ΚΛΙΝΙΚΕΣ ΜΕΛΕΤΕΣ ΚΑΙ ΚΑΘΗΜΕΡΙΝΗ ΚΛΙΝΙΚΗ ΠΡΑΚΤΙΚΗ ΤΩΝ ΝΕΟΤΕΡΩΝ ΑΠΟ ΤΟΥ ΣΤΟΜΑΤΟΣ ΑΝΤΙΠΗΚΤΙΚΩΝ ΔΙΑΦΕΡΟΥΝ Η ΤΑΥΤΙΖΟΝΤΑΙ; NΙΚΟΛΑΟΣ ΦΡΑΓΚΑΚΗΣ Επίκουρος Καθηγητής Καρδιολογίας ΑΠΘ Γ Κ/Δ Κλινική Ιπποκράτειο Νοσοκομείο Θεσ/κης
Δήλωση συμφερόντων Ο ομιλητής έχει λάβει αμοιβές για ομιλίες σε εκπαιδευτικά σεμινάρια από τις κάτωθι φαρμακευτικές εταιρείες: Bayer Healthcare, Menarini, Mylan
People with AF in the US (millions) Prevalence of AF predicted to more than double by 2050 16 14 12 10 8 6 4 2 Projected incidence of AF assuming a continued increase in age-adjusted incidence as evident in 1980 2000 Projected incidence of AF assuming no further increase in age-adjusted incidence 0 2000 2010 2020 2030 2040 Year 2050 Miyasaka Y et al. Circulation 2006;114:119 25
The Consequences of AF Thromboembolism Stroke: 4.5 increased risk Microemboli: reduced cognitive function more severe than strokes from other etiologies Mortality 2 increased risk independent of comorbid CV disease Sudden death in HF and HCM Hospitalizations Most common arrhythmia requiring hospitalization 2-3 increased risk for hospitalization AF is an enormous contributor to the growing cost of medical care
AF-related stroke is preventable Effect of VKA compared to placebo 2/3 of strokes due to AF are preventable with appropriate anticoagulant therapy with a vitamin-k-antagonist (INR 2-3) Stroke Death A meta-analysis of 29 trials in 28,044 patients showed that adjusted-dose warfarin results in a reduction in ischaemic stroke and in all-cause mortality 67% 26% Hart RG et al. Ann Intern Med. 2007;146:857-867 Fuster V, et al. JACC. 2006; 48: 854-906
Warfarin compared with Aspirin for stroke prevention in AF Warfarin better Aspirin better AFASAK I AFASAK II Chinese ATAFS EAFT PATAF SPAF II Age 75 yrs Age >75 yrs All trials RRR 38% (95% CI: 18 52%) 100 50 0 50 RRR (%)* 100 Hart RG et al. Ann Intern Med 2007;146:857 67
Οι VKA έχουν αρκετούς περιορισμούς που τους καθιστούν δύσχρηστους στην καθημερινή κλινική πράξη Μη προβλέψιμη ανταπόκριση Στενό θεραπευτικό εύρος (INR 2.0-3.0) Βραδεία έναρξη και λήξη δράσης Οι VKAs έχουν πολλούς περιορισμούς που τους καθιστούν δύσχρηστους στην καθημερινή χρήση Πολυάριθμες αλληλεπιδράσεις με τροφές Πολλές αλληλεπιδράσεις με φάρμακα Αντίσταση στους VKA Ανάγκη για τακτικό εργαστηριακό έλεγχο Συχνές τροποποιήσεις της δόσης Απόσυρση από την αγωγή
Warfarin use in eligible patients (%) The VKA, warfarin, is used in only half of eligible patients with AF 100 80 60 58% 61% 57% Overall use = 55% 40 44% 35% 20 0 <55 55 64 65 74 75 84 85 Age (yrs) Under-use of warfarin is greatest in elderly patients who are at the highest risk of stroke Go A et al. Ann Intern Med 1999;131:927
Patients (%) Kakkar et al. PLoS One 2013;8:e63479 Cohort 1: Anticoagulants not prescribed in 41% of patients with CHA 2 DS 2 -VASc score 2 100% 90% 80% 70% 60% 50% 40% 30% 20% 14.4 25.3 4.5 45.2 27.2 32.8 1.3 32.1 20.7 28.4 3.9 39.7 15.9 14.9 26.2 25.4 4.3 3.7 44.9 45.3 11.1 10.1 10 22.3 23.4 25.5 4.6 5.8 6.9 50.7 47.8 41.2 None AP FXa/DTI VKA VKA + AP 10% 0% 10.6 Overall (n=10,607) 6.6 7.4 8.8 10.7 11.2 12.8 0 (n=305) 1 (n=1345) 2 (n=2093) 3 (n=2471) CHA 2 DS 2 -VASc score 4 (n=2180) 5 (n=1311) Undertreatment with anticoagulants with CHA 2 DS 2 -VASc score 2 16.4 6 to 9 (n=902)
Warfarin has higher discontinuation rates than BP, statin and antiplatelet drugs Swedish Stroke Survivors with Atrial Fibrillation Glader E-L et al. Stroke 2010;41:397 401
Direct Oral Anticoagulants
