Scoring Systems in AF 8/10/2016. Strategies in the Prevention of Atrial Fibrillation-Related Strokes. Overview

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1 Strategies in the Prevention of Atrial Fibrillation-Related Strokes Rajat Deo, MD, MTR Assistant Professor of Medicine Division of Cardiology, Electrophysiology Section University of Pennsylvania September 14, 2016 Overview 1. AF Risk Scores: Stroke and Bleeding 2. Reviewing Warfarin Data and Limitations 3. The Ideal Anticoagulant and Improving the Net Clinical Benefit 4. NOACs: Assessing Efficacy and Safety 2 Scoring Systems in AF 1. Rationale for AF scoring systems Anticoagulation has risks (bleeding) and benefits (reduced risk of stroke) 2. Determining Net Clinical Benefit 3. No one scoring system is universally accepted or highly predictive (in individual patients) 3 1

2 Risk of Stroke Risk of Stroke 8/10/2016 CHADS 2 scores establish risk of stroke CHADS 2, developed and validated by Gage et al, is a system for establishing the risk of stroke in patients with non-rheumatic atrial fibrillation 1 Patients are awarded points based on comorbidities Condition Points C Congestive heart failure 1 H Hypertension 1 A Age 75 years 1 D Diabetes mellitus 1 S 2 Previous stroke or TIA 2 European Society of Cardiology Guidelines 2 CHADS 2 Score Treatment 0 Aspirin 1 Aspirin or warfarin* 2 Warfarin 20% 18% 15% 13% 10% 8% 5% 3% 0% Annual Risk of Stroke 18.2% 12.5% 8.5% 5.9% 4.0% 2.8% 1.9% CHADS 2 Score * Use of aspirin or warfarin is based on additional patient characteristics such as age, number of risk factors, etc. 4 1 Gage BF et al, JAMA 2001;285: Camm AJ et al, Eur Heart J 2010;31: CHA 2 DS 2 VASc is preferred scoring system CHA 2 DS 2 VASc, developed by Lip et al, is a refinement of the older CHADS 2 Score which includes additional stroke risk factors and puts greater emphasis on age as a risk factor 1 Condition/Risk Factor Points C Congestive heart failure 1 H Hypertension 1 A Age 75 years 2 D Diabetes mellitus 1 S 2 Previous stroke or TIA 2 V Vascular disease 1 A Age years 1 Sc Sex (female gender) AHA/ACC/HRS Guidelines CHA 2DS 2-VASc Score Treatment 0 No treatment 1 Aspirin or warfarin or NOAC 2 Warfarin or NOAC 18% Annual Risk of Stroke 15.2% 15% 12% 9.8% 9.6% 9% 6.7% 6.7% 6% 4.0% 3.2% 3% 2.2% 1.3% 0.0% 0% CHA 2DS 2VASc Score 1 Lip GY et al, Chest. 2010;137(2): Camm AJ et al, Eur Heart J. 2010;31: January C et al. Circulation CHA 2 DS 2 -VASc and CHADS 2 Score 0 1 Refines stroke risk stratification in AF patients: nationwide cohort 1 Year Follow-up 12 Years Follow-up Events Stroke Events Stroke Person Yrs rate (95%CI) Person Yrs rate (95%CI) CHADS 2 score ,272 1, ( ) 187,200 4, ( ) CHA 2DS 2-VASc = 0 6, ( ) 39, ( ) CHA 2DS 2-VASc = 1 8, ( ) 45, ( ) CHA 2DS 2-VASc = 2 11, ( ) 51,595 1, ( ) CHA 2DS 2-VASc = 3 11, ( ) 45,799 1, ( ) CHA 2DS 2-VASc = 4 1, ( ) 4, ( ) CHADS 2 score = 0 17, ( ) 92, ( ) CHA 2DS 2-VASc = 0 6, ( ) 39, ( ) CHA 2DS 2-VASc = 1 6, ( ) 35, ( ) CHA 2DS 2-VASc = 2 3, ( ) 16, ( ) CHA 2DS 2-VASc = ( ) 1, ( ) CHADS 2 Score = 1 22,945 1, ( ) 94, ( ) CHA 2DS 2-VASc = 1 2, ( ) 10, ( ) CHA 2DS 2-VASc = 2 8, ( ) 34, ( ) CHA 2DS 2-VASc = 3 11, ( ) 44, ( ) CHA 2DS 2-VASc = 4 1, ( ) 4, ( ) 6 2

