Discuss differences in pharmacokinetics and pharmacodynamics in the elderly Describe key considerations associated with anticoagulation in elderly

Transcription

1 Giovanni Lares, PharmD Anticoagulation Clinic, Internal Medicine, ACC October 30,

2 Discuss differences in pharmacokinetics and pharmacodynamics in the elderly Describe key considerations associated with anticoagulation in elderly patients Apply cultural sensitivity concepts to engage in discussions related to anticoagulation in elderly patients Determine an optimal anticoagulation regimen in an elderly patient Identify risks and benefits associated with new anticoagulation agents 2

3 Increase in clotting factors I, V, VIII, IX, XIIIa Increased platelet activity Increased IL 6 increased fibrinogen, PAI 1, CRP, platelet aggregation 3

4 Decreased serum albumin Increased serum concentration of protein bound drugs Increased total body fat Increased Vd of lipophilic drugs Decreased Vd for hydrophilic drugs Comorbidities (e.g. heart failure, diabetes, etc) Decreased hepatic first pass metabolism Decreased liver mass, perfusion Increased bioavailability of some drugs Impaired phase 1 metabolism Decreased renal excretion Increased bioavailability of some drugs Drug Metab Rev 2009;41:67 4

5 Treatment/prevention of thrombosis DVT, PE Prevention of stroke in patients with artificial heart valves Lifelong anticoagulation indicated in patients with mechanical valves Prevention of stroke in patients with atrial fibrillation (AF) and concomitant risk factors CHADS 2 score 1 5

6 Atrial fibrillation is highly prevalent in older adults 1.5% of adults aged 60 to 70 years 10% of adults aged >80 years AF increases the risk of stroke 4 to 5 fold, across all age groups Risk of stroke attributable to AF increases with age 1.5% risk in ages 50 to 59 years 23.5% in ages 80 to 89 years Strokes in AF are more severe and disabling, and associated with high mortality ~50% at 1 year Circulation 2011;123:

7 Off warfarin On warfarin 7

8 CHADS 2 Congestive Heart Failure = 1 point Hypertension = 1 point Age >75 years = 1 point Diabetes = 1 point Stroke or TIA = 2 points CHA 2 DS 2 VASC Congestive Heart Failure = 1 point Hypertension = 1 point Age >75 years = 2 points Diabetes = 1 point Stroke/TIA/systemic thromboembolism = 2 points Vascular disease = 1 point Age years = 1 point Sex Category (female) = 1 point Moderate-high risk: 2 points Low risk: 0 1 point 8

9 Despite its benefit in elderly patients, warfarin is underutilized Used in only one third of eligible patients >85 years despite lack of contraindications Providers & Patients Physicians underestimate stroke prevention by as much as 22% and overestimate bleeding risk by as much as 670% AF patients aged years, when educated on risk/benefits, 61% chose warfarin, 47% of those not on warfarin would have chosen it Interview study of physicians and patients with high risk of stroke Minimum number of strokes prevented (100 pts/2y) to justify warfarin was lower for patients than for physicians (1.8 vs. 2.5, p=0.009) Maximum number of bleeds acceptable to patients (100 pts/2y) was higher than for physicians (17.4 vs. 10.3, p<0.001) Ann Intern Med 1999;131: BMJ 2000;320: BMJ 2001;323:1-7 9

10 HAS BLED Score (AF) Hypertension = 1 point Abnormal renal/hepatic function = 1 point 1 point for each Stroke = 1 point Bleeding history or anemia = 1 point Labile INR = 1 point Elderly (age > 75 years) = 1 point Drugs (NSAIDs, antiplatelet, EtOH) = 1 point 1 point for each High risk (> 4%/year) 4 points Moderate risk (2 4%/year) 2 3 points Low risk (< 2%/year) 0 1 point HEMHORR(2)HAGES Score Hepatic or renal disease = 1 point 1 point for each Ethanol abuse = 1 point Malignancy = 1 point Older age (>75 years) = 1 point Reduced platelet count/function = 1 point Platelets<75,000, use of antiplatelets, NSAID Rebleeding = 2 points Hypertension = 1 point Anemia = 1 point Genetic factors = 1 point CYP2C9*2, CYP2C9*3 Excessive fall risk = 1 point Alzheimer s, Parkinson s, etc. Stroke = 1 point Chest 2010;138(5):

11 Patients >80 years II Chest 2010;138(5): Circulation 2007;115:

12 Limited data in elderly patients Risk ranges per 100 person years Increased risk with INR>4, first 90 days of warfarin use Risk of intracranial hemorrhage (ICH) is about 0.5% per year with INR 2 3 Increased risk: SBP 160mmHg, DBP 90mmHg (4 fold), concurrent high dose ASA Circulation 2007;115: Ann Intern Med1994;120:

