Paziente con fibrillazione atriale e insufficienza renale cronica

Paziente con fibrillazione atriale e insufficienza renale cronica Ph. D, MD Sergio Agosti Dir. Medico Cardiologo Ospedale San Giacomo Novi Ligure

DISCLOSURE INFORMATION Agosti Sergio negli ultimi due anni ho avuto i seguenti rapporti anche di finanziamento con soggetti portatori di interessi commerciali in campo sanitario: Bayer BMS/Pfizer Boehringer Daiichi-Sankyo

Patient profile Patient: G. R. Patient History Personal Information Medical History • Prior TIA • Hypertension • Gastroesophegal reflux disease (GERD) Sex Female Age 81 Weight 70 kg Blood Pressure 162/84 mm. Hg Heart Rate 80 bpm Renal function Creatinine 1. 2 mg/dl Presentation Personal • Retired • Family members help her with transportation • Moderately uncomfortable palpitations for the last month and for >48 hours before visit; otherwise stable • ECG shows AF rhythm; valvular disease ruled out → Newly diagnosed NVAF Medications • • Furosemide Losartan Pantoprazole ASA

What is the CHA 2 DS 2 -VASc score of this patient? Question 1 Female patient Moderate renal impairment (cl ceat 40 ml/min) Weight: 70 kg Hypertension Blood pressure: 162/84 mm. Hg Previous TIA Uses pantoprazole for GERD 81 years of age 1. CHA 2 DS 2 -VASc = 1 2. CHA 2 DS 2 -VASc = 2 3. CHA 2 DS 2 -VASc = 3 4. CHA 2 DS 2 -VASc = 4 5. CHA 2 DS 2 -VASc = 6 GERD: gastroesophageal reflux disease

The CHA 2 DS 2 -VASc score of this patient CHA 2 DS 2 -VASc 1 Score Congestive heart failure/LV dysfunction 1 Hypertension 1 Aged ≥ 75 years 2 Diabetes mellitus 1 Stroke/TIA/TE 2 Vascular disease (prior MI, PAD, or aortic plaque) 1 Aged 65 -74 years 1 Sex category (i. e. female gender) 1 Maximum score 9 LV: left ventricular; TIA: transient ischemic attack; INR: international normalized ratio; MI: myocardial infarction a. Vascular disease includes myocardial infarction, complex aortic plaque, and peripheral artery disease 1. Lip et al. CHEST. 2010; 137: 263– 272.

The CHA 2 DS 2 -VASc score of this patient CHA 2 DS 2 -VASc Score Congestive heart failure/LV dysfunction 1 Hypertension 1 Aged ≥ 75 years 2 Diabetes mellitus 1 Stroke/TIA/TE 2 Vascular disease (prior MI, PAD, or aortic plaque) 1 Aged 65 -74 years 1 Sex category (i. e. female gender) 1 Maximum score 9 LV: left ventricular; TIA: transient ischemic attack; INR: international normalized ratio; MI: myocardial infarction a. Vascular disease includes myocardial infarction, complex aortic plaque, and peripheral artery disease 1. Lip et al. CHEST. 2010; 137: 263– 272.

What is the CHA 2 DS 2 -VASc score of this patient? Question 1 Female patient Moderate renal impairment (cl ceat 40 ml/min) Weight: 70 kg Hypertension Blood pressure: 162/84 mm. Hg Previous TIA Uses pantoprazole for GERD 81 years of age 1. CHA 2 DS 2 -VASc = 1 2. CHA 2 DS 2 -VASc = 2 3. CHA 2 DS 2 -VASc = 3 4. CHA 2 DS 2 -VASc = 4 5. CHA 2 DS 2 -VASc = 6 GERD: gastroesophageal reflux disease

