NOACS for the treatment of atrial fibrillation - advantages

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1 NOACS for the treatment of atrial fibrillation - advantages Eli I. Lev Director, Interventional Cardiology Unit Hasharon Hospital Rabin Medical Center Tel-Aviv University, Israel

2 NOACS - Advantages Pahrmacological properties No need for monitoring Efficacy Safety

3 Absorption and metabolism of NOACs Dabigatran Apixaban Edoxaban * Rivaroxaban Warfarin Bioavailability 3-7% 50% 62% 66% (w/o food) ~100% with food Prodrug yes no no no Renal Clearance 80% 27% 50% 35% Liver metabolism: CYP3A4 no yes (elimination; minor CYP3A4) minimal (<4% of elimination) yes (elimination) Absorption with food no effect no effect 6-22% more +39% T Max hrs 3-4 hrs 2 4hrs 2-4 hrs hrs Elimination half-life (t 1/2 ) hrs 12 hrs 9-11 hrs 5-9 h (young) / h (elderly) hrs * not approved yet

4 Warfarin metabolism An anticoagulation effect generally occurs within 24 hrs after warfarin administration. However, peak anticoagulant effect may be delayed 72 to 96 hrs The elimination of warfarin is almost entirely by hepatic metabolism. The CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4 The terminal half-life of warfarin after a single dose is 1 week; however, the effective excretion half-life of warfarin ranges from 37 to 89 hrs

5 Drug and food interactions of warfarin CYP450 interactions with warfarin Other classes of interacting drugs: Antibiotics Antifungals Anticoagulants Antiplatelets NSAIDS Serotonin reuptake inhibitors Botanical products Foods Enzyme Inhibitors Inducers CYP2C9 CYP1A2 CYP3A4 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton aprepitant, bosentan, carbamazepine, phenobarbital, rifampin montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin

6 % of eligible patients receiving warfarin INR control with warfarin: clinical trials vs. clinical practice INR* control in clinical trial versus clinical practice (TTR**) 66% Clinical trial 1 Clinical practice 2,3 38% 44% 25% 18% 9% < >3.0 INR *INR = International normalized ratio ** TTR = Time in Therapeutic Range (INR ) 1. Kalra L, et al. BMJ 2000;320: * Pooled data: up to 83% to 71% in individualized trials; 2. Samsa GP, et al. Arch Int Med Matchar DB, et al. Am J Med 2002; 113:42-51.

7 Odds ratio VKAs have a narrow therapeutic window 20 Therapeutic range 15 Stroke 10 Intracranial bleed International normalized ratio VKAs = vitamin K antagonists ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e & Eur Heart J 2006;27:

8 NOACs Drug Interactions All 3 NOACs with antifungals Dabigatran dronedarone, verapamil (moderate) Apixaban, rivaroxaban HIV protease inhibitors All 3 NOACs rifampin, phenytoin, phenobarbital

9 Pharmacological advantages of NOACs More predictable and shorter onset time and half-life/elimination Fewer food and drug interactions Predictable effect without need for monitoring

10 Persistence Rates Higher With Dabigatran Than Warfarin US Department of Defense (October 28, 2010, and June 30, 2012) Newly diagnosed NVAF patients on Dabigatran (n=1745) Newly diagnosed NVAF patients on Warfarin (n=1745) Persistence rates were higher for dabigatran than for warfarin At 6 months: 72% versus 53% At 1 year: 63% versus 39% Higher persistence rates with Dabigatran than warfarin Kaplan Meier survival curves for propensity scores matched patients by treatment group analyzed with a 60-day medication gap Zalesak M, et al. Circ Cardiovasc Qual Outcomes 2013;6:

11 EFFICACY Primary endpoint of stroke or systemic embolism Patients with atrial fibrillation (non-valvular)

12 RELY: Stroke or Systemic Embolism Dabigatran 110 vs. Warfarin Non-inferiority p-value <0.001 Superiority p-value 0.34 Dabigatran 150 vs. Warfarin <0.001 <0.001 Margin = HR (95% CI) Dabigatran better Warfarin better Connolly et al NEJM 2009

13 Cumulative hazard rates Time to first stroke / SSE Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg RR 0.91 (95% CI: ) p<0.001 (NI) p=0.34 (Sup) RRR 34% RR 0.66 (95% CI: ) p<0.001 (NI) p<0.001 (Sup) Years RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa Connolly et al NEJM 2009

14 % per year RELY - All cause mortality RR 0.91 (95% CI: ) p=0.13 RR 0.88 (95% CI: ) 3.64 p= D110 mg BID D150 mg BID Warfarin Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa / 6, / 6,076

