• Save
Stroke and AF: Risk Stratification and Anticoagulation
Upcoming SlideShare
Loading in...5
×

Like this? Share it with your network

Share
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
No Downloads

Views

Total Views
512
On Slideshare
512
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
2
Comments
0
Likes
1

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide

Transcript

  • 1. Stroke Risk Stratification and Anticoagulation Albert L. Waldo, MD The Walter H. Pritchard Professor of Cardiology, Professor of Medicine,and Professor of Biomedical Engineering Case Western Reserve University Harrington Heart & Vascular Institute University Hospitals – Case Medical Center Division of Cardiovascular Medicine Cleveland, Ohio
  • 2. Disclosures for Albert L. Waldo, M.D. Research Contract: Gilead Consulting: *Biotronik; *St. Jude Medical; *Daiichi Sankyo; #Gilead; #Biosense Webster; *sanofi; **CardioInsight; *Atricure; **ChanRx; **Pfizer Speaker: sanofi; Janssen; Pfizer; Bristol-Myers Squibb *clinical trial steering committee **scientific advisory board #adverse events adjudication committee
  • 3. Characterizing Atrial Fibrillation Ÿ  Atrial Fibrillation (AF) is the most common sustained arrhythmia in the Western world Ÿ  Ÿ  Ÿ  Ÿ  Ÿ  Now, > 80% of individuals with AF are > 65 years old Now, just > 50% of patients with AF are > 75 years old Soon, 50% of patients with AF will be > 80 years old, and 2/3 > 75 Projected AF prevalence by 2050 5.6 -16 million Americans Lifetime incidence of AF: 1 in 4 individuals > 40 years old Go AS, et al. JAMA. 2001;285:2370-2375. Lloyd-Jones DM et al. Circulation. 2004;110:1042- 1046. Miyasaka Y, et al. Circulation. 2006;114:119-125.
  • 4. Stroke Risk Stratification in AF CHA2DS2-VASc CHADS2 Risk Factor Congestive heart failure Hypertension Age ≥75 y Diabetes Stroke Score 1 1 1 1 2 Risk Factor Congestive heart failure Hypertension Age ≥75 y Diabetes Stroke Vascular disease (MI, PAD, aortic atherosclerosis) Score 1 1 2 1 2 1 Total Score Annual Risk of Stroke (%) 0 1.9 0 Age 65-74 y 1 1 2.8 1.3 Sex category (female) 1 2 4.0 2.2 3 CHADS2 5.9 3.2 4 8.5 4.0 CHA2DS2-VASc seems to have 2 CHA2DS2-VASc 5 12.5 6.7 major benefits: it more accurately 6 18.2 9.8 identifies truly low risk pts; it reclassifies many CHADS2 score 7 9.6 0-1 pts to a higher stroke risk 8 6.7 9 15.2 Lip GY, Halperin JL. Am J Med. 2010;123(6):484-488. Camm AJ, et al. Eur Heart J. 2010;31(19):2369-2429.
  • 5. Predicted 5-Year Risk of Stroke Step 1 Age, Y •  55-59 •  60-62 •  63-66 •  67-71 •  72-74 •  75-77 •  78-81 •  82-85 •  86-90 •  91-93 •  >93 Step 2 Points 0 1 2 3 4 5 6 7 8 9 10 Sex •  Men •  Women Points 0 6 Step 3 Systolic BP Points mm Hg •  <120 0 •  120-139 1 •  140-159 2 •  160-179 3 •  > 179 4 Wang et al. JAMA 2003;290:1049-56
  • 6. Framingham Risk Score Predicted 5-Year Risk of Stroke in AF Step 3 Step 1 Age, y Pts 55-59 60-62 63-66 67-71 72-74 75-77 78-81 82-85 86-90 91-93 >93 0 1 2 3 4 5 6 7 8 9 10 Step 2 Sex Pts Men 0 Women 6 Systolic blood pressure, mm Hg <120 120-139 140-159 160-179 >179 Step 4 Diabetes Pts No 0 Yes 5 Pts pts 0 1 2 3 4 Step 5 Prior stroke or TIA No Yes Add up points from steps 1 through 5 Look up predicted 5-year-risk of stroke in table Wang et al. JAMA. 2003; 290:1049-1056. Pts 0 6 5-year risk, % 0-1 2-3 4 5 6-7 8 9 10 11 12 13 14 15 5 6 7 8 9 11 12 13 14 16 18 19 21 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 24 26 28 31 34 37 41 44 48 51 55 59 63 67 71 75
  • 7. Swedish Cohort Atrial Fibrillation Study: Hazard Ratios for Stroke Risk 182,678 patients with nonvalvular AF Mean age 76 yrs 53% Male Average FU 1.5 yrs 53% not on warfarin Camm AJ et al. Europace 2012;14:1385-1413
  • 8. ATRIA Stroke Risk Model Point Scoring System Risk Factor Age, y Without Prior Stroke Points Hazard Ratio With Prior Stroke Points Hazard Ratio ≥ 85 6 6.38 9 11.92 75 to 84 5 3.79 7 7.61 65 to 74 3 2.10 7 7.89 < 65 0 8 8.99 Female 1 1.52 1 Diabetes 1 1.40 1 CHF 1 1.27 1 Hypertension 1 1.24 1 Proteinuria 1 1.40 1 eGFR<45 or ESRD 1 1.33 1 Possible point scores range from 0 - 12 for those without a prior stroke, and from 7 - 15 for those with a prior stroke. ATRIA indicates Anticoagulation and Risk Factors in Atrial Fibrillation; CHF, congestive heart failure; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease. Singer DE et al. J Am Heart Assoc 2013;2:e000250; doi:10.1161/JAHA.113.000250.
  • 9. c-Statistic for Various Stroke Risk Stratification Schemes Risk Score Atria AF Investigators SPAF CHADS2 CHA2DS2-VaSC * c-Statistic 0.73* 0.56* 0.60* 0.58*/0.69* 0.70* Framingham 7th Am Coll Chest Physicians 0.62* 0.56* *Fang MC J Am Coll Cardiol, 2008;51:81607; *Singer DE et al. J Am Heart Assoc 2103;2:e000250;doi:10.1161/JAHA.113.000250. (full score)
  • 10. Prevalence of Eligible AF Patients Receiving Warfarin Therapy Warfarin is prescribed for only 41% to 65% of eligible pts with AF, many of whom are considered “warfarin-unsuitable” Percent patients treated with warfarin 100 65 55 54 64 52 51 50 0 41 ATRIA1 N=11,082 NABOR2 N=945 N=4053 Medicare4 N=17,272 N=116,9695 N=50,0716 Euro Heart Study7 N=2,706 ATRIA=Anticoagulation and Risk Factors in Atrial Fibrillation, NABOR=National Anticoagulation Benchmark and Outcomes Report 1. Go AS et al. Ann Intern Med. 1999;131:927-934. 2. Waldo AL et al. J Am Coll Cardiol. 2005;46:1729-1736. 3. Hylek EM et al. Stroke. 2006;37:1075-1080. 4. Birman-Deych E et al. Stroke. 2006;37:1070-1074. 5. Walker AM, Bennett D. Heart Rhythm. 2008;5:1365-1372. 6. Williams CJ et al. American College of Cardiology 58th Annual Scientific Session; March 29-31, 2009; Orlando, FL. 7. Nieuwlaat R et al. Eur Heart J. 2006;27:3018-3026.
