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GAMECHANGERS IN PHARMACY
SUNDAY/11:00AM-12:30PM
ACPE UAN: 0107-9999-18-270-L01-P 0.15 CEU/1.5 hr
0107-9999-18-270-L01-T 0.15 CEU/1.5 hr
Activity Type: Application-Based
Learning Objectives for Pharmacists & Pharmacy
Technicians:
Upon completion of this CPE activity participants should be able
to:
1. List selected Gamechangers that affect your practice.
2. Describe reasons the selected Gamechangers were chosen and
how they affect the way pharmacists care
for patients.
3. Describe possible solutions to the clinical problems
listed.
4. Assess the clinical trials used to support this
presentation.
5. Apply the information presented to your specific
practice.
Speaker: Geoffrey C. Wall, PharmD, FCP, BCPS, CGP
Dr. Geoffrey C. Wall is a Professor with the Department of
Clinical Sciences, College of Pharmacy
at Drake University and Director of the Drake Drug Information
Center. His clinical practices
include the Internal Medicine and Medical Intensive Care
Teaching Services at Iowa Methodist
Medical Center in Des Moines, IA. Dr. Wall received his Bachelor
of Science in Pharmacy from
the University of Utah in 1992 and his Doctor of Pharmacy from
Idaho State University in 1998.
He completed an ASHP-accredited Internal Medicine Specialty
Residency at Scott and White
Memorial Hospitals and Clinics in 1999. He is Board-Certified in
Pharmacotherapy and a
Certified Geriatric Pharmacist. He is a Fellow of the American
College of Clinical Pharmacy. Dr.
Wall has written a number of peer-reviewed papers and textbook
chapters on a variety of topics,
and has designed or participated in several clinical trials. His
research interests include drug
treatment of gastrointestinal disorders, clinical evaluation of
drug allergy and rheumatologic
disorders.
Speaker Disclosure: Geoffrey Wall reports that he is on the
speaker’s bureau with Boehringer Ingelheim,
Janssen and La Jolla Pharmaceuticals. Off-label use of
medications will be discussed during this presentation.
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Presented by:
Gamechangers in Pharmacy: 2018
Geoffrey C. Wall
Pharm.D., FCCP, BCPSProfessor of Pharmacy Practice, Drake
UniversityInternal Medicine Medical Center
Des Moines, IA
Disclosure
• Geoff Wall reports:• A Speaker’s bureau member for Janssen,
Boehringer Ingelheim, La Jolla Pharmaceuticals• Off-label use of
medication will be discussed during this presentation.
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Learning Objectives
• Upon successful completion of this activity, participants
should be able to:
1. List selected Gamechangers that affect your practice
2. Describe reasons the selected Gamechangers were chosen and
how they affect the way pharmacists care for patients
3. Describe possible solutions to the clinical problems
listed
4. Assess the clinical trials used to support this
presentation
5. Apply the information presented to your specific practice
What Are Gamechangers
• Facets of clinical medicine that directly impact the everyday
practice of the majority of “boots on the ground” pharmacists
• Some Gamechangers are specific to practice site• IV dug
shortages, oral blockbuster drug goes generic
• Others are more general in scope• Affordable Care Act changes,
landmark study published
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Examples of Gamechangers
• New, first-in-class drug released
• Vanguard or seminal study published
• Wide-impact practice guidelines
• Reported ADRs of widely used medications
• FDA regulations/warnings
• New or changing laws/policies
• Economic changes
Problem: How to determine a Gamechanger• Any one practitioner
will always have bias of putting weight on the
factors that influence THEIR practice
• May be unaware of a fundamental change in another area of
practice
• Evaluation of potential Gamechanger may be out of area of
expertise
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Solution: Gamechanger Panel
• Representatives from hospital, community, long-term care with
oversight by a pharmacist with expertise in regulatory affairs
• Independently select list of Gamechangers
• Meet and determine the top contenders via Modified Delphi
Method
• Peer-reviews presentation data
Gamechanger 2018 Panel Brian Benson, PharmD, FASHP
Exec. Director of Pharmacy, Unity Point Health Jennifer Moulton,
RPh
CEO, The Collaborative Education Institute Kristin Meyer,
PharmD
Clinical Pharmacist, Iowa Veterans Home Cheri Schmit, RPh
Director of Clinical Pharmacy, GRX Holdings
Sarah Derr, PharmD Director, Medication Safety and Efficacy,
Iowa Healthcare
Collaborative
Kristin Stover, PharmD Additional peer-review
Matt Pitlick, PharmD Executive Fellow, Iowa Pharmacy
Association
CS1
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Gamechanger Ground Rules
• This list was compiled by the Panel• Your Gamechanger may not
have been included
• Every effort made to be up-to date
• This presentation does not have “all the answers” in
controversial areas
• Not listed in perceived order of importance
Gamechanger #1
• The 2018 IDSA guidelines for Clostridium difficille disease• I
will avoid any poop jokes here…..
McDonald LC, et al. Clinical Infectious Diseases 2018; 66:
e1–e48.
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Why needed?
• Although, thanks to infection control measures, CDAD
infections have leveled off locally, such infections are still
common
• Associated with ABX use and recurrences
• Still has the potential to cause severe, even life-threatening
disease
• Multiple papers since the last guidelines had the potential to
change practice
How Developed
• How developed: Expert panel used a PICO format to answer
specific questions concerning CDAD. Then a systematic review was
performed and a standardized assessment of evidence was
completed.