Novel agents target specific molecules in the coagulation cascade Tissue factor/viia X IX Vitamin K antagonists VIIIa IXa Direct Factor Xa inhibitors Va Rivaroxaban Apixaban Edoxaban II Xa AT Thrombin Direct thrombin inhibitors Dabigatran Fibrinogen Fibrin Weitz J, Bates S. J Thromb Haemost 2005;3:1843 53; Monroe D, Hoffman M. Arterioscler Thromb Vasc Biol 2006;26:41 8; Crawley J et al. J Thromb Haemost 2007;5 (Suppl 1):95 101
Novel Oral Anticoagulants Σημαντικά συγκριτικά χαρακτηριστικά Dabigatran Αναστολέας Θρομβίνης Δοσολογία δύο φορές την ημέρα Νεφρική κάθαρση Rivaroxaban Αναστολέας του παράγοντα Xa Άπαξ ημερησίως Νεφρική & Ηπατική κάθαρση Apixaban Αναστολέας του παράγοντα Xa Δοσολογία δύο φορές την ημέρα Ηπατική κάθαρση Edoxaban Αναστολέας του παράγοντα Xa Δοσολογία μια φορά την ημέρα Ηπατική κάθαρση
X-fold increase in AUC vs. normal renal function Different Renal Clearance 7 6.3 Mild 6 5 Moderate Severe 4 3.2 3 2 1.4 1.5 1.6 1.2 1.3 1.4 1.5 1 0 Rivaroxaban Apixaban Dabigatran NOTE: Graphs based on data in respective SmPCs. No head to head comparison. Data for edoxaban are currently not available. 1. Rivaroxaban SmPC; 2. Apixaban SmPC; 3. Dabigatran SmPC; 4. Stangier J et al. Clin Pharmacokinet. 2010;49(4):259-268
NOAC 4-trial Meta-analysis Full Dose Pre-specified meta-analysis of all 71,683 patients Trial Stroke and Systemic Embolism p Major Bleeding p RE-LY 0.0001 0.34 ROCKET-AF 0.12 0.72 ARISTOTLE 0.012 <0.0001 ENGAGE TIMI 48 Combined 0.10 0.0002 <0.0001 0.06 Favours DOAC 0.5 1 Favours DOAC 0.5 1 Ruff C, et al. Lancet 2013
Efficacy vs Safety NOAC 4-trial Meta-analysis Full Dose Result Pooled DOAC Events /Total Pooled Warfarin Events /Total Risk Ratio 95% CIs p Efficacy Ischaemic Stroke 665 /29292 724 /29221 0.92 0.83-1.02 0.10 Hemorrhagic stroke 130 /29292 263 /29221 0.49 0.38-0.64 <0.0001 Myocardial Infarction 413 /29292 432 /29221 0.97 0.78-1.20 0.97 All Cause mortality 2022 /29292 2245 /29221 0.90 0.851-0.95 0.0003 Safety Intra-cranial hemorrhage 204 /29287 425 /29211 0.48 0.39-0.59 <0.0001 Gastrointestinal bleeding 751 /29287 591 /29211 1.25 1.01-1.55 0.043 Ruff C, et al. Lancet 2013 0.25 Favours NOAC 1 2
Comparing Phase III Trials: There are Differences in Patient Characteristics CHADS 2 -Score patient distribution ROCKET AF 1 rivaroxaban RE-LY 2 dabigatran ARISTOTLE 3 apixaban 13 % 36 % 32 % 36 % 34 % 87 % 32 % 30 % CHADS 2 score 1 2 3 6 1. Patel MR et al. N Engl J Med. 2011;365(10):883-891; 2. Connolly SJ et al. N Engl J Med. 2009;361(12):1139-1151; 3. Granger CB et al. N Engl J Med. 2011;365(11):981-992;
Camm AJ et al. Eur Heart J 2015
ROCKET AF: Effective Stroke Prevention in Patients With Non- Valvular AF vs. Warfarin RRR 21% P=0,02 ITT population= intention-to-treat population= all patients randomized Safety on-treatment analysis Patel MR et al. N Engl J Med 2011;365:883 891
Event rate (%/year) ROCKET AF: Significant Reduction of Critical Organ, ICH and Fatal Bleeding vs. Warfarin 1,5 1 0,5 0 HR 0.69 (95% CI 0.53 0.91) p=0.007 1.2 31% RRR 0.8 33% RRR Warfarin Rivaroxaban HR 0.67 (95% CI 0.47 0.93) p=0.02 HR 0.50 95% CI 0.31 0.79 p=0.003 0.7 0.5 0.5 50% RRR Critical organ bleeding ICH Fatal bleeding 0.2 No significant differences in major or NMCR bleeding vs. warfarin a Safety on-treatment analysis a HR 1.03 (95% CI 0.96 1.11); p=0.44 Patel MR et al. N Engl J Med. 2011;365(10):883-891
ROCKET AF: Consistent Benefit Across Different Co-morbidities for the Challenging AF Patients Primary Efficacy Endpoint: Stroke/SE (n=14,171) Comorbidity / risk factor Patient (%) HR (95% CI) C CHF 62 0.91 (0.74 1.13) H Hypertension 91 0.87 (0.73 1.03) A Elderly 75 years 43 0.80 (0.63 1.02) D Diabetes 40 0.74 (0.54 1.01) S 2 Prior stroke or TIA 55 0.94 (0.77 1.16) Mean CHADS 2 Score 3.5 0.1 1 1.5 2.0 Favours Favours rivaroxaban warfarin Per-protocol population Patel MR et al. N Engl J Med. 2011;365(10):883-891