15 Cumulative event rate (%) ROCKET AF Primary Efficacy Outcome Event Rate Stroke and non-cns Embolism Rivaroxaban Warfarin Warfarin Rivaroxaban HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: < Days from Randomization No. at risk: Rivaroxaban Warfarin Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population Patel et al, NEJM 2011

16 Primary Efficacy Outcome - Superiority Stroke and non-cns Embolism On Treatment N= 14,143 Rivaroxaban Event Rate Warfarin Event Rate HR (95% CI) 0.79 (0.65,0.95) P-value ITT N= 14, (0.74,1.03) Rivaroxaban better Warfarin better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations Patel et al, NEJM 2011

17 Granger et al, NEJM 2011 ARISTOTLE - Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism P (non-inferiority)< % RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, ); P (superiority)=0.011 No. at Risk Apixaban Warfarin

18 Event rate (% / year) ARISTOTLE: all-cause mortality All-cause mortality* 11% RRR HR: % CI: ; p= % 669/ % 603/9120 Warfarin Apixaban Granger et al. N Engl J Med 2011;365: *Key secondary efficacy endpoint

19 Comparative Efficacy / Safety among Trials Subgroup of patients with CHADS 2 > 3

20 SAFETY Major Bleeding Intra-cranial hemorrhage

21 % per year RELY - Major bleeding rates RR 0.80 (95% CI: ) 2.71 p=0.003 (sup) RRR 20% RR 0.93 (95% CI: ) 3.11 p= D110 mg BID D150 mg BID Warfarin Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa / 6, / 6, / 6,022 Connolly et al NEJM 2009

22 Number of events RELY - Hemorrhagic stroke RR 0.31 (95% CI: ) 50 p<0.001 (sup) RR 0.26 (95% CI: ) p<0.001 (sup) 40 RRR 69% RRR 74% % % % 0 D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022 Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa Connolly et al NEJM 2009

23 Number of events Intra-cranial bleeding rates RR 0.31 (95% CI: ) 27 0,23 % p<0.001 (sup) RRR 69% RR 0.40 (95% CI: ) 36 0,30 % p<0.001 (sup) RRR 60% 87 0,74 % 0 D110 mg BID D150 mg BID Warfarin Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa Connolly et al NEJM 2009

24 ROCKET-AF - Primary Safety Outcomes Rivaroxaban Warfarin Event Rate Event Rate HR P- or N (Rate) or N (Rate) (95% CI) value Major (0.90, 1.20) >2 g/dl Hgb drop (1.03, 1.44) Transfusion (> 2 units) (1.01, 1.55) Critical organ bleeding (0.53, 0.91) Bleeding causing death (0.31, 0.79) Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) Event Rates are per 100 patient-years Based on Safety on Treatment Population Patel et al, NEJM 2011

25 ROCKET-AF - Primary Safety Outcomes Major and non-major Clinically Relevant Rivaroxaban Event Rate Warfarin Event Rate HR (95% CI) P- value (0.96, 1.11) Major (0.90, 1.20) Non-major Clinically Relevant (0.96, 1.13) Event Rates are per 100 patient-years Based on Safety on Treatment Population Patel et al, NEJM 2011

26 ARISTOTLE - Major Bleeding ISTH definition 31% RRR Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, ); P<0.001 No. at Risk Apixaban Warfarin Significant decrease also for intracranial bleeding: 0.33% vs. 0.8% / year (apixa vs. warfarin) Granger et al, NEJM 2011

27 ARISTOTLE Bleeding Outcomes Primary safety outcome: ISTH major bleeding* Outcome Apixaban (N=9088) Event Rate (%/yr) Warfarin (N=9052) Event Rate (%/yr) HR (95% CI) P Value (0.60, 0.80) <0.001 Intracranial (0.30, 0.58) <0.001 Hemorrhagic stroke (0.35, 0.75) <0.001 Gastrointestinal (0.70, 1.15) 0.37 Major or clinically relevant non-major bleeding (0.61, 0.75) <0.001 GUSTO severe bleeding (0.35, 0.60) <0.001 TIMI major bleeding (0.46, 0.70) <0.001 Any bleeding (0.68, 0.75) <0.001

28 Comparative analysis trial results Efficacy endpoint Safety endpoint ESC working group on thrombosis, JACC 2012

29 Relative Risk: NOACs vs. Warfarin: Meta-analysis of > 50,000 patients * * Mortality Stroke/SE ICH Maj. Bleed MI *Some heterogeneity in results for major bleeding and myocardial infarction Dentali et al. Circulation 2013

30 Death Within 30 days of Major Bleed Time (months from enrolment) Hylek et al, JACC 2014 Majeed et al, Circulation 2013