• Level of evidence: Strong , Moderate, Low, Very low based on
strength of data and safety vs efficacy and cost
• It should be noted that many recommendations do not have
moderate-to-strong levels of guiding evidence
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Introduction
• Case definition: (1) the presence of diarrhea or evidence of
megacolon or severe ileus and (2) either a positive laboratory
diagnostic test result or evidence of pseudomembranes demonstrated
by endoscopy or histopathology
• Risk factors for severe disease: Elderly, IBD, Transplant,
Cancer, CKD/Dialysis
• ABX with highest association with CDAD:
third-/fourth-generation cephalosporins , fluoroquinolones,
carbapenems , and clindamycin
• Its worth noting that overall incidence rates of the above are
similar
Diagnosis and Prevention
• Diagnosis: Test if new-onset ≥3 unformed stools in 24 hours
(Weak Rec)
• Toxin A and B enzyme immunoassays (EIA) detects the actual
toxins and should be used in combination with another test like PCR
to improve sensitivity and specificity (Weak Rec)
• Remember Stool FA is PCR and does not detect toxin
• Do not perform repeat testing (within 7 days) during the same
episode of diarrhea and do not test stool from asymptomatic
patients, except for epidemiological studies ( >60% of patients
may remain C. difficile positive even after successful treatment)
(Strong Rec)
• Infection Control: Gowns and Gloves are a must. Continue
contact precautions for at least 48 hours after diarrhea has
resolved. Soap and water are preferred to alcohol based hand gels
(Weak Rec)
• But hand gels are better than nothing!
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ATLAS ScoreParameter 0 points 1 point 2 points
Age < 60 years 60 – 79 years ≥ 80 years
Treatment with systemic antibiotics during CDI therapy (≥
1 day)
No --------- Yes
Temperature ≤ 37.5°C 37.6 – 38.5°C ≥ 38.6°C
Leukocyte count (total)
< 16,000 16,000 –25,000
> 25,000
Albumin (serum)
> 35 g/L 26 – 35 g/L ≤ 25 g/L
Serum creatinine (as a measure of renal function)
≤ 120 μmol/L 121 –179 μmol/L
≥ 180 μmol/L
Miller et , al. BMC Infectious Diseases2013:148
https://doi.org/10.1186/1471-2334-13-148
Role of scoring systems?
• IDSA does NOT recommend any one severity scoring system and
instead bases treatment decisions on presence of hemodynamic
instability and recurrence
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Treatment• First episode: Vanco 125 po QID or fidaxomicin 200
mg
twice daily for 10 days (note metronidazole removal and no
recommendations concerning assessment of severity of disease)
(Strong Rec)
• Fulminant disease (hypotension or shock, ileus, or megacolon):
vancomycin 500 mg orally QID OR 500 mg in approximately 100 mL
normal saline per rectum every 6 hours as a retention enema + IV
metronidazole 500mg q8h (Strong Rec)
• First Recurrence: Pulsed Vancomycin (eg, 125 mg 4 times per
day for 10–14 days, 2 times per day for a week, once per day for a
week, and then every 2 or 3 days (over 6 weeks) OR Fidaxomicin x 10
days (Weak Rec)
• Metronidazole removed because of several studies showing
recurrence rates more common compared to PO vanco
Other Treatment Recommendations
• >1 Recurrence: FMT (Strong Rec) OR Tapered PO vanco ((eg,
125 mg 4 times per day for o 10–14 days, 2 times per day for a
week, once per day for a week, and o then every 2 or 3 days or po
vanco X 10 days followed by rifaximin 400 mg 3 times daily for 20
days or Fidaxomicin x 10 days (Weak Rec)
• No recommendation on prophylaxis in patients requiring other
ABX at high risk of recurrence of CDAD, but one study suggested
Vanco 125 po BID is reasonable
• No recommendations for probiotics for prevention or during
treatment of CDAD
• No recommendation for withholding PPIs during treatment, but
is probably reasonable unless patient has an absolute indication
for PPI use like a recent GIB. H2RAs can be substituted during CDAD
treatment
Van Hise HW, et al. Clin Infect Dis. 2016 Sep 1;63(5):651-3
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Some treatment pearls
• Remember COST!• PO vanco capsule cost is about $1000 for 14
days• A commercially available liquid was just given FDA
approval
• Why could this a problem??
• 10 days of fidaxomicin = $3000• Numerous patient assistance
programs exist from new manufacturer
• Chaser of Rifaximin = $1500• Most insurance companies will not
pay as this is not an approved indication
• Cost of FMT• $3000, but freeze-dried encapsulated stool may be
available this year…
• Cost of recurrence is about $15,000
While on the subject of ABX• FDA reinforces safety information
about serious
low blood sugar levels and mental health side effects with
fluoroquinolone antibiotics; requires label changes
• Strengthened warning about hypoglycemia—may be more common
then generally thought
• NEW warnings about CNS adverse effects• disorientation,
agitation, nervousness, memory impairment,
and delirium have all been reported
• TRY NOT TO USE THESE DRUGS FOR “COMMON” infections such as
sinusitits or uncomplicated UTIs if possible
• Should have come up with this warning 20 years ago…..
https://www.fda.gov/Drugs/DrugSafety/ucm611032.htm. Accessed
11/5/18
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Gamechanger #2
• Update of the use of aspirin to prevent vascular disease
events• After reading the studies you’ll need an aspirin for a
headache….
Total Cardiovascular Disease Death Rates by State, Age
Adjusted
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CVD and DM
• Risk of CV events is increased from 2- to 4-fold in type 2
diabetes1
• Aspirin is recommended for primary prevention in patients with
type 2 diabetes in many guidelines, including AHA2,3
• Previous aspirin primary prevention trials have had diabetic
subgroups but data were limited from European and North American
populations4,5 and nonexistent from Japan
1. Haffner SM, et al. N Engl J Med. 1998;339:229-234; 2.
American Diabetes Association. Diabetes Care. 2007;30(suppl
1):S4-S41; 3. AHA/ADA Scientific Statement. Circulation.
2007;115:114-126;4. Antithrombotic Trialists’ Collaboration. BMJ.
2002;324:71-86; 5. Sacco M, et al. Diabetes Care.
2003;26:3264-3272.
CVD and the Frail Elderly• The US Preventive Services Task Force
44 in 2016
noted that among individuals with a 10-year cardiovascular
disease risk of 10% or higher based on the ACC/AHA pooled cohort
equation, 3 the greatest benefit of aspirin was in those ages 50 to
59. In this age group, 225 nonfatal myocardial infarctions and 84
nonfatal strokes were prevented per 10,000 men treated, with a net
gain of 333 life-years. Similar findings were noted in women.
• However, in those ages 60 to 69, the risks of harm begin to
rise and the benefit of starting daily aspirin necessitates
individualized clinical decision-making, with particular attention
to bleeding risk and life expectancyOrakby AR, et al. Cleveland
Clinic Journal of Medicine. 2018; 85:55-64
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• Well established over dozens of studies• Myocardial infarction
[MI], stroke, and vascular death in patients
who have experienced an MI or a stroke. The absolute risk
reduction for treatment over 2 years is 36 ± 5 per 1,000 in
patients who have had an MI, 36 ± 6 per 1,000 in patients who have
had a stroke or transient ischemic attack
• But in PRIMARY prevention the data is much less clear the
benefit outweighs the risk—particularly of GI bleeding
• THREE new studies in the last year have clarified this
conundrum • In general patients with moderate CV risk factors• In
patients with DM• In patients over age 75
Secondary Prevention
Fanaroff AC et al. Int J Cardiol. 2017;241:87-96.
• R, DB, PC, international study, n = 12, 546
• Inc: Men age > 55, Women age> 60 + 3 CV risk factors:
HLP, HTN, Smoking, + FH
• COULD be on treatment for modifiable risk factors
• Exc: known vascular disease, including CV or stroke, CHF, or
high risk for bleeding, DM patients, on antiplatelet or
anticoagulants for another reason
• Intervention: ASA 100mg daily (EC) or matching placebo,
• Median follow-up: 60 months
• Outcomes:• Efficacy: composite outcome: MI, CVS, USA, CV
death,
TIA• Safety: Major bleeding by GUSTO criteria
The ARRIVE study
Gaziano JM, et al. Lancet 2018; 392: 1036–46
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Selected Baseline Characteristics
Aspirin (n=6270)
Placebo (n=6276)
% Male 70.5 70.4
% Smoker 28.8 28.5
SBP, Mean, mm Hg
145 145
Mean Framingham
Score
13.9 14.1
Outcomes
• No difference in any efficacy outcome
• NNH = 197
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The ASPREE Study• R, PC trial to determine if use of aspirin in
healthy, community-dwelling older
adults would prolong healthy life span, free from dementia and
persistent physical disability
• INC: Australia and the U.S. patients > age 70 (or ≥65 years
of age among blacks and Hispanics in U.S. arm) WITHOUT dementia or
serious physical disability
• EXC: known diseases that would limit life span to < 5
years, known CV disease of stroke history
• Intervention: ASA 100mg daily or placebo
• Trial ended at average 4.7 years follow-up, n = 19,114
• Outcomes: • Efficacy: disability-free survival, death from any
cause• Safety: Major bleed
• Stratified numerous ways, including age and weight
McNeil JJ, et al. N Engl J Med 2018;379:1499-508.
Selected Baseline Characteristics
Aspirin (n=6270)
Placebo (n=6276)
% Male 43.6 43.6
Age 74 or >, mean, yrs
50.5 49.7
HTN % 74.2 74.5
BMI, mean 28.1 28.1
% Frail 58.8 58.8
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Outcomes
• No difference in primary outcome or any secondary outcome
• Incidence of major bleed 3.8% vs 2.8% (p < 0.001), NNH =
100
• No difference in death from any cause
• R, DB, PC, U.K. study, n = 15, 480
• Inc: Any patient with DM over age 40 without known CV disease
who did not have another indication for antiplatelet or
anticoagulant therapy
• Exc: Likely to not complete a 5 year study, C/I to ASA
• Intervention: ASA 100mg daily (EC) or matching placebo
• 2X2 factoral design also look at omega-3 fatty acids
• Median follow-up: 7.4 years
• Outcomes:• Efficacy: 1st serious vascular event, which was
defined as a
composite of MI, CVA, Death from vascular cause, TIA• Safety:
Major bleeding
The Ascend study
Bowman L, et al N Engl J Med 2018;379:1529-39.
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Selected Baseline Characteristics
Aspirin (n=7740)
Placebo (n=7740)
% Male 62.6 62.5
Age, yr, mean 63.2 63.3
BMI, Mean 30.8 30.6
Statin Use, % 75.6 74.9
Outcomes
ASA reduced vascular events by 12% but increased risk for major
bleed by 29%NNT = 91, NNH = 111
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And while we are on the subject….• Is body weight a factor in
ASA effectiveness?
• Recent patient data level review of several studies looking at
ASA use in primary prevention
• Trials were eligible if they randomly assigned > 1000
participants to daily or alternate-day aspirin versus no
aspirin
• Patient level data extracts from original databases• Results:
Found that low dose ASA was effective only in patients up to 70
kg (p-interaction=0·0072), while higher dose (325mg+) was
effective only in patients above 70 kg (p-interaction=0·0072)
• Explanation of these findings is largely unknown as
antiplatelet effects of ASA occur at low doses
• I WOULD NOT SWITCH OBESE PTS TO HIGH DOSE ASA BASED ON THIS
INFORMATION
Rothwell, PM et al. Lancet 2018; 392: 387–99
So what does it all mean?