Stroke or SE b (%/year)* Primary safety endpoint ROCKET AF: Consistent Results in NVAF Patients With Moderate Renal Impairment Efficacy 1 ITT analysis Safety 1 Safety on-treatment analysis 4 3 3.4 3.0 20 15 18.3 17.8 2 (%/year) # 10 1 5 0 Warfarin Rivaroxaban 15 mg OD 0 Warfarin Rivaroxaban 15 mg OD Rivaroxaban, the novel OAC with a prospectively tested, specific renal dose in patients with moderate renal impairment (CrCl 30 49 ml/min) 2 *Primary efficacy endpoint: Composite of all stroke (ischaemic and haemorrhagic) and SE; # Primary safety endpoint: Major or NMCR bleeding. Fox KA et al. Eur Heart J. 2011;32(19):2387-2394; Patel MR et al. N Engl J Med. 2011;365(10):883-891
Real world evidence vs interventional clinical trial data
Rivaroxaban Provides a Consistent Dataset Covering the Full Patient-Risk Spectrum Randomized clinical trial Prospective, non-interventional study 3 Prospective registry 1 Dresden NOAC Registry Retrospective databases 2,4 US PMSS 1. Beyer-Westendorf J et al, Blood 2014;124;955 962; 2. Tamayo S et al, Clin Cardiol 2015;38:63 68; 3. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466; 4. Coleman CI et al. Presentation at ECAS 2016 Available at:http://clinicaltrialresults.org/slides/revisit_us_slides.pptx
XANTUS: Prospective Design To collect real world data on adverse events in patients with NVAF treated with rivaroxaban to determine the safety profile of rivaroxaban across the broad range of patient risk profiles encountered in routine clinical practice Primary outcomes: major bleeding (ISTH definition), all-cause mortality, any other adverse events Population: Adult patients with NVAF receiving rivaroxaban for stroke/non-cns SE prevention N=6,784 Rivaroxaban; treatment duration and dose at physician s discretion Data collection at initial visit, hospital discharge (if applicable) and quarterly* 1 year Prospective, single-arm, observational, non-interventional phase IV study Statistical analyses were descriptive and exploratory in nature *Exact referral dates for follow-up visits not defined (every 3 months recommended); # for rivaroxaban discontinuation 1 year, observation period ends 30 days after last dose. Observational design means no interference with clinical practice was allowed 1. Camm AJ et al, Vasc Health Risk Manag 2014;10:425 434; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466 Final visit: 1 year #
Incidence rate, %/year* Main Efficacy Outcomes: XANTUS & ROCKET AF CHADS 2 Prior stroke # XANTUS 1 2.0 19% CHADS 2 Prior stroke # ROCKET AF 2 3.5 55% 2 1.9 2 1.7 1.7 1.9 1 0.8 0.7 1 0 0 Stroke/SE All stroke Death Stroke/SE All stroke Death # Includes prior stroke, SE or TIA; *Events per 100 patient-years 1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466; 2. Patel MR et al, N Engl J Med 2011;365:883 891
Incidence rate, %/year* Main Safety Outcomes: XANTUS & ROCKET AF CHADS 2 Prior stroke # XANTUS 1 2.0 19% ROCKET AF² CHADS 2 Prior stroke # 3.5 55% 4 4 3.6 3 3 2 2.1 2 2.0 1 0.4 0.9 1 0.5 0 0 Major bleeding ICH GI bleeding Major bleeding ICH GI bleeding # Includes prior stroke, SE or TIA; *Events per 100 patient-years 1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466; 2. Patel MR et al, N Engl J Med 2011;365:883 891
