Anticoagulation in Atrial Fibrillation. Thomas DeLoughery, MD MACP FAWM Oregon Health & Sciences University DISCLOSURE

Transcription

1 Anticoagulation in Atrial Fibrillation Thomas DeLoughery, MD MACP FAWM Oregon Health & Sciences University DISCLOSURE Relevant Financial Relationship(s) Speaker s Bureau none 1

2 Talk Atrial Fibrillation New Oral Anticoagulants Iron! What is the Risk of Stroke in Afib? Afib common > 10% in patients over 80 years Annual stroke rate is 4.5%/yr Afib increases risk of stroke 4-5 fold Afib is the "cause" of 15% of all strokes 2

3 Age and Incidence of AF 10 8 >40 y/o: 2.3% Total US Population: 0.89% Age, years Atrial Fibrillation and Stroke Stroke Rate (% per Year) Year of Age 3

4 Is Warfarin of Benefit in Preventing Strokes in Afib? 5 key trials demonstrated benefit of warfarin in preventing stroke 4.5% to 1.5%/yr Need to treat 32 patients with warfarin/yr to prevent one stroke Despite differences in study design findings consistent across trials Stroke Prevention in AF: Warfarin Vs Placebo AFASAK BAATAF CAFA SPAF SPINAF Combined Warfarin Better Risk Reduction, % Warfarin Worse 4

5 Strokes Warfarin prevents strokes in atrial fibrillation NNT for first stroke 12 for second stroke Patients with CHADS2 1 or more should be considered for anticoagulation and 2 or more recommended INR Goals Target INR of 2.5 with range of 2-3 Steady dietary intake of vitamin K Monitor with changes in health or medications Never go longer than one month between INRs Home monitoring 5

6 What about the New Drugs? 4 new drugs with phase III trial data Apixaban: Xa inhibitor Dabigatran: II inhibitor Edoxaban: Xa inhibitor Rivaroxaban: Xa inhibitor 6

7 Direct Oral Anticoagulants All Stroke or SE Dabigatran 150 mg BID 1 HR=0.65 Rivaroxaban 20 mg daily 2* HR=0.88 Apixaban 5 mg BID 3 HR=0.79 Edoxaban 60 mg daily 4 HR=0.79 Edoxaban 30 mg daily 4 HR= Favors DOA Favors Warfarin Ischemic Stroke Dabigatran 150 mg BID 1 HR=0.76 Rivaroxaban 20 mg daily 2 HR=0.94 Apixaban 5 mg BID 3 HR=0.92 Edoxaban 60 mg daily 4 HR=1.00 Edoxaban 30 mg daily 4 HR= Favors DOA Favors Warfarin Dabigatran 150 mg BID 1 Rivaroxaban 20 mg daily 2 Apixaban 5 mg BID 3 Edoxaban 60 mg daily 4 Edoxaban 30 mg daily 4 HR=0.40 HR=0.59 HR=0.51 HR=0.54 HR=0.33 HR=0.93 Dabigatran 150 mg BID 1 HR=1.04 Rivaroxaban 20 mg OD 2 HR=0.69 Apixaban 5 mg BID 3 HR=0.80 Edoxaban 60 mg QD 4 HR=0.47 Edoxaban 30 mg QD 4 Hemorrhagic Stroke Favors DOA Favors Warfarin 0.0 Major Bleeding Favors DOA Favors Warfarin 1. NEJM. 2009;363: NEJM2011;365: NEJM. 2011;365: NEJM. 2013;369: Direct Oral Anticoagulants All are just as effective as warfarin in stroke prevention Apixaban and dabigatran superior All same or less risk of bleeding Apixaban and edoxaban less bleeding All have less intracranial hemorrhage 7

8 Atrial Fibrillation Drug Stroke Bleeding Apixaban Better Safer Dabigatran Better Equal Edoxaban Equal Safer Rivaroxaban Equal Equal ICH Atrial Fibrillation Events/ 100 years Stroke RR Intracranial Hemorrhage Events/ 100 years Apixaban ( ) ( ) Dabig ( ) ( ) Dabig ( ) ( ) Edox ( ) ( ) Edox ( ) ( ) Rivaroxaban ( ) ( ) RR Potential for 10-12,000 less ICH in USA 8

