Anticoagulation For Atrial Fibrillation New Agents In A New Era Arjun V Gururaj, MD Arrhythmia and Electrophysiology Nevada Heart and Vascular Center
Disclosures Biotronik Speaker Clinical investigator Trainer
A 72 yo man arrives for a routine visit. He states he has had palpitations occasionally for months. His ECG today shows atrial fibrillation with a ventricular rate of 90 bpm. He is quite comfortable. He has no symptoms of congestive heart failure and he has no history of cardiovascular disease. In fact, he exercises avidly. PMH includes hypertension and diabetes both well treated. On further examination of older records you realize has had paroxysmal atrial fibrillation for at least 6 months. He has no significant abnormalities on routine blood work include a comprehensive metabolic panel and CBC
Regarding an anticoagulation strategy (if warranted), which of the options below would you choose? A. Warfarin B. Dabigatran C. Rivaroxaban D. ASA E. None of the above
What do you think is the most likely reason for clinicians limited use of new anticoagulant agents? A. Unfamiliar with drugs B. Bleeding risks C. Lack of convincing data D. Reported adverse effects E. Why change?
AF: A Growing Epidemic Projected 4-5 million people affected 1 in 4 lifetime risk in men and women >40 years old AF may contribute to 15% of all strokes Independent mortality risk 12-16 million affected by 2050 (projections)
Incidence of AF: Framingham 80 Rate/1000 Person Exams 60 40 20 Men Women 0 55-64 65-74 75-84 85-94 Age
Prevalence of AF
Risk Of Stroke: CHADS2 Variable Score 20 CHF 1 Hypertension 1 Age>75 1 Diabetes 1 % Risk 15 10 5 CVA 2 0 0 1 2 3 4 5 6 Gage B et al. JAMA 2001;285:2864
Anticoagulants VKA Novel Agents Anti-Xa Apixaban Rivaroxaban Edoxaban Warfarin Direct Thrombin Inhibitors Dabigatran Ximelagatran
What s An Ideal Anticoagulant? Properties Once-daily dosing Rapid onset Predictable effect Non-renal clearance Rapid offset of action Antidote Benefit Ease of administration No bridging therapy No monitoring Safe for CKD patients Bleeding management Emergency management
Stroke Reduction With Warfarin 15 12 %/year CVA 9 6 3 0 AFASAK BAATAF CAFA SPAF1 SPINAF EAFT Warfarin Placebo
ACTIVE W 6700 patients(mean CHADS: 2.0) ASA+clopidogrel vs. warfarin non-inferiority design warfarin superior and safer Active Writing Grp Lancet 2006;367:1903
ACTIVE A 7500 patients (mean CHADS: 2.0) ASA vs. ASA + clopidogrel combination was superior (RR 0.72, P<0.001) Increased major bleeds with combination (RR 1.57) CVA risk reduced by 28% in combination drug group ACTIVE Investigators NEJM 2009;360:2066
The Novel Agents: An Overview TRIAL RE-LY ROCKET-AF AVERROES ARISTOTLE Drug Dabigatran Rivaroxaban Apixaban Apixaban CHADS2 2.1 3.5 2.0 2.1 PAF (%) 32 17.5 27 15 Male (%) 64 60 60 65 Prior CVA (%) 20 55 14 19 Control warfarin warfarin ASA warfarin Age (mean) 71 73 71 70
Dabigatran: Direct Thrombin Inhibitor Oral pro-drug converted to dabigatran 1/2 life: 12-17 hours 80% renal excretion Rapid onset of action (within 2 hours) Predictable effects BID dosing
RE-LY Trial: Dabigatran Is Superior to Warfarin 18,000 patients (mean CHADS: 2.1) warfarin dabigatran 110 mg BID dabigatran 150 mg BID F/U 2 years Primary outcome: CVA or systemic embolism
Dabigatran 150 mg BID Is Superior To Warfarin 64% patients with therapeutic INR Dabi 110 mg BID noninferior to warfarin Dabi 150 mg BID superior to warfarin RR 0.66 (p<0.001) Connolly S et al. NEJM 2009;361:1139
Bleeding Complications In RE-LY 17 Dabi 150 BID and warfarin comparable for MAJOR bleeds Dabi 110 BID had less MAJOR bleeds %/yr 12.75 8.5 4.25 Both doses had less minor bleeding 0 Dabi 110 Dabi 150 Warfarin Major bleeding Minor bleeding Intracranial bleed
Does Dabigatran Increase Risk Of MI? Controversial issue 38% increase in RE-LY (RR 1.38, p=0.48) Dabi 110 Dabi 150 Warfarin Inconsistent results in analyses Is warfarin cardioprotective? Value Title 0.8 0.6 0.4 0.2 0.72 0.74 0.53 Mechanism unknown 0