13 Fall risk is frequently listed as a barrier to anticoagulation in the elderly 33% of people >65 fall each year Average number of falls is 1.8 per year A Markov decision model using 49 published studies: Average stroke risk 6%, average fall risk 33%, life expectancy average 13 years Conclusion: A patient with AF would have to fall 295 times in one year for the risk of anticoagulation to outweigh its benefits Arch Intern Med 1999;159:

14 57 elderly patients enrolled in an anticoagulation clinic were screened with the mini mental state exam (MMSE): Conclusion: The presence of cognitive impairment should not necessarily preclude the use of warfarin in elderly patients enrolled in an anticoagulation clinic. Drugs Aging 2012; 29(4):

15 15

16 Tablet Strength Color 1mg 2mg 2.5mg 3mg 4mg 5mg 6mg 7.5mg 10mg Pink Purple Green Tan Blue Peach Teal Yellow White 16

17 Mechanism of Action Interferes with the production of vitamin-k dependent clotting factors (II, VII, IX, and X) by inhibiting vitamin K oxide reductase Route PK PO Onset of anticoagulant effect: h Full therapeutic effect: 5 7 days Duration: 2 5 days Metabolism: CYP2C9, CYP1A2, CYP3A4 Adverse Effects Skin necrosis and limb gangrene 17

18 Chest 2012; 141(2):e44s-e88s 18

19 Warfarin interferes with the production of clotting factors from their inactive form it has no effect on existing, active clotting factors Anticoagulant activity relies on the natural catabolism of existing clotting factors and their corresponding half lives. Protein Half-Life (hr) VII 4 6 IX X II Protein C 9 Protein S 60 19

20 Consider warfarin 2.5mg daily in the following: Age >75 years old BMI<18.5, Body weight <50kg CHF Liver disease Clinical hyperthyroidism GI, genitourinary, or CNS bleed within last 2 months Concomitant meds known to increase warfarin sensitivity E.g. amiodarone High bleeding risk 20

21 Drug Drug interactions Major: Antibiotics, NSAIDs, steroids, OCs, Amiodarone EtOH, smoking Warfarin Disease interactions Warfarin Diet interactions Consistency in vitamin K intake, NOT avoidance 21

22 Complete blood count Monitor for possible bleeding complications PT and INR Monitor for therapeutic effectiveness 22

23 Advantages (relative to warfarin) Less interactions with drugs and foods No routine monitoring; fixed dosing Reduced risk of intracranial hemorrhage Faster onset Disadvantages (relative to warfarin) No readily available test to monitor dosing No antidote Dosage adjustment for CKD III IV; CKD V contraindicated Limited data in older patients with comorbidities Cost Increased risk of stroke with abrupt discontinuation Black Box warning 23

24 Mechanism of Action Approved Indications Dosing Dabigatran* (Pradaxa ) Direct Thrombin Inhibitor Non-valvular AF 110mg BID 150mg BID Rivaroxaban (Xarelto ) Factor Xa inhibitor Non-valvular AF DVT/PE treatment DVT prophylaxis 10mg daily 15mg daily 20mg daily Apixaban (Eliquis ) Factor Xa inhibitor Non-valvular AF 2.5mg BID 5mg BID Metabolism Renal Renal/Hepatic Renal Drug-Drug Interactions P-gp inhibitor CYP3A4 substrate P-gp inhibitor CHADS2 studied CYP3A4 substrate P-gp inhibitor *Listed on 2012 Beers Criteria as Use with caution due to increased risk of bleeding in adults 75 years, lack of evidence of safety in CrCl<30ml/min NEJM 2009; 361: , NEJM 2011;365:883-90, NEJM 2011;365:

25 RE LY (Dabigatran) ROCKET AF (Rivaroxaban) ARISTOTLE: (Apixaban) Inclusion Criteria AF + 1 of: TIA/CVA, LVEF <40%, or HF Age 75 or DM, HTN, or CAD AF and prior TIA /CVA/systemic embolus or AF and CHADS 2 2 or AF and Age 75 or plus DM, HTN, or CAD AF and CHADS 2 1 Exclusion Criteria Valvular disease CVA within 14 days CrCl<30ml/min Active liver disease Pregnancy Valvular disease/prosthetic valve CVA within 14 days or severe CVA within 3 months CrCl <30 ml per minute Known significant liver disease Pregnancy Condition with bleeding predisposition Aspirin >100 mg qd Valvular disease/prosthetic valve CVA within 7 days CrCl <25 ml per minute Condition with bleeding predisposition Aspirin >165 mg qd, or aspirin plus clopidogrel 25

