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10/19/2016
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Society of Hospital Medicine
October 29, 2016
Katie Harris, MD
Mike Farley, PharmD, BCPS
Cases in Hospital Medicine
Dr. Harris and Dr. Farley report no actual or potential conflicts of interest associated with this presentation.
Disclosure
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Discuss anticoagulant treatment options in the context of the management of hospitalized patients
Review hyperkalemia treatment options and formulate a treatment plan for a case scenario.
Evaluate asymptomatic hypertensive patients and discuss treatment options.
Discuss peri-procedure management of medications
Synthesize a case specific antimicrobial treatment plan that includes the transition from hospital to home.
Learning Objectives
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75 year old gentleman presents with “ICD firing” and dyspnea
PMH: Atrial fibrillation, HF with EF of 20%, s/p ICD and pacemaker placement, COPD (very severe)
Meds: Warfarin, Lisinopril, Carvedilol, Tiotropium, Albuterol, Furosemide, Spironolactone
Case 1
Physical exam:T 36.5 HR 82 RR 30() BP 100/68
O2 86%() on RA
CV: Irregularly irregular, no m/c/r, No JVD
Resp: Diffuse wheezes on inhalation and exhalation
Abd: Positive bowel sounds, NT, ND
Ext: No LEE, 2+ pulses
Case 1 (cont)
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Na 132 (), K 4.1, Cl 110, HCO3 28, BUN 30 ()
SCr 1.5 () (baseline 1.2), GFR 45 ()
Hb 12.5, WBC 4.5, Plt 322
INR 1.8 (goal 2-3)
CXR: No focal infiltrates, findings consistent with emphysematous changes
ICD interrogation reveals no shocks delivered
Imaging, Testing, and Labs
Treated for COPD exacerbation and improved, but needing home O2.
Discussed sub-therapeutic INR and he notes that he has a very hard time keeping his INR 2-3.
He notes that he would like to change his anti-coagulation regimen. Prefers once daily administration
Case 1 (cont)
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Dabigatran (Pradaxa)
Rivaroxaban (Xarelto)
Apixaban (Eliquis)
Edoxaban (Savaysa)
Which new oral anticoagulant (NOAC or DOAC) would you choose?
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Indications for Anticoagulants 2016VTE
PreventionVTE
Treatment
(↑ doses)
HIT Bridging A. Fib -
Long Term
ACS(Acute, in
addition to anti-platelet tx)
Heparin ✔ ✔ No ✔ ✔
Enoxaparin ✔ ✔ No ✔ ✔
Fondaparinux
✔ ✔ ✔ ✔
Warfarin ✔ ✔ ✔ϕ ✔*
Dabigatran ✔ ✔ ? ✔
Rivaroxaban ✔ ✔ ? ✔
Apixaban ✔ ✔ ? ✔
Edoxaban ✔ ? ✔
Bivalirudin ✔ ✔ ✔
Argatroban ✔ ✔
* Warfarin is only PO agent for mechanical heart valve anticoagulation ϕ Only when platelets >150K
Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban
Brand Name Coumadin Pradaxa Xarelto Eliquis Savaysa
Target Vit K Dependent Factors
Thrombin Factor Xa Factor Xa Factor Xa
Bioavailability 100% 7% 80% 60% 62%
Dosing OD BID OD (BID) BID OD
Time of peak effect
5‐7 days 1‐3 hours 2‐4 hours 1‐3 hours 1‐3 hours
Half‐life 40 hrs 14‐17 hrs 7‐11 hrs 8‐14 hrs 5‐11 hrs
Renal clearance
0% (unchanged)
80% 33‐66% 27% 35‐50%
Drug Interactions
Many P‐GP 3A4/P‐GP 3A4/P‐GP P‐GP
Cost (per month AWP)
$10‐$23 $260‐$420 $260‐$430 $300‐$430 $350
Yeh CH, Gross PL, Weitz JI. Evolving use of new oral anticoagulants for treatment of venous thromboembolism. Blood. 2014 Aug 14;124(7):1020-8, Lexi-Comp 2016 www.lexi.com
Direct Oral Anticoagulants (DOACs) and Warfarin
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0 4 8 12
Frydman AM et al. J Clin Pharmacol 1988; 28: 609‐18Rohde G. J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Sep 1;872(1‐2):43‐50
Enoxaparin vs DOAC (1st Dose)
Pla
sma
Con
cent
ratio
n
Time to peak effectEnox: 2-4 hoursRivaroxavan: 2-4 hrs
Half-lifeEnox: 5-8 hoursRivaroxavan: 7-12 hrs
I => Insurance covers new agents
and NO major drug Interactions (P‐GP, CYP3A4)
C => Patient is Compliant with meds
B => No history of serious Bleeding?
