WHAT S NEW: HOT TOPICS IN INPATIENT INTERNAL MEDICINE

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1 WHAT S NEW: HOT TOPICS IN INPATIENT INTERNAL MEDICINE Emmeline Tran, PharmD, BCPS Clinical Assistant Professor emmeline.tran@wsu.edu DISCLOSURE I have no actual or potential conflict of interest in relation to this program/presentation I will be discussing off-label uses and/or investigational use of the following medication in my presentation: Azithromycin OBJECTIVES At the completion of this program, the pharmacist will be able to: Identify and evaluate recent literature pertinent to the practice of internal medicine Compare and contrast latest literature findings with current standards of care Integrate recent evidence-based recommendations into clinical practice 1

2 OBJECTIVES At the completion of this program, the technician will be able to: Identify medications examined in recent literature pertinent to the practice of internal medicine Distinguish between latest literature findings with current standards of care Integrate recent evidence-based recommendations into clinical practice HOT TOPICS Lungs Liver Asthma exacerbations COPD Portal hypertension Joints Gout Blood Venous thromboembolism Anticoagulation in ESRD HOT TOPICS Lungs Liver Asthma exacerbations COPD Portal hypertension Joints Gout Blood Venous thromboembolism Anticoagulation in ESRD 2

3 LUNGS asthma exacerbation Macrolides Antibiotic Antiviral Immunomodulatory Lancet Respir Med Aug;2(8): NHLBI Guidelines Antibiotics are NOT recommended (except as needed for comorbid conditions) 2017 GINA Guidelines Antibiotics are NOT routinely recommended ginasthma.org nhlbi.nih.gov 3

4 TELICAST N = 278, duration = 10 days Telithromycin 800 mg PO daily x 10 days vs placebo symptoms, lung-function tests N Engl J Med Apr 13;354(15): AZISAST N = 109, duration = 26 weeks Azithromycin 250 mg PO daily x 5 days, then 250 mg three times per week vs placebo exacerbations and lower respiratory tract infections in non-eosinophilic severe asthma patients Thorax Apr;68(4):

5 AZALEA Study Design Randomized, placebo-controlled N = 199; duration = 10 days Intervention Azithromycin 500 mg PO daily x 3 days Placebo Results No difference in asthma symptom scores, any measures of lung function, or time to 50% reduction of symptoms No difference in serious adverse events Comments > 10 patients excluded for each randomized Need for systemic corticosteroids Asthma severity Step 2 to 3: 59% Positive test for atypical bacterial infection: 5.2% JAMA Intern Med Nov 1;176(11): TAKE HOME > 10 patients excluded for each randomized Baseline characteristics Received systemic corticosteroids Positive for atypical bacterial infection: ~5% Efficacy No benefit in symptom improvement Safety More gastrointestinal events in the azithromycin group More respiratory adverse events in the placebo group JAMA Intern Med Nov 1;176(11): LUNGS asthma exacerbation Considerations Heterogeneous disease Use of biomarkers C-reactive protein Procalcitonin BMC Infect Dis Dec 17;13:596. Crit Care Sep 5;18(5):471. Nat Med May 4;18(5): Chest Jun;139(6):

6 LUNGS COPD EXACERBATION HISTORY Group C high risk less symptoms Group A low risk less symptoms Group D high risk more symptoms Group B low risk more symptoms SYMPTOMS goldcopd.org N Engl J Med Oct 2;371(14): Chest Aug;148(2): goldcopd.org Am J Respir Crit Care Med Nov 15;166(10): Thorax Jun;60(6): goldcopd.org 6

7 Group C LAMA + LABA LABA + ICS Group D other LAMA + LABA + ICS LAMA Group A Continue, stop, or try alternative LAMA Group B LAMA + LABA LAMA + LABA LABA + ICS bronchodilator LAMA OR LABA preferred treatment ICS = inhaled corticosteroid; LABA = long-acting beta agonist; LAMA = longacting muscarinic antagonist goldcopd.org COPE and COSMIC COPE: N = 244; duration 6 months COSMIC: N = 373; duration = 1 year Corticosteroid withdrawal lung function, frequency of exacerbations, QOL QOL = quality of life Am J Respir Crit Care Med Nov 15;166(10): Thorax Jun;60(6): N Engl J Med Oct 2;371(14):