26 Outcome (RR ± 95% CI) RE-LY (Dabigatran 150mg BID) ROCKET AF (Rivaroxaban 20mg/day) ARISTOTLE (Apixaban 5mg BID) Warfarin TTR 64% 55% 62.2% Stroke/Systemic 0.66 ( ) 0.88 ( ) 0.79 ( ) Embolic Event Ischemic stroke 0.76 ( ) 0.94 ( ) 0.92 ( ) Hemorrhagic 0.26 ( ) 0.59 ( ) 0.51 ( ) stroke Major bleeding 0.93 ( ) 1.04 ( ) 0.69 ( ) Intracranial hemorrhage 0.40 ( ) 0.67 ( ) 0.42 ( ) NEJM 2009; 361: NEJM 2011;365: NEJM 2011;365:

27 Close monitoring & lifestyle modification when using warfarin Management of excessive anticoagulation Control of hypertension Interventions to reduce the risk of falls Avoid NSAIDs Treatment of GI pathology (Ulcers, H. Pylori) Close attention to patients with cognitive impairment Interventional procedures Catheter ablation Left atrial appendage closure devices (still being investigated) Surgical MAZE and LAA resection Treatment decisions are not final they should evolve and adapt as patient s risk factors and therapy goals change. 27

28 28

29 Circulation 2011;123:e269-e367 29

30 ACC/AHA/ESC 2011 Focused Update Recommendation: CHADS 2 = 0 May also use with CHADS 2 = 1, though warfarin is preferred Use in addition to clopidogrel in patients with AF in whom warfarin therapy is considered unsuitable due to patient preference or assessment of patient s ability to safely sustain anticoagulation Aspirin and low intensity warfarin (INR<2) not recommended Circulation 2011;123:e269-e367 Lancet 1996;348:633 30

31 Circulation 2011;123:e269-e367 31

32 32

33 AA is a healthy 72 year old male with a history of non valvular atrial fibrillation and hypertension. He has been on warfarin for 10 years (TTR 70%) and is interested in starting Pradaxa. He is currently taking the following medications: Hydrochlorothiazide 25mg daily Amiodarone 200mg daily Warfarin 2.5mg QHS Pertinent labs (10/30/13): <98 Hct/Hgb/PLT: 40.6/14.0/ INR 2.0 BP: 132/79 HR: 65 Ht: 6 0 Wt: 82kg 33

34 Stroke Risk: CHA 2 DS 2 VASC = 2 (HTN, age) 2.2% risk of stroke Bleed Risk: HAS BLED = 1 (low risk) Is this patient eligible for Pradaxa? Non valvular afib CrCl=48.9mL/min CrCl>30mL/min: dabigatran 150mg BID CrCl 15 30mL/min: dabigatran 75mg BID CrCl<15mL/min: not recommended 34

35 The decision has been made to start AA on Pradaxa. How do you instruct him to start? Pradaxa should be started when INR<2 INR = 2.0 on 10/30/13 Have patient skip tonight s warfarin dose, start Pradaxa tomorrow evening 35

36 AA returns to the clinic several weeks later. He states that he developed a fungal infection a couple days ago and was prescribed ketoconazole 200mg daily by the local urgent care facility. Dose adjustments for concomitant administration with strong P gp inhibitors (dronedarone, ketoconazole) CrCl 30 50mL/min: Decrease dose to dabigatran 75mg BID No dose adjustments necessary for other P gp inhibitors (verapamil, amiodarone, quinidine, clarithromycin) 36

37 A few months later, AA returns to the clinic. He states that his insurance will lapse at the end of the month and he will no longer be able to afford Pradaxa. How do you proceed? CrCl>50mL/min: start warfarin 3 days before discontinuing Pradaxa CrCl 30 50mL/min: start warfarin 2 days before discontinuing Pradaxa CrCl 15 30mL/min: start warfarin 1 day before discontinuing Pradaxa 37

38 BB is an 84 year old woman recently discharged from the hospital for new onset atrial fibrillation. She is discharged with warfarin 3mg daily and referred to your office for INR monitoring. PMH: HTN, OA, DM Home Meds: Aspirin 81mg daily, amlodipine 10mg daily, metoprolol 50mg daily, Ibuprofen 400mg Q8hr prn Social Hx: Ambulates with walker, occasional mechanical falls, grand daughter helps with medications Pertinent Labs (10/30/13): <108 Hct/Hgb/PLT: 40.6/14.0/ INR 2.2 BP: 153/85 HR: 65 Ht: 5 2 Wt: 50kg 38

39 Stroke Risk: CHA 2 DS 2 VASC = 5 HTN, age, DM, female 6.7% risk of stroke Bleed Risk: HAS BLED = 4 (high risk) HTN, elderly (age>75 years), Drugs (Aspirin, Ibuprofen) Is the patient a candidate for novel anticoagulants? Dabigatran: not recommended in patients >75 years Rivaroxaban, apixaban No absolute contraindications, though caution with: Advanced age, low body weight, concomitant antiplatelet/nsaid use, renal insufficiency (CrCl 33mL/min) 39

