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

Stefano Savonitto S.C. Cardiologia La terapia anticoagulante fra warfarin e nuovi anticoagulanti orali cosa fare?

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

Indications for VKA-treated patients in Italy Data from quality control Of FCSA 16.39% 16.88% 66.73% FA AF VTE PVM

AF PREVALENCE INCREASES WITH AGE 9 8 7 9.0% AF prevalence (%) 6 5 4 3 2 3.8% 1 0 0.95% General population 60 yrs Age 80 yrs Go AS, et al. JAMA 2001;285:2370-2375

Conditions predisposing to AF 2010 ESC Guidelines 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 Eur Heart J 2010;31:2369-2429

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

Trombosi a tappo del TC Coronarie peraltro indenni

AF SIGNIFICANTLY INCREASES THE RISK OF STROKE AF is associated with a pro-thrombotic state 1 ~5-fold increase in stroke risk 2 Up to 3 million people worldwide suffer strokes related to AF each year 2-4 AF-related strokes tend to be especially severe and disabling with 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 AF 6,7 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 The American Heart Association estimates that the direct and indirect cost of stroke in the US is $65.5 billion 1 A German Registry has shown that the overall first-year cost of stroke is 18,517 2 A 15% reduction in hospital admissions due to AF-related strokes in the UK would save an estimated 30 million/year 3 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..

ACC/AHA/ESC 2006 GUIDELINES FOR ANTITHROMBOTIC THERAPY IN AF Risk category CHADS 2 score Recommended therapy No risk factors 0 Aspirin 81 325 mg daily One moderate-risk factor 1 Any high-risk factor or 2 moderate-risk factors Less validated/ weaker-risk factors Female gender Age 65 74 yrs Coronary artery disease Thyrotoxicosis 2 Moderate-risk factors Age 75 yrs Hypertension Heart failure LVEF 35% Diabetes mellitus Aspirin 81 325 mg daily or warfarin (INR 2.0 3.0, target 2.5)* Warfarin (INR 2.0 3.0, target 2.5) High-risk factors Previous stroke, TIA or embolism Mitral stenosis Prosthetic heart valve* * 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. Fuster V, et al. Circulation 2006;114:e257 354.

Antithrombotic drug prescription per risk category according to CHADS 2 score in an italian survey (y 2001-2004) Mazzaglia G et al. Thromb Haemost 2010;103:968-75

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 Age % 30-64 28 65-74 40 75-84 33 >85 15 N p 1140 <0.001 1698 1946 636 Age % 30-64 24 65-74 34 75-84 40 >85 52 0.5 1 2 3 4 Probability of being on antiplatelet agents 0.5 1 2 3 4 Mazzaglia G et al. Thromb Haemost 2010;103:968-75 N p 1140 <0.001 1698 1946 636

SIMILAR RATES OF MAJOR BLEEDING FOR ORAL ANTICOAGULATION VS. ANTIPLATELET THERAPY Rate of major bleeding (% per year) 4 3 2 0 Superior stroke prevention with anticoagulation Oral anticoagulation N=3,371 In ACTIVE-W trial 1 P=0.53 Clopidogrel + Aspirin N=3,335 Rate of all major bleeding (%) 1 1 42% risk of stroke with oral anticoagulation vs. clopidogrel + Aspirin 4 3 2 0 In BAFTA trial 2 patients 75 yrs of age (N=973) Warfarin P=0.9 Aspirin 52% risk of stroke, intracranial haemorrhage, systemic embolism with warfarin vs. Aspirin 1. Connolly S for the ACTIVE Investigators. Lancet 2006;367:1903-1912. 2. Mant J, et al. Lancet 2007;370:493-503.

MANAGEMENT OF AF IN CLINICAL PRACTICE: PRESCRIPTION OF VKAs in AF patients No anticoagulation VKAs 64% 67% 55% N=23,657 Medicare cohort, USA Birman-Deych E, et al. Stroke 2006;37:1070-1074 N=5,333 EuroHeart survey Nieuwlaat R, et al. Eur Heart J 2005;26:2422-2434 N=11,409 ATRIA cohort (managed care system, California, USA) Go AS, et al. JAMA 2003;290:2685-2692

One and two-year persistence on OAC in AF patients italian survey on 400 primary care physicians: years 2001-2004 Mazzaglia G et al. Thromb Haemost 2010;103:968-75

Limitations of VKA therapy Unpredictable response Narrow therapeutic window (INR range 2-3) Need for routine monitoring of INR Slow onset/offset of action VKA therapy has limitations that render their use difficult in clinical practice Need for frequent dose adjustments Numerous food-drug interactions Numerous drug-drug interactions Warfarin resistance

The narrow therapeutic window of VKA Gersh B. Rev Esp Card 2011;64;260-8

TIME-IN-THERAPEUTIC-RANGE WITH WARFARIN USE IN CLINICAL PRACTICE 100 Time in therapeutic range (%) 80 60 40 20 47 36 51 56 49 52 63 55 42 51 0 Samsa 2000 2 N=61 Samsa 2000 2 N=125 McCormick 2001 3 N=174 Matchar 2003 4* N=363 Matchar 2003 4* N=317 Matchar 2003 4* N=317 Go 2003 5 N=7,445 Shen 2007 6 N=11,016 Nichol 2008 7* N=756 Average 1 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. JAMA 2003;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.