8 WISDOM Study Design Randomized, noninferiority N = 2485; duration = 12 months Intervention Glucocorticoid-withdrawal (reduction every 6 weeks) Glucocorticoid-continuation Results Met noninferiority for time to first moderate or severe exacerbation 38 ml greater mean reduction from baseline in trough FEV 1 in withdrawal group Comments Mean FEV 1 after bronchodilation: 0.93 liters (32.8% of predicted value) GOLD 3: ~61% FEV 1 = forced expiratory volume in 1 second N Engl J Med Oct 2;371(14): Chest Aug;148(2): GLP2 Study Design Randomized, N = 58; duration = 30 months Intervention Glucocorticoid-withdrawal Results lung function (FEV 1-68 ml/year to -73 ml/year) in withdrawal group AHR and QOL in withdrawal group Comments Not use any ICSs: 71% Time ICSs were used: 0% to 50% Mean daily ICS dose: 960 µg (beclomethasone equivalents) Mean FEV 1 after bronchodilation: 1.97 liters (62% of predicted value) AHR = airway hyperresponsiveness; FEV 1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroid; QOL = quality of life Chest Aug;148(2):

9 TAKE HOME Baseline characteristics Moderate to severe COPD Efficacy No difference in exacerbations Greater decline in lung function Safety No difference in rate of pneumonia N Engl J Med Oct 2;371(14): Chest Aug;148(2): LUNGS COPD Considerations Heterogeneous disease Blood eosinophil counts Inhaler cost Combination therapies Methodology of glucocorticoid withdrawal BMJ Open Respir Res Sep 8;3(1):e RED BOOK Online. Lancet Respir Med Jun;3(6): Lancet Respir Med May;4(5): Clin Drug Investig Oct;35(10): HOT TOPICS Lungs Liver Asthma exacerbations COPD Portal hypertension Joints Gout Blood Venous thromboembolism Anticoagulation in ESRD 9

10 LIVER portal hypertension inferior vena cava stomach liver portal vein kidney spleen Cardiac reserve RAAS activity Gut bacterial translocation Mortality Sympathetic nervous system activity Disease progression Early cirrhosis Decompensated cirrhosis End-stage cirrhosis Beta-blockers have no effect on survival, may adverse effects Start beta-blocker Beta-blockers improve survival by reducing variceal bleeding and gut bacterial translocation Stop beta-blocker Beta-blockers reduce survival due to negative impact on cardiac reserve RAAS = renin-angiotensinaldosterone system Gut Jul;61(7): Gut Jul;64(7): Ann Hepatol Mar-Apr;15(2): Hepatology Jun;63(6): Hepatology Sep;46(3): Hepatology Sep;52(3): Gastroenterology Jun;146(7): e1. 10

11 Patient Beta-blocker? Cirrhosis + no varices Cirrhosis + small varices + no bleed ± Cirrhosis + medium or large varices + no bleed X Hepatology Sep;46(3): Sersté et al. N = 151; duration = 8 months BBs vs no BBs risk of death patients with cirrhosis and refractory ascites BB = beta blocker Hepatology Sep;52(3): Mandorder et al. N = 607; duration = 8 months NSBBs vs no NSBBs transplant-free survival, risk for HRS and AKI patients with SBP AKI = acute kidney injury; HRS = hepatorenal syndrome; NSBB= nonselective beta blockers; SBP = spontaneous bacterial peritonitis Gastroenterology Jun;146(7): e1. 11

12 Leithead et al. N = 322; duration = 72 days NSBBs vs no NSBBs mortality NSBB= nonselective beta blockers patients with ascites and refractory ascites Gut Jul;64(7): Baveno VI Close monitoring needed dose or discontinue in patients who develop low blood pressure and impairment in renal function Ann Hepatol Mar-Apr;15(2): Hepatology Jun;63(6):

13 Bossen et al. Study Design Meta-analysis N = 1198; duration = 1 year Intervention NSBBs users NSBBs non-users Results No difference in all-cause mortality overall, in subgroup analysis of patients with refractory ascites, or relating to cirrhosis Comments Lack of information regarding presence of esophageal varices NSBB discontinuation rate: 29% NSBB = non-selective beta blocker Hepatology Jun;63(6): TAKE HOME Baseline characteristics Mean MELD score: 12, 68% Child-Pugh B Mean MAP: 84 mmhg Efficacy Not studied Safety No difference in mortality MELD = model for end-stage liver disease Hepatology Jun;63(6): LIVER portal hypertension Considerations Indication Safety Blood pressure Renal function Pleiotropic effects Hepatology Apr;37(4): Am J Gastroenterol Mar;107(3): Gastroenterology Dec;133(6): Liver Int Sep;29(8):