What is the HAS-BLED score of this patient? Question 2 Female patient Moderate renal impairment (cl ceat 40 ml/min) Weight: 70 kg Hypertension Blood pressure: 162/84 mm. Hg Previous TIA Uses pantoprazole for GERD 81 years of age 1. HAS-BLED = 1 2. HAS-BLED = 2 3. HAS-BLED = 3 4. HAS-BLED = 4 5. HAS-BLED = 5 GERD: gastroesophageal reflux disease

The HAS-BLED score of this patient HAS-BLED Score Hypertension 1 Renal disease 1 Liver disease 1 Stroke history 1 Prior major bleeding or predisposition to bleeding 1 Labile INR 1 Age >65 1 Medication usage predisposing to bleeding 1 Alcohol use 1 Uncontrolled, >160 mm. Hg systolic Dialysis, transplant, Cr >2. 26 mg/d. L or >200 µmol/L Cirrhosis or bilirubin >2 x normal with AST/ALT/AP >3 x normal Unstable/high INRs, time in therapeutic range <60% Aspirin, clopidogrel, NSAIDs ≥ 8 drinks/week Maximum score 9 1. Lip et al. CHEST. 2010; 137: 263– 272.

The HAS-BLED score of this patient HAS-BLED Score Hypertension 1 Renal disease 1 Liver disease 1 Stroke history 1 Prior major bleeding or predisposition to bleeding 1 Labile INR 1 Age >65 1 Uncontrolled, >160 mm. Hg systolic Dialysis, transplant, Cr >2. 26 mg/d. L or >200 µmol/L Cirrhosis or bilirubin >2 x normal with AST/ALT/AP >3 x normal Unstable/high INRs, time in therapeutic range <60% Medication usage predisposing to bleeding Aspirin, clopidogrel, NSAIDs Alcohol use ≥ 8 drinks/week Maximum score 1 1 9 1. Lip et al. CHEST. 2010; 137: 263– 272.

What is the HAS-BLED score of this patient? Question 2 Female patient Moderate renal impairment (cl ceat 40 ml/min) Weight: 70 kg Hypertension Blood pressure: 162/84 mm. Hg Previous TIA Uses pantoprazole for GERD 80 years of age 1. HAS-BLED = 1 2. HAS-BLED = 2 3. HAS-BLED = 3 4. HAS-BLED = 4 5. HAS-BLED = 5 GERD: gastroesophageal reflux disease

ESC 2016 Guideline recommendations 1 1. Kirchhoff et al. Eur Heart J 2016.

Question 3 • GR is newly diagnosed with NVAF and has a CHA 2 DS 2 -VASc score of 4 • Which NOAC would you initiate for this patient’s stroke prevention? 1. Apixaban 2. Dabigatran 110 mg twice-daily 3. Dabigatran 150 mg twice-daily 4. Edoxaban 5. Rivaroxaban 6. VKA