3 Principles of Bleeding Risk Scores 1. Variety of scoring systems to predict bleeding risk in patients initiating anticoagulation 2. Overall, less predictive than stroke risk scores 3. Each score: clinical characteristics 4. Unclear whether to include risk scores in decision making for individual patients 7 Bleeding Risk Scores in AF HAEMORRHAGES 1 HASBLED 2 ATRIA Score 3 1.Gage BF, et al. Am Heart J Mar;151(3): PMID: Pub Med PMID: Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. Chest Nov;138(5): PMID: Fang MC, et al. J Am Coll Cardiol Jul 19;58(4): Pub Med PMID: Bleeding Risk Scores in AF ATRIA HAS-BLED HEMORR 2 HAGES Anemia 1 3 Hypertension 4 1 Severe renal disease 2 3 Abnormal Renal 5 or Liver function Hepatic 10 or Renal disease Ethanol abuse 1 Age 75 yrs 2 Stroke 1 Malignancy 1 Any prior hemorrhage 1 Bleeding 1 Older Age (>75 yrs) 1 Hypertension 3 1 Labile INR 8 1 Reduced platelet number or function 11 Elderly (>65 yrs) 1 Rebleeding 12 2 Drugs 9 or Alcohol 1. Hemoglobin <13 g/dl men; <12 g/dl women 2. Estimated glomerular filtration rate <30 ml/min or dialysis-dependent 3. Diagnosed hypertension 4. Systolic blood pressure >160 mmhg 5. Presence of chronic dialysis or renal transplantation or serum creatinine 200 mmol/l 6. Chronic hepatic disease (eg cirrhosis) or biochemical evidence of significant hepatic derangement (eg bilirubin 2 x upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.) 8. Unstable/high INRs or poor time in therapeutic range (eg <60%) 9. Concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse etc. 10. Cirrhosis, two-fold or greater elevation of AST or APT, or albumin <3.6 g/dl 11. Platelets <75,000, use of antiplatelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasia 12. Prior hospitalization for bleeding 13. Most recent hematocrit <30 or hemoglobin <10 g/dl 14. CYP2C9*2 and/or CYP2C9*3 15. Alzheimer's dementia, Parkinson's disease, schizophrenia, or any condition predisposing to repeated falls 1 1 Hypertension 4 1 Anemia 13 1 Genetic factors 14 1 Excessive fall risk 15 1 Stroke

4 Anticoagulation in non-valvular AF Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT All trials Reduction of all-cause mortality RRR 26% Reduction of stroke RRR 62% 100% 50% 0-50% -100% Hart et al. Ann Intern Med. 1999;131: Anticoagulation for nonvalvular AF Pooled data from AFASAK, SPAF, and BAATAF For every 1000 patients with nonvalvular AF in clinical trials treated with warfarin for 1 year: Benefit Risk 31 fewer thromboembolic events* 1 more intracranial or major bleed* Stroke risk reduced from 4.5% to 1.4% / yr *Compared with control 35 more minor bleeds occurred with warfarin Intention-to-treat analysis Albers GW et al. Ann Neurol. 1991;30: Warfarin effective but limitations exist When taken appropriately, warfarin is effective Monitoring required to ensure therapeutic range (INR) Narrow therapeutic window Time in therapeutic range 55-66% Many foods and medicines interact with warfarin Despite efficacy, warfarin exposes patients to risks (e.g. intracranial hemorrhage and hemorrhagic stroke) Warfarin use represents a challenge to surgeries High rates of discontinuation and non-adherence to therapy Warfarin tops the list for emergency hospitalizations for adverse drug events in older Americans 12 1 Budnitz DS, et al. NEJM 2011, 365:

5 The Coagulation Cascade Antiplatelet agents: Aspirin, clopidogrel, NSAIDS, dipyridamole Rivaroxaban, Apixaban, Edoxaban Dabigatran 13 Novel Oral Anticoagulants 14 Non-valvular atrial fibrillation (NVAF) Excludes those with a prosthetic heart valve, those with mitral stenosis, and those with decompensated valvular heart disease likely to require replacement soon Based on patient populations included in clinical trials Those with the following conditions enrolled: Mitral valve prolapse Non-rheumatic moderate severity or less mitral regurgitation Moderate severity or less aortic valvular conditions 15 5