• Secondary prevention with ASA is still unequivocally
beneficial • BUT• Million of primary prevention patients take ASA
for “heart health” that
are gaining no benefit and perhaps harm by doing so
• Pharmacist’s role:• Ask patients about their CV risk before
recommending ASA to all older
patients
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Gamechanger #3
• Legislative Update (Iowa)
• Big changes from the statehouse
Technician Role
• ARC4030C
• Proposed law allowing technicians to transfer
noncontrolledprescriptions and receive transfers of noncontrolled
prescriptions
• Proposed law allowing technicians to dispense medications to
patients that do not need counseling while a pharmacist is on a
“break of limited duration”
• All at the discretion of the pharmacist on duty
CS2CS4
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Expanded Tech Roles
• Usually requires additional:• Experience• Education• Training•
Competencies (including analytical and problem-solving skills)
• Certification• Competence Assessment• Supervision of
pharmacists• State Board of Pharmacy approval• Liability issues??•
Pharmacist resistance??
CS3CS5
What do you Value?
• Statement 1: We need a competent and capable technician
workforce to allow pharmacists to perform patient care
activities
• Statement 2: If techs can dispense, I will be out of a job
• Statement 3:??
CS10
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Pharmacy-Interns
• ARC4091C
• Proposed amendment that removes limitation of number of
interns being supervised under one pharmacist concurrently
Naloxone
• Pharmacists must complete at least 1-hour of ACPE-approved CE
related to naloxone prior to dispensing naloxone
• Prior to dispensing naloxone pursuant to the statewide
protocol, provide training and education to the patient
• Written materials shall not be in lieu of direct pharmacist
consultation with the patient
• After, the pharmacist shall notify the patient’s primary
health care provider of the transaction
• If the patient does not have a primary health care provider,
the authorized pharmacist will provide a written record of the
naloxone provided to the patient and advise the patient to consult
a physician
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Naloxone Formulations AvailableProduct Route of
Adminis-tration
AvailableStrengths
Dosing Advantage Price per Dose*(7/2015)
FDA Status
Auto-injector
IM 0.4mg/ml 0.4mg No training requiredEasy to useNo
assemblyDecreased risk of needle stick
$345 Yes
Multi-useVial
IM, IV, SC 0.4mg/ml 0.4mg Multiple doses $11.84 Yes
Single Dose Vial
IM, IV, SC 0.4mg/ml 0.4mg Individual dose $18.99 Yes
Prefilled Syringe
Intranasal 1mg/ml 1mg Easy to useDecreased risk of needle
stick
$19.80 Yes
Tobacco Cessation• Pharmacists must complete at least 1-hour of
ACPE-
approved CE related to nicotine replacement tobacco cessation
product utilization
• Prior to dispensing tobacco cessation products pursuant to the
statewide protocol, provide training and education to the
patient
• After, the pharmacist shall notify the patient’s primary
health care provider of the transaction
• If the patient does not have a primary health care provider,
the authorized pharmacist will provide a written record of the
naloxone provided to the patient and advise the patient to consult
a physician
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Cannabis
• 5 dispensaries in Iowa opening Dec. 1st
• ARC4085C• Approved 10/3/18
• Any drugs approved by the FDA which contain cannabidiol (CBD)
derived from cannabis and no more than 0.1 percent
tetrahydrocannabinols (THC) are placed into Schedule V Controlled
Substances
• Physician must fill out application form and certify that
patient is suffering from a ‘debilitating condition’
• Medical cannabis card is valid for 1 year from approval date
and may be cancelled at any time
Cannabis Cont.• Patients may NOT smoke medical cannabidiol
or
consume ‘edibles’• Tablet, Capsule, Liquid, Tincture,
Sublingual, Topical forms,
Nebulizable inhaled forms, rectal/vaginal forms
• 90-day supply max of each product, as determined by dispensary
staff/manufacturers/literature
• No physicians or pharmacists on staff
• Manufacturers are required to collect and dispose of excess
cannabidiol from dispensaries, including medical cannabidiol that
was returned to a dispensary from a patient or primary
caregiver
• Provider FAQ•
https://www.legis.iowa.gov/docs/iac/chapter/641.154.pdf
CS6
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Gamechanger #4
• 2018 ADA/EASD Guidelines for the treatment of DM 2
• Improved macrovascular outcomes—but at a cost??
Mohamed S, et al. JAMA. 2017;318:132-145.
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Can DM drugs by themselves reduce CV risk? Apparently Yes•
FDA-approved for reduced CV risk
• SGLT-2 inhibitors• Empagliflozin (Jardiance)• Canagliflozin
(Invokana)
• GLP-1 agonists• Liraglutide (Victoza)
? Class effect
Literature Review
• What’s the evidence?• Canagliflozin (CANVAS trial 2017)
• Included 10,142 participants with DMII• 30 years old w/ ASCVD•
50 years old with two + CV risk factors (see below)• Randomized to
300mg daily, 100mg daily, or placebo
• Results• Reduced combined risk of MI, stroke, and CV death by
14%
• (hazard ratio [HR], 0.86; 95% CI, 0.75 - 0.97; P < .0001
for noninferiority, P = .0158 for superiority).
• Patients with CVD risk reduction =18% • (HR, 0.82; 95% CI,
0.72 - 0.95)).
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Literature Review
• What’s the evidence (cont.)• Empagliflozin (EMPA-REG 2015)
• Enrolled 7,020 patients with DMII• Patients were 18 years +•
BMI < 45• GFR > 30 mL/min/1.73m2
• Randomized to Empagliflozin 20mg, 10mg, or placebo
• Results• Reduced risk of death from MI or CV causes by 13%
• (HR 0.86; 95.02% confidence interval [CI], 0.74 to 0.99; P
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Considerations
• SGLT-2 Inhibitors• FDA Black Box: Increased risk of
amputation
• Well noted HR 1.98 in CANVAS trial
• Renal insufficiency• CrCl < 30 mL/min use is
contraindicated
• GLP-1 Agonists• FDA Black Box: Increased risks of thyroid
cancer
• Avoid use in patients with personal/family hx of thyroid
cancer
Considerations
• Some drugs may worsen CV outcomes
• 2nd Generation Sulfonylureas• FDA warning of worsened CV
outcomes based on studies with Tolbutamide
• Thiazolidenones• FDA Black Box: Increased risk of HF
• Both Pioglitazone (Actos) and Rosiglitazone (Avandia)
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Medication/Class Impact on CV Outcomes
Recs for Use in DM2 patients with
CVD
Insulin Neutral Use if failed 2+ therapies or
diagnosis A1C ≥ 10%
Metformin ↓ MI risk First line therapy
Sulfonylureas Overall neutral, may ↑risk of MI
Use if other therapies cost
prohibitive
GLP-1 Liraglu de ↓CVD, others neutral
Consider liraglutideearly, esp in obese
patients
DPP-IV Saxagliptin ↑ HF others neutral
Avoid saxagliptin in HF
SGLT2 Class ↓ CVD, CV death, ACM
Consider early in these patients
Recommendations
Gale SE, et al. Pharmacotherapy 2018;38:739-57
Gamechanger #5
• The Updated Beer’s Criteria 2018
• No, not that kind of beer’s list
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Introduction
• What is the Beers Criteria (aka the Beers List)???
• List of POTENTIALLY inappropriate medications for use in older
adults
• Published by the American Geriatrics Society
• Originally created in 1991 by the late geriatrician, Mark
Beers, MD
History of the Beer’s List• Beers Criteria: History and
Utilization
• Original 1991 – Nursing home patients
• Updates• 1997 All older adults; adopted by CMS in 1999 for
nursing home regulation• 2003 Era of generalization to Med D, NCQA,
Healthcare• Effectiveness Data and Information Set (HEDIS)• 2012
Further adoption into quality measures• 2015 Introduction of
drug‐drug interactions (DDI), renal dosage tables, how to
use, and alternatives papers• 2018: Updated list completed
Marcum ZA, et al. Am J Geriatr Pharmacother.
2012;10:151–159.
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Key Changes to Beer’s 2018*
• Glimepiride – sulfonylureas to avoid• Try to avoid SU in the
elderly if possible*
• SNRIs – avoid in patients with history of falls or Fractures•
One study found increased risk of both compared to other
antidepressants*
• ASA for primary prevention of CV disease – age to use with
caution lowered to >70 yrs
• See previous Gamechanger*
• Rivaroxaban for treatment of VTE or a fib in adults >75
yrs• GI bleeding increased compared to warfarin & other
NOACs
• DPP‐4 inhibitors in patients with heart failure • Tramadol
added to drugs associated with SIADH or hyponatremia
Key Changes to Beer’s 2018
• Cotrimoxazole (trimethoprim-sulfamethoxazole)• Increased risk
of hyperkalemia in pts Drug Interactions
• Additions:• Opioids + benzodiazepines• Opioids +
gabapentinoids• Some antibiotic interactions• Concomitant drugs
that can increase potassium• Modification:
• Simplified CNS depressant interactions• Avoid 3 or more
concomitantly
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Gabapentanoids and ADRs
• Pregabalin and the Risk for Opioid‐Related Death
• Design: Nested case–control study
• Sample: 1417 cases with fatal opioid overdose matched with
5097 controls (median age 48) •
• Results: Any recent pregabalin use increased the risk of
overdose• Adj. OR 1.68; (95% CI, 1.19 to 2.36)
• Those taking > 300mg/d of pregabalin had higher risk• Adj.
OR, 2.51; (95% CI 1.24‐5.06)
Gomes T, et al. Ann Int Med 2018; DOI: 10.7326/M18‐1136
Dosing of Gabapentin/Pregabalin in the elderlyGabapentinoid
Renal Dosing
Drug est CrCl (ml/min) Max. Dosage (mg)
Gabapentin 30‐59 600 bid
15‐29 300 bid
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“Start Low and Go Slow…”• Start one medication at a time.
• Start with a low dose and increase gradually.
• Once daily is usually best.
• Monitor for response and adverse effects.
• Assess adherence with regimen.
“…But, Go All The Way!”• Be conservative, but don’t miss the
target!
• What is your goal? Are you achieving it?
• Can you keep increasing the dose or are you limited by side
effects?
• Are you observing a clinical benefit at lower doses?
• Consider stopping if you can’t “go all the way” and the
benefit is not clear.
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“Deprescribing”
“Systematic process of identifying and discontinuing drugs in
instances in which
existing or potential harms outweigh existing or potential
benefits within the
context of an individual patient’s care goals, current level of
functioning, life
expectancy, values, and preferences.”
JAMA Intern Med. 2015;175(5):827-834
“Deprescribing” Should Be Considered
• New symptom or clinical syndrome suggestive of ADE
• Advanced disease, terminal illness, extreme frailty
• High-risk drugs or combinations
• Preventive drugs for scenarios associated with no increased
risk despite stopping drug
• Stopping alendronate after 5 years of treatment results•
Stopping statins for primary prevention
• Patient/family willing to participate in shared decision
JAMA Intern Med. 2015;175(5):827-834
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“Deprescribing”• Instruct patient to bring all medications to
visit
(prescription and non-prescription)
• What Are Current Indications for Each Drug?
• Is the Patient Actually Taking the Drug?
• Does the Likely Benefit of the Drug Outweigh Its Potential for
Harm?
• This is where looking at the Beers Criteria can have the most
clinical impact
• Time to benefit for preventive medications
JAMA Intern Med. 2015;175(5):827-834
Gamechanger #6
• The 2018 CHEST guidelines on antithrombotic therapy in atrial
fibrillation
More Choices = More problems??
Liip GYH, et al. CHEST 2018; 154:1121-1201
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Background
• In the “old days” the CHEST guidelines were a tome released
published every 3-4 years
• The “bible” of antithrombotic therapy
• Now, like other medicine groups periodic guidelines are
released more frequently
• NEW guidelines in AF needed because of the NOACs and data
surrounding their use
• Note that the rate of AF is tied to an aging population so
incidence of AF is expected to dramatically increase
• Focused only on antithrombotic therapy in AF
Methodology
• Designed in a Clinical Question/Answer format
• Evidence-Based results is the highest priority
• In depth process for procuring/analyzing data
• “Consensus” recommendations given lower priority
• Systematic reviews/meta-analyses included
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Recommendation Grading
• Overall Recommendations• Grade 1 = Benefits clearly outweigh
risks, strongest recommendation• Grade 2 = Less clear risk/benefit
ratio
• Methodologic Quality• Grade A = RCTs with clear results• Grade
B = RCTs with inconsistent results, or poor quality• Grade C =
Observational studies, other data
• Grades combined in final score
Key recommendations for Pharmacists
• 1- Use the CHADS2Vasc Score AS WELL as the HAS-BLED scoring
systems to assess benefit and risk of antithrombotic therapy
(strong, mod)
• “A high HAS-BLED score (> 3) is rarely a reason to avoid
anticoagulation” but warrants closer follow-up
• 2-Do NOT use ASA or ASA + Clopidogrel for stroke prevention in
AF (Strong, Mod)
• WHY? Only the SPAF-1 study suggested ASA is beneficial for AF
no other subsequent study has been able to demonstrate this AND
risk for bleeding—especially ICH—is nearly as high with ASA as with
warfarin
Lancet. 2006;367(9526):1903-1912.Circulation.
1991;84(2):527-539.
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Key recommendations for Pharmacists
• 3-NOACs are now PREFERRED over warfarin for AF (Strong,
Mod)
• Generally all of these drugs have been found to be at least as
efficacious as warfarin and generally safer—especially in ICH
• 4-In patients on warfarin a TTR of > 70% should be
targeted, (Consensus only)
• If cannot maintain this, switch to NOAC if possible
• 5-In AF patients in which aspirin is concomitantly used with
antithrombotic therapy use baby ASA + a PPI to minimize gastropathy
(Weak, low)
• In stable CVD a patient started on antithrombotic therapy can
OMIT ASA—no extra benefit and increased risk for bleeding
Circulation. 2014;129:1577-1585
Key recommendations for Pharmacists
• 3-NOACs are now PREFERRED over warfarin for AF (Strong,
Mod)
• Generally all of these drugs have been found to be at least as
efficacious as warfarin and generally safer—especially in ICH
• 4-In patients on warfarin a TTR of > 70% should be
targeted, (Consensus only)
• If cannot maintain this, switch to NOAC if possible
• 5-In AF patients in which aspirin is concomitantly used with
antithrombotic therapy use baby ASA + a PPI to minimize gastropathy
(Weak, low)
• In stable CVD a patient started on antithrombotic therapy can
OMIT ASA—no extra benefit and increased risk for bleeding
Circulation. 2014;129:1577-1585
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Key recommendations for Pharmacists
• 6-In AF patients after acute ischemic stroke, start
anticoagulation within 2 weeks of even—but exact time unknown
(consensus)
• 7-In patients with Chronic Kidney Disease• Stage III (CrCl
30-59 mL/min), Warfarin or label adjusted
NOAC can be used • Stage IV (CrCl 15-30 mL/Min) Warfarin or
selected NOACs:
rivaroxaban 15 mg QD, apixaban 2.5 mg bid, edoxaban 30 mg QD,
dabigatran 75 mg bid) can be used
• Stage V (CrCl < 15 mL/min or dialysis) warfarin is
preferred (all low (all recs, weak, very Low)
Bottom line
• New CHEST guidelines on antithrombotic therapy is out—all 1200
pages of it!
• If you work with these patients at least being familiar with
the summary document is important
• Not everyone is on board with these guidelines---but they will
almost certainly become the standard by which treatment is
determined in this area of medicine
• If you work in anticoagulation management, brew a lot of
coffee and get ready to read….
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Gamechanger #7
• Drug Pricing update: CIVIA, Hyperinflation and “brown bagging”
it
What Is Brown or White bagging?• “White bagging” refers to the
distribution of patient‐specific
medication from a pharmacy, typically a specialty pharmacy, to
the physician’s office, hospital, or clinic for administration. It
is often used in oncology practices to obtain costly injectable or
infusible medications that are distributed by specialty pharmacies
and may not be available in all non‐specialty pharmacies.
• “Brown bagging” refers to the dispensing of a medication from
a pharmacy (typically a specialty pharmacy) directly to a patient,
who then transports the medication(s) to the physician’s office for
administration.
• Clear bagging - People have started using the term to refer to
when you dispense a drug from your own specialty Rx or outpatient
RX to be administered at a system owned facility, clinic, or
infusion center.
NABP White paper: White and Brown Bagging Emerging
Practices,
Emerging Regulation. Accessed 11/6/18
CS7
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How Common is it?• Several Reports suggest that—especially in
oncology—”brown
bagging” is done approximately 30% of the time
• As specialty pharmacies continue to grow—and third parties
adopt this model—”brown bagging” will be expected to grow
• BUT, very few state boards of pharmacy even define the
practice, let alone provide guidance or rules for its proper
use
• In particular outpatient infusion centers may be particularly
affected• In the brown bag model, the administering pharmacy is
expected to dispense,
keep records, monitor the patient, and dispose of (often
chemotoxic) remnant of the infusion FOR FREE
https://www.drugchannels.net/2013/09/payers-want-specialty-drug-distribution.html.
Accessed 11/8/18
But you know who likes “brown bagging”?• Physicians offices:
They don’t have costs associated with
purchasing and stocking expensive medications nor have to bill
third parties for reimbursement, BUT, is paid for professional
services associated with the drug’s administration.
• Third parties: Negotiate lower prices with specialty
pharmacies
• Does it help with adherence??
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Problems
• Outpatient/Inpatient pharmacies who stock infusion centers and
the infusion centers themselves are not reimbursed for usual and
proper pharmacy practice
• A patient may have to transport chemotoxic
medications—especially important in the age of USP 800
• Are appropriate storage criteria made in transport?
• Lack of coordination/communication between specialty pharmacy
and hospital/physician office/infusion center can lead to wrong
doses, or other errors
• Does “track and trace” play a role here??
CS9
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BOP action
• NABP paper discusses issues• Cost issues listed above•
Specialty pharmacy is still the pharmacy of record who dispensed
medication
to patient– responsibility for record keeping, MUE, patient
counseling and education, the provision of disposal instructions,
etc should be theirs
• Communication issues should be anticipated and polices adopted
to avoid
• State boards of Pharmacy• New regulations? New Rules?
• Third parties• Separate contracts or communications between
payers and administration
facility?
Hyperinflation in Generic Drug Prices
Elsevier White Paper: The impact of rising generic drug prices
on U.S. Supply Chain. Accessed 11/10/18
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Some Deflation since 2014 but not enough
We know why…
• Fewer generic houses = less competition• Drugs with a
projected small market attract fewer competitors
• Supply issues and shortages
• Market Consolidation and Monopolistic Pricing
• Safety issues result in drug removal and less competition
• Lagging FDA approval process
• Unapproved Drugs Initiative of the FDA• Neostigmine,
colchicine, vasopressin, others
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It isn’t just community pharmacies
• Example: Sodium Nitroprusside• For decades one of the DOC for
hypertensive emergencies
• Despite the risk of cyanide poisoning
• In 2014, Marathon Pharmaceuticals purchased the rights to the
drug from Hospira and increased the price from ∼$50 per vial to
∼$215 per vial
• In 2015, SNP was purchased by Valeant Pharmaceuticals, and the
price was increased further to ∼$650 per vial,
• In late 2016, Sagent Pharmaceuticals introduced another
generic SNP product to market with an average wholesale price (AWP)
of $900 per vial.
Alternatives to SNP
• Nicardipine? Labetalol? Hydralazine?
• All have pros and cons—and must be approached on an individual
basis
• Nicardipine• Equivalent to SNP for post op hypertension and
hypertensive emergencies• May lower intracranial pressure
• Labetalol• Blunted affect on HR compared to traditional
beta-blockers• Effects may be more long lasting and more difficult
to titrate
• Hydralazine• Not given as an IV drip• Reflex tachycardia can
be a problem
Neutel JM, et al. Am J Hypertens. 1994;7:623–628
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Potential Solutions?
• Compounding generic• Obvious barriers include: facilities,
quality control, manufacturing rules, etc
• Select alternative therapy• Barriers: Does one exist?, Safety
issues? Cost issues?
• Work with prescribers to examine patients taking the drug
proactively to see if it can be stopped temporarily or changed to
something else
• Example: nadolol for portal hypertension, Digoxin for atrial
fibrillation
• No one answer will solve every issue
Should hospitals enter the generic drug market?• NY Times
reported that a group of 300 nonprofit hospitals, led by
Intermountain Healthcare and including Ascension, Trinity Health
and SSM are planning to enter the generic drug manufacturing
market
• Stemming from price increases in 2013-2014 & shortages in
2015-2017
• 77 drugs currently listed by the FDA are experiencing API
(active pharmaceutical ingredient) shortages or have had
manufacturing process interruptions
• Of the top 50 products dispensed in the hospital channel
(which make up roughly 10% of hospital pharmaceutical sales), 42
are injectables
Nephron Research, Should Hospitals Enter the Generic Market?
(Part II), January 2018. Accessed 11/7/18
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Civica Rx• Not-for-profit generic drug company• 120 health
organizations representing about a third of the nation’s
hospitals have contacted Civica Rx and expressed a commitment or
interest in participating with the new company
• Has identified 14 hospital-administered generic drugs as the
initial focus of the company’s efforts
• It will be an FDA approved manufacturer and will either
directly manufacture generic drugs or sub-contract manufacturing to
reputable contract manufacturing organizations
• First Priority: to stabilize the supply of essential generic
medications administered in hospitals
https://intermountainhealthcare.org/news/2018/09/not-for-profit-generic-drug-company-officially-established-named-civica-rx/.
Accessed 11/11/18
Questions above Civica Rx• What drugs will be targeted for
manufacture?
• When will they be released?
• What does the FDA say about this• Surprisingly not much to
date
• How will then maintain supply and development lines?
• How does the supply chain work?• What wholesalers? OR direct
to pharmacies?
• Total cost impact?• Their own FAQ says some costs may go
up
• Other drugs in the future?
Civica Rx Operations FAQ. Accessed 11/11/18
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Bottom Line
• Brown bagging can put undue and unfair expense on the
facilities administering the drug, and has a lot of logistic issues
as well
• Rapid shifts in the generic price market has left both
pharmacies and drug manufacturers in a state of uncertainty—to say
nothing of patients
• Generic drug hyperinflation is often driven by drug shortages•
Innovative solutions such as Civica Rx may provide solutions—if
they can
actually get product to market
• Inventory control an issue for both community and hospital
pharmacy
Gamechanger #8
• Update on Penicillin and beta-lactam allergy
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Penicillin Allergy
• Approximately 10-15% of hospital patients claim this allergy•
Positive skin reactions in one study in children was 10%
• About 90% of patients who had a childhood reaction to PCN
become tolerant to the molecule by adulthood and will have a
negative skin test
• Only drug allergy with standardized testing (Type I reactions
only)
Cetinkaya, et al. Pediatr Allergy Immunol 2004;15:278-80Khan DA,
et al. Drug allergy. J Allergy Clin Immunol 2010, 125: S126-37
But we have lots of other antibiotics, right?
• Inpatients with a reported history of PCN allergy (n = 52,000
in a large database):
• More hospital days than controls (about 1 day)• More total
exposure to ABX and days on ABX• Significantly more vancomycin,
quinolone and clindamycin use (p < 0.001)
Macy E, et al. J Allergy Clin Immunol. 2014;133:790-6
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Reported Reactions to PenicillinPopulation: 5063 STD Clinic
Outpatients
Other (29%)
Uncertain (9%)
Anaphylaxis (7%)
Urticaria (35%)
Exanthem(20%)
Gadde J, et al. JAMA. 1993;270:2456-63
Cross-Reactivity With Other Beta-Lactams• Cephalosporins
• Side chains determine cross-reactivity—see later slides
• Carbapenems• Imipenem originally thought to be about 50%
cross-
reactive• Prospective and retrospective data suggests that
any
carbapenem has little or no cross reactivity in PCN allergic
patients
• Monopenems (aztreonam) safe in PCN allergyMcConnell, et al
Clin Infect Dis 2000;31:1512-4Wall GC, et al. J Chemother 2014;
26:150-3Romano A, et al. Ann Intern Med. 2007;146:266-9. Romano A,
et al. N Engl J Med. 2006;354:2835-7. Gaeta F, et al J Allergy Clin
Immunol. 2014 Nov 22.pii: S0091-6749(14)01481-X. doi:
10.1016/j.jaci.2014.10.011
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Cephalosporin Cross-Reactivity
• N = 128 patients with IgE reaction + skin reactivity
• Skin tested with various cephalosporins then oral
challenges
• Results: 14/128 (11%) had positive skin tests for
cephalosporins—mostly to first generation drugs
• About 1% for 3rd and 4th generation cephalosporins
• More recent study found almost same results in T-cell/delayed
reactions such as DRESS syndrome
Romano A, et al. Ann Intern Med 2004;141:16-22
Buinomo A, et al. J Investig Allergol Clin Immunol.
2014;24:331-7
Side chain relationships between PCNS and Cephs
Kim HE, et al. Allergy Asthma Immunol Res. 2014; 6: 485–495
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Side chain relationships between different Cephs
Kim HE, et al. Allergy Asthma Immunol Res. 2014; 6: 485–495
Bottom line on Cross-reactivity
• If poor history or non-threatening reaction history any
cephalosporin may be used in a patient with a claimed PCN
allergy
• If recent and life-threatening reaction would be cautious with
1stgeneration cephalosporins only.
• Carbapenems have no cross-reactivity
• Use side-chains to help determine beta-lactam to use
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PCN Allergy Skin Test
• The ONLY standardized drug allergy test • 99% Negative
predictive value (NPV)• Safe even in extremely allergic patients IF
scratch testing used first• Can be used “preemptively” for future
uses of ABX• Relatively simple procedure
Annals of Allergy, Asthma & Immunology 1999:83:665-700
The impact of penicillin skin testing on clinical practice and
antimicrobial stewardship
• ID fellows trained to administer and interpret PCN skin
testing
• 146 patients tested who have history of past IgE mediated
reaction
• Tested no matter the acuity (ED, ICU, Medical Floors, Surgery,
L&D)
• 145 tested negative and had antibiotics changed based on
results
• Estimated $82,000 saved just on this cohort of patients
• Same group found it very hard to “remove” allergy from EHR
Journal of Hospital MedicineVolume 8, Issue 6, pages 341-345, 3
APR 2013 DOI:
10.1002/jhm.2036http://onlinelibrary.wiley.com/doi/10.1002/jhm.2036/full#jhm2036-fig-0001
Aztreonam most commonly given before test, Pip/TazoAfter
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What about pharmacists?
• Depending on state law and training YES pharmacists ARE
performing allergy assessment and skin testing in a variety of
settings and in a variety of models
• Rph alone, or with RNs, MDs, residents, etc.
• Check with your state board!
• Training for pharmacists by pharmacists does exist
Jones BM, et al. Am J Health Syst Pharm. 2017 15;74:232-237
Conclusions
• A lot of information I know
• Perhaps a Focus on:• Areas that impact your practice•
Variations that may change these recommendations• The “bottom line”
slides
• PLEASE give us feedback • Gamechangers for 2019?
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[email protected]: @nuwavepharm
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Gamechangers Cover Page.pdfWall- Gamechangers.pdf