9 But What About Aspirin? 9

10 Is Aspirin Safer than Warfarin? Aspirin often given to afib patients because it is perceived to be safer But is it??? BAFTA N = 973 with afib All over 75 year of age (mean 81.5) RCT Warfarin 2-3 vs aspirin 81mg/day f/u 2.7 years Lancet 2007; 370: ,

11 BAFTA End point Warfarin Aspirin Hazard ratio (95% CI) Stroke (%/yr) ( ) Major extracranial hemorrhage (%/yr) All major hemorrhages (%/yr) ( ) ( ) Mant JW et al. Lancet 2007; 370: , Hazard Ratios For Bleeding Compared To Aspirin Drug/combination Adjusted hazard ratio 95% CI Clopidogrel VKA Aspirin/clopidogrel Aspirin/VKA VKA/clopidogrel VKA/clopidogrel/aspirin Sørensen R et al. Lancet 2009; 374:

12 Aspirin vs Warfarin 52% reduction in ischemic stroke with warfarin History of stroke ARR = 6%/yr No history of stoke ARR = 1.2%/yr Low risk of stroke ARR = 0.4%/yr Aspirin: Bottom Line Limited to no effectiveness Not effective in older patients Not effective in preventing disabling strokes Not the safer choice 12

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14 But What about my Patient who Falls a Lot? Most commonly cited reason not to anticoagulate older patients But what is the data? Falls: Man-Son-Hang Elaborate decision analysis by Man- Son-Hang demonstrate that the average patient would have to fall 295 times in one year for warfarin to be too dangerous to use. Retrospective review of hospital falls show only 1 SDH in 2500 falls 14

15 Donze Prospective study of 515 patients on warfarin 60% at high risk of falls No higher risk of bleeding 0.6%/yr bleeds after falls Am J Med 125: , 2012 Bond Looked at falls in anticoagulated patients 2635 falls in 1861 inpatients Thromb J. 2005; 3: 1. 15

16 Major bleeding Bond Warfarin vs nothing 6% vs 11%; p = 0.01 No difference with INR 3-5 vs normal Aspirin vs nothing OR 1.45% ( ) Clopidogrel vs nothing OR 2.2 ( ) Falls: Bottom Line Excess bleeding due to falls is markedly overstated Patients at risk of falls are those at risk of stroke Risk: benefit heavily in favor of treatment This is never should be an excuse to deny patients anticoagulation 16

17 New Drugs in VTE Abundant data for direct oral anticoagulants in venous thrombosis No monitoring No food interactions Minimal drug interactions 17

18 Rivaroxaban: Acute Venous Thrombosis N = 3,449 with DVT/ 4,832 with PE RCT Rivaroxaban 15mg BID then 20mg after 3 weeks Enoxaparin -> Warfarin N Engl J Med 2010; 363: N Engl J Med 2012; 366: Results Rivaroxaban (4150) LMWH/Warfarin (4131) Recurrent VTE 86 (2%) 96 (2.3%) Any Bleeding 388 (9%) 412 (10%) Major Bleeding 40 (1.0%) 70 (1.7%) ICH 5 (0.1%) 14 (0.3%) 18

19 Apixaban: Acute Venous Thrombosis N = 5395 with VTE 33% with PE RCT Apixaban 10mg BID then 5 mg BID after 7 days Enoxaparin -> Warfarin N Engl J Med 2013; 369: Results Apixaban (2691) LMWH/Warfarin (2704) Recurrent VTE 59 (2.3%) 71 (2.7%) Any Bleeding 115 (4.3%) 261 (9.7%) Major Bleeding 15 (0.6%) 49 (1.8%) ICH 3 (0.1%) 6(0.2%) 19

