OCTOBER 7-10 PHILADELPHIA, PENNSYLVANIA

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1 OMED 17 OCTOBER 7-10 PHILADELPHIA, PENNSYLVANIA 29.5 Category 1-A CME credits anticipated ACOFP / AOA s 122 nd Annual Osteopathic Medical Conference & Exposition ACOFP - The Heart of the Matter - An Evidence Based Approach to Common Cardiovascular Concerns: Atrial Fibrillation - Keeping Your Patients Safe Bruce Kornberg, DO The American College of Osteopathic Family Physicians is accredited by the American Osteopathic Association Council to sponsor continuing medical education for osteopathic physicians. The American College of Osteopathic Family Physicians designates the lectures and workshops for Category 1-A credits on an hour-for-hour basis, pending approval by the AOA CCME, ACOFP is not responsible for the content.

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3 Outline Introduction: Stroke and atrial fibrillation (AF) Assessing stroke risk in patients with AF Safety, efficacy, and selection of appropriate antithrombotic therapy Clinical case Clinical guidelines Emerging antithrombotic therapies Potential clinical application Concluding remarks/q&a 1

4 Atrial Fibrillation (AF) Estimated to affect 2.7 to 6.1 million patients in US Most common arrhythmia requiring hospitalization More than 750,000 yearly secondary to AF Associated with advanced age and chronic heart disease especially heart failure as well as high blood pressure, obesity, diabetes, and hyperthyroidism Independent risk factor for stroke Increases stroke risk by four to five times compared to those without AF Underdetected Fuster V, et al. Circulation. 2006;114: ; Thom T, et al. Circulation. 2006;113:e85-e151.; Mozaffarian D. Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman, M, et al. Heart Disease and Stroke Statistics-2015 update: a report from the American Heart Association, Circulation. 2015;131:e29-e322 Classification of AF ACC/AHA/ESC Guidelines First Detected Paroxysmal (Self-terminating) Persistent (Not self-terminating) Permanent Fuster V, et al. J Am Coll Cardiol. 2006;48:e149-e246. 2

5 AF Underdetection Cardiovascular Health Study: 30% unaware of AF documented by ECG SPAF III: 44% of AF detected by ECG without AF symptoms Sparks et al: 48/110 pacemaker patients noted to be in AF during routine interrogation; most were high risk for stroke Furberg CD, et al. Am J Cardiol.1994;74: Blackshear JL, et al. Lancet. 1996;348(9028): Sparks PB, et al. Pacing Clin Electrophysiol.1998;21: AF and Stroke AF is responsible for 15% to 20% of ischemic strokes AF increases one s risk of suffering an ischemic stroke fivefold AF is responsible for ~30% of strokes in patients >80 years old Pathogenesis: Caused by atrial thrombosis and thromboembolism (principally from the left atrial appendage) 3

6 AF and Stroke AF-related strokes more severe; result in higher mortality Patients with AF are not always appropriately risk-stratified for stroke Appropriate anticoagulation for patients at risk is underutilized Poorly controlled anticoagulation is associated with elevated stroke risk Appropriate antithrombotic treatment requires weighing the risks and benefits of stroke prevention vs hemorrhagic complication Paroxysmal vs Chronic AF Risk of stroke is the same Symptomatic vs asymptomatic: does not affect stroke risk assuming same level of treatment AFFIRM trial: rate vs rhythm control Most strokes occurred with discontinuation of anticoagulation after perception of rhythm control One ECG showing SR does not rule out possibility of recurrent AF Wyse DG, et al. N Engl J Med. 2002;347(23): ; Furberg CD. Am J Cardiol. 1994;74:236.; Blackshear JL, et al. Lancet. 1996;348(9028): ; Sparks PB, et al. Pacing Clin Electrophysiol.1998;21:

7 Thromboembolic Complications AFFIRM Central Nervous System Event Overall (N = 4060) Rate Control Group (N = 2027) Rhythm Control Group (N = 2033) P Value Total 211 (8.2) 105 (7.4) 106 (8.9).93 Ischemic stroke 157 (6.3) 77 (5.5) 80 (7.1).79 After discontinuation of warfarin During warfarin but with INR < Concurrent atrial fibrillation Primary intracerebral hemorrhage 34 (1.2) 18 (1.1) 16 (1.3).73 Subdural or subarachnoid hemorrhage 24 (0.8) 11 (0.8) 13 (0.8).68 61% of strokes in pseudo Rhythm Control Group occurred after stopping or with inadequate warfarin; documented asymptomatic AF in ~ 50% Wyse DG, et al. N Engl J Med. 2002;347(23): CHADS 2 VASc Risk Stratification Scheme CHA2DS2-VASc Stroke rate %/year Congestive heart failure 1 Hypertension 1 Age > 75 2 Diabetes 1 Stroke/TIA/TE 2 Vascular disease (MI, PAD, aortic plaque) 1 Age Female sex 1 0 0% 1 1.3% 2 2.2% 3 3.2% 4 4.0% 5 6.7% 6 9.8% 7 9.6% 8 6.7% % Gage BF, et al. JAMA. 2001;285(22):