REVISIT-US 12th Annual Congress ECAS 2016 Paris, France 12th Annual Congress of the European Cardiac Arrhythmia Society April 17-19, 2016 Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with atrial Fibrillation in the United States (REVISIT-US) [Presentation at ECAS 2016] Available at: http://clinicaltrialresults.org/slides/revisit_us_slides.pptx
REVISIT-US Study Design to Optimize Internal Validity Retrospective analysis performed using US MarketScan data (Jan 2012 Oct 2014) Assesses real-world effectiveness and safety of newlyinitiated Rivaroxaban or Apixaban versus VKA in patients with non-valvular atrial fibrillation (NVAF) Endpoints: ischemic stroke, intracranial hemorrhage (ICH), and the combination thereof No data on other bleeding events Propensity score matching was used Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with atrial Fibrillation in the United States (REVISIT-US) [Presentation at ECAS 2016] Available at: http://clinicaltrialresults.org/slides/revisit_us_slides.pptx
REVISIT-US Baseline Characteristics Rivaroxaban vs Warfarin Newly initiated on rivaroxaban or warfarin meeting selection criteria N=38,831 Characteristics of included patients (matched cohorts) Parameter Rivaroxaban (n=11,411) 7,715 PYs Warfarin (n=11,411) 6,271 PYs Age in years, mean (SD) 70.70 (10.99) 70.72 (11.35) Rivaroxaban n=12,748 Warfarin n=26,083 Following propensity-score matching stratified by exposure status. 11,411 warfarin and 11,411 rivaroxaban users were identified Male, % 53.6 53.9 CHADS 2 Score, 180 day; mean (SD) CHA 2 DS 2 -VASc Score, 180 day; mean (SD) HASBLED Score, 180 day; mean (SD) 1.92 (1.08) 1.94 (1.08) 3.46 (1.37) 3.48 (1.35) 1.62 (0.69) 1.62 (0.71) Reduced dose, % 17.3 NA Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with atrial Fibrillation in the United States (REVISIT-US) [Presentation at ECAS 2016] Available at: http://clinicaltrialresults.org/slides/revisit_us_slides.pptx
REVISIT US - Significant Reduction in the Combined Endpoint for Rivaroxaban vs warfarin Rivaroxaban was associated vs warfarin with a Significant 47% reduction in ICH Non-significant 29% decrease in ischemic stroke Significant 39% reduction in the combined endpoint of ICH and ischemic stroke Rivaroxaban Warfarin HR (95% CI) rivaroxaban vs. warfarin Rate (%/year) Rate (%/year) ICH 0.49 0.96 0.53 (0.35 0.79)* HR (95% CI) rivaroxaban vs. warfarin Ischemic stroke 0.54 0.83 0.71 (0.47 1.07) Combined 0.95 1.6 0.61 (0.45 0.82)* *p<0.05 Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with atrial Fibrillation in the United States (REVISIT-US) [Presentation at ECAS 2016] Available at: http://clinicaltrialresults.org/slides/revisit_us_slides.pptx 0,125 0,25 0,5 1 2 4 Favors rivaroxaban Favors warfarin
Safety in real world
Safety Profile of Rivaroxaban Confirmed Through Real-World Evidence Regardless of Data Source Randomized clinical trial ROCKET AF 1* n=7111 Prospective registry Dresden NOAC 2# n=1200 Retrospective database US DoD PMSS 3 n=27,467 Observational study XANTUS 4* n=6784 Major bleeding event rate/year 3.6% 3.0% 2.9% 2.1% Mean CHADS 2 score 3.5 2.4 2.2 2.0 Results are not intended for direct comparison *Major bleeding definition according to ISTH; # modified ISTH definition (additionally included surgical revision from bleeding); major bleeding defined by the Cunningham algorithm 5 ; No major bleeding cohort (representative of >98% of the patient population) 1. Patel MR et al, N Engl J Med 2011;365:883 891; 2. Hecker J et al, Thromb Haemost 2016 Jan 21;115(5) [Epub ahead of print]; 3. Tamayo S et al, Clin Cardiol 2015;38:63 68; 4 Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466; 5. Cunningham A et al, Pharmacoepidemiol Drug Saf 2011;20:560 566
