8/3/2015

49th Annual Meeting Disclosure

I do not have a vested interest in or affiliation with

any corporate organization offering financial support
Hot Topics in Internal Medicine or grant monies for this continuing education activity,
or any affiliation with an organization whose
Denise Kelley, PharmD, BCPS
philosophy could potentially bias my presentation
Internal Medicine Pharmacist
UF Health Jacksonville

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 Liver

Renal
Compare and contrast latest literature
recommendations with present standards of care Infectious Disease

Incorporate current evidence-based Cardiology

recommendations into clinical practice
Anticoagulation

Liver Alcoholic Hepatitis Liver Alcoholic Hepatitis

Alcoholic Hepatitis (AH)
Controversial management Maddrey (1978): Reduced mortality
30-50% mortality Prednisolone Meta-analysis did not favor use
40 mg Qday* Reduced early mortality if MDF 32
Maddreys discriminant
function (MDF) Akriviadis (2000): Reduced mortality
Pentoxifylline
Reduced hepatorenal syndrome as
4.6 x (PT-control PT) + 400 mg TID* cause of death (50% vs. 92%)
bilirubin

Score 32 believed to COPE (2012): No survival benefit

Combination Mathurin (2013): No survival benefit
merit drug therapy
*Given for 28 days
Lucey MR, et al. N Engl J Med 2009;360:2758-69 Lucey MR, et al. N Engl J Med 2009;360:2758-69

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Liver Alcoholic Hepatitis Liver Alcoholic Hepatitis

Endpoints Pentoxifylline No Pentoxifylline p-value
Prednisolone or Pentoxifylline for Alcoholic Hepatitis - STOPAH
28-day mortality 85/518 (16%) 83/535 (16%) NS
90-day mortality 139/478 (29%) 146/490 (30%) NS
1103 patients
or transplant
1-year mortality 205/365 (56%) 216/382 (57%) NS
or transplant
Placebo Prednisolone Pentoxifylline Combination
(n=276) (n=277) (n=276) (n=274) 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
Primary outcome:
45/269 38/266
Mortality at50/258
28 days 35/260
or transplant
Secondary outcomes:
(17%) (14%) Mortality(19%)
or liver transplant
(13%) at 1-year mortality 210/371 (57%) 211/376 (56%) NS
or transplant
90 days, 1 year; adverse events
Thursz MR, et al. NEJM 2015;372:1619-28 Thursz MR, et al. NEJM 2015;372:1619-28

Liver Alcoholic Hepatitis Liver Beta-blocker therapy

Considerations: 1. Reduced
Statistical evaluation blood flow Compensatory
through liver Responses:
Incidence of infection and mortality
1. Increase
Exclusion criteria sympathetic
2. Portal vein response
hypertension 2. Increase renin-
Possible angiotensin-
short-term aldosterone
mortality Prednisolone No
system
mortality
benefit Pentoxifylline benefit
3. Mesenteric
3. May form
splanchnic collaterals
vasodilation
Thursz MR, et al. NEJM 2015;372:1619-28 Krag A, et al. Gut 2012;61(7):967-969

Liver Beta-blocker therapy Liver Beta-blocker therapy

Role of non-selective beta blocker (NSBB) in cirrhosis
Hemodynamic
Reduce sympathetic response
Decreases cardiac output
Splanchnic vasoconstriction
Prevent esophageal varices
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
Non-hemodynamic
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
Reduce bacterial translocation Evolving role of beta-blockers
Varying literature of beneficial or detrimental effect in the following:
hepatorenal syndrome (HRS)
spontaneous bacterial peritonitis (SBP)
Window hypothesis
Krag A, et al. Gut 2012;61(7):967-969 Ge PS, et al. Journ of Hepatol 2014; 60:643-653

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Liver Beta-blocker therapy Liver Beta-blocker therapy

Non Selective Beta-Blocker in Spontaneous Bacterial Peritonitis

Inclusion 607 patients with cirrhosis, undergoing first paracentesis

362 no NSBB, 245 NSBB
Primary Impact of NSBB on transplant-free survival
outcome Development of HRS
Secondary Rates of HRS, Rates of AKI, Hemodynamic parameters
outcomes
Hypothesis Development of SBP closes the window of opportunity for NSBB
treatment
No
Improve Reduce
effect on
survival survival
survival

Ge PS, et al. Journ of Hepatol 2014; 60:643-653 Mandorfer M, et al. Gastroenterol 2014;146:1680-1690

Liver Beta-blocker therapy Liver Beta-blocker therapy

Non Selective Beta-Blocker in Spontaneous Bacterial Peritonitis
Conclusions
Transplant Free Survival NSBB provides benefit up to development of SBP
mortality after SBP diagnosis in NSBB group
HR 1.644 (p=0.007) Worsened transplant-free survival in pts with SBP
SBP may close the therapeutic window of benefit
Acute Kidney Injury
incidence of AKI in NSBB group Considerations
(17/86, 20% vs. 7/90, 8%; p=0.021)
Limitations of study
Hepatorenal Syndrome
incidence of HRS in NSBB group
Management after SBP resolves
(20/83, 24% vs. 9/82, 11%; p=0.027)