  • 11. Eligible Patients ICD-9-CM 427.31 atrial fibrillation n = 945 High or Moderate Stroke risk 91.2% First Event n = 209 22.1% Warfarin n = 86 41.1% No Treatment n = 50 23.9% Paroxysmal n = 486 51.4% Warfarin n = 230 47.3% No Treatment n = 110 22.6% p < 0.01 p = 0.57 Not Available n=6 0.6% p < 0.01 p = 0.43 Recurrent n = 276 29.2% Warfarin n = 144 52.2% No Treatment n = 60 21.7% First Event n = 109 11.5% Warfarin n = 65 5 59.6% No Treatment n = 24 22.0% Waldo A et al. J Am Coll Cardiol 2005; 46: 1729 - 36. Persistent Permanent n = 453 47.9% Warfarin n = 274 60.5% No Treatment n = 92 20.3% p = 0.83 p = 0.61 High or Moderate Stroke risk 94% Recurrent n = 344 36.4% Warfarin n = 209 60.8% No Treatment n = 68 19.8%
  • 12. Stroke Risk Factor Distribution The SPORTIF Trials Number of CHADS2 risk factors 5 4 100% 3 80% 6 5 4 2 60% 3 40% 2 20% 0% 1 <75 1 >75
  • 13. Oral Anticoagulation in Patients with AF 70 % TAKING WARFARIN 60 N = number of pts with AF N = 52 50 N = 45 40 30 N = 46 N =16 20 N =13 10 0 69-74 75-79 80-84 85-89 90+ AGE GROUP (Yrs) White RH, et al. Am J Med 1999;106:165 Proprietary and Confidential 13
  • 14. Warfarin for Stroke Prevention in AF Strokes (% / yr) 8 Intention-To-Treat Analysis Control Warfarin 6 4 4.5 2 1.4 0 AFASAK Risk Reduction 95% CI SPAF BAATAF CAFA SPINAF TOTAL 58% 67% 86% 42% 79% 68% p < 0.03 p < 0.01 p < 0.002 p > 0.2 p < 0.002 p < 0.001 7 – 81 27 – 85 51 – 96 - 68 – 80 52 – 90 50 – 79 AF Investigators. Arch Intern Med 1994;154:1449-57 Atwood et al. Herz 1993;18:27-38
  • 15. Warfarin for Stroke Prevention in AF Strokes (% / yr) 8 On Treatment Analysis Control Warfarin 6 4 4.3 2 0.8 0 AFASAK SPAF BAATAF CAFA SPINAF TOTAL 79% 83% 83% 73% 79% 83% Reduction p = 0.09 p < 0.007 p < 0.01 p = 0.17 p < 0.002 p < 0.001 95% CI -27 – 97 38 – 95 33 – 96 -73 – 96 52 – 90 69 - 90 Risk Albers et al. Ann Neurol 1991;30:511-8 Atwood et al. Herz 1993;18:27-38
  • 16. Annualized Incidence of Stroke or ICH According to INR Ischemic Stroke INR 2.0 1.7 1.5 1.3 OR 1.0 2.0 3.3 6.0 Hylek et al. N Engl J Med 2003;349:1019-26
  • 17. ACTIVE W: 1° Outcome by Center INR Control Interaction P = 0.013 RR = 1.11 0.08 0.08 RR = 1.83 P < 0.0001 P = 0.47 0.06 0.06 0.04 0.04 C+A C+A 0.02 OAC 0.0 0.02 OAC 0.0 Cumulative Hazard Rates <65% INR in Range 0.10 65% INR in Range 0.10 ≥ 0.0 0.5 1.0 1.5 ACTIVE Investigators. Lancet. 2006;367;1903-12. 0.0 Years 0.5 1.0 1.5
  • 18. Interactions With Warfarin Specific drugs reported to increase or decrease the INR –  Acetaminophen, alcohol, allopurinol, aminoglutethimide, aminosalicylic acid, amiodarone, amobarbital, aspirin, atorvastatin, azathioprine, azithromycin, butabarbital, butalbital, carbamazepine, cefamandole, cefazolin, cefoperazone, cefotetan, cefoxitin, ceftriaxone, celecoxib, chenodiol, chloral