Class effect? DABI 150 DABI 110 RIVA API EDO 60 EDO 30 STROKE/SSE 0. 65 (0. 52 -0. 81) <. 001 SUP 0. 89 (0. 73 -1. 09) <. 001 NON INF 0. 88 (0. 75 -1. 03) . 001 NON INF 0. 79 (0. 66 -0. 95) . 01 SUP 0. 87 (0. 73 -1. 04) . 001 NON INF 1. 13 (0. 96 -1. 34) . 005 NON INF ISCHEMIC STROKE 0. 76 (0. 59 -0. 97) . 03 1. 10 (0. 88 -1. 37) 0. 94 (0. 75 -1. 17) 0. 92 (0. 74 -1. 13) 1. 00 (0. 83 -1. 19) 1. 41 (1. 19 -1. 67) . 001 HEMORR. STROKE 0. 26 (0. 14 -0. 49) <. 001 0. 31 (0. 17 -0. 56) <. 001 0. 59 (0. 35 -0. 75) <. 001 0. 51 (0. 35 -0. 75) <. 001 0. 54 (0. 38 -0. 77) <. 001 0. 33 (0. 22 -0. 50) <. 001 MAJOR BLEEDING 0. 94 (0. 82 -1. 08) 0. 80 (0. 70 -0. 93) . 003 1. 04 (0. 90 -2. 30) 0. 69 (0. 60 -0. 80) <. 001 0. 80 (0. 71 -0. 91) <. 001 0. 47 (0. 41 -0. 55) <. 001 INTRACRAN. BLEEDING 0. 42 (0. 29 -0. 61) <. 001 0. 29 (0. 19 -0. 45) <. 001 0. 67 (0. 47 -0. 93) . 02 0. 42 (0. 30 -0. 58) <. 001 0. 39 (0. 34 -0. 63) <. 001 0. 30 (0. 21 -0. 43) <. 001 1. 48 (1. 19 -1. 86) <. 001 1. 04 (0. 82 -1. 33) 1. 61 (1. 30 -1. 99) <. 001 0. 89 (0. 70 -1. 15) MI 1. 27 (0. 94 -1. 71) 1. 29 (0. 96. 1. 75) 0. 81 (0. 63 -1. 06) 0. 88 (0. 66 -1. 17) 0. 94 (0. 74 -1. 19) 1. 19 (0. 95 -1. 49) DEATH 0. 88 (0. 77 -1. 00) 0. 91 (0. 80 -1. 03) 0. 85 (0. 70 -1. 02) 0. 89 (0. 80 -0. 99) <. 05 0. 92 (0. 83 -1. 01) 0. 87 (0. 79 -0. 96) . 006 CHADS 2. 1 3. 5 2. 1 2. 8 GI MAJOR BLEEDING 1. 23 (1. 02 -1. 50) 0. 67 (0. 53 -0. 83) <. 01. 03

Eur Heart J. 2017 Mar 21; 38(12): 860 -868 C. Diener, J. Eikelboom, G. Lip

Reviewing the options: dabigatran How does GERD factor into treatment? • Gastroesophageal reflux disease may predispose toward GI problems such as dyspepsia 1 • Standard treatment includes proton pump inhibitors (PPIs)2 • Dabigatran showed an increased risk of dyspepsia in the RE-LY trial vs. warfarin: 3 – Warfarin: 348 patients (5. 8%) – Dabigatran 110 mg: 707 patients (11. 8% ) (p<0. 001 vs. warfarin) – Dabigatran 150 mg: 688 patients (11. 3%) (p<0. 001 vs. warfarin) 1. Harmon et al. Ther Adv Gastroenterol 2010; 3: 87 -98; 2. Pettit. Pharm World Sci 2005; 27: 417 -20; 3. Connolly et al. New Engl J Med 2009; 361: 1139– 51.

Question 3 • GR is newly diagnosed with NVAF and has a CHA 2 DS 2 -VASc score of 6 • Which NOAC would you initiate for this patient’s stroke prevention? 1. Apixaban 2. Dabigatran 110 mg twice-daily 3. Dabigatran 150 mg twice-daily 4. Edoxaban 5. Rivaroxaban 6. VKA

Question 4 • Her cardiologist decides to start GR on apixaban • Co-medications are losartan, furosemide, pantoprazole and bisoprolol • What dose of apixaban is recommended for GR’s stroke prevention? A. 2. 5 mg twice-daily B. 5 mg twice-daily Moderate renal impairment (cl ceat 40 ml/min)

The recommended dose of apixaban is 5 mg taken orally twice daily (BD) to be taken with or without food 1 • Relevant characteristics for GR regarding potential dose adjustment: – Age: 81 years (> 80 years) – Body weight: 70 kg (not below 60 kg) – Creatinine in serum 1. 2 mg/dl (≥ 1. 5 mg/d. L) 1. Apixaban Sm. PC. Available at http: //www. ema. europa. eu.