Mandorfer M, et al. Gastroenterol 2014;146:1680-1690 Mandorfer M, et al. Gastroenterol 2014;146:1680-1690

News You Can Use Renal

Liver Progression to ESRD

Renal

Infectious Disease Bone/Mineral

disorders Anemia Acidosis
Cardiology

Anticoagulation
Phosphate binders Erythropoeitin Bicarbonate
Vitamin D products stimulating agents (ESA) supplementation
Calcimimetic Iron supplementation Resolves with dialysis

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Renal Renal Ferric Citrate

Iron 441 patients on dialysis

Ferric citrate
Phosphate Binders based
Ferric citrate 52 weeks Active control
Calcium Non
based elemental Primary outcome: safety, iron parameters
4 week washout period
Calcium acetate Sevelamer carbonate
Calcium carbonate Lanthanum carbonate 192 patients on dialysis re-randomized

Magnesium Aluminum Ferric citrate 4 weeks Placebo

Magnesium carbonate based based Aluminum hydroxide

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

Renal Ferric Citrate Renal Ferric Citrate

Well tolerated, minimal side effects FDA approved Fall 2014

Comparable to standard phosphorus binders 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 Considerations of iron supplementation
ESA dose (units/wk) 5303 (2023-9695) 6954 (2665-12,375) 0.04

Lewis JB, et al. J Am Soc Nephrol 2014;26 Lewis JB, et al. J Am Soc Nephrol 2014;26

Renal Vitamin D Renal Vitamin D

Benefits of Vitamin D
Maintain
skeletal health Vitamin D2
ergocalciferol
Pleiotropic
effects Liver Renal
25(OH)D 1,25(OH)2D
Immunomodulating, antitumor, renal protective, CV Vitamin D3
cholecalciferol

25-hydroxyvitamin D levels Interpretation

(ng/mL)
<20 Deficiency Inactive Vitamin D Vitamin D analogs Active Vitamin D
Ergocalciferol Doxercalciferol Calcitriol
20-29 Insufficiency
Cholecalciferol Paracalcitol
30 Sufficiency

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

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Renal Vitamin D Renal Vitamin D

Vitamin D3 vs. doxercalciferol

Dialysis Infection and Vitamin D in New England
105 dialysis patients with 25(OH)D 32 ng/mL
First randomized controlled trial in 2010, CKD stages 3-4
Vitamin D3 had greater impact on PTH levels in CKD stage 3
Ergocalciferol Ergocalciferol Placebo
25-OH supplementation in dialysis weekly monthly daily
(n=36) (n=33) (n=36)
Inconsistent effects of 25(OH)D supplementation
25(OH)D levels 30 associated with maximal PTH suppression
25(OH)D levels >32 ng/mL in 90.9%, 64.5%, 35.3%
Recommendations Similar rate of hospitalization, infection, CV events
No consensus from guidelines, clinical judgement
DIVINE and VITAL studies ongoing
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 Infectious Disease (ID)

850,000 hospital admissions
Liver
14.2 million outpatient visits
Clinda
Renal TMP/
SMX
Most common pathogens:
Infectious Disease Staphylococcus aureus Doxy
Cardiology Streptococcus pyogenes

Anticoagulation 2014 IDSA updated guidelines

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

Conclusions
524 patients with
cellulitis or abscess Similar cure rates
Similar adverse events

Clindamycin TMP/SMX
Considerations
10 days
300 mg TID duration 1 DS BID Dosing strategies
(n=264) (n=260)
Limitations to study
Exclusion criteria
Choosing an agent
Outcomes: Cure rates at 1-month follow-up, adverse events

Miller LG, et al. N Engl J Med 2015;372:1093-103 Miller LG, et al. N Engl J Med 2015;372:1093-103

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ID Probiotics ID Probiotics
Antibiotic associated diarrhea (AAD) common occurrence PLACIDE (2013)
15-39% caused by Clostridium difficile (CD) Inpatient adults 65 years randomized
Mechanism not fully elucidated Lactobacillus/bifidobacterium vs. placebo
-High-risk antibiotics Incidence of AAD within 8 wks, CD within 12 wks
-Cumulative antibiotic exposure
-Prolonged hospital stay, previous hospitalization Probiotic (n=1493) Placebo (n=1488)
-Age 65 years Incidence of AAD 159 (10.8%) 153 (10.4%)
-Proton pump inhibitor, nasogastric tube
Incidence of CD 12 (0.8%) 17 (1.2%)
-Antimicrobial stewardship No difference in side effects
-Infection control
-Probiotics? 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
Liver
Complexity of lactobacillus preparations
170 species, 17 subspecies Renal

Safety of probiotics Infectious Disease

Serious infections rare in literature, associated with Cardiology
severe comorbidities (malignancy, GI conditions)
Anticoagulation
Update in Clinical Infectious Diseases journal

