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Stroke Prevention in AF – A new Paradigm ROHAN JAYASINGHE Professor of Cardiology Gold Coast Hospital Learning Objectives 1. To assess stroke risk in patients with non-valvular atrial fibrillation (NVAF) 2. To assess bleeding risk in patients with NVAF 3. To comprehend and apply the current evidence regarding choice and use of antithrombotic therapy to reduce stroke risk in NVAF 4. To evaluate the efficacy and safety of contemporary antithrombotic therapies in the reduction of stroke risk in NVAF Aetiology of AF Age Hypertension Valvular heart disease (esp. mitral valve disease) Coronary Disease / MI CHF Obesity / OSA Diabetes Alcohol/Caffeine/Drugs Thyrotoxicosis Acute illness (e.g. infections / surgery) Myocarditis / Infiltration Pericardial disease (e.g. pericarditis) Electrolyte abnormalities Anaemia The Ageing Population of Australia 25 65-84 yrs > 85 yrs 20 Per cent 15 10 5 0 1970 1990 2010 2030 2050 Consequently, the prevalence of AF will increase Intergenerational Report 2010. Commonwealth of Australia AF is a Frequent and Increasing Cause of Hospitalisation in Australian Public Hospitals AIHW separations statistics 148 Atrial fibrillation and flutter 45,619 67% increase 27, 245 Australian Institute of Health and Welfare. Interactive national hospital morbidity data. Principal diagnosis data cubes. Available at: http://d01.aihw.gov.au/cognos/cgi-bin/ppdscgi.exe?DC=Q&E=/ahs/pdx0607 Goals of Management in AF Management of AF has two broad objectives: 1. Relief of symptoms 2. Prevention of complications, including thromboembolism (particularly stroke) and heart failure These objectives can be achieved by: 1. Rate control 2. Rhythm control 3. Risk-stratified antithrombotic therapy Goals of Management in AF Management of AF has two broad objectives: 1. Relief of symptoms 2. Prevention of complications, including thromboembolism (particularly stroke) and heart failure These objectives can be achieved by: 1. Rate control 2. Rhythm control 3. Risk-stratified antithrombotic therapy AF Increases Stroke Risk by Nearly 500% Risk ratio = 4.8 P < 0.001 Wolf PA, et al. Stroke. 1991;22:983-988. Adapted with permission. Strokes Due to AF: …are due to large artery cerebral occlusion and are associated with a doubling of poor outcome (death or non-fatal stroke) two weeks after ischaemic stroke International Stroke Trial. Lancet 1997; 349: 1569-1581 Higher Mortality After Stroke, at 2 Weeks and 6 Months, in AF Patients 45% without AF 40% with AF 35% Mortality 30% 25% 20% 15% 10% 5% 0% Dead at 2 weeks Dead at 6 months International Stroke Trial, Lancet 1997; 349: 1569-81 Patients With AF Are More Likely to Die Within 1 Year of a Stroke P < 0.001 Kaarisalo MM ,et al. Stroke. 1997;28:311-315 Severe Disability Is Increased in Patients With Stroke due to AF Lin HJ, et al. Stroke. 1996;27:1760-1764 Stroke Risk Persists Even in Asymptomatic/Intermittent AF The risk of stroke with asymptomatic or intermittent AF is comparable to that with permanent AF1,2 Observed rate of ischaemic stroke1 Annual risk of stroke, % 14 12 Intermittent AF Sustained AF 10 8 6 4 2 0 Low Moderate High Stroke risk category 1. Hart RG, et al. J Am Coll Cardiol 2000;35:183–7 2. Flaker GC, et al. Am Heart J 2005;149:657–63 The Cost of AF to the Australian Economy $1.25 billion every year $5,200 per person with AF 64% of this cost arises as a direct result of stroke, heart failure or death Pricewaterhouse Coopers, 2010 CHADS2 Score Helps Predict Stroke Risk in Patients With AF CHADS2 criteria 0 CHADS2 score 1 2 3 Score Congestive heart failure 1 Hypertension 1 Age >75 yrs 1 Diabetes mellitus 1 Stroke/transient ischaemic attack 2 4 5 6 0 5 10 15 20 25 30 Annual stroke rate (%)* Error bars = 95% CI; *Adjusted stroke rate = expected stroke rate per 100 patient-years based on exponential survival model, assuming Aspirin not taken Gage BF, et al. JAMA 2001;285:2864–70 Summary of Canadian Cardiology Society Guidelines for Thromboembolic Management in AF Assess Thromboembolic Risk (CHADS2) and Bleeding Risk (HAS-BLED) CHADS2 = 0 CHADS2 = 1 CHADS2 ≥ 2 Aspirin OAC OAC No antithrombotic may be appropriate in selected young patients with no stroke risk factors Aspirin is a reasonable alternative in some as indicated by risk-benefit Novel agents preferred OAC over warfarin in most patients Cairns JA, et al. Canadian Journal of Cardiology. 2011;27:74-90 AF – Warfarin compared with Placebo: Effect on Stroke/Systemic 6 trials, 2,900 patients Relative Risk Reduction 95% CI Absolute RR % / year AFASAK I 2.6 SPAF 4.7 BAATAF 2.4 CAFA 1.2 SPINAF 3.3 EAFT 8.4 2.7 PP 8.4 SP All trials All Trials RRR = 64 % (49 to 74%) 100% 50% 0 -50% -100% Hart RG, et al. Ann. Intern Med 2007; 146: 857-67 AF – Related Stroke is Preventable 2/3 of strokes due to AF are preventable with appropriate anticoagulant therapy with a vitamin-K-antagonist (VKA) (INR 2-3)1 Anticoagulation with a VKA is recommended for patients with more than 1 moderate risk factor2 Effect of VKA compared to placebo Stroke Stroke Death Death 67% 67% 26% 26% 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 mortality1 1. Hart RG, et al. Ann Intern Med. 2007;146:857-867 2. Fuster V, et al. JACC. 2006; 48: 854-906 Questions? Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation Rivaroxaban Selective, direct Factor Xa inhibitor1 High oral bioavailability2 TF/VIIa X IX Rapid onset of action3 VIIIa Half-life:2–4 IXa Rivaroxaban Va 5–9 hours in young individuals 11–13 hours in the elderly Xa Dual mode of elimination:5 1/3 of active drug excreted unchanged by the kidneys 2/3 of drug metabolized by the liver; half of which is excreted renally, half excreted via the hepatobiliary route 1. Perzborn et al, 2005; 2. Kubitza et al, 2005a; 3. Kubitza et al, 2005b; 4. Kubitza et al, 2008; 5. Weinz et al, 2009 II IIa Fibrinogen Fibrin Adapted from Weitz et al, 2005; 2008 New Anticoagulants Coagulation cascade Initiation Drug TF/VIIa X IX IXa VIIa Propagation Xa Va II TFPI NAPc2 Fondaparinux Idraparinux Razaxaban Rivaroxaban Apixiban Thrombin activity IIa Fibrinogen Fibrin Ximelagatran Dabigatran Adapted with permission from Weitz J,, Hirsh J. Chest. 2001;119:95S-107S. ROCKET AF – study design Randomized, double-blind, double-dummy, event-driven Non-valvular AF N=14,264 OR ≥2* of the following: R CHF Hypertension Age ≥75 years Diabetes 30-day follow-up Rivaroxaban 20 mg once daily# End of study History of stroke, TIA or non-CNS SE Warfarin target INR 2–3 ~14 – 40 months‡ *Enrolment of patients with <3 risk factors or without prior stroke/TIA or non-CNS SE was limited to 10%. #Patients with CrCl 30–49 ml/min: 15 mg rivaroxaban once daily. ‡Duration of therapy varied for each patient as study was event-driven. Patel MR et al. N Engl J Med 2011;365:883–891 25 ROCKET AF – study design Atrial fibrillation Rivaroxaban 20 mg once daily (15 mg once daily for CrCl 30–49 ml/min) Randomized double blind / double dummy Risk factors • Stroke, TIA or systemic embolus OR • CHF At least 2 • Hypertension or 3 • Age 75 required* • Diabetes Warfarin INR target: 2.5 (2.0–3.0 inclusive) Monthly monitoring Adherence to standard-of-care guidelines Primary endpoint: stroke or non-CNS systemic embolism *Enrolment of patients without prior stroke, TIA or SE and only two factors capped at 10% Patel MR et al. N Engl J Med 2011;365:883–891 26 ROCKET AF – study endpoints Primary efficacy endpoint Composite of stroke and sytemic embolism (SE) Secondary efficacy endpoints Composite of stroke, SE and cardiovascular death Composite of stroke, SE, cardiovascular death and MI Individual components of the above endpoints Principal safety endpoint Composite of major and non-major clinically relevant bleeding Patel MR et al. N Engl J Med 2011;365:883–891 27 ROCKET AF – patient flow Rivaroxaban Warfarin Randomized (n=14,264) 7131 7133 –50 –43 7081 ITT population: all patients randomized (n=14,171) 7090 –20 –8 7061 Safety population: all ITT patients who received ≥1 dose of study drug (n=14,143) 7082 –103 –78 Per-protocol population: 6958 all ITT patients without major predefined protocol violations (n=13,962) Patel MR et al. N Engl J Med 2011;365:883–891 7004 28 Rationale for the rivaroxaban dose in ROCKET AF 20 mg once daily was chosen as the rivaroxaban dose for the phase III ROCKET AF trial based on the phase II dose-finding programme for DVT treatment EINSTEIN DVT1 and ODIXa DVT2 both demonstrated: Efficacy of rivaroxaban did not increase with increasing total daily dose (20, 40, 60 mg in ODIXa-DVT; 20, 30, 40 mg in EINSTEIN DVT) Major bleeding was similar irrespective of total daily dose and comparable to the standard of care – Supports 20 mg total daily dose (as lowest effective dose evaluated) Early clinical pharmacology studies showed that rivaroxaban inhibited thrombin generation (and thereby continued to prevent coagulation) beyond 24 hours after administration3 – Supports once-daily dosing 1. Büller HR et al, 2008; 2. Agnelli G et al, 2007; 3. Harder S et al, 2004. 29 ROCKET AF – baseline characteristics (1) Rivaroxaban (N=7,131) Warfarin (N=7,133) 73 (65, 78) 73 (65, 78) Female, % 39.7 39. 7 Body mass index, median, kg/m2 28.3 28.1 Systolic 130 130 Diastolic 80 80 Persistent 5,786 (81.1) 5,762 (80.8) Paroxysmal 1,245 (17.5) 1,269 (17.8) 100 (1.4) 102 (1.4) Previous ASA use 2,586 (36.3) 2,619 (36.7) Previous VKA use 4,443 (62.3) 4,461 (62.5) Characteristic Age, median (25th, 75th), years Blood pressure, median, mmHg Clinical presentation, n (%) Type of atrial fibrillation Newly diagnosed/new onset ITT population Patel MR et al. N Engl J Med 2011;365:883–891 30 ROCKET AF – baseline characteristics (2) Rivaroxaban (N=7,131) Warfarin (N=7,133) 3.48±0.94 3.46±0.95 2, n (%) 925 (13.0) 934 (13.1) 3, n (%) 3,058 (42.9) 3,158 (44.3) 4, n (%) 2,092 (29.3) 1,999 (28.0) 5, n (%) 932 (13.1) 881 (12.4) 6, n (%) 123 (1.7) 159 (2.2) Previous stroke/TIA or SE 3,916 (54.9) 3,895 (54.6) Congestive heart failure 4,467 (62.6) 4,441 (62.3) Hypertension 6,436 (90.3) 6,474 (90.8) Diabetes mellitus 2,878 (40.4) 2,817 (39.5) Previous MI 1,182 (16.6) 1,286 (18.0) Peripheral vascular disease 401 (5.6) 438 (6.1) Chronic obstructive pulmonary disease 754 (10.6) 743 (10.4) 67 (52, 88) 67 (52, 86) Characteristic CHADS2 score, mean ± SD Co-existing conditions, n (%) CrCl, median (25th, 75th), ml/min ITT population Patel MR et al. N Engl J Med 2011;365:883–891 31 ROCKET AF – primary efficacy endpoint Stroke or systemic embolism Cumulative event rate (%) 6 HR=0.79 (0.66, 0.96) 5 Warfarin p<0.001 (non-inferiority) 4 3 Rivaroxaban 2 1 0 0 Number of subjects at risk Rivaroxaban 6,958 Warfarin 7,004 120 240 480 600 360 Days since randomization 720 840 6,211 6,327 5,786 5,911 2,472 2,539 1,496 1,538 5,468 5,542 4,406 4,461 3,407 3,478 Per-protocol population – as treated Patel MR et al. N Engl J Med 2011;365:883–891 32 ROCKET AF – primary efficacy endpoint Stroke or systemic embolism p-value Rivaroxaban (% per year) Warfarin (% per year) Non-inf. Per-protocol, on treatment 1.7 2.2 <0.001 Safety, on treatment 1.7 2.2 ITT 2.1 2.4 Hazard ratio and 95% CIs Sup. 0.02 <0.001 0.12 0.5 Favours rivaroxaban Patel MR et al. N Engl J Med 2011;365:883–891 1 2 Favours warfarin 33 ROCKET AF – primary efficacy endpoint ITT 6 Stroke or systemic embolism Warfarin Cumulative event rate (%) 5 HR=0.88 (0.75, 1.03) p<0.001 (non-inferiority) p=0.12 (superiority) 4 Rivaroxaban 3 2 1 0 0 Number of subjects at risk Rivaroxaban 7,081 Warfarin 7,090 120 240 360 480 600 Days since randomization 720 840 6,879 6,871 6,683 6,656 2,951 2,944 1,785 1,783 6,470 6,440 5,264 5,225 4,105 4,087 ITT population Patel MR et al. N Engl J Med 2011;365:883–891 34 ROCKET AF – primary efficacy endpoint components Hazard ratio and 95% CIs Rivaroxaban (N=7,061) Warfarin (N=7,082) n (% per year) n (% per year) Hazard ratio (95% CI) 189 (1.7) 243 (2.2) 0.79 (0.65, 0.95)* 184 (1.7) 221 (2.0) 0.85 (0.70,1.03) Haemorrhagic stroke 29 (0.3) 50 (0.4) 0.59 (0.37,0.93)* Ischaemic stroke 149 (1.3) 161 (1.4) 0.94 (0.75,1.17) 7 (0.1) 11 (0.1) 0.65 (0.25,1.67) 5 (0.04) 22 (0.2) 0.23 (0.09, 0.61)* Endpoints Primary efficacy endpoint All-cause stroke Unknown stroke type Non-CNS SE 0.2 Safety population – on-treatment analysis *Statistically significant Patel MR et al. N Engl J Med 2011;365:883–891 0.5 Favours rivaroxaban 1 2 5 Favours warfarin 35 ROCKET AF – bleeding analysis Rivaroxaban (N=7,111) Parameter Warfarin (N=7,125) n (% per year) n (% per year) Hazard ratio (95% CI) Principal safety endpoint 1,475 (14.9) 1,449 (14.5) 1.03 (0.96,1.11) Major bleeding 395 (3.6) 386 (3.4) 1.04 (0.90,1.20) Haemoglobin drop (≥2 g/dl) 305 (2.8) 254 (2.3) 1.22 (1.03,1.44)* Transfusion 183 (1.6) 149 (1.3) 1.25 (1.01,1.55)* Critical organ bleeding 91 (0.8) 133 (1.2) 0.69 (0.53,0.91)* 55 (0.5) 84 (0.7) 0.67 (0.47,0.93)* 27 (0.2) 55 (0.5) 0.50 (0.31,0.79)* 1,185 (11.8) 1,151 (11.4) 1.04 (0.96,1.13) Intracranial haemorrhage Fatal bleeding Non-major clinically relevant bleeding Major bleeding from gastrointestinal site (upper, lower and rectal): rivaroxaban=224 events (3.2%); warfarin=154 events (2.2%); p<0.001* Safety population – on-treatment analysis; *Statistically significant Patel MR et al. N Engl J Med 2011;365:883–891 Hazard ratio and 95% CIs 0.2 0.5 1 2 5 Favours Favours rivaroxaban warfarin 36 ROCKET AF – secondary efficacy endpoints Rivaroxaban (N=7,061) Warfarin (N=7,082) n (% per year) n (% per year) Hazard ratio (95% CI) Composite of stroke, nonCNS SE, vascular death 346 (3.1) 410 (3.6) 0.86 (0.74, 0.99)* Composite of stroke, non-CNS SE, vascular death and MI 433 (3.9) 519 (4.6) 0.85 (0.74, 0.96)* All-cause stroke 184 (1.7) 221 (2.0) 0.85 (0.70, 1.03) Non-CNS SE 5 (0.04) 22 (0.2) 0.23 (0.09, 0.61)* MI 101 (0.9) 126 (1.1) 0.81 (0.63, 1.06) Vascular death 170 (1.5) 193 (1.7) 0.89 (0.73, 1.10) 208 (1.9) 250 (2.2) 0.85 (0.70, 1.02) Endpoints Components of major secondary endpoints All-cause mortality Safety population – on-treatment analysis. *Statistically significant Patel MR et al. N Engl J Med 2011;365:883–891 37 ROCKET AF – primary efficacy endpoint subgroup analysis# Rivaroxaban Overall Sex Male Female Age (years) <75 ≥75 Weight (kg) ≤70 70–≤90 >90 CrCl (ml/min) <50 50–80 >80 n/N 189/7,061 (%) 2.7 Hazard ratio and 95% CIs Warfarin n/N 243/7,082 (%) 3.4 p-value* 0.92 103/4,270 86/2,791 2.4 3.1 136/4,283 107/2,799 3.2 3.8 0.11 107/3,988 82/3,073 2.7 2.7 119/4,005 124/3,077 3.0 4.0 0.78 63/2,004 92/3,022 34/2,033 3.1 3.0 1.7 78/2,008 129/3,133 36/1,940 3.9 4.1 1.9 0.72 50/1,485 91/3,290 47/2,278 3.4 2.8 2.1 60/1,456 128/3,396 54/2,221 Safety population – on-treatment analysis *p-value for interaction #Stroke or systemic embolism Patel MR et al. N Engl J Med 2011;365:883–891 4.1 3.8 2.4 0.1 0.2 0.5 Favours rivaroxaban 1 2 5 Favours warfarin 10 38 ROCKET AF – primary efficacy endpoint subgroup analysis# Rivaroxaban n/N 189/7,061 Overall CHADS2 2 21/922 3 56/3,025 4 71/2,073 5 35/918 6 6/122 Congestive heart failure Yes 106/4,428 No 83/2,632 Hypertension Yes 174/6,372 No 15/689 Diabetes Yes 70/2,842 No 119/4,219 Previous MI Yes 25/1,169 No 164/5,892 Previous stroke/TIA/Non-CNS Yes 136/3,881 No 53/3,180 (%) 2.7 Hazard ratio and 95% CIs Warfarin n/N 243/7,082 (%) 3.4 p-value* 0.74 2.3 1.9 3.4 3.8 4.9 24/931 87/3,131 88/1,988 36/875 8/155 2.6 2.8 4.4 4.1 5.2 0.66 2.4 3.2 141/4,409 102/2,672 3.2 3.8 0.85 2.7 2.2 223/6,429 20/653 3.5 3.1 0.60 2.5 2.8 94/2,793 149/4,289 3.4 3.5 0.25 2.1 2.8 SE 3.5 1.7 46/1,269 197/5,813 3.6 3.4 0.04 151/3,869 92/3,213 Safety population – on-treatment analysis *p-value for interaction #Stroke or systemic embolism Patel MR et al. N Engl J Med 2011;365:883–891 3.9 2.9 0.1 0.2 0.5 Favours rivaroxaban 1 2 5 10 Favours warfarin 39 ROCKET AF – primary efficacy endpoint subgroup analysis# Rivaroxaban Overall Hazard ratio and 95% CIs Warfarin n/N (%) n/N 189/7,061 2.7 243/7,082 p(%) value* 3.4 Race 0.49 White 151/5,856 2.6 194/5,909 3.3 Black 5/94 5.3 5/85 5.9 Asian 27/894 3.0 41/887 4.6 Other 6/217 2.8 3/201 1.5 Region 0.62 North America 20/1,334 1.5 36/1,339 2.7 Latin America 33/939 3.5 37/938 3.9 West Europe 28/1,040 2.7 34/1,049 3.2 East Europe 78/2,696 2.9 91/2,704 3.4 Asia-Pacific 30/1,052 2.9 45/1,052 4.3 Safety population – on-treatment analysis *p-value for interaction #Stroke or systemic embolism Patel MR et al. N Engl J Med 2011;365:883–891 0.1 0.2 0.5 Favours rivaroxaban 1 2 5 10 Favours warfarin 40 ROCKET AF – conclusions Based on the prespecified primary efficacy outcome: A once-daily fixed dose regimen of rivaroxaban was non-inferior to warfarin for prevention of stroke or non-CNS systemic embolism Rivaroxaban was superior to warfarin while patients were taking study drug Safety: Similar overall incidence of bleeding and adverse events Increase in gastrointestinal bleeds but importantly fewer intracranial haemorrhages and less fatal bleeding with rivaroxaban Implication: Rivaroxaban, once approved in the indication, is a once-daily, proven alternative to warfarin with superior efficacy ‘on treatment’, similar overall bleeding and fewer intracranial haemorrhages 41 New Oral Anticoagulants dabigatran (Pradaxa) rivaroxaban (Xarelto) apixaban 80% 66% 25% T1/2 12-14 hours 9-13 hours 8-15 hours Tmax 1.25-3 hours 2-4 hours 1-4 hours P-gp inhibitors CYP3A4 / P-gp inhibitors CYP3A4 / P-gp inhibitors 6.5% (human) 67-86% (animals) 49% (human) Protein binding 35% 92-95% 87% Prodrug Yes No No Renal excretion Drug-drug interactions Bioavailability Eriksson BI, et al. Clin. Pharmacokinet. 2009; 48(1): 1-22 ROCKET AF some additional points of value ROCKET AF: principal inclusion criteria Age ≥18 years Persistent or paroxysmal AF documented on ≥2 episodes (one of which is electrocardiographically documented within 30 days of enrollment) Risk for future stroke, including the history of stroke/TIA or systemic embolism OR ≥2 of the following: Congestive heart failure or left ventricular ejection fraction ≤35% Hypertension (systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg) Age ≥75 years Diabetes mellitus Patel MR et al: Am Heart J 2010;159:340-347.e1 ROCKET AF: principal exclusion criteria 1 Cardiovascular-related conditions Prosthetic heart valve Planned cardioversion AF secondary to reversible disorders (ie, thyrotoxicosis) Known presence of atrial myxoma or left ventricular thrombus Active endocarditis Hemodynamically significant mitral stenosis Patel MR et al: Am Heart J 2010;159:340-347.e1 ROCKET AF: principal exclusion criteria 2 Hemorrhage risk-related criteria Active internal bleeding History of, or condition associated with, increased bleeding risk, including – Major surgical procedure or trauma within 30 days before randomization – Clinically significant gastrointestinal bleeding within 6 months – before randomization – History of intracranial, intraocular, spinal, or atraumatic – intraarticular bleeding – Chronic hemorrhagic disorder – Known intracranial neoplasm, arteriovenous malformation, or aneurysm – Planned invasive procedure with potential for uncontrolled bleeding, including major surgery Patel MR et al: Am Heart J 2010;159:340-347.e1 ROCKET AF: principal exclusion criteria 3 Concomitant conditions: Any stroke within 14 days before randomization TIA within 3 days before randomization Indication for anticoagulant therapy for a condition other than AF (eg, VTE) Anemia (hemoglobin level b10 g/dL) at the screening visit Pregnancy or breastfeeding Known HIV infection at time of screening Calculated creatinine clearance b30 mL/min at the screening visit Known significant liver disease (eg, acute clinical hepatitis, chronic active hepatitis, cirrhosis) or alanine aminotransferase N3× the upper limit of normal Patel MR et al: Am Heart J 2010;159:340-347.e1 Comparison of phase III studies of new oral anticoagulants for stroke prevention in atrial fibrillation Study design and inclusion ROCKET AF1 RE-LY2 ARISTOTLE3,6 AVERROES4 ENGAGE AFTIMI 485 14,264 18,113 18,201 5,599 20,500 Statistical objective Non-inferiority Non-inferiority Non-inferiority Superiority Non-inferiority No. study arms 2 3 2 2 3 Study drug Double-blind rivaroxaban Two doses of double-blind dabigatran Double-blind apixaban Double-blind apixaban Two doses of double-blind edoxaban Control Double-blind warfarin (INR 2–3) Open-label warfarin (INR 2–3) Double-blind warfarin (INR 2–3) Double-blind ASA Double-blind warfarin (INR 2–3) Non-valvular Non-valvular All except mechanical valves Non-valvular Non-valvular No. of patients AF type of pts included 1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010; 4. Connolly SJ et al, 2011; 5. Ruff CT et al, 2010; 6.Granger CB et al, 2011. 49 Dosing and dose evaluation for special populations ROCKET AF1 RE-LY2 ARISTOTLE3 & AVERROES4 ENGAGE AF-TIMI 485 Rivaroxaban Dabigatran Apixaban Edoxaban 20 mg od (15 mg od) 110 mg bid or 150 mg bid 5 mg bid (2.5 mg bid) (randomized to two separate arms) Dose adjustment for patients with: Moderate renal impairment CrCl 3049 ml/min No dose adjustment 30 mg od (15 mg od) or 60 mg od (30 mg od) (randomized to two separate arms) Dose adjustment for patients fulfilling 2 of the following criteria at baseline: Age 80 years Dose adjustment for patients fulfilling ≥1 of the following criteria at baseline: Body weight 60 kg verapamil or quinidine Serum creatinine 1.5mg/dl (133 µmol/l) Body Concomitant CrCl 1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010; 4. Connolly SJ et al, 2011; 5. Ruff CT et al, 2010. weight 60 kg 3050 ml/min 50 Cross-trial comparisons Cross-trial comparisons are hazardous ROCKET AF and others: Different drugs Different trial designs Different patient populations The best method to compare drugs is head-to-head, randomization in large populations 51 ROCKET AF vs RE-LY (150 mg) Rivaroxaban 20/15 mg vs warfarin in ROCKET AF1 Dabigatran 150 mg vs warfarin in RE-LY2,3 Design Double blind Open label Efficacy Non-inferior to warfarin Non-inferior to warfarin Superior to warfarin on treatment Superior to warfarin Safety Similar rates of major haemorrhage Similar rates of major haemorrhage Less ICH Less ICH *Data from initial publication,2 in a post hoc analysis published 2010 the addition of newly identified MIs led to the loss of significance for MI3 1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Connolly SJ et al, 2010. 52