A => Age <80
R => Normal Renal function (CrCl >50)?
Is the patient an ideal candidate for a new anticoagulant? (IC BAR or CRABI)
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He was started on Rivaroxaban Dabigatran not used due to AKI and not the best for those
with CAD due to increased risk of MI compared to warfarin
Rivaroxaban is once daily dosing vs apixaban is twice daily
Edoxaban was not available
Three days later, presented with a near syncopal event. Found to have a large Pulmonary Embolism (PE)
thought to be due to his subtherapeutic INRs while on Warfarin
Case 1
Rivaroxaban, Apixaban No bridging required (onset similar to enoxaparin) Higher dose for first 21 days with Rivaroxaban
15mg PO BID x 21 days Then 20 mg daily
Higher dose for first 7 days with Apixaban 10mg PO BID x 7 days Then 5mg BID
Dabigatran, Edoxaban After 5‐10 days of parenteral anticoagulant
Not bridging, sequential treatment
A.Fib dosing
Non‐inferior vs. Warfarin in DVT and PE trials
DOAC Treatment of DVT & PE
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DOAC VTE Treatment Courses
5-10 days
Major and All-Cause Bleeding (VTE tx)
Hazard ratios (HR) for major bleeding or major plus clinically relevant non-major bleeding (CRNB) and their 95% confidence intervals (CI) in phase 3 trials comparing NOACs with conventional therapy for acute VTE treatment.
Yeh CH, Gross PL, Weitz JI. Evolving use of new oral anticoagulants for treatment of venous thromboembolism. Blood. 2014 Aug 14;124(7):1020-8.
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A. Fib vs VTE DOAC & Renal Function
TRADE
NAME
OK FOR CrCl >95
Normal Renal Fxn(50‐94 ml/min)
CrCl
30‐50
CrCl
15‐30
CrCl
<15
Rivaroxaban
AFIB
Xarelto YES 20 mg QD 15mg QD Ø
Rivaroxaban
‐VTE‐
Xarelto Yes 15mg BID x 21 days then 20mg daily Ø
Apixaban
AFIB
Eliquis YES 5‐2.5mg BID* Ø(SCr >2.5 or CrCl <25 ml/min
not studied)
Apixaban
‐VTE‐
Eliquis YES 10mg BID x 7 days then 5mg BID
Ø(SCr >2.5 or CrCl <25 ml/min
not studied)
* 5 mg twice daily unless patient has any 2 of the following: Age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL, then reduce dose to 2.5 mg twice daily
A. Fib vs VTE DOAC & Renal Function
TRADE
NAME
OK FOR CrCl >95
NORMAL DOSE
CrCl
30‐50
CrCl
15‐30
CrCl
<15
Dabigatran
AFIB
Pradaxa YES 150 mg BID 75mg BID
Ø
Dabigatran
‐VTE‐(after 5‐10 days of parenteral)
Pradaxa YES 150 mg BID Ø(CrCl < 30 ml/min
not studied)
Edoxaban
AFIB
Savaysa NO 60mg QD 30mg QD Ø
Edoxaban
‐VTE‐(after 5‐10 days of parenteral)
Savaysa Not stated (not rec)
60mg QD 30mg QD Ø
Note: Presence of p-glycoprotein inhibitors changes dosing or limits use
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One week later, presented with pulmonary hemorrhage
No reversal agent
Palliative care
Case 1 cont
N Engl J Med 2015; 373:511-520 August 2015.
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N Engl J Med 2015; 373:2413-2424. Dec. 2015
A 66 yo woman presents for her perioperative evaluation prior to undergoing a left total hip arthroplasty. She has a history of atrial fibrillation, stroke in 2014, HTN, T2DM, and hyperlipidemia
Medications: Warfarin, lisinopril, HCTZ, metformin, simvastatin, Aspirin
Case 2
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Yes, I recommend bridging with Enoxaparin (Lovenox).
Yes, I recommend bridging with a new oral anticoagulant.
No, I do not recommend bridging.
Her CHA2DS2-VASc score is 6 and CHADS2 score is 4. Do you recommend bridging her prior to the procedure?