hydrate, chloramphenicol, chlordiazepoxide, chlorpropamide, chlorthalidone, cholestyramine, cimetidine, ciprofloxacin, clarithromycin, clofibrate, corticotropin, cortisone, cyclophosphamide, danazol, danshen (Chinese herb), dextran, dextrothyroxine, diazoxide, diclofenac, dicloxacillin, dicumarol, diflunisal, disulfiram, doxycycline, erythromycin, ethacrynic acid, ethchlorvynol, fenofibrate, fenoprofen, fluconazole, fluorouracil, fluoxetine, flutamide, fluvastatin, fluvoxamine, gemfibrozil, glucagon, glutethimide, griseofulvin, haloperidol, halothane, heparin, ibuprofen, ifosfamide, indomethacin, influenza virus vaccine, itraconazole, ketoprofen, ketorolac, levamisole, levothyroxine, liothyronine, lovastatin, methyl salicylate ointment (topical), metronidazole, miconazole, hydrochloride, nafcillin, oxymetholone, paraldehyde, paroxetine, penicillin G, intravenous pentobarbital, pentoxifylline, phenobarbital, phenylbutazone, phenytoin, piperacillin, piroxicam, predisone, primidone, propafenone, propoxyphene, propranolol, propylthiouracil, quinidine, quinine, ranitidine, rifampin, secobarbital, sertraline, simvastatin, spironolactone, stanozolol, streptokinase, sucralfate, sulfamethizole, sulfamethoxazole, sulfinpyrazone, sulfisoxazole, sulindac, tamoxifen, tetracycline, thyroid, ticarcillin, ticlopidine, tolbutamide, tramadol, trazodone, trimethoprim/sulfamethoxazole, urokinase, valproate, zafirlukast, zileuton –  Also, foods: diets high in vitamin K (green leafy vegetables, kiwi, etc.) vitamins (C at high dose; E; K), mangoes, dietary deficiencies, licorice, prolonged hot weather, cranberries Physicians’ Desk Reference. 2004.
  • 19. Aspirin Eligible AF Patients Anticoagulation Eligible Group I Warfarin Aspirin Placebo (n=206) (n=211) 1 event 18 events Group I Risk reduction 94% p < 0.001 SPAF Investigators. A differential effect of aspirin on prevention of stroke in atrial fibrillation. Anticoagulation Ineligible Group II Aspirin (n=346) 25 events Placebo (n=357) 26 events Group II Risk reduction 8% p = 0.75 SPAF I Analysis Risk reduction 42% p = 0.02 J Stroke Cerebrovasc Dis 1993;3:181-8
  • 20. Aspirin Eligible AF Patients Anticoagulation Eligible Group I Warfarin n=210 6 events Aspirin Placebo (n=206) (n=211) 1 event 18 events Group I Risk reduction 94% p < 0.001 Anticoagulation Ineligible Group II Aspirin (n=346) 25 events Placebo (n=357) 26 events Group II Risk reduction 8% p = 0.75 SPAF I Analysis Risk reduction 42% p = 0.02 J Stroke Cerebrovasc Dis 1993;3:181-8; Circulation 1991:84:527-39
  • 21. Cumulative Rate of Ischemic Stroke or Systemic Embolism Stroke Rate in Adjusted-Dose Warfarin vs. Combination Therapy (low dose warfarin plus ASA) Cumulative event rate (% per year) SPAF III 20 18 16 14 Combination therapy 12 10 8 6 4 Adjusted-dose warfarin 2 0 365 0 730 Days from randomisation Number at Risk Combination therapy 521 378 265 166 61 Warfarin therapy 523 397 273 173 65 SPAF Investigators. Lancet. 1996;348:633-8.