40 What can be done to minimize risk in this patient? OA: switch ibuprofen to acetaminophen (gold standard) 500mg q 6 hr prn BP 153/85: optimize BP medication Increased blood pressure increases risk of ICH Increase metoprolol 100mg daily Minimize fall risk Close INR follow up (1 2 weeks) Recently started on warfarin at hospital discharge 40

41 BB returns to clinic 2 weeks later for anticoagulation follow up. Her INR is 2.3 and her BP is now 135/80. She reports that the acetaminophen given at last visit has not helped with her OA. She states that she is now bed ridden all day and is requesting to switch back to her ibuprofen. 41

42 Arch Intern Med 2002;162:

43 Three weeks following her last visit, BB returns to the clinic for anticoagulation follow up. Her INR is 6.1. What questions should be asked? Are you experiencing any bleeding? What dose of warfarin are you taking? Did you take an extra warfarin dose by mistake? Have any of your medications changed? What about over thecounter medications? Have you had any alcohol recently? Have you experienced any illness recently? E.g. vomiting, diarrhea, flu symptoms 43

44 BB denies any signs and symptoms of bleeding, denies doubling up on her warfarin dose, recent alcohol or medication changes, or recent illness. Both she and her granddaughter insist that she has been taking warfarin 3mg daily since her initial hospital discharge 5 weeks ago. How do you proceed? 44

45 GOAL INR 2 3 INR WEEKLY WARFARIN DOSE < % %* 2 3 NO CHANGE %* HOLD X 1 DOSE, THEN 5 15% HOLD X 1 2 DOSES, THEN 10 20% HOLD X 3 4 DOSES, RECHECK INR, THEN 25 50% >10.0 RECOMMEND VITAMIN K PO 2.5 5MG 45

46 BB returns to clinic 3 days later as instructed for anticoagulation follow up. Her INR is 3.1 and she still denies any signs or symptoms of bleeding. What is her new warfarin dose? Previous dose: warfarin 3mg daily (21mg/wk) New dose should be ~30% less than original weekly dose 0.7 x 21mg/wk = 14.7mg/wk Warfarin 1.5mg daily except 3mg on Mon/Wed/Fri (15mg/wk) 1.5mg x 4 days = 6mg 3mg x 3 days = 9mg INR follow up: 1 week 46

47 Assess need for oral anticoagulation (CHA2DS2VASC) Assess bleeding risk (HAS BLED) Is there a compelling indication for a newer anticoagulant? Patient refuses warfarin Patient has unstable INRs on warfarin Are there contraindications to newer agents? Severe renal and/or liver disease, valve disease Do NOT use if history of noncompliance Remember, the benefit of anticoagulation will most often outweigh the risk 47

48 References 1. Abbate R, Prisco D, Rostagno, et al. Age related changes in the hemostatic system. Intl J Clin Lab Res 1993;23(1): Go AS, Hylek EM, Borowsky LH, et al. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med1999;131: Sinnaeve PR, Brueckmann M, Clemens A, et al. Stroke prevention in elderly patients with atrial fibrillation: challenges for anticoagulation. J Int Med 2011;271: Jones M, McEwan P, Morgan CL, et al. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non valvular atrial fibrillation: a record linkage study in a large British population. Heart 2005; Wann LS, Curtis AB, January CT, et al ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation. Circulation 2011;123: Pisters R, Lane DA, Nieuwlaat R, et al. A Novel user friendly score (HAS BLED) to assess 1 year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5): Fuster V, Ryden LE, Cannom DS, et al ACCF/AHA/HRS Focused Updates Incorporated Into the ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:e Hylek EM, Evans Molina C, Shea C, et al. Major Hemorrhage and Tolerability of Warfarin in the First Year of Therapy Among Elderly Patients With Atrial Fibrillation. Circulation 2007;115: Hylek EM, Singer DE, et al. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med1994;120: Man Son Hing M, at al. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med 1999; 159: Khreizat HS, Whittaker P, Curtis KD, et al. The Effect of Cognitive Impairment in the Elderly on the Initial and Long Term Stability of Warfarin Therapy. Drugs Aging 2012; 29(4): Protheroe J, Fahey, Montgomery AA, et al. The impact of patients' preferences on the treatment of atrial fibrillation: observational study of patient based decision analysis. BMJ 2000;320: Devereaux PJ, Anderson DR, Gardner MJ, et al. Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study. BMJ 2001;323: Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: Granger CB, Alexander JH, McMurray JJ et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365: Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365: Man Son Hing M, Laupacis A. Balancing the risks of stroke and upper gastrointestinal tract bleeding in older patients with atrial fibrillation. Arch Intern Med 2002;162: