NUOVI ANTICOAGULANTI NELL ANZIANO: indicazioni e controindicazioni. Mario Cavazza Medicina d Urgenza Pronto Soccorso AOU di Bologna

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1 NUOVI ANTICOAGULANTI NELL ANZIANO: indicazioni e controindicazioni Mario Cavazza Medicina d Urgenza Pronto Soccorso AOU di Bologna

2 Two major concerns

3

4 Atrial Fibrillation: Epidemiology The No. 1 preventable cause of stroke In the United States, up to 16 million individuals will be affected by the year 2050 Increasing survival from heart attack and increasing age ( the graying of America ) help explain rise in incidence of AF

5 Atrial Fibrillation: An Epidemic Projected Number of People with AF (millions) Prevalence 16 million Miyakasa Y, et al. Circulation Year

6 AF & STROKE Framingham,1987

7 CHA 2 DS 2 -VASc Score Weight (points) Congestive heart failure or LVEF < 35% 1 Hypertension 1 Age > 75 years 2 Diabetes mellitus 1 Stroke/TIA/systemic embolism 2 Vascular Disease (MI/PAD/Aortic plaque) 1 Age years 1 Sex category (female) 1 Moderate-High risk > 2 Low risk 0-1 Lip GYH, Halperin JL. Am J Med 2010

8 HAS-BLED Score Weight (points) Hypertension (> 160 mm Hg systolic) 1 Abnormal renal or hepatic function 1-2 Stroke 1 Bleeding history or anemia 1 Labile INR (TTR < 60%) 1 Elderly (age > 75 years) 1 Drugs (antiplatelet, NSAID) or alcohol 1-2 High risk (> 4%/year) > 4 Moderate risk (2-4%/year) 2-3 Low risk (< 2%.year) 0-1 Pisters R, et al. Chest 2010 Lip GYH, et al. J Am Coll Cardiol 2010

9 AF PIE: FUTURE AF PIE: PAST Fuster V. Circulation 2012; epubl April 18

10 Modest Use of VKA Even in High-Risk Pts OAC therapy (%) European Heart Survey 5333 AF patients in 35 countries: CHADS 2 score Nieuwlaat et al. Eur Heart J 2006; Gage et al. JAMA 2001

11 Summary of Garfield Data Cohort One: ESC 2012 Newly diagnosed patients carry high risk for stroke 57% with CHADS 2 score >2 83% with CHA 2 DS 2 -VASc score >2 VKAs not prescribed in: 38% of pts with CHADS 2 score >2 40% of pts with CHA 2 DS 2 -VASc score >2

12 Despite its demonstrated effectiveness in preventing stroke, warfarin is underused in patients with AF, an estimated one third to one-half of eligible patients do not receive anticoagulation and among patients who are treated, approximately 25% discontinue treatment within 1 year.

13 Patients receiving warfarin spend only 50% to 65% of their time on treatment in this therapeutic range. Among warfarin-treated patients with AF who experienced stroke, 64% - 68% had subtherapeutic INR levels at presentation.

14 Reasons for not prescribing VKA Advanced Age High falls risk Dementia Poor INR control Renal insufficiency History previous haemorrhage/ risk factors for bleeding

15 VKA prescription to AF pts at discharge Hylek, STROKE 2006

16 Failure to Prophylax Syndrome

17 Major Advances In Oral Anticoagulation for SPAF 6 Trials of Warfarin vs Placebo ROCKET AF (Rivaroxaban) 2010 ENGAGE AF (Edoxaban) 2013 RE-LY (Dabigatran) 2009 ARISTOTLE (Apixaban) 2011

18 Sites of Action of Novel FXa and DT Inhibitors Steps in Coagulation Pathway Drugs Initiation X TF/VIIa IXa VIIIa IX Propagation Fibrin formation Va Xa II IIa Rivaroxaban Apixaban Edoxaban Dabigatran Fibrinogen Fibrin Hankey GJ and Eikelboom JW. Circulation 2011

19 Comparison overview of New Oral Anticoagulants with Warfarin Features Warfarin New Agents Onset Slow Rapid Dosing Variable Fixed Food effect Yes No Drug interactions Many Few Monitoring Yes No Half-life Long Short Antidote Yes No

20 Novel Oral Anticoagulants Important Comparative Features Dabigatran Rivaroxaban Apixaban Oral direct thrombin inhibitor Twice daily dosing Renal clearance Direct factor Xa inhibitor Once daily (maintenance), twice daily (loading) Renal clearance Direct factor Xa inhibitor Twice daily dosing Hepatic clearance Edoxaban Direct factor Xa inhibitor Once daily dosing Hepatic clearance Circulation 2010;121:1523

21 The RE-LY Trial: Dabigatran

22 RE-LY: efficacy Stroke/Systemic Embolic Event Non-inferioritySuperiority P-value P-value Dabigatran 110 vs Warfarin < Dabigatran 150 vs Warfarin < < Margin = 1.46 Connolly, NEJM HR (95% CI)

23 RE-LY:safety Dabigatran 110 mg Dabigatran 150 mg Major Bleed 0.80 ( ) 0.93 ( ) ICH 0.31 ( ) 0.40 ( ) GI Bleed 1.10 ( ) 1.50 ( ) Connolly, NEJM Dabigatran Better Warfarin Better

24 RE-LY: efficacy stratified by CHADS 2 Annualized Rate Stroke/SEE (%) D110 mg D150 mg CHADS P = 0.44 P = Dabigatran better Warfarin better Dabigatran better Warfarin better Oldgren, JACC 2010

25 ROCKET AF: Rivaroxaban

26 ROCKET AF:efficacy Stroke/Systemic Embolic Event Rivaroxaban Warfarin Event Rate Event Rate HR (95% CI) P-value On Treatment N = 14, (0.65, 0.95) ITT N = 14, (0.74, 1.03) Rivaroxaban better Warfarin better Patel, N Engl J Med 2011

27 ARISTOTLE: Apixaban

28 ARISTOTLE: efficacy HR 0.79 ( ) (1.60 %/yr) 21% RRR (1.27 %/yr ) P (non-inferiority) < P (superiority) = Granger CB, NEJM 2011

29 ARISTOTLE: safety Event Apixaban (%/yr) Warfarin (%/yr) Hazard Ratio (95% CI) P- value ISTH Major Bleeding ICH ( ) 0.42 ( ) < < Gastrointestinal ( ) 0.37

30 AVERROES: vs ASA

31 AVERROES: efficacy & safety Stroke or Systemic Embolic Event Major Bleeding Aspirin Apixaban P < Apixaban P < Aspirin HR 0.45 ( ) HR 1.13 ( ) Connolly, NEJM 2011

32 ENGAGE AF-TIMI 48: edoxaban

33 ENGAGE AF-TIMI 48: efficacy

34 ENGAGE AF-TIMI 48: safety

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36 Pivotal Atrial Fibrillation Trials Drug Dose (mg) RE-LY ROCKET-AF ARISTOTLE Dabigatran 110 bid 150 BID Rivaroxaban 20 mg qd Apixaban 5 mg bid ITT cohort: Stroke + SEE non-infer Superior non-infer. On Rx cohort: Superior Superior ICH Superior Superior Superior Superior Bleeding lower similar similar Lower Mortality similar P = similar Superior: P = Ischemic stroke similar Lower similar similar Mean TTR 64% 55% 62% Stopped drug 21% 23% 23%

37 Efficacy of NOACS Stroke & SEE Ischemic & Unsp. Stroke 13% Hemorraghic Stroke Miller CS, et al. Am J Cardiol 2012 Favors NOACs Favors Warfarin

38 Safety of NOACS Bleeding Major ICH 51% GI Miller CS, et al. Am J Cardiol 2012 Favors NOACs Favors Warfarin

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40 ESC 2012 Atrial Fibrillation Guidelines Update: Risk Assessment Risk Profile Class / Level CHA 2 DS 2 -VASc = 0 CHA 2 DS 2 -VASc = 1 CHA 2 DS 2 -VASc 2 No antithrombotic therapy I B VKA (INR 2-3) Or Dabigatran / Rivaroxaban / Apixaban IIa A (Favored) VKA (INR 2-3) Or Dabigatran / Rivaroxaban / Apixaban I A (Favored)

41 The management of AF patients in 2012 has adapted to recent evidence and guideline recommendations. Oral anticoagulant therapy with VKA (majority) or NOACs is given to over 80% of eligible patients, including those at risk for bleeding.

42 2013

43 F E A R A restriction on appropriate warfarin use in patients of advanced age is the limited ability of risk-stratification schemes to predict stroke risk in patients aged >75 years and perceived difficulty assessing when the benefits of anticoagulation outweigh the risks

44 F E A R Elderly patients falling (leading to an increased risk of bleeding and ICH) is a frequently cited reason why clinicians do not prescribe anticoagulant therapy to older patients. This perceived risk of bleeding or ICH due to falls appears to be higher than the actual.

45 F E A Mild-to-moderate cognitive impairment does not necessarily interfere with warfarin use. R

46 AF PIE: FUTURE AF PIE: PAST Fuster V. Circulation 2012; epubl April 18

47 ASA Trials comparing aspirin and warfarin have found aspirin treatment to be less effective in stroke prevention and to cause more bleeding events than treatment with warfarin.

48 This review highlights the benefits of NOACs for the elderly population with AF; these novel agents reduce stroke risk in this population, providing a suitable alternative to warfarin.

49 Although the NOACs are often discussed collectively, consideration of the pharmacologic properties of individual agents may help clinicians to identify the most appropriate agent for individual patients.

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51 Dabigatran Apixaban Edoxab an * When CrCl CrCl ml/min: ml/min, 150 mg BID is possible but 110 mg BID if high risk of bleeding or recommended 2.5 mg BID is possible Serum creatinine 1.5 mg/dl in combination with age 80 years or weight 60 kg : 2.5 not available Rivaroxaba n 15 mg OD when CrCl ml/min mg BID

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54 Frail elderly people were not represented in NOACinvestigating trials because of various exclusion criteria, and only one-third of patients were aged > 75 ys

55 At present, further data are needed before NOAC can be widely recommended for elderly patients with AF. The high prevalence of renal insufficiency and the mainly unknown risk of drug drug and drug food interactions are further arguments against the use of NOAC in the elderly.

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57 6. Are the NOACs effective and safe in multimorbid geriatric people (who commonly have AF and are at high risk of stroke but also bleeding)? The NOACs do not appear to have been studied sufficiently in multimorbid geriatric patients with AF to reassure geriatricians of their safety and efficacy.

58 In participants of clinical trials aged 75 and older, NOACs did not cause excess bleeding and were associated with equal or greater efficacy than conventional therapy.

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61 The benefit of antithrombotic therapy is well established in elderly adults, also who are at high risk of falling or bleeding. The current study suggests that NOACs are more effective than conventional anticoagulant in elderly adults.

62 Old age per se should not be a criterion for withholding anticoagulation with NOACs.

63 Two major concerns

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65 RE-COVER Study 2.4% Dabigatran = 150mg, BID 2.1% INR = 60% TTR HR = 1.1 ( ) TTR = Therapeutic Time in Range Schulman S, et al NEJM 2009;361:

66 RE-COVER Study Dabigatran Major Bld 1.6% Warfarin Major Bld 1.9% Schulman S, et al NEJM 2009;361:

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68 Einstein Acute DVT Study Acute DVT Study INR = 57.7% TTR 3.0% 2.1% TTR = Therapeutic Time in Range Einstein Investigators NEJM 2010;363:

69 2013

70 AMPLIFY study

71 AMPLIFY study

72 The new oral anticoagulants rivaroxaban, dabigatran etexilate, apixaban and the investigational oral anticoagulant edoxaban all appear to be effective and safe for treatment of acute venous thromboembolism, but data in older and sicker patients are limited.

73 TAKE HOME MESSAGE NOACS are probably more effective than warfarin NOACS are surely more effective than ASA NOACS are probably more safe than warfarin We need specific trial with elderly patients ( a look at frailty)

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