IV 1.31 (1.02 to 1.69).03 RE 1.32 (1.02 to 1.69).03 Risk difference M-H 0.27% (0.04% to 0.50%).02 0% for all IV 0.14% ( 0.03% to 0.31%).10 RE 0.14% ( 0.03% to 0.32%).10 Dabigatran And Risk Of MI Abbreviations: ACS, acute coronary syndrome; IV, inverse variance; M-H, Mantel-Haenszel; MI, myocardial infarction; R Evaluation of Long-term Anticoagulant Therapy. RE-NOVATE, 10 2007 RE-MODEL, 11 2007 PETRO, 12 2007 RE-LY original, 2,3 2009 RE-COVER, 13 2009 RE-DEEM, 14 2011 RE-NOVATE II, 15 2011 FE model Dabigatran, No. Study, y ACEv No Event ACEv No Event Odds Ratio (95% CI) 13 10 2 175 4 32 1 2296 1372 443 11 916 1269 1458 1009 Control, No. 9 4 0 63 2 4 1 1133 690 70 5959 1264 313 1002 0.04 0.20 1.00 5.00 Odds Ratio (Log Scale) 0.71 (0.30-1.67) 1.26 (0.39-4.02) 0.79 (0.04-16.73) 1.39 (1.04-1.86) 1.99 (0.36-10.90) 1.72 (0.60-4.89) 0.99 (0.06-15.90) 1.33 (1.03-1.71) Figure 2. Risk of myocardial infarction and acute coronary syndrome across 7 studies, including original Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) results. ACEv indicates acute coronary events; FE, fixed effects; PETRO, Prevention Uchino of Embolic K, et al. andarch Thrombotic Int Med Events 2012:172(5);397-402 in Patients With Persistent AF Study; rectangles, odds ratios; limit lines, 95% CIs; diamond, overall odds ratio and 95% CI; and arrows, 95% CIs that exceed the limits of the graph (0.04-5.00). Our m risk o dabig contro adjust or pla analyt tion m consis increa increa We logic m dabig or AC multi risks a
Rivaroxaban: Direct Xa Inhibitor Direct, competitive factor Xa inhibitor 1/2 life 5-15 hours Once daily dosing 2/3 hepatic metabolism Effective for DVT
ROCKET AF: Higher CHADS2 Scores 14,000 patients, double-blind trial warfarin vs. 20 mg daily rivaroxaban high CHADS2 score (3.4) Low TTR for warfarin patients (55%) FDA approved recently
ROCKET AF: Non-inferior to Warfarin Rivaroxaban noninferior to warfarin in intention-to-treat analysis (HR 0.88, p<0.001 for inferiority) Non-inferiority trials can be treacherous TTR for warfarin was low
ROCKET AF: Bleeding Complications 15 no./100 pt-yr 11.25 7.5 11.8 11.4 Major bleeding Nonmajor bleeding Intracranial bleed 3.75 3.6 3.4 0 Rivarox 0.8 Warfarin 1.2
Apixaban: Xa Inhibitor Oral selective Xa inhibitor 1/2 life 12 hours 25% renal excretion Apixaban safe for VTE Not FDA approved yet (in review)
AVERROES: Apixaban Superior to ASA 5600 patients CHADS2 mean 2.0 but unable to receive warfarin ASA vs. apixaban (5 mg BID) mean F/U 1.1 years Primary endpt: CVA or systemic embolism
AVERROES: Results 1.6% event rate for apixaban vs 3.7% event rate for ASA (HR 0.45, p<0.001) Composite endpt: 5.3% apixaban vs. 7.2% ASA (HR 0.74, p=0.003) Study terminated early in 2010 Connolly S et al. NEJM 2011;364:806-17
AVERROES: CVA Breakdown 3 3 % per yr 2.25 1.5 2.3 Ischemic Hemorrhagic Fatal or disabling 0.75 1.1 1 0 0.2 Apixaban 0.3 ASA
ASA Is Not Always Benign 1.5 1.4 % per yr 1.125 0.75 1.2 Major bleed Intracranial bleed GIB Non-GIB Fatal 0.6 0.6 0.375 0.4 0.4 0.4 0.4 0.2 0 Apixaban 0.1 ASA
So Is Apixaban Better Than Warfarin? ARISTOTLE trial enrolled 18,000 patients Mean CHADS2: 2.1 Apixaban vs. warfarin F/U 1.8 yrs Endpt: CVA or systemic embolism
Apixaban Superior to Warfarin TTR 66% Primary outcome 1.3 % apixaban grp 1.6 % warfarin grp HR 0.79, p<0.001 All cause mortality decreased in apixaban grp Granger C et al. NEJM 2011;365:981-92
ARISTOTLE: Less Bleeding With Apixaban 7 5.25 6.01 %/yr 3.5 4.07 3.09 Major bleeding Intracranial bleeding Nonmajor bleeding 1.75 2.13 0 0.33 Apixaban 0.8 Warfarin
In Summary: Observations And Questions Raised Novel anticoagulants seem to be as effective and safe as warfarin Cost-effective data pending Which patient gets which drug? Is the lack of monitoring comforting for patient and MD? Safety in surgery? Are warfarin s days numbered?