14 HOT TOPICS Lungs Liver Joints Asthma exacerbations COPD Portal hypertension Gout Blood Venous thromboembolism Anticoagulation in ESRD JOINTS gout Purine catabolism Hypoxanthine allopurinol Xanthine allopurinol Uric acid Int J Cardiol Jun 15;213:8-14. Ann Intern Med Jan 3;166(1): Ann Intern Med Jan 3;166(1): Ann Rheum Dis Mar 17. pii: annrheumdis Arthritis Care Res (Hoboken) Oct;64(10): Arthritis Care Res (Hoboken) Oct;64(10): Ann Rheum Dis Jan;76(1): Ann Rheum Dis Apr;76(4):

15 2012 ACR Guidelines and 2016 EULAR Guidelines Target serum urate level < 6 mg/dl (< 5 mg/dl in patients with severe gout) Ann Rheum Dis Jan;76(1): Ann Rheum Dis Apr;76(4): Arthritis Care Res (Hoboken) Oct;64(10): Arthritis Care Res (Hoboken) Oct;64(10): ACP Guidelines Evidence is insufficient for monitoring of serum urate levels in patients with gout Ann Intern Med Jan 3;166(1): Ann Intern Med Jan 3;166(1): Stamp et al. Study Design Randomized N = 183; duration = 12 months Intervention Allopurinol dose escalation until serum uric acid < 6 mg/dl Continuation of current dose Results Greater in serum uric acid percentage of individuals with serum uric acid < 6 mg /dl No difference in serious adverse events Comments Mean serum uric acid level: 7.2 mg/dl CrCl < 60 ml/min: 51.9% ; CrCl < 30 ml/min: 13.1% Asian ancestry: 5% Mean dose of allopurinol: 269 mg/day 390 mg/day Ann Rheum Dis Mar 17. pii: annrheumdis

16 TAKE HOME Baseline characteristics New Zealand European ethnicity: 42% CrCl < 60 ml/min Mean dose of allopurinol: 290 mg per day Efficacy Greater serum uric acid and achievement of serum uric acid < 6 mg/dl Safety Similar incidence of allopurinol-related rash Ann Rheum Dis Mar 17. pii: annrheumdis JOINTS gout Considerations Serum uric acid level Alternative options Am J Ther Nov-Dec;21(6): J Rheumatol Jun;36(6): Rev Med Chir Soc Med Nat Iasi Oct-Dec;118(4): HOT TOPICS Lungs Liver Asthma exacerbations COPD Portal hypertension Joints Gout Blood Venous thromboembolism Anticoagulation in ESRD 16

17 HEMATOLOGY venous thromboembolism DOAC VKA DOAC = direct oral anticoagulant; PK = pharmacokinetics; VKA = vitamin K antagonist Drugs. Sep ;72(13): N Engl J Med Oct 10;369(15): Circulation Feb 18;129(7): Chest Feb;141(2 Suppl):e419S-94S. Chest Feb;149(2): N Engl J Med Dec 10;361(24): N Engl J Med Dec 23;363(26): N Engl J Med Apr 5;366(14): N Engl J Med Aug 29;369(9): DOAC = direct oral anticoagulant; LMWH = low molecular weight heparin; VKA = vitamin K antagonist 2012 CHEST Guidelines VKA or LMWH over dabigatran or rivaroxaban 2016 CHEST Guidelines DOAC over VKA VKA over LMWH **patients without cancer Chest Feb;149(2): Chest Feb;141(2 Suppl):e419S-94S. 17

