19 October 2010

FDA approves dabigatran for stroke prevention, embolism, in AF patients

The drug will be available in two doses: 75 mg and 150 mg

4 August 2011

EMA approves PRADAXA with the flexibility of two dosing regimens

Overall the 150 mg bid dose is recommended

The 110 mg bid dose is indicated for: elderly patients aged 80 years at higher risk of bleeding and for those taking verapamil




Downloaded from nejm.org on April 14, 2011.




Gersh B. Rev Esp Card 2011;64:260-8

Hurdles and difficulties in the adoption of new anticoagulants




Ansell J. Circulation 2012;125:165-70

Rates of stroke and systemic embolism according to TTR in RE-LY




Ansell J. Circulation 2012;125:165-70

Rates of stroke and systemic embolism according to TTR in ROCKET-AF




010

2030

Per

cent

o

0 20 40 60 80 100Età (anni)

AGE DISTRIBUTION OF VKS TREATED PTS IN CLINICAL PRACTICE (ITALY) AND TRIALS

MEAN AGE = 76 YEARS

Data from quality controlOf FCSA

85-

80-

75-

70-

65-

7673

71.5 70

FCSA ROCKETAF

RE-LY ARISTOTLE

Age (years)




Hohnloser SH. Circulation 2012;125:669-76

Unexpected excess in MI rates with dabigatran vs warfarin in RE-LY?




Hohnloser SH. Circulation 2012;125:669-76

Unexpected excess in MI rates with dabigatran vs warfarin in RE-LY?

1/3 of MIs occurred >6 days off drugs




Lakireddy D. JACC 2012; published online february 1

Feasibility of periprocedural dabigatran during ablation for AF




Guide to the management of bleeding in patients taking dabigatran

Hankey G J , Eikelboom J W Circulation 2011;123:1436-1450




Stroke risk reductions from randomized trials of antithrombotic agents in atrial fibrillation.

Granger CB , Armaganijan LV Circulation 2012;125:159-164




What Do We Spend In Society To Save A Life?

http://www.cbe.wwu.edu/Krieg/Econ.%20Documents/how_much_for_a_life.htm

New York Times, January 29, 1995, p. F3.

Dol

lars

Spe

nt T

o Sa

ve A

Life