20 Apixaban: Chronic Venous Thrombosis N = 2482 with VTE 34% with PE 6-12 months of therapy RCT Apixaban 5 mg BID Apixaban 2.5 mg BID Placebo N Engl J Med 2013; 368: Results Apixaban 2.5mg BID (840) Apixaban 5mg BID (813) Placebo (829) Recurrent VTE 32 (3.8%) 34 (4.2%) 96 (11.6%) Any Bleeding 27 (3.2%) 35 (4.3%) 19 (2.3%) Major Bleeding 2 (0.2%) 1 (0.1%) 4 (0.5%) 20

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22 New Direct Oral Anticoagulants Easier to use and safer Both rivaroxaban and apixaban tested without heparin Both use higher initial doses Direct Oral Anticoagulants Renal Disease Renal Function All renally cleared: Apixaban dose reduced to 2.5 mg bid if Creatinine > 1.5 plus age over 80 or weight < 60kg Dabigatran not for CrCl < 50 Rivaroxaban 15mg CrCl

23 Direct Oral Anticoagulants Drug Interactions Apixaban and Rivaroxaban CYP3A4 + p-glycoprotein inhibitors HIV drugs or azoles Dabigatran - p-glycoprotein Dronedarone, azoles, rifampin, St John s wort, carbamazepine Reversal Drugs we have no antidote for: Low molecular weight heparin, fondaparinux, aspirin, abciximab, tirofiban, eptifibatide, clopidogrel, ticagrelor, prasugrel, dabigatran, rivaroxaban, apixaban, edoxaban, vorapaxar 23

24 Who Should Get the Direct Agents? Unstable INR Older patients Patients with risk factors for stroke Renal insufficiency Patients at risk for bleeding Who Should Stick with Warfarin? Stellar INR control Mechanical valves Dialysis patients Extreme of weight < 50kg > kg 24

25 Role of New Drugs Cost effective in acute thrombosis Need to be sure patient gets follow-up Low dose options for long term care Safer! 25

26 Iron Deficiency Common! Treatable Sign of GI pathology Other Effects of Fe Deficiency Iron is important in a variety of enzyme system Muscle second greatest user of iron CNS iron also important Iron deficiency important above and beyond just anemia 26

27 Iron for Fatigue Two RCT with oral iron show benefit with ferritin < 50 Iron replacement should be consider for fatigue and ferritin < 50 Statistical Iron Deficiency Laboratory values for ferritin reflect arbitrary criteria and not physiology Ranges of "normal" unrealistic for: Woman Older patients 27

28 Women and Iron No physiologic reason that women should have different ranges of normal for ferritin 85% of 20 year old men have ferritin over 50 ng/ml 25% of 20 year old women do Often overlooked cause of fatigue Benefit of raising ferritin > 50 ng/ml Iron Requirements Men: 14 ug/kg/day ~ 1mg/day Women: ~ mg/day 28

29 Gender and Ferritin Most Women have Low Iron Stores JAMA, Mar 1967; 199:

30 Serum Ferritin Serum ferritin proportional to iron stores Needs iron to be produced Acute phase reactant only in presence of iron Most accurate non-invasive test of iron stores! N Engl J Med May 30;290(22):

31 Iron Deficiency Serum ferritin is BEST non-invasive test of iron status > 100 ng/ml rules out iron deficiency Lower limit changes with age and condition Patient over 65 with ferritin < 50 ng/ml all iron deficient Age and Ferritin 31

32 Guyatt Review Ferritin only blood test to order Laboratory cut-off not optimal Likelihood of iron deficiency does not fall until ferritins > 40ng/mL > 70ng/mL with inflammation Ferritins > 100 ng/ml rule-out iron deficiency J Gen Intern Med Mar-Apr;7(2): Ferritin: Bottom Line Ignore lab reference ranges! < 15 ng/ml 100% specific > 100 ng/ml rules-out In older patients ferritins < 100ng/ml consider GI work-up Iron supplementation to women with ferritins < 50ng/ml improves fatigue 32