  • 22. ACTIVE* W: Cumulative Risk of Stroke * Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events. Cumulative hazard rates 0.1 RR = 1.72 (1.24-2.37), P=.001 0.08 0.06 Clopidogrel + aspirin 0.04 0.02 Oral anticoagulation therapy 0 Number at risk 0 0.5 Clopidogrel + aspirin 3335 3168 Oral anticoagulation therapy 3371 3232 1 Years 1.5 2419 941 2466 930 Primary outcome: Stroke, Systemic Embolus, MI, Vascular Death CL+ASA = 5.6% Risk/Year vs W = 3.93% Risk/Year Connolly S, et al. Lancet. 2006;367:1903-12
  • 23. BAFTA Study: Nature of Primary Events Warfarin vs aspirin for stroke prevention in an elderly community with atrial fibrillation Warfarin (n=488) Aspirin (n=485) Warfarin vs Aspirin n Risk/yr n Risk/yr RR (95% CI) P 21 1.6% 44 3.4% 0.46 (0.26-0.79) 0.003 Fatal 13 1.0% 21 1.6% 0.59 (0.27-1.24) 0.14 Disabling non-fatal 8 0.6% 23 1.8% 0.33 (0.13-0.77) 0.005 Ischemic 10 0.8% 32 2.5% 0.30 (0.13-0.63) 0.0004 Hemorrhagic 6 0.5% 5 0.4% 1.15 (0.29-4.77) 0.83 Unknown 5 0.4% 7 0.5% 0.69 (0.17-2.51) 0.53 Other ICH (subdural)** 2 0.2% 1 0.1% 1.92 (0.10-1113.3) 0.65 Systemic embolism*** 1 0.1% 3 0.2% 0.32 (0.01-3.99) 0.36 Total number of events 24 1.8% 48 3.8% 0.48 (0.28-0.80) 0.0027 Stroke By severity Type of stroke* RR=relative risk. ICH=intracranial hemorrhage. *Type of stroke was determined by the endpoint committee. ** 2 of these were fatal (1 in each treatment group). ***Two of the systemic emboli were fatal (1 in each treatment group). Mant J et al. Lancet 2007;370:493-503.
  • 24. Danish National Patient AF Registry Study Followed 132,372 patients for up to 12 years • The risk for TE was not decreased with ASA alone vs no treatment, even when patients had a high bleeding risk (HAS-BLED >3) or vascular disease • Overall, high risk patients treated with VKAs had the lowest bleeding risk, according to CHADS2 score and CHA2DS2-VASc score, whereas ASA was associated with a higher bleeding risk • VKAs were also associated with a neutral or positive net clinical benefit in patients with CHADS2 score of > 0 and CHA2DS2-VASc score of > 1 • This very large patient cohort study strongly supports the use of VKAs for stroke prophylaxis in patients with AF • Although that is not really news, the most impressive finding was that ASA showed absolutely no efficacy, but did increase bleeding risk • The take-home message is that use of ASA to prevent stroke in patients with AF remains very poorly justified (no net clinical benefit) Modified after Olesen JB et al. Thromb Haemost 2011;106:739-49; and Roden D. Cardiology Today Nov. 2011
  • 25. ASA 0.03 0.05 Relative Risk = 0.46 95% CI, 0.33-0.64 P<.001 Apixaban 0.0 0.01 Cumulative Risk AVERROES: Stroke or Systemic Embolic Event 0 3 6 12 18 21 Months Number at Risk ASA 2791 Apixaban 2809 9 2720 2761 2541 2567 2124 2127 1541 1523 626 617 Connolly SJ, et al. N Engl J Med. 2011 364:806-17 329 353
  • 26. Primary Outcome Events Apixaban Outcome ASA Apixaban vs. ASA events Annual rate events Annual rate RR 95% CI P Stroke or SEE 50 1.7 109 3.9 0.45 0.32-0.63 <0.001 Stroke 48 1.7 100 3.6 0.48 0.34-0.67 <0.001 Ischemic 34 1.2 89 3.2 0.38 0.25-0.56 <0.001 Hemorrhagic 8 0.2 8 0.2 1.01 0.38-2.68 0.99 Type not determined 7 0.2 4 0.1 1.76 0.51-6.01 0.37 2 0.0 14 0.5 0.14 0.03-0.63 0.01 SEE Connolly SJ, et al. N Engl J Med. 2011 364:806-17