No Significant Increase in the Risk of GI Bleeding with Rivaroxaban Versus Warfarin Meta-analysis of eight cohort studies including 10,713 rivaroxaban users and 106,626 dabigatran users Summary risk ratio for gastrointestinal bleeding RR (95% CI) Rivaroxaban vs warfarin 1.09 (0.92 1.30) Dabigatran vs warfarin 1.21 (1.05 1.39) 0,5 1.0 5 Favours NOAC Favours warfarin He Y et al, Br J Clin Pharmacol 2016;doi:10.1111/bcp.12911
XANTUS: Management of Major Bleeding XANTUS: 1 major bleeding 1.9% (128/6784) (fatal bleeding 0.2% [n=12]) Conservative measures 0.8% Transfusions of 2 units of packed RBCs or whole blood (n=53) In the majority of cases, neither transfusions/whole blood nor pharmacological measures were used to manage bleeding events Non-specific agents 0.05% PCC: n=2 Tranexamic acid: n=3 Etamsylate: n=1 Findings consistent with ROCKET AF 2 and the Dresden NOAC Registry 3 1. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466; 2. Patel MR et al, N Engl J Med 2011;365:883 891; 3. Beyer-Westendorf J et al, Blood 2014;124:955 962
Europace Advance Access published February 17, 2015
Ensuring compliance with NOAC intake
Definition: Adherence and Persistence Start medication or observation Adherence The extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen Percentage of doses taken as prescribed Persistence Duration of time from initiation to discontinuation of therapy Days taking medication (without exceeding permissible gap) Stop medication or end observation Cramer JA et al. Value Health 2008;11(1):44 47
XANTUS: Treatment Persistence and Patient Satisfaction Persistence with rivaroxaban in XANTUS was 80% at 1 year Over 75% of patients were very satisfied/satisfied with their treatment 1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466
Patient persistence (%) Persistence with Rivaroxaban in NVAF Patients in Real World the Dresden NOAC Registry Prospective Dresden NOAC registry 1,204 AF patients treated with Rivaroxaban (39.3% switched from VKAs and 60.7% newly treated patients) 100 80 81.5 60 40 Follow-up: median 544 days 20 0 Rivaroxaban Persistence rates were similar for newly treated Rivaroxaban patients and patients switched from VKA to Rivaroxaban with discontinuation rates of 14.1%/year and 12.7%/year, respectively Beyer-Westendorf J et al. Europace 2015;17(4):530-538
Simple Communication and Regimen Influences Adherence
Ποσοστό One-Third of BID Prescribed Medications Were Being Taken OD Therapy adherence 1 100 80 Taking OAC OD 94 73 Taking OAC BID 70 86 60 40 20 0 27 30 14 6 Rivaroxaban Dabigatran Apixaban Warfarin Andrade et al, Canadian Journal of Cardiology - (2016) 1e7
You need to put all four Dimensions into Perspective to Judge on Real World Evidence Data
Rivaroxaban clinical trials program: Over 275,000 studied after finilization of study program Stroke prevention Arterial thromboembolism Venous thromboembolism Registries N >100,000 Ongoing N >75,000 Completed N >100,000
ΣΥΜΠΕΡΑΣΜΑΤΑ Αποτελεσματική προστασία από τα ισχαιμικά εγκεφαλικά στους ασθενείς με Κολπική Μαρμαρυγή Μειώνει κατά 50% τις θανατηφόρες αιμορραγίες, καθώς και τις ενδοκρανιακές και σε κρίσιμες θέσεις προοπτικά τεκμηριωμένη δοσολογία (15mg) για τους ασθενείς με ελαττωμένη νεφρική λειτουργία Δοσολογικό σχήμα που ευνοεί τη συμμόρφωση: 1 δισκίο 1 φορά την ημέρα, μαζί με το φαγητό Υπάρχουν προοπτικά δεδομένα από την καθημερινή κλινική πρακτική (μελέτες XANTUS, XALIA, REVISIT US) που επιβεβαιώνουν τα ευρήματα των κλινικών μελετών έγκρισης (ROCKET AF, EINSTEIN).