6 The Ideal Anticoagulant Oral administration Rapid onset/offset of action Wide therapeutic window Predictable therapeutic effect with fixed dosing Minimal food or drug-drug interactions No monitoring required (but able to if desired) Defined PK in the presence of renal or hepatic disease Easily reversible Cost effective 16 Dabigatran 17 Design of RE-LY: A Non-inferiority Trial Randomized Evaluation of Long-Term Anticoagulation Therapy NVAF plus 1 Stroke risk factors (age 75, previous stroke/tia, LVEF<40%, or NYHA II-IV, or age 65-74y w/ DM, HTN, or CAD Blinded event adjudication R Primary outcome: Stroke or systemic embolism Open Blinded Warfarin (Adjusted INR ) n = 6022 Dabigatran 110 mg bid n = 6015 Dabigatran 150 mg bid n = 6076 Follow up: 1-yr minimum, 2-yr median, 3-yr maximum Connolly SJ et al. N Engl J Med. 2009;361:

7 Cumulative hazard rate 8/10/2016 RE-LY: Stroke or Systemic Embolism Rate of primary outcome: Warfarin: 1.69% /y Dabigatran (150): 1.53/y Dabigatran (110): 1.11%/y % P < Warfarin Months Dabigatran 110 Dabigatran 150 Connolly SJ et al. N Engl J Med. 2009;361: RE-LY: Bleeding and Net Clinical Benefit Net clinical benefit = Composite of stroke, systemic embolism, MI, pulmonary embolism, death, or major bleeding D 110 mg Annual rate D 150 mg Warfarin Annual rate Annual rate D 110 mg vs warfarin RR (95% CI) P D 150 mg vs warfarin RR (95% CI) P Major bleeding 2.71% 3.11% 3.36% 0.80 ( ) ( ) 0.31 Minor bleeding 13.16% 14.84% 16.37% 0.79 ( ) < ( ) Intracranial bleeding 0.23% 0.30% 0.74% 0.31 ( ) < ( ) <0.001 Net clinical benefit 7.09% 6.91% 7.64% 0.92 ( ) ( ) 0.04 D = dabigatran Connolly SJ et al. N Engl J Med. 2009;361: Rivaroxoban 21 7

8 ROCKET AF: Protocol Schema Atrial fibrillation Rivaroxaban 20 mg daily 15 mg for CrCl Randomize Double-blind; Double dummy (N = 14,264) Warfarin INR target ( inclusive) 2 of: CHF Hypertension Age 75 Diabetes AND/OR Stroke, TIA, or systemic embolus Monthly monitoring and adherence to standard of care guidelines Primary endpoint: Stroke or non-cns systemic embolism Statistics: Non-inferiority, >95% power, 2.3% warfarin event rate ROCKET AF Investigators. Am Heart J. 2010;159: ITT Analysis: HR 0.88 (95% CI, 0.74 to 1.03); P<0.01 noninferiority; p=0.12 for superiority 23 Primary Safety Endpoint Major and nonmajor bleeding events remained similar between 2 groups. - Event rate: riva 14.9/100 py versus warfarin 14.5/100 py; HR 1.03 (95% CI ) Intracranial bleeding was less in the rivaroxaban group - Event rate: riva 0.5/100 py versus warfarin 0.7/100 py; HR 0.67 (95% CI ) 24 8

9 Apixaban Atrial Fibrillation with at Least One Additional Risk Factor for Stroke Inclusion risk factors Age 75 years Prior stroke, TIA, or SE HF or LVEF 40% Diabetes mellitus Hypertension 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) Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death