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http://www.sparctool.com/
SPARC Tool
Risk Stratum Mechanical Heart Valve
Atrial fibrillation
VTE
High • Any mitral valve prosthesis
• Any caged-ball or tilting disc aortic valve prosthesis
• Recent (within 6 mo) stroke or TIA
• CHADS2 score of 5 or 6 or CHADS-Vascof >/=6
• Recent (w/i 3 mo) stroke or TIA
• Rheumatic valvular heart disease
• Recent (w/i 3 mo)VTE
• Severe thrombophilia (Protein C and S def, deficiency of antithrombin, antiphospholipid Ab, multiple abnls)
Moderate • Bileaflet aortic valve prosthesis and one or more RF: A fib, prior stroke or TIA, HTN, DM, CHF, age>75 yo
• CHADS2 score of 3 or 4 or CHADS-Vasc4-5
• VTE w/i past 3-12 mo
• Nonsevere thrombophilia (heterozgous Factor V leiden or prothrombin)
• Active cancer (treated w/i 6 mo or palliative)
• Recurrent VTE
Low • Bileaflet aortic valve prosthesis without a fib and no other RFfor stroke
• CHADS2 score of 0 to 2 (assuming no prior stroke or TIA) or CHADS-Vasc 2-3
• VTE>12 mo and no other risk factors
Table 1-Suggested Risk Stratification for Perioperative Thromboembolism (Chest 2012)
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Bridging recommended ONLY for VERY HIGH or HIGH risk patients CHADS2 score of 5-6 or CHADS-Vasc >/=6
Moderate risk patients-consider risk vs benefit Individual patient and surgery-related criteria
If patient is on Warfarin, bridging medication of choice is Enoxaparin (Lovenox)
Generally: Stop Warfarin 5 days prior to procedure
INR day prior to procedure to ensure </=1.5
Douketis JD et al. Perioperative management of patients who are receiving warfarin therapy: an evidence-based and practical approach. Blood. 2011; 117(19):5044.BRIDGE trial, ORBIT-AF and Dresden registries
Current Recommendations for Pre-Operative Bridging in A Fib
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Enoxaparin 1 mg/kg twice daily
Enoxaparin 40 mg twice daily
Enoxaparin 40 mg once daily
What dose of Enoxaparin do you use to bridge?
Data not available, so use clinical judgment
Therapeutic dose (Enoxaparin 1 mg/kg BID, 1.5 mg/kg daily)-
Arterial thromboembolic source (a fib, mechanical heart valve) or
VTE within 1 month
Intermediate dose (Enoxaparin 40 mg BID)- A fib or VTE within preceding month when bridging is needed, but
concerns for bleeding are greater
Prophylactic dose (Enoxaparin 40 mg daily)- Typically not used for bridging in A fib,
May be used in those with VTE event within past 2-3 months.
Bridging Doses
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Package insert recommends adjustment for CrCl < 30 ml/min
How do you handle borderline cases? (CrCl 37 ml/min?)
Any best practices within approved package insert options?
LMWH and Renal Adjustment
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Increased bleeding risk noted… (Arch Intern Med. 2012;172(22):1713-1718)
Those with moderate renal function (CrCl 30-50mg) had an increased rate of major bleeding 22% vs 5.7% in in 164 patients. Greater accumulation with no dose adjustment
Options to consider: 1.5mg/kg/QD vs 1mg/kg/BID (Thromb Res. 2005;116(1):41-50.)
100 kg patient 150 mg vs 200mg per day, less enoxaparin
Rounding down to next lowest via size 90 kg patient using 1mg/kg BID, use 80mg SQ BID instead of
100mg
Using a lower dose per kg after first dose (0.8 mg/kg)
Enoxaparin in CrCl 30-50 ml/min
Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016; 41: 165–186.
Start LMWH 3 days prior to surgery (2 days after stopping Warfarin)
Stop LMWH 24 hours prior to surgery If BID dosing-OMIT evening dose on the night prior to
surgery
If DAILY dosing-give ½ dose the morning prior to surgery
Bridging Timing
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Pre-procedural DOAC recommendations by major/minor sx
Daniels et al. BMJ 2015;351:h2391
Pre-procedural DOAC recommendations by major/minor sx
Nutescu et al. AJHP. Nov. 2013, Vol 70 1914-1929
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2 hours following surgery
12 hours following surgery
24 hours following surgery
48 hours following surgery
Following her total hip arthroplasty, when do you recommend restarting LMWH?
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It depends on…. Adequate hemostasis
Expected post-op bleeding
Surgical site
Generally-if you are using therapeutic doses, waiting over 24 hours is recommended
Discuss with surgeon!
Note: Generally safe to restart Warfarin the evening of surgery
Resumption of bridging anticoagulation
A 52 yo woman with history of HTN, DM, and osteoarthritis presents to the hospital with DVT and PE following an extended car trip.
Baseline labs were obtained in the ETC:
She is given lactated ringers for presumed pre-renal AKI and admitted to your hospital service
Lab Result Normal Range
Na 130 mEq/L 135-145
K 5.4 mEq/L 3.5-5.0
Cl 105 mEq/L 96-107
HCO3 24 mEq/L 21-28
BUN 35 mg/dL 10-20
SCr 2.5 mg/dL
(baseline 1) 0.5.-1.1
Case 3
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Hyponatremia
Hyperkalemia
Hyperchloridemia
What electrolyte abnormality will you be concerned about?
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Your patient does well overnight, but morning labs show:
You obtain an EKG and no peaked T waves are noted.
Case 3 continued
Lab Yesterday Today Normal Range
Na 130 mEq/L 135 mEq/L 135-145
K 5.4 mEq/L 6.0 mEq/L 3.5-5.0
Cl 105 mEq/L 108 mEq/L 96-107
HCO3 24 mEq/L 24 mEq/L 21-28
BUN 35 mg/dL 30 mg/dL 10-20
SCr 2.5 mg/dL
(baseline 1) 2.0 mg/dL
(baseline 1) 0.5.-1.1
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Insulin/D5
Albuterol
Kayexalate
Sodium Zirconium Cyclosillicate
Partiromir
Furosemide
What treatment would you administer to lower her potassium?
Rapid Acting, Transient: Stabilize cardiac membrane
Calcium Gluconate
Shift K into cells: Insulin and glucose Albuterol Sodium bicarb
Remove K Cation exchange resins (sodium polystyrene sulfonate-
Kayexalate) Loop or thiazide diuretic Lactulose/Cathartics (GI Loss) Hemodialysis
Hyperkalemia Treatment
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TRUE
or
FALSE
“Kayexalate efficacy in acutehyperkalemia has been proven in a large prospective trial”
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Introduced in 1950s, prior to modern FDA requirements efficacy (& safety) largely un-proven
Recent publications have questioned current use Efficacy data for acute use indicate similar simple laxative Usually infective in a single dose
Bowel Necrosis reports (with Sorbitol) New warnings added
Sorbital suspension use discouraged Avoid with lack of GI motility
Post-op, ileus, constipation, opiate or anti-cholinergic use
Potential that Katexalate binds oral drugs
Sodium Polystyrene Sulfonate (Kayexalate) controversy
Nephrol Dial Transplant. 2012 Dec;27(12):4294-7., Kidney Int. 2016 Mar;89(3):546-54.
Kayexalate controversy
Nephrol Dial Transplant. 2012 Dec;27(12):4294-7., Kidney Int. 2016 Mar;89(3):546-54.
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Nonabsorbable organic polymer, binds potassium in the colon in exchange for calcium 8.4 g PO once daily
FDA approved October 2015
NOT for emergency hyperkalemia treatment 0.5-1.0 meq/L serum K+ at 4 weeks in trials
Boxed warning:
Patiromer binds many orally administered medications -stagger 6 hours before or after other medications
Patiromir (Veltassa)
Veltassa (patiromer) [prescribing information]. Relypsa Inc; May 2016, N Engl J Med. 2015;372(3):211
Oral K+ binding agent (exchanges Na+ & H+ for K+) acute and long term use potential in hyperkalemia
Acute effects (at 48hrs) 0.5-0.7 mmol/L
Update: Rejected by FDA May 2016 Manufacturing failings
Still potential for re-submission of NDA at a later date.
N Engl J Med. 2015;372(3):222.
Sodium Zirconium Cyclosilicate (ZS-9)
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Despite hype, no great new agents for inpatient use.
Kayexalate is probably used too often Effectiveness questioned
More potential for harm that once thought
What to do? Consider greater diuretic (or lactulose) use when feasible
Avoid the “Kayexalate reflex”
Hyperkalemia Summary
A 58 year old gentleman with hypertension, hyperlipidemia, and T2DM presents with pancreatitis. He is held NPO except meds, given IV fluids, and pain medications. While hospitalized, he is noted to have increased BPs. He is continued on his home medications for hypertension (lisinopril, metoprolol).
On day 3, his BP is 190/90 and nursing calls for an order. He is asymptomatic.
Case 4
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IV hydralazine
IV labetalol
IV clonidine
No treatment
How do you respond to the nurse regarding the asymptomatic hypertension?
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Published data do not show improvement of short or long-term outcome with aggressive treatment of asymptomatic HTN
Lipari et al study from March 2016: Retrospective, pts receiving at least 1 dose of IV hydralazine,
enalaprilat, labetalol, metoprolol
Adverse outcome: >/=25% decrease in BP w/i 6 hrs
Lipari M et al. As-needed intravenous antihypertensive therapy and blood pressure control. J Hosp Med. 2016 Mar; 11(3)193-8.
Inpatient Asymptomatic HTN
Who Placed the Orders: Medical residents-49%, Attendings 16%, APPs 35%
Medications used: Hydralazine 80.1%, B-blockers 15.6%
Criteria: 84.5% has SBP threshold<180
Only 52% of pts had PO regimen intensified following IV administration
Adverse events: 32.6% Greater than 25% reduction of BP, 4.4% of hydralazine group had HR>20 bpm increase, 1 labetalol pt had bradycardia
Lipari M et al. As-needed intravenous antihypertensive therapy and blood pressure control. J Hosp Med. 2016 Mar; 11(3)193-8.
Analysis
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Lack of data to recommend IV anti-hypertensive medications in asymptomatic HTN
Even in HTN urgency, oral medication is preferred
Overzealous BP lowering can be devastating Induced hypotension leading to target-organ ischemia
Other considerations: IV meds much more costly than PO, increased monitoring when giving IV meds
Conclusions
75 YOF presents to hospital with femur fracture
Also complains of foul smelling urine with dysuria
Past medical history is significant for: COPD
Obesity (BMI 31)
Depression
Poor mobility s/p knee replacement
Allergies: Penicillin (Hives) and Macrobid (Anaphylactic)
Case 5
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UA + Leukocyte esterase +35 WBC/HPF + nitrites
WBC - 13.6 K
Afebrile
Scr - 1.1 (CrCl 34 ml/min)
Culture Results
ESCHERIA COLI >100,000 CFU/mL, ESBL confirmed R - Ampicillin R - Amp/Sulbactam S - Aztreonam S - Nitrofurantoin R - Cefazolin I - Ceftriaxone S - Cefepime S - Gentamicin R - Levofloxacin S - Ertapenem S - Meropenem R - Tetracycline R - Trimethoprim/Sulfa
ENTEROCOCCUS FAECIUM >10,000 but less than 100,000 CFU/mL R – Ampicillin S - Quinupristin/Dalfopristin S - Nitrofurantoin R – Vancomycin (VRE) S – Linezolid
Lab Results
What antibiotic regimen would you choose for UTI treatment?
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• Nitrofurantoin
• Linezolid and Ertapenem
• Fosfomycin
• Cefepime and Linezolid
• What antibiotic regimen would you choose for UTI treatment?
Discovered in 1969, Phosphonic acid antibiotic No other FDA approved medications in this class No Allergic cross-reactivity known
Fosfomycin inhibits synthesis of bacterial cell wall Inhibits enzyme enolpyruvyl transferase (unique MOA)
Limited rapid culture data available Disk diffusion testing CLSI approved for E. Coli, E. Faecalis
Limited systemic absorption FDA approved (1996) for uncomplicated UTI (3gm PO x 1, ~$50)
Not to be used for severe pyelonephritis/urosepsis.
Fosfomycin
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First line Agent for Uncomplicated Cystitis in IDSA Guideline (2011) Nitrofurantoin, TMP/SMX, Fosfomycin
Growing interest in use against organisms with significant resistance profiles: VRE
MRSA
ESBL E.Coli
Carbapenemase-producing Enterobacteriaceae
MDR Pseudomonas aeruginosa (variable activity)
Fosfomycin (cont.)
Clinical Infectious Diseases; 2011 ; 52:e103-e120, John Hopkins Antibiotic Guide 2016
IndicationDosing (US) Dosing (Other
countries)
Uncomplicated UTIFosfomycin tromethamine, 3 gm po x 1 dose
Same as USA
Complicated UTIFosfomycin tromethamine, 3 gm, po every 3 days x3 doses
Same as USA
ProstatitisFosfomycin tromethamine, 3 gm, po every 3 days x 7 doses
Same as USA
Systemic infection: Parenteral therapy. Often in combination.
Only via emergency single patient Investigational New Drug (IND) request(Supply from the FDA)
Fosfomycin disodium 6 gm IV q6h, infuse each dose over 2 hrs. Note: large sodium load
Fosfomycin (cont.)
Sanford Guide 2016 www.sanfordguide.com
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Questions?