  • 27. Bleeding Events Apixaban Outcome ASA Apixaban vs. ASA events Annual rate events Annual rate RR 95% CI P Major 47 1.6 40 1.4 1.18 0.77-1.78 0.45 Clinically Relevant Nonmajor 92 3.3 80 2.9 1.15 0.85-1.53 0.37 Minor 155 5.7 120 4.4 1.35 1.05-1.78 0.02 Fatal   4   0.1   7   0.2   0.57   0.17-­‐1.96   0.38   Intra-cranial 13 0.4 11 0.3 1.19 0.53-2.66 0.43 Connolly SJ, et al. N Engl J Med. 2011 364:806-17
  • 28. Vitamin K Antagonists vs Newer OACs Numerous food and drug interactions No predictable dose response Less intracerebral bleeding
  • 29. ~50%
  • 30. TTR 64%
  • 31. Nonhemorrhagic Stroke & Systemic Embolism: 150 mg Dabi vs Warf <57.1% 57.1-65.5% 65.5%-72.6% >72.6% Trend that with better TTR, the difference between dabigatran and warfarin becomes less, and maybe not even any, but does not apply to intracerebral bleeding
  • 32. Mean CHADS2 Score = 3.5 Median TTR 57.8% ;365:833-91
  • 33. : ENGAGE AF Timi-48
  • 34. ENGAGE AF TIMI - 48 (2.8 years median f/u) Giugliano RP et al. NEJM 2013;369: 2093-104.
  • 35. ENGAGE AF TIMI - 48 Giugliano RP et al. NEJM 2013;369: 2093-104.
  • 36. Absolute Diffs in Hemorrhagic Stroke and Intracranial Bleeding with W vs NOAC are Small Absolute Diffs: Hemorrhagic Stroke – 0.19%/y IC Bleed - 0.41%/yr TRIAL Drug RE-LY Dab Dab ROCKET AF War Api ENGAGE AF 20 mg 5 mg War Edox 60 mg 0.12 0.23 0.70 0.10 0.30 0.74 0.26 0.49 0.80 0.24 0.39 0.47 War Riv ARISTOTLE 150 mg 0.74 0.47 War %/year 0.44 110 mg %/year 0.31 War Intracranial Bleeding Rate 0.38 Dose Hemorrhagic Stroke Rate 0.85 0.26 0.39 Edox 30 mg 0.16 0.26 Connolly SJ et al. NEJM 2009;361:1139-51; Patel MR et al. NEJM 2011,365:883-91; Granger CB et al. NEJM 2011;365:981-82; Giugliano RP et al. NEJM 2013;369:2093-104
  • 37. Clinical Challenges With New Oral Anticoagulants •  •  •  •  •  •  •  •  •  •  No validated tests to measure anticoagulation effect No established therapeutic range No antidote for most agents Need to monitor renal function Twice daily dosing for dabigatran and rivaroxaban Whom and how to switch from warfarin Assessing compliance more difficult than with VKAs Potential for unknown long-term adverse events Balancing cost against efficacy Lack of head-to-head studies comparing new agents Sobieraj-Teague M, et al. Semin Thromb Hemost. 2009;35:515-24.
  • 38. Advantages of Warfarin •  Long half life •  Established therapeutic range •  Once daily dosing •  Antidote available •  Assessment of compliance available •  Role in cardioversion understood •  Cheap •  No dosage adjustment necessary for patients with renal impairment •  As or more effective than dabigatran when TTR is >72% •  Better for CAD/MI •  ~ 60 years of use has characterized its +s and –s
  • 39. Who is Not or May Not Be a Candidate for the New Oral Anticoagulants Ø Patients: •  who are stable on warfarin •  whose creatinine clearance is < 30 mL/min, and even 30 to 40 mL/min •  who have severe hepatic dysfunction (the new oral anticoagulants have significant liver metabolism) •  with mechanical heart valves •  who were noncompliant with warfarin •  who may forgo a small reduction in risk of intracranial hemorrhage, but should benefit as we gain more experience with the novel agents Modified after Waldo, AL; Impressions from the 2012 Boston AF symposium; Cardiology Today, 3/2012
  • 40. Left Atrial Appendage Occluders Lariat AtriClip