Allen SJ, et al. Lancet 2013;382:1249-57

Cardiovascular (CV) CV DAPT

Dual antiplatelet therapy (DAPT) recommendations Benefit of dual antiplatelet therapy beyond 1 year
Bare metal: Continue for 1 month, ideally 1 year Randomization after drug eluting stent placed
Drug eluting: Continue for 3-6 months depending on
2004 type, up to 1 year if low risk of bleed
12 months 18 months 3 months
Bare metal: Continue for 1 month, ideally 1 year
Aspirin + Aspirin + placebo vs.
Drug eluting: Continue for at least 12 months Aspirin alone
2007 thienopyridine Aspirin + thienopyridine

Primary outcomes:
Bare metal: Continue for at least 12 months Stent thrombosis
Drug eluting: Continue for at least 12 months
2009 Major cardiovascular or cerebrovascular events
Kushner FG, et al. Circulation 2009;120:2271-2306 Mauri L. N Engl J Med 2014;371:2155-66

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CV DAPT CV DAPT

Results 12-month 30-month p-value Dual anti-platelet therapy

(n=4941) (n=5020) showed reduced events with
Stent thrombosis 65 (1.4%) 19 (0.4%) p<0.001 higher risk of bleed compared
Major events 285 (5.9%) 211 (4.3%) p<0.001 to aspirin alone
Increased bleeding in 30-month group
1.6% vs. 2.5%, p=0.001 Conclusions/Considerations
Higher all cause mortality in 30-month group Study population selected
1.5% vs. 2.0%, p=0.05 Duration of DAPT still in question
Increased events in 3-month observational group 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
Ticagrelor 90 mg BID Age >50 years, at least 1 major risk factor
All
patients Median follow-up duration 33 months
MI in last
received
1-3 Ticagrelor 60 mg BID Ticagrelor 90 mg Ticagrelor 60 mg Placebo
low- (n=7050) (n=7045) (n=7067)
years
dose
Composite 493 (7.85%) 487 (7.77%) 578 (9.04%)
aspirin endpoint
Placebo
Major bleeding 127 (2.60%) 115 (2.30%) 54 (1.06%)

Primary outcome: composite of cardiovascular death,

Fatal bleeding 32 (0.63%) 33 (0.71%) 30 (0.60%)
myocardial infarction (MI), stroke
Bonaca MP, et al. N Eng J Med 2015;372:1791-800 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 Aspirin Thienopyridine Anticoagulant
of CV death,
MI, or stroke
Aspirin/clopidogrel/warfarin vs.
WOEST clopidogrel/warfarin
Less bleeding, no increased stent thrombosis

Increased
risk of major PIONEER-AF DAPT vs. triple therapy with rivaroxaban
In progress - evaluating incidence of
bleeding PCI 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

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Anticoagulation Anticoagulation - Apixaban

Atrial fibrillation Renal DVT/PE Renal Apixaban dosing in hemodialysis (HD)
Dosing Dosing
Dabigatran 150 mg PO BID CrCl <30: Heparin x 5-10 days, CrCl <30:
8 patients with ESRD, 8 healthy individuals
(Pradaxa) 75 mg BID 150 mg PO BID Do not use 5 mg 5 mg
CrCl <15: HD 7-day washout HD
dose dose
Do not use
Rivaroxaban 20 mg PO Qday CrCl <50: 15 mg PO BID x 3 wk CrCl <30: Levels obtained up to 72 hours after each dose
(Xarelto) 15 mg Qday 20 mg PO Qday Do not use
CrCl <15:
Do not use % Drug recovered:
39% higher AUC in
Apixaban 5 mg PO BID 2.5 mg PO 10 mg PO BID x 1 wk CrCl <30: ESRD: 7% of dose
ESRD patients
(Eliquis) BID if >80 5 mg PO BID Do not use Healthy: 18% of dose
yrs, <60 kg,
or SCr >1.5* FDA approved dosing regimen for hemodialysis for AF
*Dose adjust if two of three criteria are met
Adam SS, et al. Ann Intern Med 2012;157:796-807 Wang X, et al. Clinical Pharm in Drug Dev 2012. [Abstract]

Anticoagulation Headlines
New developments/Future uses Liver
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
Renal
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 Headlines
Infectious Disease Anticoagulation
No difference between TMP/SMX or clindamycin for skin Apixaban has FDA approved dosing for atrial fibrillation
and soft tissue infections (SSTI) in ESRD patients based on small study population
Questionable benefit of probiotics in preventing Potential role of new anticoagulants in HIT
Clostridium difficile infections Rivaroxaban and apixaban are contraindicated with
protease inhibitors per HIV guidelines
Cardiovascular
Continuing DAPT beyond 12 months associated with
reduced CV events, increased bleeding
Literature surrounding triple therapy in the pipeline

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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 Infectious Diseases 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.
References
12. Wang X, et al. Presented at 2012 American College of Clinical Pharmacology Annual Meeting September 23rd25th 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