Established and new Anticoagulants a. Bypasses the CYP450 pathway. b: withdrawan due to hepatotoxcicity Gersh B. Rev Esp Card 2011;64;260-8

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) 150, 110 20 (15*) 5 (2.5*) 60*, 30* Freq BID QD BID 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/see PROBE = 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 CHADS 2 Mean 0-1 (%) 2 (%) 3+ (%) ROCKET AF Comparison of Trial Metrics C. Michael Gibson, M.S., M.D. 2.1 32.6 34.7 32.7 2.2 32.2 35.2 32.6 Rivaroxaban 2.1 30.9 37.0 32.1 Warfarin CHADS 2 Mean 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) 3.5 13 43 29 13 2 3.5 13 44 28 12 2 3+ 87% ARISTOTLE Rivaroxaban Warfarin CHADS 2 Mean 0-1 (%) 2 (%) 3+ (%) 2.1 34 35.8 30.2 2.1 34 35.8 30.2

Comparison of Trial Metrics C. Michael Gibson, M.S., M.D. RE-LY ROCKET AF ARISTOTLE Time in Therapeutic Range (TTR) 64% 67% warfarinexperienced 61% warfarinnaïve 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

Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis C. Michael Gibson, M.S., M.D. Non Inferiorirty p vs warfarin RE-LY Dabigatran 110 mg Dabigatran 150 mg Warfarin 1.53% per year 1.11% per year 1.69% per year HR = 0.91 HR = 0.66 ITT Analysis p<0.001 p<0.001 ROCKET AF Rivaroxaban 20mg Warfarin 1.7% per year 2.2% per year HR = 0.79 Modified ITT p<0.001 ARISTOTLE Apixaban 5 mg Warfarin 1.27% per year 1.60% per year HR = 0.79 ITT Analysis p<0.001 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. 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

All Cause Mortality RELY HR ITT p-value Dabigatran 110 mg 3.75% / yr 0.91 0.35 Dabigatran 150 mg 3.64% / yr 0.88 0.051 Warfarin 4.13% / yr ROCKET Rivaroxaban 20 mg 4.52% / yr 0.92 0.152* Warfarin 4.91% / yr ARISTOTLE Apixaban 5 mg 3.52% / yr 0.89 0.01 Warfarin 3.94% / yr *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. 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 C. Michael Gibson, M.S., M.D.

Ischemic Stroke RELY ITT HR P-value Dabigatran 110 mg 1.34% / yr 1.20 0.35 Dabigatran 150 mg 0.92% / yr 0.76 0.03 Warfarin 1.20% / yr ROCKET Rivaroxaban 20 mg 1.62% / yr 0.99 0.92* Warfarin 1.64% / yr ARISTOTLE Apixaban 5 mg 0.97% / yr 0.92 0.42 Warfarin 1.05% / yr *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. 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

Hemorrhagic Stroke RELY HR ITT P-value Dabigatran 110 mg 0.12% / yr 0.31 <0.001 Dabigatran 150 mg 0.10% / yr 0.26 <0.001 Warfarin 0.38% / yr ROCKET Rivaroxaban 20 mg 0.26% / yr 0.59 0.012* Warfarin 0.44% / yr ARISTOTLE Apixaban 5 mg 0.24% / yr 0.51 <0.001 Warfarin 0.47% / yr *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. 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

Major Bleeding RE-LY HR Dabigatran 110 mg 2.71% / yr 0.8 0.003 Dabigatran 150 mg 3.11% / yr 0.93 0.31 Warfarin 3.36 150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00 1.34) p = 0.052 ROCKET ITT P-value Rivaroxaban 20 mg 3.60% / yr 0.92 0.58* Warfarin 3.45% / yr *There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY. On Treatment P-value ARISTOTLE P-value Apixaban 5 mg 2.13% / yr 0.69 <0.001 Warfarin 3.09% / yr 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

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

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

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Hurdles and difficulties in the adoption of new anticoagulants Gersh B. Rev Esp Card 2011;64:260-8

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 Ansell J. Circulation 2012;125:165-70

AGE DISTRIBUTION OF VKS TREATED PTS IN CLINICAL PRACTICE (ITALY) AND TRIALS Percento 0 10 20 30 Data from quality control Of FCSA MEAN AGE = 76 YEARS 0 20 40 60 80 100 Età (anni) Age (years) 85-80- 75-70- 65-76 73 71.5 70 FCSA ROCKET AF RE-LY ARISTOTLE

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 Hohnloser SH. Circulation 2012;125:669-76

Feasibility of periprocedural dabigatran during ablation for AF Lakireddy D. JACC 2012; published online february 1

Feasibility of periprocedural dabigatran during ablation for AF Lakireddy D. JACC 2012; published online february 1

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

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