Hot Topics in Internal Medicine

49th Annual Meeting Disclosure Hot Topics in Internal Medicine Denise Kelley, PharmD, BCPS Internal Medicine Pharmacist UF Health Jacksonville I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation OWNING CHANGE: Taking Charge of Your Profession Objectives News You Can Use Identify and evaluate recent primary literature pertinent to the practice of Internal Medicine Compare and contrast latest literature recommendations with present standards of care Incorporate current evidence-based recommendations into clinical practice Cardiology Alcoholic Hepatitis Alcoholic Hepatitis Alcoholic Hepatitis (AH) Controversial management 30-50% mortality Maddrey s discriminant function (MDF) 4.6 x (PT-control PT) + bilirubin Prednisolone 40 mg Qday* Pentoxifylline 400 mg TID* Maddrey (1978): Reduced mortality Meta-analysis did not favor use Reduced early mortality if MDF 32 Akriviadis (2000): Reduced mortality Reduced hepatorenal syndrome as cause of death (50% vs. 92%) Score 32 believed to merit drug therapy Combination COPE (2012): No survival benefit Mathurin (2013): No survival benefit Lucey MR, et al. N Engl J Med 2009;360:2758-69 *Given for 28 days Lucey MR, et al. N Engl J Med 2009;360:2758-69 1

Alcoholic Hepatitis Prednisolone or Pentoxifylline for Alcoholic Hepatitis - STOPAH (n=276) Prednisolone (n=277) 1103 patients Pentoxifylline (n=276) Primary outcome: Mortality at 28 days 45/269 38/266 50/258 Combination (n=274) 35/260 (17%) Secondary outcomes: (14%) Mortality (19%) or liver transplant (13%) at 90 days, 1 year; adverse events Thursz MR, et al. NEJM 2015;372:1619-28 Alcoholic Hepatitis Endpoints Pentoxifylline No Pentoxifylline p-value 28-day mortality 85/518 (16%) 83/535 (16%) NS 90-day mortality 139/478 (29%) 146/490 (30%) NS or transplant 1-year mortality or transplant 205/365 (56%) 216/382 (57%) NS Endpoints Prednisolone No Prednisolone p-value 28-day mortality 73/526 (14%) 95/527 (18%) 0.056 90-day mortality 144/484 (30%) 141/484 (29%) NS or transplant 1-year mortality or transplant 210/371 (57%) 211/376 (56%) NS Thursz MR, et al. NEJM 2015;372:1619-28 Alcoholic Hepatitis Statistical evaluation Incidence of infection and mortality Exclusion criteria Possible short-term mortality benefit Prednisolone Considerations: Pentoxifylline No mortality benefit 1. Reduced blood flow through liver 2. Portal vein hypertension 3. Mesenteric splanchnic vasodilation Compensatory Responses: 1. Increase sympathetic response 2. Increase reninangiotensinaldosterone system 3. May form collaterals Thursz MR, et al. NEJM 2015;372:1619-28 Krag A, et al. Gut 2012;61(7):967-969 Role of non-selective beta blocker (NSBB) in cirrhosis Hemodynamic Reduce sympathetic response Decreases cardiac output Splanchnic vasoconstriction Prevent esophageal varices Non-hemodynamic Reduce bacterial translocation Krag A, et al. Gut 2012;61(7):967-969 Secondary prevention of esophageal varices Lebrec (1981): 96% in propranolol arm vs. 50% on placebo free of GIB at 1 year Targeted a 25% reduction in heart rate Primary prevention of esophageal varices Pascal (1987): 74% in propranolol arm free of GIB at 1 year vs. 39% in placebo Targeted a 20-25% reduction in heart rate Evolving role of beta-blockers Varying literature of beneficial or detrimental effect in the following: hepatorenal syndrome (HRS) spontaneous bacterial peritonitis (SBP) Window hypothesis Ge PS, et al. Journ of Hepatol 2014; 60:643-653 2

Non Selective Beta-Blocker in Spontaneous Bacterial Peritonitis Inclusion 607 patients with cirrhosis, undergoing first paracentesis 362 no NSBB, 245 NSBB Primary outcome Impact of NSBB on transplant-free survival Development of HRS Secondary outcomes Rates of HRS, Rates of AKI, Hemodynamic parameters No effect on survival Improve survival Reduce survival Hypothesis Development of SBP closes the window of opportunity for NSBB treatment Ge PS, et al. Journ of Hepatol 2014; 60:643-653 Mandorfer M, et al. Gastroenterol 2014;146:1680-1690 Non Selective Beta-Blocker in Spontaneous Bacterial Peritonitis Transplant Free Survival mortality after SBP diagnosis in NSBB group HR 1.644 (p=0.007) Acute Kidney Injury incidence of AKI in NSBB group (17/86, 20% vs. 7/90, 8%; p=0.021) Hepatorenal Syndrome incidence of HRS in NSBB group (20/83, 24% vs. 9/82, 11%; p=0.027) Conclusions NSBB provides benefit up to development of SBP Worsened transplant-free survival in pts with SBP SBP may close the therapeutic window of benefit Considerations Limitations of study Management after SBP resolves Mandorfer M, et al. Gastroenterol 2014;146:1680-1690 Mandorfer M, et al. Gastroenterol 2014;146:1680-1690 News You Can Use Progression to ESRD Cardiology Bone/Mineral disorders Anemia Acidosis Phosphate binders Vitamin D products Calcimimetic Erythropoeitin stimulating agents (ESA) Iron supplementation Bicarbonate supplementation Resolves with dialysis 3

Ferric Citrate Phosphate Binders Iron based Ferric citrate Ferric citrate 441 patients on dialysis 52 weeks Active control Calcium based Non elemental Primary outcome: safety, iron parameters Calcium acetate Calcium carbonate Sevelamer carbonate Lanthanum carbonate 4 week washout period 192 patients on dialysis re-randomized Magnesium carbonate Magnesium based Aluminum based Aluminum hydroxide Ferric citrate 4 weeks Primary outcome: mean change in phosphorus Lewis JB, et al. J Am Soc Nephrol 2014;26 Lewis JB, et al. J Am Soc Nephrol 2014;26 Ferric Citrate Ferric Citrate Well tolerated, minimal side effects Comparable to standard phosphorus binders FDA approved Fall 2014 Cost comparison Increased iron stores, reduced IV iron and ESA dosing Outcome Ferric citrate Active control p-value Ferritin (ng/ml) 858 (568-1105) 576 (333-883) <0.001 TSAT (%) 36.0 (27.5-47.0) 28.0 (21.0-34.5) <0.001 IV iron (mg/wk) 12.9 (1.0-28.9) 26.8 (13.4-47.6) <0.001 ESA dose (units/wk) 5303 (2023-9695) 6954 (2665-12,375) 0.04 Considerations of iron supplementation Lewis JB, et al. J Am Soc Nephrol 2014;26 Lewis JB, et al. J Am Soc Nephrol 2014;26 Vitamin D Vitamin D Benefits of Vitamin D Maintain skeletal health Pleiotropic effects Immunomodulating, antitumor, renal protective, CV Vitamin D2 ergocalciferol Vitamin D3 cholecalciferol 25(OH)D 1,25(OH) 2 D 25-hydroxyvitamin D levels Interpretation (ng/ml) <20 Deficiency 20-29 Insufficiency 30 Sufficiency Inactive Vitamin D Vitamin D analogs Active Vitamin D Ergocalciferol Doxercalciferol Calcitriol Cholecalciferol Paracalcitol Kramer H, et al. Am J Kidney Dis 2014;64(4):499-509 Kramer H, et al. Am J Kidney Dis 2014;64(4):499-509 4

Vitamin D Vitamin D3 vs. doxercalciferol First randomized controlled trial in 2010, CKD stages 3-4 Vitamin D3 had greater impact on PTH levels in CKD stage 3 25-OH supplementation in dialysis Inconsistent effects of 25(OH)D supplementation 25(OH)D levels 30 associated with maximal PTH suppression Recommendations No consensus from guidelines, clinical judgement DIVINE and VITAL studies ongoing Vitamin D Dialysis Infection and Vitamin D in New England 105 dialysis patients with 25(OH)D 32 ng/ml Ergocalciferol weekly (n=36) Ergocalciferol monthly (n=33) daily (n=36) 25(OH)D levels >32 ng/ml in 90.9%, 64.5%, 35.3% Similar rate of hospitalization, infection, CV events All-cause mortality lower in ergocalciferol arms (p=0.02) Kramer H, et al. Am J Kidney Dis 2014;64(4):499-509 Bhan I, et al. J Am Soc Nephrol 24: 2013 [Abstract] News You Can Use Cardiology (ID) 850,000 hospital admissions 14.2 million outpatient visits Most common pathogens: Staphylococcus aureus Streptococcus pyogenes 2014 IDSA updated guidelines TMP/ SMX Doxy Clinda Skin and soft tissue infections Miller LG, et al. N Engl J Med 2015;372:1093-103 ID Skin/Soft tissue ID Skin/Soft tissue Clindamycin 300 mg TID (n=264) 524 patients with cellulitis or abscess 10 days duration TMP/SMX 1 DS BID (n=260) Outcomes: Cure rates at 1-month follow-up, adverse events Conclusions Similar cure rates Similar adverse events Considerations Dosing strategies Limitations to study Exclusion criteria Choosing an agent Miller LG, et al. N Engl J Med 2015;372:1093-103 Miller LG, et al. N Engl J Med 2015;372:1093-103 5

ID Probiotics Antibiotic associated diarrhea (AAD) common occurrence 15-39% caused by Clostridium difficile (CD) Mechanism not fully elucidated -High-risk antibiotics -Cumulative antibiotic exposure -Prolonged hospital stay, previous hospitalization -Age 65 years -Proton pump inhibitor, nasogastric tube -Antimicrobial stewardship -Infection control -Probiotics? ID Probiotics PLACIDE (2013) Inpatient adults 65 years randomized Lactobacillus/bifidobacterium vs. placebo Incidence of AAD within 8 wks, CD within 12 wks Probiotic (n=1493) (n=1488) Incidence of AAD 159 (10.8%) 153 (10.4%) Incidence of CD 12 (0.8%) 17 (1.2%) No difference in side effects Insufficient evidence to support use of probiotic Allen SJ, et al. Lancet 2013;382:1249-57 Allen SJ, et al. Lancet 2013;382:1249-57 ID Probiotics News You Can Use Considerations of PLACIDE in clinical practice Complexity of lactobacillus preparations 170 species, 17 subspecies Safety of probiotics Serious infections rare in literature, associated with severe comorbidities (malignancy, GI conditions) Update in Clinical s journal Cardiology Allen SJ, et al. Lancet 2013;382:1249-57 Cardiovascular (CV) Dual antiplatelet therapy (DAPT) recommendations 2004 2007 2009 Bare metal: Continue for 1 month, ideally 1 year Drug eluting: Continue for 3-6 months depending on type, up to 1 year if low risk of bleed Bare metal: Continue for 1 month, ideally 1 year Drug eluting: Continue for at least 12 months Bare metal: Continue for at least 12 months Drug eluting: Continue for at least 12 months CV DAPT Benefit of dual antiplatelet therapy beyond 1 year Randomization after drug eluting stent placed 12 months 18 months 3 months Aspirin + thienopyridine Primary outcomes: Stent thrombosis Aspirin + placebo vs. Aspirin + thienopyridine Aspirin alone Major cardiovascular or cerebrovascular events Kushner FG, et al. Circulation 2009;120:2271-2306 Mauri L. N Engl J Med 2014;371:2155-66 6

CV DAPT CV DAPT Results 12-month (n=4941) Increased bleeding in 30-month group 1.6% vs. 2.5%, p=0.001 Higher all cause mortality in 30-month group 1.5% vs. 2.0%, p=0.05 30-month (n=5020) p-value Stent thrombosis 65 (1.4%) 19 (0.4%) p<0.001 Major events 285 (5.9%) 211 (4.3%) p<0.001 Increased events in 3-month observational group Dual anti-platelet therapy showed reduced events with higher risk of bleed compared to aspirin alone Conclusions/Considerations Study population selected Duration of DAPT still in question Choice of thienopyridine Mauri L. N Engl J Med 2014;371:2155-66 Mauri L. N Engl J Med 2014;371:2155-66 CV PEGASUS CV - PEGASUS Median time since MI 1.7 years MI in last 1-3 years Ticagrelor 90 mg BID Ticagrelor 60 mg BID All patients received lowdose aspirin Age >50 years, at least 1 major risk factor Median follow-up duration 33 months Ticagrelor 90 mg (n=7050) Ticagrelor 60 mg (n=7045) (n=7067) Composite 493 (7.85%) 487 (7.77%) 578 (9.04%) endpoint Major bleeding 127 (2.60%) 115 (2.30%) 54 (1.06%) Primary outcome: composite of cardiovascular death, myocardial infarction (MI), stroke Bonaca MP, et al. N Eng J Med 2015;372:1791-800 Fatal bleeding 32 (0.63%) 33 (0.71%) 30 (0.60%) Bonaca MP, et al. N Eng J Med 2015;372:1791-800 CV PEGASUS Cardiovascular Ticagrelor + low-dose aspirin >1 year after MI Reduced risk of CV death, MI, or stroke Aspirin Thienopyridine Anticoagulant WOEST Aspirin/clopidogrel/warfarin vs. clopidogrel/warfarin Less bleeding, no increased stent thrombosis Increased risk of major bleeding PIONEER-AF PCI DAPT vs. triple therapy with rivaroxaban In progress - evaluating incidence of bleeding and CV events Bonaca MP, et al. N Eng J Med 2015;372:1791-800 Dewilde WJ, et al. Lancet 2013;381:1107-15 Gibson CM, e al. Am Heart J 2015;169:472-478 7

- Apixaban Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Atrial fibrillation *Dose adjust if two of three criteria are met Dosing 150 mg PO BID CrCl <30: 75 mg BID CrCl <15: 20 mg PO Qday CrCl <50: 15 mg Qday CrCl <15: 5 mg PO BID 2.5 mg PO BID if >80 yrs, <60 kg, or SCr >1.5* DVT/PE Heparin x 5-10 days, 150 mg PO BID 15 mg PO BID x 3 wk 20 mg PO Qday 10 mg PO BID x 1 wk 5 mg PO BID Dosing CrCl <30: CrCl <30: CrCl <30: Adam SS, et al. Ann Intern Med 2012;157:796-807 Apixaban dosing in hemodialysis (HD) 8 patients with ESRD, 8 healthy individuals 5 mg dose HD 7-day washout HD 5 mg dose Levels obtained up to 72 hours after each dose % Drug recovered: ESRD: 7% of dose Healthy: 18% of dose 39% higher AUC in ESRD patients FDA approved dosing regimen for hemodialysis for AF Wang X, et al. Clinical Pharm in Drug Dev 2012. [Abstract] New developments/future uses Headlines In AH, no mortality benefit with pentoxifylline, possible short-term mortality benefit with prednisolone Beta-blocker in SBP could lead to increased development of HRS and increased mortality Newly approved ferric citrate is comparable phosphate binder while reducing iron and ESA requirements Inactive vitamin D should be utilized in ESRD patients for its nutritional efficacy benefit and mortality benefit Linkins LA, et al. J Thromb Thrombolysis 2014; 38:485-492 Gulick RM, et al. Dept of Health and Human Services 2015; 216 Headlines No difference between TMP/SMX or clindamycin for skin and soft tissue infections (SSTI) Questionable benefit of probiotics in preventing Clostridium difficile infections Cardiovascular Continuing DAPT beyond 12 months associated with reduced CV events, increased bleeding Literature surrounding triple therapy in the pipeline Headlines Apixaban has FDA approved dosing for atrial fibrillation in ESRD patients based on small study population Potential role of new anticoagulants in HIT Rivaroxaban and apixaban are contraindicated with protease inhibitors per HIV guidelines 8

References References 1. Lucey MR, Mathurin P, Morgan T. Alcoholic Hepatitis. N Engl J Med 2009;360:2758-69. 2. Thursz MR, Richardson P, Allison M, Austin A, et al. Prednisolone or Pentoxifylline for Alcoholic Hepatitis. N Engl J Med 2015;372:1619-28. 3. Krag A, Wiest R, Albillos A, Gluud LL. The Window Hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease. Gut 2012;61(7):967-969. 4. Ge PS, Runyon BA. The changing role of beta-blocker therapy with patients in cirrhosis. Journ of Hepatol 2014; 60:643-653. 5. Mandorfer M, Bota S, Schwabl P, Bucsics T, et al. Nonselective beta-blocker increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterol 2014;146:1680-1690. 6. Lewis JB, Sika M, Koury MJ, Chuang P, et al. Ferric Citrate Controls Phosphorus and Delivers Iron in Patients on Dialysis. J Am Soc Nephrol 2014;26. 7. Kramer H, Berns JS, Choi MJ, Martin K, et al. 25-Hydroxyvitamin D Testing and Supplementation in CKD: An NKF-KDOQI Controversies Report. Am J Kidney Dis 2014;64(4):499-509. 8. Miller LG, Daum RS, Creech CB, Young D, et al. Clindamycin versus trimethoprim-sulfamethoxazole for uncomplicated N Engl J Med 2015;372:1093-103. 9. Allen SJ, Wareham K, Wang D, Bradley C, et al. Lactobacilli and bifidobacterium in the prevention of antibiotic-associated diarrhea and clostridium difficile diarrhea in older inpatients: a randomized, double blind, placebo controlled, multicentre trial. Lancet 2013;382:1249-57. 10. Stevens DL, Bisno AL, Chambers HF, Dellinger EP, et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the s Society of America. Clin Infect Dis 2014; 1-43. 11. Evans C, Safdar N, Chopra T, Goldstein EJC, et al. Clin Infect Dis 2015;60(suppl 2):S66-S158. 12. Wang X, et al. Presented at 2012 American College of Clinical Pharmacology Annual Meeting September 23 rd 25 th San Diego, California. Clinical Pharm in Drug Dev, 1: 175. [Abstract]. 13. Kushner FG, Hand M, Smith SC, King SB, et al. 2009 Focused: ACC/AHA Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention. Circulation 2009;120:2271-2306. 14. Mauri L Kereiakes DJ, Yeh RW, Driscoll-Shempp P, et al. Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents. N Engl J Med 2014;371:2155-66. 15. Bonaca MP, Bhatt DL, Cohen M, Steg PG, et al. Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. N Eng J Med 2015;372:1791-800. 16. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation (RE-LY). N Engl J Med 2009; 361:1139-51. 17. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation (ROCKET AF). N Engl J Med 2011; 365:883-91. 18. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE). N Engl J Med 2011; 365:981-92. 19. Pradaxa (dabigatran) [package insert]. Boehringher Ingleheim, Ridgefield (CT): October 2010. 20. Xarelto (rivaroxaban) [Package Insert]. Janssen Pharmaceuticals, Titusville (NJ): December 2011. 21. Eliquis (apixaban) [Package Insert]. Bristol Myers Squibb, Princeton (NJ). December 2012. 22. Gulick RM, Hirsch MS, Lane HC, Pau AK, et al. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. 2015; 216. 23. Bhan I, Dobens DA, Trottier CA, Wenger JB, et al. The DIVINE Trial: Dialysis Infection and Vitamin D in New England. J Am Soc Nephrol 24:2013 [Abstract: SA-PO1082). 49th Annual Meeting Hot Topics in Internal Medicine Denise Kelley, PharmD, BCPS Internal Medicine Pharmacist UF Health Jacksonville OWNING CHANGE: Taking Charge of Your Profession 9