Question 3 • Her cardiologist decides to start GR on apixaban • Co-medications are losartan, furosemide, pantoprazole and bisoprolol • What dose of apixaban is recommended for GR’s stroke prevention? A. 2. 5 mg twice-daily B. 5 mg twice-daily

La pratica clinica corrente: 1 PREFER AF PROLUNGATION Registry

Challenges in comparing the non-vitamin K antagonist oral anticoagulants for atriale fibrillationrelated stroke prevention. Camm AJ, Fox KAA, Peterson E. Europace. 2017 Oct 13.

Q 13: Nella scelta di un NAO quanto pesano le seguenti caratteristiche? pochissimo poco abbastanza molto moltissimo ARCA Liguria NAO Survey: our results. Sergio Agosti, Laura Casalino, Bruno Tarabella, Mauro Barra, Giovanni Battista Zito. CARDIOLOGIA AMBULATORIALE, 2016, 4: 247 -257

Raccomandazioni dell’EHRA nei pazienti con IR (Update 2017)

ARISTOTLE: Major bleeding rates in the elderly (≥ 75 years) in relation to renal function 1 Cockroft–Gault e. GFR m. L/min No. of patients ≥ 75 years No. events/patients (%/year) Apixaban Warfarin 596 11 (2. 10) 15 (3. 39) e. GFR >50– 80 m. L/min 2, 912 85 (3. 53) 104 (4. 45) e. GFR >30– 50 m. L/min 1, 898 47 (3. 32) 87 (6. 27) 221 7 (4. 64) 17 (13. 4) e. GFR >80 m. L/min e. GFR 30 m. L/min HR of major bleeds (95% CI) Interaction P value 0. 1635 0. 1 1. 0 1. 4 Favours apixaban Favours warfarin 1. Halvorsen S, et al. Eur Heart J 2014; 35: 1864– 1872; 2. Apixaban Sm. PC. Available at http: //www. ema. europa. eu.

Apixaban Pharmacokinetics at Steady State in Hemodialysis Patients Thomas A. Mavrakanas, J Am Soc Nephrol 28: 2241– 2248, 2017

Studio retrospettivo cl creat <25 ml/min creat >2. 5 mg/dl. Pharmacotherapy 2017; 37(4): 412– 419

Pharmacotherapy 2017; 37(4): 412– 419

RENAL-AF: RENal hemodialysis patients ALlocated apixaban versus warfarin in Atrial Fibrillation patients Sponsor: Christopher Granger, Duke University Medical Center Clinicaltrials. gov: Study Number NCT 02942407; : https: //clinicaltrials. gov/show/NCT 02942407

XARENO – An Ongoing Real-World Study of Rivaroxaban in Renally Impaired Patients Official study title: Factor XA – inhibition in RENal patients with non-valvular atrial fibrillation Observational registry Objective: To assess CKD progression and safety of anticoagulation strategies in NVAF patients with e. GFR 15– 49 ml/min /1. 73 m 2 in routine clinical practice Pre-study phase Study population: Patients with NVAF (N=2500) and e. GFR/Cr. Cl 15– 49 ml/min Patient selection and choice of type, dose and duration of drug used at discretion of attending physician www. clinicaltrials. gov/ct 2/show/NCT 02663076 Follow-up phase Rivaroxaban for ≥ 3 months n≥ 1000 VKA for ≥ 3 months n≥ 1000 No OAC (ASA or no treatment) for ≥ 3 months n<500 Day 0 90 Short design: Observational, open-label, active-controlled, multicentre study (N=2500) 180 Investigators to collect data at initial visit, at 3 months and then quarterly 270 … … … 720

Conclusioni § DOACs sono rivoluzione farmacologica nei pazienti con FANV e TEV § La scelta del farmaco antitrombotico dovrebbe essere bilanciata sul rischio tromboembolico ed emorragico del paziente, calcolati con gli score di rischio § Apixaban sembra avere il profilo di sicurezza più favorevole nei pazienti con CHD moderata-severa § La riduzione del dosaggio dei DOACs va fatta seguendo le indicazioni da label

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