8 Case Study Choice of Therapy You estimate that your patient s annual stroke risk is around 6%-9%. What is her bleeding risk? What is her best management to reduce long term stroke risk? Discuss risks and benefits of antithrombotic therapy with patient Determine patient preference & ability to safely take anticoagulant Establish protocol for monitoring What About Bleeding Risk? Risk factors for anticoagulation-related bleeding complications: Advanced age Uncontrolled hypertension History of myocardial infarction or ischemic heart disease Cerebrovascular disease Anemia or a history of bleeding Concomitant use of other drugs such as antiplatelet agents Many risk factors for anticoagulation-related bleeding are also indications for the use of anticoagulants in AF patients, given the increasing bleeding risk with increasing CHADS 2 VASc score Various bleeding risk stratification schema have been proposed, but more validation of their value is required in prospective cohorts of AF patients 6

9 HAS-BLED Hypertension=1 Abnormal renal/liver function=1 Stroke=1 Bleeding history or disposition=1 Labile INR=1 Elderly=1 Drugs/Alcohol=1 Clinically Relevant Bleeding Major Bleeding 0 7% 1% 1 8% 1% 2 11% 2% 3 16% 3% 4 15% 3% >5 38% 8% American College of Chest Physicians (ACCP) Guidelines Recommendations CHADS 2 Score Risk Factor 2 points Recommended Therapy Warfarin (target INR 2.5, range ) 1 point Aspirin 75 mg to 325 mg QD or warfarin (target INR 2.5, range ) Age 75 years with no risk factors Aspirin 75 mg to 325 mg QD CHADS 2 Score risk factors: (1) age >75 years; (2) history of hypertension; (3) diabetes mellitus; and (4) moderately or severely impaired left ventricular systolic function and/or heart failure Singer DE, et al. Chest. 2008;133:546S 592S. 7

10 Warfarin Most commonly used oral anticoagulant >60 years of use Well-studied Reduces vitamin K dependent clotting factors Very effective if INR kept in therapeutic range Effect measured using the INR; therapeutic range: 2-3 Well-known and defined drug and food interactions Relatively inexpensive Meta-Analysis of Warfarin Efficacy and Safety 15 large studies comparing warfarin to ASA or placebo in patients with atrial fibrillation Warfarin vs placebo = 71% RRR Warfarin vs ASA = 50% RRR Both statistically significant Warfarin vs placebo increased risk of major bleed by OR = 3.0 Andersen LV, et al. Heart. 2008;94(12):

11 Efficacy of Warfarin Stroke Risk Reductions Warfarin Better Control Better AFASAK SPAF BAATAF Reduction of all-cause mortality RRR 26% CAFA SPINAF EAFT All trials = 6 Reduction of stroke RRR 62% 100% 50% 0-50% -100% Andersen LV, et al. Heart. 2008;94(12): Hart RG, et al. Ann Intern Med. 1999;131: AFASAK I SPAF I EAFT ESPS II LASAF UK-TIA Aspirin vs Placebo Stroke Risk Reductions Relative Risk Reduction (95% CI) All trials = 6 22% (2%-38%) Hart RG, et al. Ann Intern Med. 1999;131: Aspirin 9

12 Cumulative Hazard Rates Relative Risk Reduction, % Efficacy of Aspirin vs Warfarin % 60 52% % 0 Warfarin vs No Therapy ASA vs No Therapy Warfarin vs ASA AFI. Arch Int Med. 1994;154: ; van Walraven C, et al. JAMA. 2002; 288(19): ACTIVE-A: Asprin vs. Clopidogrel + Aspirin Cumulative Risk of Stroke HR = 0.72 ( ), P = Aspirin Clopidogrel + aspirin No. at Risk Years C+A ASA Connolly SJ, et al. New Engl J Med. 2009;360:

13 Cumulative Hazard Rates Clopidogrel + Aspirin vs Oral Anticoagulation Active-W: Cumulative Risk of Stroke RR = 1.72 ( ), P =.001 Clopidogrel + aspirin 0.01 Oral anticoagulation therapy 0 Number at risk Clopidogrel Years aspirin Oral anti coagulation therapy *ACTIVE = Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; Primary outcome: stroke, systemic embolus, MI, vascular death; Clopidogrel + aspirin = 5.6% risk/year vs warfarin = 3.93% risk/year. Connolly S, et al. Lancet. 2006;367: Rates of Intracranial Hemorrhage (ICH) With Anticoagulation in Patients With AF Precise estimates of anticoagulant-associated ICH are not available Generally thought to be in 1%-2% per yr range Some studies as low as 0.4% per yr; some as high as 3%-4% per yr* Several risk factors Age, HTN, prior strokes, leukoaraiosis, high INR, cerebral amyloid angiopathy *Includes heparin use Flaherty ML, et al. Neurology. 2007;68(2):

14 Warfarin Time in Range Meta-analysis of 8 studies 14 unique warfarin treated groups Mean, 95% confidence intervals for time in range = 55% (51%-58%) Baker WL, et al. J Manag Care Pharm. 2009;15: Warfarin Time in Range Time in range correlates with freedom from stroke: retrospective study of 6108 patients in the United Kingdom Morgan CL, et al. Thromb Res. 2009;124(1):

15 Interactions* With Warfarin Partial List Drugs Supplements Foods/Beverages Acetaminophen Antibiotics (some) Amiodarone Aspirin or aspirincontaining products GI medications (some) Non-steroidal anti - inflammatory drugs (NSAIDs) Thyroid medications Bromelains Coenzyme Q10 Danshen Dong quai Fish oil and omega- 3 supplements Garlic Ginkgo biloba Ginseng St. John's wort Vitamin K Alcohol Foods high in vitamin K (eg, soybean and canola oils, spinach or broccoli) Garlic Black licorice Cranberries/juice *The degree of interaction varies considerably. New and Investigational Agents for Stroke Prevention in AF Direct thrombin inhibitors Dabigatran (RE-LY): FDA approved for prevention of stroke in patients with AF Direct factor Xa inhibitors Rivaroxaban (ROCKET AF): FDA approved for prevention of stroke in patients with AF Apixaban (ARISTOTLE) Edoxaban (ENGAGE-AF) Betrixaban (EXPERT) YM150 (ONYX-2) Indirect Xa inhibitors Idraparinux (BOREALIS-AF) Indirect inhibitors (eg, odiparcil) US Food and Drug Administration. Available at: Accessed October 21, Usman MH, et al. Curr Treat Options Cardiovasc Med. 2008;10:

16 New and Investigational Agents Mechanisms Intrinsic pathway XII XI Extrinsic pathway Tissue factor IX VIII VII X V Direct FXa inhibitors (rivaroxaban, apixaban edoxiban) II Fibrinogen Direct thrombin inhibitors (dabigatran) Fibrin clot FXa = factor Xa Adapted from: Nutescu EA, et al. Cleve Clin J Med. 2005;72(suppl 1):S2-S6. NOAC SPAF Trials Meta-Analysis of 71,683 Patients 14

17 RE-LY AF with at least 1 additional risk factor for stroke Randomized (N ) Age 75 years Age of 65 to 74 years plus diabetes mellitus, hypertension, or coronary artery disease Blinded Dabigatran 110 mg BID or Dabigatran 150 mg BID Unblinded/open label Adjusted-dose warfarin Primary outcome: stroke or systemic embolism Primary safety outcome: major bleeding Other outcomes: stroke, systemic embolism, and death 2.0 year median follow-up RE-LY = Randomized Evaluation of Long Term Anticoagulant Therapy Connolly SJ, et al. New Engl J Med. 2009;361: RE-LY Primary Outcome Dabigatran 110 mg (n = 6015) Dabigatran 150 mg (n = 6076) Warfarin ( n = 6022) Dabigatran 110 mg vs Warfarin Dabigatran 150 mg vs Warfarin Annual Rate Annual Rate Annual Rate RR 95 % CI P Value RR 95% CI P Value Stroke or systemic embolism 1.5% 1.1% 1.7% <.001 for noninferiority, <. 001 for noninferiority, <.001 Stroke 1.4% 1.0% 1.6% <.001 Connolly SJ, et al; and the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361:

18 RE-LY Bleeding Events Dabigatran 110 mg Dabigatran 150 mg Warfarin Annual Rate Annual Rate Annual R ate Major 2.7% 3.1% 3.4% Lifethreatening (major) Gastrointestinal (major) 1.2% 1.5% 1.8% 1.1% 1.5% 1.0% Dabigatran 110 mg vs Dabigatran 150 mg vs Warfarin Warfarin RR 95% CI P Value RR 95% CI P Value < <.001 Minor 13.2% 14.8% 16.4% < Major or minor 14.6% 16.4% 18.2% < Connolly SJ, et al; the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361: RE-LY MI, Death, and Net Clinical Benefit Dabigatran 110 mg Dabigatran 150 mg Warfarin Dabigatran 110 mg vs Warfarin Dabigatran 150 mg vs Warfarin Annual Rat e Annual Rat e Annual R ate RR 95% CI P Value RR 95% CI P Value MI 0.7% 0.7% 0.5% Death from any cause 3.8% 3.6% 4.1% Net clinical benefit 7.1% 6.9% 7.6% Net clinical benefit includes vascular events, death and major bleed. Connolly SJ, et al; the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361:

19 Oral Factor Xa Inhibitors Ongoing Phase III Trials for Prevention of Stroke and Systemic Embolism in Patients With AF Trial Acronym Drug Dose Comparator N Risk factors ROCKET- AF (recently concluded) Rivaroxaban 20 mg a QD Warfarin (INR 2-3) ARISTOTLE Apixaban 5 mg BID Warfarin (INR 2-3) ENGAGE-AF Edoxaban 30 mg BID 60 mg* QD Warfarin (INR 2-3) a Adjusted based on renal function. Rocket AF Study Design Atrial Fibrillation Risk Factors CHF Hypertension Age 75 Diabetes OR Stroke, TIA or Systemic embolus At least 2 or 3 required* Rivaroxaban 20 mg daily 15 mg for Cr Cl ml/min Randomize Double Blind / Double Dummy (n: 14,264) Warfarin INR target ( inclusive) 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% Rocket AF Investigators, AHA

20 Cumulative event rate (%) Primary end point, noninferiority Vascular death, stroke, embolism ROCKET-AF Primary Outcomes Rivaroxaban Warfarin Hazard ratio p (n=7081) (n=7090) (95% CI) ( ) < ) Hemorrhagic stroke ( ) Ischemic stroke ( ) Unknown stroke ( ) Days from Randomization Califf R. LBCT I: Abstract Presented at: American Heart Association Scientific Sessions 2010; Nov , 2010; Chicago. 6 ROCKET-AF Primary Outcomes Warfarin Rivaroxaban HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <

21 Cumulative incidence (%) Cumulative incidence (%) ROCKET-AF Bleeding Events Major & nonmajor bleeding Rivaroxaban Warfarin Hazard ratio p (n=7081) (n=7090) (95% CI) ( ) Major bleeding ( ) Intracranial hemorrhage ( ) Califf R. LBCT I: Abstract Presented at: American Heart Association Scientific Sessions 2010; Nov , 2010; Chicago. WOEST WOEST study (N=573) compared safety outcomes with triple therapy (VKA + clopidogrel + ASA) vs dual therapy (VKA + clopidogrel) 69% of WOEST patients had AF, included prosthetic heart valves Safety outcomes Efficacy outcomes 19

22 TIMI Major, TIMI Minor, or Bleeding Requiring Medical Attention (%) Pre-Randomization Choice of Duration of DAPT & Thienopyridine: PIONEER AF-PCI XARELTO 15 mg qd* Clopi 95%, Ticag 4%, Prasugrel 1% WOEST Like 2100 patients with NVAF Coronary stenting No prior stroke/tia, GI bleeding, Hb<10, CrCl<30 72 hours After Sheath removal R A N D O M I Z E 1 mo: 16% 6 mos: 35% 12 mos: 49% XARELTO 2.5 mg bid Clopi 95%, Ticag 4%, Prasugrel 1% Aspirin mg qd 1 mo: 16% 6 mos: 35% 12 mos: 49% XARELTO 15mg QD Aspirin mg qd ATLAS Like VKA (target INR ) Clopi 95%, Ticag 4%, Prasugrel 1% Aspirin mg qd VKA (target INR ) Aspirin mg qd TTR 65% Triple Therapy Gibson et al. AHA 2016 Kaplan-Meier Estimates of First Occurrence of Clinically Significant Bleeding Events 26.7% p< % 16.8% Riva + P2Y 12 v. VKA + DAPT HR=0.59 (95% CI: ) p < ARR=9.9 NNT=11 HR = 0.63 (95% CI ) HR ARR = 0.59 = (95% 8.7 Riva + CI DAPT ) v. VKA + DAPT ARR NNT = 9.9 = 12HR=0.63 (95% CI: ) NNT = 11 p < ARR=8.7 NNT=12 No. at risk Riva + P2Y 12 Riva + DAPT VKA + DAPT Days Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Clinically significant bleeding is the composite of TIMI major, TIMI minor, and BRMA. Hazard ratios as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank P-values as compared to VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) two-sided log rank test. Gibson et al. AHA

23 Cardiovascular Death, Myocardial Infarction, or Stroke (%) Kaplan-Meier Estimates of First Occurrence of CV Death, MI or Stroke Riva + P2Y % 6.0% 5.6% Riva + DAPT VKA + DAPT Riva + P2Y 12 v. VKA + DAPT HR=1.08 (95% CI: ) p=0.750 Riva + DAPT v. VKA + DAPT HR=0.93 (95% CI: ) p=0.765 No. at risk Riva + P2Y 12 Riva + DAPT VKA + DAPT Days Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Composite of adverse CV events is composite of CV death, MI, and stroke. Hazard ratios as compared to VKA group are based on the (stratified, only for the Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank P-values as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/115 mg QD comparing VKA) two-sided log rank test. 6 Subjects were excluded from all efficacy analyses because of violations in Good Clinical Practice guidelines Gibson et al. AHA 2016 RE-DUAL PCI Comparing efficacy for bleeding risk and CV event prevention with triple therapy (ASA + VKA and P2Y12 Inhibitor) against Dual therapy with: Dabigatran 110mg + P2Y12 Inhibitor Or Dabigatran 150mg + P2Y12 inhibitor 21

24 Kaplan-Meier Estimates of Primary End-Point First Occurrence of Clinically Significant Bleeding or Major Bleeding Events P<0.001 for non-inferiority P<0.001 for non-inferiority Kaplan-Meier Estimates of Secondary End- Point of MI, CVA, Systemic Embolic, Death or Unplanned Revasculatization P=0.005 for noninferiority 22

25 WATCHMAN Device Minimally Invasive, Local Solution Available sizes: 21, 24, 27, 30, 33 mm diameter Intra-LAA design Avoids contact with left atrial wall to help prevent complications Nitinol Frame Conforms to unique anatomy of the LAA to reduce embolization risk 10 active fixation anchors - designed to engage tissue for stability Proximal Face Minimizes surface area facing the left atrium to reduce post-implant thrombus formation 160 micron membrane PET cap designed to block emboli and promote healing PROTECT AF Clinical Trial Design» Prospective, randomized study of WATCHMAN LAA Device vs. Longterm Warfarin Therapy» 2:1 allocation ratio device to control» 800 Patients enrolled from Feb 2005 to Jun 2008 Device Group (463) Control Group (244) Roll-in Group (93)» 59 Enrolling Centers (U.S. & Europe)» Follow-up Requirements TEE follow-up at 45 days, 6 months and 1 year Clinical follow-up biannually up to 5 years Regular INR monitoring while taking warfarin» Enrollment continues in Continued Access Registry 23

26 Event-free probability Intent-to-Treat All Stroke 1.0 Device Control Posterior probabilities Events Total Rate Events Total Rate RR Non- Superiority Cohort eve pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority pt-yr (1.9, 5.5) (1.5, 6.3) (0.43, 2.57) pt-yr (1.5, 4.1) (1.7, 5.7) (0.36, 1.76) WATCHMAN Randomization allocation (2 device:1 control) patient-year analysis Control ITT cohort: Non-inferiority criteria met Days WATCHMAN Device 24

27 Take-Home Messages NoACs are noninferior to Warfarin for ischemic prevention but reduce major bleeding, ICH and mortality NoACs are the preferred therapy for patient with AF who starting primary stroke prevention NoACs may be considered for patients who are already taking a VKA Antiplatelet agents are not recommended for stroke prevention in AF Aspirin does not work in the seconary prevent of ischemic stroke in AF and carries a substantial bleeding risk Summary Adjusted-dose warfarin remains the most effective therapy for stroke prevention Aspirin offers modest protection Poor outcomes from stroke off warfarin generally exceed those from warfarin-associated hemorrhage Emerging therapies have the potential to overcome many of warfarin s limitations and improve the management of stroke prevention in patients with AF 25