33 Summary RDW, serum iron, saturation: worthless TIBC: specific but not sensitive Ferritin: best non-invasive test Bone marrow: gold standard 33

34 Dietary Iron Heme iron 10x better absorbed than non-heme iron Meat protein improves iron absorption 34

35 Dietary Iron Calcium, fiber can block iron absorption Overcome by vitamin C Tea decreases 75-80% Coffee decreases 60% (5 oz!) 35

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37 What I Tell my Patients If feasible increase meat in diet Try not to drink tea or coffee with meat Vitamin C helps Oral Iron Pills Gut can only absorb a limited amount of iron Maxed out at ~ 10mg 37

38 Oral Iron Pills Years of studies have shown that the best iron preparation is. 38

39 Oral Iron Pills.the one that the patient can tolerate No consistent difference in any brand Many patients can t tolerate any pill on an empty stomach Ok with meals 15 vs 50 vs 150mg Oral Iron Am J Med Oct;118(10):

40 Cheapest iron pill Ferrous sulfate What I Do Once a day with meals Vitamin C 500 No tea or coffee If intolerant can try lower dose When to Use IV Iron Unable to tolerate oral iron Unable to be replaced with oral iron Risk of anaphylaxis >1% with older high molecular weight preparations Options LMW Iron Dextran (1000mg) Iron Gluconate Iron Sucrose (200mg x5) Ferumoxytol Ferric carboxymaltose 40

41 B 12 Deficiency Increasingly common cause of anemia Up to 10% of older folks deficient Can also be associated with neurologic disease 41

42 Why Do People Get B 12 Deficient? Diet: rare Failure to absorb Lack of stomach acid Lack of intrinsic factor Lack of pancreatic enzymes Lack of bowel Something else eating B 12 Metformin PPI Metformin Blocks B 12 absorption Known for 40 years to lead to B 12 deficiency Evidence B 12 lack may contribute to neuropathy Consider B 12 supplementation for patients on metformin 42

43 Folate Deficiency Subtle deficiencies very common More than 90% of the population do not get the RDA of folic acid!! 43

44 Methylmalonic Acid Only excreted in excess if tissue lack of B 12 Elevated MMA correlates with in vivo assays of B 12 lack Levels correlated with red cell and neurologic response to B 12 therapy Much less technical problems with assay than B 12 B12 vs MMA Bailey R L et al. Am J Clin Nutr 2011;94:

45 Homocysteine Elevated with both B 12 and folate deficiency Decreased B 12 stores often overlooked cause of Hcy elevation Lack of B 12 plays major role in Hcy elevation of renal disease Need to consider in patients with elevated Hcy Gee, can't I just get a MMA if the B 12 is borderline? MMA price is compatible with B 12 levels and more accurate Problems with cut-offs < 100: deficiency (over label pregnant women and HIV) > 300: not B 12 deficiency (miss 1-5% of deficient?) The use of biomarker cutoffs of vitamin B-12 to estimate the prevalence of inadequate nutrient status is challenging. 45

46 Folate Deficiency Serum folate levels are worthless Tremendous genetic variation Little correlation with tissue stores Homocysteine tracks closer to tissue levels MMA and Hcy as Diagnostic Tests MMA Hcy B 12 Def INC INC Folate NL INC 46

47 B 12 Deficiency: Therapy Oral therapy is now standard Start with 2mg for 3 months than mg po Dose finding study suggest can go as low as 500ug The Rational Work-Up 47

48 Bad Things I Don t Want to Miss: I Hemolysis Autoimmune Congenital Acquired TTP/HUS Bad Things I Don t Want to Miss: II Myeloma CRAB signs hypercalcemia Renal Anemia Bone symptoms SPEP/light chains 48

49 Work-Up: I Reticulocyte Count Smear Review Nutritional Ferritin Methylmalonic acid Homocystine Copper Neutropenia Sensory deficits/ataxia Work-Up II ACD/Renal Erythropoietin Level CMP Hemolysis Reticulocyte count LDH Bilirubin total and direct Direct antibody test Haptoglobin SPEP/Light Chains 49

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