18 Drug Apixaban Dabigatran Edoxaban Rivaroxaban Standard Dosing VTE: 10 mg daily x 7 days, then 5 mg BID RR: 2.5 mg BID VTE: 150 mg BID RR: 150 mg BID VTE: 60 mg daily 60 kg: 30 mg daily VTE: 15 mg BID x 21 days, then 20 mg daily RR: 20 mg daily Renal Impairment Dosing CrCl < 15 ml/min: avoid CrCl 30 ml/min: avoid CrCl 15 to 50 ml/min: 30 mg daily CrCl < 15 ml/min: avoid CrCl < 30 ml/min: avoid RR = risk reduction; VTE = venous thromboembolism Hepatic Impairment Dosing Child-Pugh B: avoid Child-Pugh C: avoid None listed Child-Pugh B: avoid Child-Pugh C: avoid Child-Pugh B: avoid Child-Pugh C: avoid Edoxaban [package insert] Rivaroxaban [package insert] Apixaban [package insert] Dabigatran [package insert] On an Inappropriate Regimen Tellor et al. Rivaroxaban 12.4% Barra et al. Apixaban and rivaroxaban 100% Trujillo-Santos et al. Apixaban, dabigatran, and rivaroxaban Initial therapy: 50% on apixaban and 18% on rivaroxaban Long-term therapy: 36% on apixaban, 46% on dabigatran, and 14% on rivaroxaban Thromb Haemost Jan 26;117(2): J Clin Pharm Ther Aug;40(4): Am J Med Nov;129(11): Drug Trial Weight Categories Apixaban Dabigatran AMPLIFY RE-COVER I RECOVER-II 100 kg BMI > kg BMI 35 > 100 kg BMI > 35 Number of patients (%) 19 (522/2691) 13 (349/2691) 20 (502/2539) 12 (306/2539) 34 (438/1280) 24 (302/1280) Edoxaban HOKUSAI VTE > 100 kg 15 (611/4118) Rivaroxaban EINSTEIN DVT > 100 kg 14 (245/1731) EINSTEIN PE > 100 kg 14 (345/2419) EINSTEIN EXTENSION > 100 kg 14 (85/602) N Engl J Med Aug 29;369(9): N Engl J Med Oct 10;369(15): Circulation Feb 18;129(7): N Engl J Med Dec 10;361(24): N Engl J Med Dec 23;363(26): Expert Rev Cardiovasc Ther Jul;9(7): N Engl J Med Apr 5;366(14):

19 factor Xa chromophore factor Xa substrate color change cleaved substrate Circulation Jul 26;112(4):e Finnegan and Cusforth Study Design In vitro N = 88 Intervention UFH or LMWH Rivaroxaban or apixaban Results Anti-Xa ranges for rivaroxaban and apixaban > anti-xa ranges for UFH or LMWH Overlap of rivaroxaban or apixaban with UFH or LMWH additive effects Comments Ranges of anti-xa not provided LMWH = low molecular weight heparin; UFH = unfractionated heparin Am J Health Syst Pharm Dec 15;73(24): Abstract (A-195) presented at American Association for Clinical Chemistry 2015 Annual Meeting and Clinical Expo. Atlanta, GA; 2015 Jul HEMATOLOGY venous thromboembolism Effects of oral factor Xa inhibitors on anticoagulation monitoring assays Drug Apixaban Edoxaban Monitoring Assay AntiXa aptt PT Strong effect Strong effect Rivaroxaban Strong effect Little to no effect Minor to little or no effect Minor effect Minor to little or no effect Minor effect Moderate effect J Am Coll Cardiol Sep 16;64(11): Am J Health Syst Pharm Dec 15;73(24):

20 HEMATOLOGY venous thromboembolism 1. Determine time of last dose 2. Determine estimated half-life 3. Monitor via an aptt assay 4. Switch to anti-xa assay if desired Am J Health Syst Pharm Dec 15;73(24): Drug and Dose Apixaban BID Edoxaban Daily Rivaroxaban Daily CrCl (ml/min) > to 49 < 15 > to to 29 < 15 > to to 29 < 15 Estimated Half-life (hours) 7to 8 17 to 18 unknown 8 to 9 9 to unknown unknown J Thromb Thrombolysis Jan;41(1): HEMATOLOGY venous thromboembolism Considerations Indication Weight Monitoring Thromb Res Jul;136(1):

21 HEMATOLOGY anticoagulation in ESRD End-stage renal disease (ESRD) Necessitates initiation of renal replacement therapy Excluded from pivotal clinical trials kdoqi.org Drug Apixaban Dabigatran Edoxaban Rivaroxaban Apixaban [package insert] Dabigatran [package insert] Edoxaban [package insert] Rivaroxaban [package insert] Study Exclusion Criteria Atrial Fibrillation SCr > 2.5 mg/dl OR CrCl < 25 ml/min CrCl < 30 ml/min CrCl < 30 ml/min CrCl < 30 ml/min FDA-approved Renal Dosing 2.5 mg BID (2 x age 80 years, body weight 60 kg, or SCr 1.5 m g/dl) 75 mg BID (CrCl 15 to 30 ml/min) 30 mg daily (CrCl 15 to 50 ml/min) 15 mg (CrCl 30 to 50 ml/min) N Engl J Med Sep 17;361(12): N Engl J Med Sep 8;365(10): N Engl J Med Sep 15;365(11): N Engl J Med Nov 28;369(22): Drug Apixaban Dabigatran Edoxaban Rivaroxaban FDA-approved Study Exclusion Criteria Renal Dosing Venous Thromboembolism SCr > 2.5 mg/dl OR CrCl < 25 ml/min CrCl < 30 ml/min CrCl < 30 ml/min CrCl < 30 ml/min Avoid (CrCl < 15 ml/min) Avoid (CrCl 30 ml/min) 30 mg daily (CrCl 15 to 50 ml/min) Avoid (CrCl < 30 ml/min) Circulation Feb 18;129(7): Apixaban [package insert] Dabigatran [package insert] Edoxaban [package insert] Rivaroxaban [package insert] N Engl J Med Dec 10;361(24): N Engl J Med Dec 23;363(26): N Engl J Med Apr 5;366(14): N Engl J Med Aug 29;369(9): N Engl J Med Oct 10;369(15):

22 HEMATOLOGY anticoagulation in ESRD End-stage renal disease (ESRD) Necessitates initiation of renal replacement therapy Excluded from pivotal clinical trials Literature mainly focused on prevention of stroke in atrial fibrillation vs venous thromboembolism Chest Apr;149(4): Pharmacotherapy Apr;37(4): J Am Soc Nephrol Mar 16. pii: ASN Kidney Int Sep;80(6): Apixaban [package insert] J Clin Pharmacol May;56(5): KDIGO Guidelines Anticoagulation NOT recommendation for primary prevention Kidney Int Sep;80(6):

23 Dahal et al. Meta-analysis; N = 13 Warfarin for atrial fibrillation No difference in efficacy, risk of major bleeding Chest Apr;149(4): Apixaban [package insert] J Clin Pharmacol May;56(5): PK Fold Change and 90% CI Cmax AUC FDA-approval of apixaban for HD and Wang et al. No changes Based on PK and PD data following a single dose of apixaban 5mg HD = hemodialysis; PD = pharmacodynamics; PK = pharmacokinetic Apixaban [package insert] J Clin Pharmacol May;56(5):

24 Stanton et al. Study Design Retrospective, matched cohort N = 88 Intervention Apixaban Warfarin Results Major bleeding: apixaban 9.6%, warfarin 17.8% CRNM bleeding: apixaban 11.0%, warfarin 8.2% No difference in stroke or recurrent VTE Comments Included patients with CrCl < 25 ml/min or a SCr > 2.5 mg/dl, or receiving PD or HD (9.6% ESRD, 27.4% on dialysis) Appropriate dose by discharge: 80.8% CRNM = clinically relevant non-major); HD = hemodialysis; PD = peritoneal dialysis; VTE = venous thromboembolism Pharmacotherapy Apr;37(4): Mavrakanas et al. Study Design Retrospective, matched cohort N = 7 N = 5 Intervention Apixaban 2.5 mg BID x 8 days Apixaban 5 mg BID x 8 days Results Drug exposure for apixaban 2.5 mg BID in patients on HD comparable with that of 5 mg BID in patients with preserved renal function Minor bleeding event: 1 patient Comments Indication for anticoagulant: nonvalvular AF AF = atrial fibrillation; HD = hemodialysis J Am Soc Nephrol Mar 16. pii: ASN

25 TAKE HOME Baseline characteristics HD = hemodialysis ESRD on HD: 27.4% Nonvalvular atrial fibrillation: 72.6% (CHA2DS2VASC = 6) Concomitant antiplatelet agents: 57% Efficacy No difference in occurrence of stroke or recurrence venous thromboembolism Safety No difference in major bleeding or composite of bleeding J Am Soc Nephrol Mar 16. pii: ASN Pharmacotherapy Apr;37(4): HEMATOLOGY anticoagulation in ESRD Considerations Warfarin in ESRD Type of study clinicaltrials.gov Clin J Am Soc Nephrol Nov 7;11(11): Clin J Am Soc Nephrol Nov 7;11(11): CONCLUSIONS Lungs Liver Asthma exacerbations COPD Portal hypertension Joints Gout Blood Venous thromboembolism Anticoagulation in ESRD 25

26 QUESTIONS WHAT S NEW: HOT TOPICS IN INPATIENT INTERNAL MEDICINE Emmeline Tran, PharmD, BCPS Clinical Assistant Professor emmeline.tran@wsu.edu 26