10 Primary Safety Endpoint Major bleeding events: apixaban had significantly fewer major bleeding events - Event rate: apixaban 2.13% per year versus warfarin 3.09% per year; HR 0.69 (95% CI ) Intracranial bleeding was less in the apixaban group - Event rate: apixaban 0.33% per year versus warfarin 0.8% per year; HR 0.42 (95% CI ) Study Design 21,105 PATIENTS AF on electrical recording within last 12 m CHADS 2 2 RANDOMIZATION 1:1:1 randomization is stratified by CHADS 2 score 2 3 versus 4 6 and need for edoxaban dose reduction* Double-blind, Double-dummy Warfarin (INR ) High-dose Edoxaban 60* mg QD Low-dose Edoxaban 30* mg QD *Dose reduced by 50% if: - CrCl ml/min - weight 60 kg - strong P-gp inhibitor 1º Efficacy EP = Stroke or SEE 2º Efficacy EP = Stroke or SEE or CV mortality 1º Safety EP = Major Bleeding (ISTH criteria) Non-inferiority Upper 97.5% CI <1.38 CI = confidence interval; CrCl = creatinine clearance; ISTH = International Society on Thrombosis and Haemostasis; P-gp = P-glycoprotein; SEE=systemic embolic event CI = confidence interval; CrCl = creatinine clearance; ISTH=International Society on Ruff CR et al. Am Heart J 2010; 160:

11 Warfarin TTR 68.4% Edoxaban 60* mg QD vs warfarin Edoxaban 30* mg QD vs warfarin Primary Endpoint: (2.8 years median f/u) Noninferiority Analysis (mitt, On Treatment) Hazard ratio (97.5% CI) edoxaban noninferior Rates of Primary Events: Warfarin: 1.5%/y; Edox (60): 1.18%/y; Edox (30): 1.61%/y P Values Non-inferiority Superiority P< P=0.017 P=0.005 P=0.44 Edoxaban 60* mg QD vs warfarin Edoxaban 30* mg QD vs warfarin *Dose reduced by 50% in selected pts Superiority Analysis (ITT, Overall) Hazard ratio (97.5% CI) edoxaban superior edoxaban inferior P Value for Superiority P=0.08 P= Edoxaban 60* mg QD vs warfarin Main Safety Results - Safety Cohort on Treatment - Edoxaban 30* mg QD vs warfarin ISTH Major Bleeding Warfarin TTR 68.4% 0.47 Fatal Bleeding Intracranial Hemorrhage 0.30 Gastrointestina l Bleeding HR (95% CI) 1.23 P Value vs warfarin P<0.001 P<0.001 P=0.006 P<0.001 P<0.001 P<0.001 P=0.03 P< *Dose reduced by edoxaban superior edoxaban inferior 50% in selected pts Safety cohort=all patients who received at least 1 dose by treatment actually received 11 Summary Compared to well-managed warfarin (TTR 68.4%) once-daily edoxaban: Non-inferior for stroke/see (both regimens) - High dose stroke/see on Rx (trend ITT) Both regimens significantly reduced: - Major bleeding (20%/53%) - ICH (53%/70%) - Hem. stroke (46%/67%) - CV death (14%/15%) Superior net clinical outcomes No excess in stroke or bleeding during transition oral anticoagulant at end of trial 3 11

12 Summary of the NOACs 34 Pivotal Warfarin-Controlled Trials Stroke Prevention in AF Warfarin vs. Placebo 2,900 Patients NOACs vs. Warfarin 71,683 Patients 6 Trial of Warfarin vs. Placebo ROCKET AF (Rivaroxaban) 2010 ENGAGE AF-TIMI 48 (Edoxaban) 2013 RE-LY (Dabigatran) 2009 ARISTOTLE (Apixaban) Comparative PK/PD of NOACs Dabigatran Rivaroxaban Apixaban Edoxaban Target IIa (thrombin) Xa Xa Xa Hours to C max Half-life, hours Renal Clearance, % 80 33* Transporters P-gp P-gp P-gp P-gp CYP Metabolism, % None 32 <32 <4 CYP = cytochrome P450; P-gp = P-glycoprotein *33% renally cleared; 33% excreted unchanged in urine Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc Weinz et al. Drug Dispos Metab 2009;37: ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK Matsushima et al. Am Assoc Pharm Sci 2011; abstract Ogata, et al. J Clin Pharmacol 2010;50: Mendell, et al. Am J Cardiovasc Drugs 2013;13: Bathala, et al. Drug Metab Dispos 2012;40:

13 NOAC SPAF Trials RE-LY ROCKET-AF ARISTOTLE ENGAGE AF Drug Dabigatran Rivaroxaban Apixaban Edoxaban # Randomized 18,113 14,266 18,201 21,105 Dose (mg) 150, , 30 Frequency Twice Daily Once Daily Twice Daily Once Daily Dose Adjustment No At Baseline After Randomization No No No >9% Target INR (Warfarin) Design PROBE* 2x blind 2x blind 2x blind *PROBE = prospective, randomized, open-label, blinded end point evaluation Connolly SJ, et al. N Engl J Med 2009;361: Patel MR, et al. N Engl J Med 2011;365: Granger CB, et al. N Engl J Med 2011;365: Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI: /NEJMoa Baseline Characteristics RE-LY (Dabigatran) ROCKET-AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF (Edoxaban) # Randomized 18,113 14,264 18,201 21,105 Age, years 72 ± 9 73 [65-78] 70 [63-76] 72 [64-78] Female, % Paroxysmal AF VKA naive Aspirin Use CHADS Connolly SJ, et al. N Engl J Med 2009;361: Patel MR, et al. N Engl J Med 2011;365: Granger CB, et al. N Engl J Med 2011;365: Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI: /NEJMoa Trial Metrics RE-LY (Dabigatran) ROCKET-AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF (Edoxaban) Median Follow-Up, years Median TTR Lost to Follow-Up, N *TTR, time in therapeutic range Connolly SJ, et al. N Engl J Med 2009;361: Patel MR, et al. N Engl J Med 2011;365: Granger CB, et al. N Engl J Med 2011;365: Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI: /NEJMoa

14 All NOACS: Stroke or SEE Risk Ratio (95% CI) RE-LY [150 mg] 0.66 ( ) ROCKET AF 0.88 ( ) ARISTOTLE 0.80 ( ) ENGAGE AF-TIMI 48 [60 mg] 0.88 ( ) Combined 0.81 ( ) [Random Effects Model] p=< N=58, Favors NOAC Favors Warfarin Heterogeneity p=0.13 Ruff CT, et al. Lancet 2013 [in-press] 40 Secondary Efficacy Outcomes Risk Ratio (95% CI) Ischemic Stroke 0.92 ( ) p=0.10 Hemorrhagic Stroke 0.49 ( ) p< MI 0.97 ( ) p=0.77 All-Cause Mortality 0.90 ( ) p= Favors NOAC Favors Warfarin Heterogeneity p=ns for all outcomes Ruff CT, et al. Lancet 2013 [in-press] 41 All NOACS: Major Bleeding Risk Ratio (95% CI) RE-LY [150 mg] 0.94 ( ) ROCKET AF 1.03 ( ) ARISTOTLE 0.71 ( ) ENGAGE AF-TIMI 48 [60 mg] 0.80 ( ) Combined 0.86 ( ) p=0.06 [Random Effects Model] N=58, Favors NOAC Favors Warfarin Heterogeneity p= Ruff CT, et al. Lancet 2013 [in-press] 14

15 Secondary Safety Outcomes Risk Ratio (95% CI) ICH 0.48 ( ) p< GI Bleeding 1.25 ( ) p= Favors NOAC Favors Warfarin Heterogeneity ICH, p=0.22 GI Bleeding, p=0.009 Ruff CT, et al. Lancet 2013 [in-press] 43 NOAC Conclusions NOACs significantly reduce stroke ( 19%) Primarily driven by reduction in hemorrhagic stroke ( 51%) NOACs significantly reduce mortality ( 10%) Trend toward less bleeding Substantial reduction in ICH ( 52%) Increased GI bleeding ( 25%) The relative efficacy and safety of NOACs consistent across a wide spectrum of AF patients Even less bleeding when INR not as well controlled Low dose NOAC regimens reduce mortality and have a very favorable bleeding profile but more ischemic events Differences in agents, patients, and trials may not be accounted for Heterogeneity major bleeding and GI bleeding

16 Summary of recommendations 46 Summary of Recommendations 47 Dosing Recommendations 48 16

17 Conclusions PROTECT THE BRAIN! PROTECT THE BRAIN! PROTECT THE BRAIN! Many AF patients, who should be anticoagulated, are not being treated Variety of anticoagulants that can be used to protect against thromboembolic risk in AF Rate and rhythm control are important for symptom control and to reduce AF complications 49 17