31 NOACS Antidote status All 3 NOACS have antidotes tested in phase 2 studies A phase 3 study designed to test an antidote to factor Xa inhibitors met its primary efficacy end point, according to an announcement from Portola Pharmaceuticals ] (Theheart Oct. 2014) An IV bolus of andexanet alfa immediately and sig. reversed the anticoagulation of apixaban in the ANNEXA-A study. 33 healthy volunteers in the study were treated with apixaban 5 mg bid daily for 4 days and then randomized to andexanet alfa 400 mg or placebo (results will be presented in AHA 2014)

32 NOACS Advantages Summary Pahrmac. properties - more predictable and shorter onset time and elimination t 1/2 ; No need for monitoring Efficacy all 3 NOACS are at least as effective as warfarin in prevention of stroke and systemic embolism (dabigatran 150 mg and apixaban more effective) Safety - all 3 NOACS are at least as safe as warfarin in terms of the risk of major bleeding (dabigatran 110 mg and apixaban associated with lower rates of major bleeding). All 3 NOACs associated with risk of intra-cranial bleeding

33 ESC Atr Fib 2012 Guidelines Atrial fibrillation Valvular AF* Yes Yes <65 years and lone AF (including females) No (i.e. nonvalvular) No Assess risk of stroke CHA 2 DS 2 -VASc score Oral anticoagulant therapy Assess bleeding risk (HAS-BLED score) Consider patient values and preferences No antithrombotic therapy NOAC VKA line: solid = best option ; dashed = alternative option Choice of anticoagulant

34 THANK YOU

35 New anticoagulants site of action

36 RE-LY: A Non-inferiority Trial Atrial fibrillation 1 Risk Factor Absence of contra-indications Mean CHADS score = 2.1 Blinded Event Adjudication. R Open Blinded Warfarin adjusted (INR ) N=6000 Dabigatran Etexilate 110 mg BID N=6000 Dabigatran Etexilate 150 mg BID N=6000 Mean TTR = 64% Median follow up = 2 years Connolly et al NEJM 2009

37 ROCKET AF - Study Design Atrial Fibrillation Risk Factors CHF Hypertension At least 2 or Age 75 3 required* Diabetes OR Stroke, TIA or Systemic embolus Mean CHADS score = 3.5 Rivaroxaban 20 mg daily 15 mg for Cr Cl ml/min Randomize Double Blind / Double Dummy (n ~ 14,000) Warfarin INR target ( inclusive) mean TTR = 55% Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10% Patel et al, NEJM 2011

38 Granger et al, NEJM 2011 AF with at least one risk factor for stroke ARISTOTLE Inclusion risk factors Age 75 years Prior stroke, TIA, or SE HF or LVEF 40% Diabetes mellitus Hypertension Mean CHADS score = 2.1 Randomize double blind, double dummy (n = 18,201) Major exclusion criteria Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients) Warfarin (target INR 2-3) mean TTR = 62% Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism

39 AVERROES: Study Design Mean follow-up: 1.1 years Patient Population Patients 50 years with NVAF and 1 risk factors for stroke Not receiving VKA therapy (demonstrated or expected to be unsuitable for VKA) N=5599 Randomised, double-blind, double-dummy Event Driven Apixaban 5.0 mg BD (2.5 mg in select patients* [6.4%]) ASA mg OD** *Patients with 2 of the following: age 80 years, weight 60 kg, serum creatinine 1.5 mg/dl (133 μmol/l). **The selection of an ASA dose of 81, 162, 243, or 324 mg was at the discretion of the investigator with 91% of subjects receiving either an 81-mg (64%) or 162-mg (27%) dose at randomization. The primary objective of the trial was to determine if apixaban was superior to ASA for the prevention of the composite outcome of stroke or systemic embolism. Primary efficacy outcome: Stroke or systemic embolism Primary safety outcome: Major bleeding Connolly et al. N Engl J Med 2011;364:

40 Cumulative Hazard AVERROES: primary efficacy endpoint: stroke or systemic embolism ASA 55% RRR 0.03 Apixaban HR 0.45 (95% CI: ) p<0.001 for superiority 0.00 No. at Risk Connolly et al. N Engl J Med 2011;364: Months Apixaban ASA

41 Cumulative Hazard AVERROES: Primary safety endpoint major bleeding Apixaban ASA HR 1.13 (95% CI: ); p= No. at Risk Months Apixaban ASA Connolly et al. N Engl J Med 2011;364:

42 RECENT ANALYSES AND POST MARKETING DATA REGARDING DABIGATRAN

43 Real Life Safety with Pradaxa Active surveillance system sponsored by the FDA: Safety Announcement 2/11/2012 Published in NEJM (March 2013) FDA has not changed its recommendations regarding Pradaxa. Pradaxa provides an important health benefit when used as directed Bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin, which is consistent with observations from the RE-LY trial. The incidence rate of gastrointestinal hemorrhage events per 100,000 days at risk was 1.6 to 2.2 times higher for warfarin new users than for Pradaxa new users, and the incidence rate of ICH events per 100,000 days at risk was 2.1 to 3.0 times higher with warfarin than with Pradaxa. Data collected during the time period from Oct Dec 2011

44 EMA updates patient & prescriber information for Pradaxa The Committee found that the frequency of occurrence of fatal bleedings with Pradaxa seen in post-marketing data was significantly lower than what was observed in the clinical trials that supported the authorisation of the medicine On the basis of the available evidence, the CHMP concluded that the benefits of Pradaxa continue to outweigh its risks and that it remains an important alternative to other blood-thinning agents. 46

45 Myocardial ischaemic events subanalysis: cardiac outcomes Annual rate (%) D110 vs warfarin D150 vs warfarin D110 D150 War HR (95% CI) P value HR (95% CI) P value Total MI ( ) ( ) 0.12 Clinical MI ( ) ( ) 0.09 Silent MI ( ) ( ) 0.72 Fatal MI ( ) ( ) 0.88 There was a numerical imbalance in the rate of MI that was not statistically significant for either dose of dabigatran vs warfarin D110 = dabigatran 110 mg twice daily; D150 = dabigatran 150 mg twice daily; MI = myocardial infarction; war = warfarin Hohnloser SH et al. Circulation doi: /circulationaha

46 RELY-ABLE During 2.3 years of additional treatment after RE-LY (total f/u 4.3 years): results highly consistent with RE-LY: Rates of stroke and major bleeding remain low on dabigatran There were no new safety signal observed during this extended follow up period Both doses have very low rates of haemorrhagic stroke over 4+ years With dabigatran 150, there is a lower rate of ischaemic stroke but a higher rate of major bleeding Both doses have similar mortality Connolly SJ, et al. RELY-ABLE presented at AHA 2012 Scientific Sessions,

47 CHADS 2 score subgroup analysis: stroke/systemic embolism Benefits of dabigatran vs warfarin are independent of CHADS 2 score Dabigatran 110 mg BID vs warfarin Dabigatran 150 mg BID vs warfarin Annual rate (%) CHADS 2 score D110 mg BID D150 mg BID Warfarin P=0.37* P=0.84* *P values for interaction; D = dabigatran Oldgren J et al. Ann Int Med 2011;155: Favours Favours dabigatran warfarin Favours Favours dabigatran warfarin 49

48 ARISTOTLE - Stroke/Systemic Embolism, by CHADS and HASBLED Lopes et al, Lancet 2012

49 ARISTOTLE - ISTH Major Bleeding by CHADS and HASBLED Lopes et al, Lancet 2012

50 ARISTOTLE - Mortality by CHADS and HASBLED Lopes et al, Lancet 2012

51 NOACs vs. warfarin in moderate CKD (ecrcl <50 ml/min) Stroke or Systemic Embolism HR (95% CI) Dabigatran 110 mg BID 1, ( ) Dabigatran 150 mg BID 1, ( ) Rivaroxaban 15 mg QD ( ) Apixaban 2.5/5 mg BID ( ) HR (95% CI) New Agent Better Warfarin Better Dabigatran is contraindicated in patients with severe renal impairment (CrCl<30 ml/min) 1. Connolly SJ, et al. N Engl J Med 2009; 361: ; 2. Pradaxa Product Information 4th edition revised, 2012; 3. Fox KAA, et al. Eur Heart J 2011; 32: ; 4. Hohnloser SH, et al. Eur Heart J 2012; 33:

52 NOACs vs. warfarin in moderate CKD (ecrcl <50 ml/min) Major bleeding HR (95% CI) Dabigatran 110 mg BID 1, ( ) Dabigatran 150 mg BID 1, ( ) Rivaroxaban 15 mg QD ( ) Apixaban 2.5/5 mg BID ( ) HR (95% CI) New Agent Better Warfarin Better Dabigatran is contraindicated in patients with severe renal impairment (CrCl<30 ml/min) 1. Connolly SJ, et al. N Engl J Med 2009; 361: ; 2. Pradaxa Product Information 4th edition revised, 2012; 3. Fox KAA, et al. Eur Heart J 2011; 32: ; 4. Hohnloser SH, et al. Eur Heart J 2012; 33: