continuing educ ation credit - duke...
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1
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Welcome to Spring Symposium 2013!
• June 10, 2013 from 5:30 p.m. until 9:30p.m.
• Duke University Hospital Room 2002
• Eight great topics by nine great speakers
• Dinner and Fellowship with Colleagues
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And continuing education credit!
Continuing Education Credit
This symposium, ACPE # 0046-9999-13-117-L01-P will provide 3.0 contact hour of continuing
pharmacy education credit. No partial credit will be given. To Receive CE credit, attendance
must be acknowledged at the registration desk upon arrival at and departure of the program.
Statements of credit can be viewed and printed from CPE Monitor. Participants will receive an
email once credit processing has been completed and credit has been uploaded to the CPE
Monitor site. This process can take up to 4 weeks to appear on the CPE Monitor site.
The University of North Carolina Eshelman School of Pharmacy is accredited by the
Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
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Meredith T. Moorman, PharmD, BCOP
Hematology/Oncology Clinical Pharmacist
Duke University Hospital Spring Symposium
June 10, 2013
New Therapies for Chronic
Myelogenous Leukemia (CML)
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Disclosures
• The author of this presentation has nothing to
disclose concerning possible financial or personal
relationships with commercial entities that may have
a direct or indirect interest in the subject matter of this
presentation
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Objectives
At the conclusion of this knowledge-based presentation,
the participant should be able to:
1. Name three new agents approved for the treatment
of CML
2. Identify how these agents differ from previously
approved therapies for CML
3. Compare and contrast side effect profiles of
bosutinib, ponatinib, and omacetaxine
2
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CML Incidence and Mortality
Sellers WR. Cell 2011;147(1):26-31.
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The Philadelphia Chromosome
http://www.mayoclinic.com/health/medical/IM03579
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Phases of CML Phase of
Disease
Criteria
Chronic
(CP)
•BCR-ABL positive
•Not classified as accelerated or blast phase
Accelerated
(AP)
•Presence of any of the following:
•Persistent or rising leukocytosis >10 x109/L and/or persistent or increasing
splenomegaly unresponsive to therapy
•Persistent thrombocytosis (>1000 x109/L) uncontrolled by therapy
•Persistent thrombocytopenia (<100 x109/L) unrelated to therapy
•Clonal cytogenetic evolution from diagnostic karyotype
•≥20% basophils in peripheral blood
•10-19% myeloblasts in the blood or bone marrow
Blast (BP) •≥20% blasts in peripheral blood or of bone marrow nucleated cells
•Extramedullary blast proliferation
(Blast lineage is myeloid in 70% of cases, lymphoid in 20%, and may be mixed
phenotype)
Swerdlow SH et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (4th edition). IARC Press: Lyon 2008.
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Response criteria in CML
Hematologic Response Cytogenetic Response Molecular Response
Complete
(CHR) •Platelets < 450 x
109L
•WBC < 10 x 109L
•No immature
granulocytes and
<5% basophils on
differential
•Spleen not
palpable
Complete
(CCyR) Ph+ 0%
Complete
(CMR)
Transcripts
nonquantifiable
and undetectable
Partial
(PCyR) Ph+ 1-35%
Minor Ph+ 36-65%
Minimal Ph+66-99% Major
(MMR) ≤ 0.1%
None Ph+ >95%
Adapted from http://www.epgonline.org/images/cml/2141-b.gif
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Warning signs about response
• At any time:
– Loss of CHR, CCyR, MMR (confirmed on 2
occasions)
– Rise in transcript levels
– Development of other (or new) chromosomal
abnormalities
3 months 6 months 12 months 18 months
Treatment
Failure No HR <CHR
<PCyR <CCyR No CyR
Suboptimal
Response <CHR <PCyR <CCyR <MMR
Adapted from http://www.epgonline.org/images/cml/2141-c.gif
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Timeline of Recent Drug Approvals in CML
May 2001 - Gleevec® (imatinib)
June 2006 - Sprycel® (dasatinib)
October 2007 - Tasigna® (nilotinib)
September 2012 – Bosulif® (bosutinib)
October 2012 – Synribo® (omacetaxine)
December 2012 – Iclusig® (ponatinib)
3
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Bosutinib
• Approved for use in adults with all phases of Ph+
CML with resistance or intolerance to prior tyrosine
kinase inhibitors (TKIs)
• Active against BCR-ABL TKI, as well as Src, Lyn,
Hck kinases
• Inhibits 16/18 imatinib-resistant Bcr-Abl forms (not
active against T315I and V299L)
• Investigated in both CP CML patients with resistance
or intolerance and compared to imatinib in newly
diagnosed CP CML (BELA trial)
Cortes J et al. Blood 2011;118(17): 4567-4576.
Cortes J et al. J Clin Onc 2012;30(28):3486-3492.
Khoury H et al. Blood 2012;119(15):3403-3412.
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http://images-mediawiki-sites.thefullwiki.org/07/2/3/0/91613632266212093.png
Mechanism of Action of Bosutinib
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Bosutinib in TKI resistant CML
Response Criteria Imatinib-
Resistant
(n=287)
Multiple TKI Resistant
(n=118)
Hematologic response 86% 73%
Cytogenetic response
Major
Complete
31
41
32
24
Molecular response
Major
Complete
64
53
15
11
• Median time to MCyR = 12.3 weeks
• Major AEs: diarrhea (84%), N/V (44/35%)
Cortes J et al. Blood 2011;118(17): 4567-4576.
Khoury H et al. Blood 2012;119(15):3403-3412.
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Bosutinib vs. Imatinib in Newly
Diagnosed CML (BELA trial)
Response Criteria Bosutinib
(n=250)
Imatinib
(n=252)
P value
Hematologic response 71% 85% >0.999
Cytogenetic response
Major
Complete (at 12 mos)*
73
70
78
68
0.601
Molecular response
Major
Complete
41
12
27
3
<0.001
<0.001
• Bosutinib 500 mg po daily vs. imatinib 400 mg po daily
• Median time to response: 12.9 vs. 24.6 weeks (p<0.001)
• Fewer bosutinib treated patients with progression to AP/BP
(4 patients vs. 10 patients) Cortes J et al. J Clin Onc 2012;30(28):3486-3492.
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Adverse reactions with bosutinib
• Gastrointestinal
– Diarrhea (82%), nausea (46%), vomiting (39%),
abdominal pain (37%)
• Hematologic
– Thrombocytopenia (41%), anemia (27%),
neutropenia (17%)
• Other
– Edema (14%), AST/ALT increases (~15%), rash
(35%)
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Bosutinib – dosing and dose modifications
• Dosing: 500 mg po daily
– Escalate to 600 mg po daily in patients not
achieving CHR at 8 weeks or CCyR at 12 weeks
and do not have > grade 3 toxicity
• Dose modifications
– Elevated liver function tests (>5x ULN)
– Diarrhea (>7 stools/day over baseline)
– Neutropenia (ANC < 1000)
– Thrombocytopenia (platelets < 50K)
• Drug interactions
– Caution with CYP3A4 inducers/inhibitors
4
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Ponatinib
• Approved for use in adults with all phases of Ph+
CML or Ph+ ALL with resistance or intolerance to
prior TKIs
• Active against BCR-ABL, VEGFR, PDGFR, FGFR,
Src, KIT, RET, FLT3
• Demonstrated significant activity in patients harboring
T315I mutation
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PACE (Ponatinib Ph+ ALL and CML
Evaluation) Trial
• Open label trial in Ph+ ALL and Ph+ CML patients
resistant or intolerant (R/I) to nilotinib or dasatinib,
with or without T315I mutation
• Patients divided into cohorts based on disease stage
and mutation status
• Primary endpoints:
– Ph+ ALL: major HR at any time within 6 months
– Ph+ CML: MCyR at any time within 12 months
• Heavily pretreated population – 53% of patients
exposed to all 3 approved TKI
Cortes JE (2012). Abstract 163 from 2012 ASH Annual Meeting Abstracts.*
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• Median follow-up was 11 months
• Responses considered durable: probability of maintaining
primary endpoint at 1 year was 91% (CP-CML), 42% (AP-CML),
35% (BP-CML/ALL)
• Higher response rates seen in patients with less exposure to
TKI and shorter disease duration
• Most common AEs: thrombocytopenia (36%), rash (33%), dry
skin (31%)
• Pancreatitis most common serious AE (5%)
PACE trial results
CP-CML
n/N (%)
AP-CML
n/N (%)
BP-CML/Ph+ ALL
n/N (%)
R/I 101/203 (50) 38/65 (58) 17/48 (35)
T315I 45/64 (70) 9/18 (50) 15/46 (33)
Total 146/267(55) 47/83 (57) 32/94 (34)
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Ponatinib – dosing and dose
modifications
• Dosing: 45 mg po daily
– Can be taken with or without food
• Dose modifications:
– Neutropenia (ANC<1000)
– Thrombocytopenia (platelets<50K)
– Elevated LFTs (>3x ULN or AST/ALT≥3x ULN +
bilirubin > 2x ULN and alk phos <2x ULN)
– Elevated lipase or pancreatitis
• Caution with CYP3A4 inhibitors/inducers
– Reduce dose to 30 mg po daily with strong
inhibitors
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Adverse reactions with ponatinib
• Black box warning
– Arterial thrombosis (serious, 8% patients)
– Hepatotoxicity (LFT elevations in 56% patients)
• Clinically significant
– Hypertension (53-71%)
– Pleural effusion (3-19%)
– Peripheral edema (13-22%)
– Rash (34-54%)
– Arthralgia/myalgia (6-31%)
– Glucose increased (58%)
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Omacetaxine
• Approved for use in adult patients with CP or AP
CML with resistance and/or intolerance to two or
more TKI
• Reversible protein translation inhibitor, not affected
by mutations in BCR-ABL
• Like ponatinib, it has demonstrated activity in patients
with T315I
• Studied in patients with any phase of CML, T315I
mutation positive, and who had failed 1 or more TKI
therapies
5
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Omacetaxine study results
• Study included 62 patients with T315I mutation
• 74% had failed at least two TKIs
• Primary endpoint was number of patients achieving
either CHR (77%) or MCyR (23%)
• Median # cycles to achieve CHR = 1, MCyR = 2.5
• Duration of response = 9.1 months (CHR), 6.6
months (MCyR)
• AEs: thrombocytopenia (76%), neutropenia (44%),
anemia (39%), diarrhea (40%), nausea (34%), fever
(29%)
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Omacetaxine – dosing and dose
modifications
• Dosing:
– Induction: 1.25 mg/m2 SubQ BID for 14 days in 28
day cycle
– Maintenance: 1.25 mg/m2 SubQ BID for 7 days in
28 day cycle
• Dose modifications
– If ANC < 500 or platelets < 50K during cycle, hold
therapy until ANC>1000 or platelets > 50K
– Reduce number of dosing days in next cycle by 2
(to 12 or 5)
– Manage other toxicities symptomatically
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Cost of CML medications
• Estimated annual cost of newly approved agents:
– Bosutinib - $118,000
– Omacetaxine - $28,000 (induction), $14,000 (each
maintenance cycle)
– Ponatinib - $138,000
• Recent article highlights variable cost of agents in
different geographic areas
• Transplant may be considered earlier in course of
therapy, or as only option, because of limited one
time cost ~$70,000-80,000
Experts in Chronic Myeloid Leukemia. Blood 2013;121(22):4439-4442.
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Conclusions
• Several new agents are available for treatment of
adults with Ph+ CML, including those with T315I
mutation
• Omacetaxine demonstrates a new mechanism of
action compared with other therapies available for
CML
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Assessment Question
1. Which new agent for CML demonstrates a novel
mechanism of action compared to previously FDA
approved therapies?
A. Bosutinib
B. Omacetaxine
C. Ponatinib
D. All of the above
E. None of the above
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Assessment Question
1. Which new agent for CML demonstrates a novel
mechanism of action compared to previously FDA
approved therapies?
A. Bosutinib
B. Omacetaxine
C. Ponatinib
D. All of the above
E. None of the above
6
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Treatment Updates for
Advanced Prostate Cancer
Russell A. Moore, Pharm.D., BCOP
Clinical Pharmacist
Genitourinary Medical Oncology
Duke University Hospital
June 10, 2013
31
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Disclosures
• The author of this presentation has nothing to
disclose concerning possible financial or personal
relationships with commercial entities that may have
a direct or indirect interest in the subject matter of this
presentation
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1. Compare and contrast outcomes for new and emerging
treatment strategies for advanced prostate cancer
2. Assess toxicities and patient management
considerations associated with the use of novel agents
in the treatment of castration-resistant prostate cancer
(CRPC)
3. Explain the results and implications of clinical trials for
newly approved and emerging agents for CRPC, and
discuss the safety, efficacy, and mechanism of action of
each of these agents
Objectives
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Cancer Facts and Figures 2013. Available at: www.cancer.org.
Prostate Cancer: 2013 Estimates
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Prostate Cancer Management
• Early stage disease
– Treatment Options: • Active surveillance, radiation therapy (RT), radical prostatectomy, or
androgen deprivation therapy (ADT) (in select patients)
• Advanced disease
– Progression after initial definitive therapy • RT + ADT
• Radical prostatectomy
– At initial diagnosis • Metastatic to lymph node or other site (N1 or M1)
– Treatment Options: medical / surgical castration
• Castration-Resistant Prostate Cancer (CRPC)
– Disease progression despite medical / surgical castration
– Testosterone level < 50 ng/dL
Prostate Cancer. NCCN Guidelines Version 3.2012. Available at: www.nccn.org
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Treatment Paradigm by Disease State: 2010 Hormone Sensitive
Newly diagnosed Localized disease
Active Surveillancea
Radiation
Radiation + ADTa,b
Prostatectomy
Non-metastatic, Biochemical relapse
Prostatectomy Observation
Salvage radiationa
Brachytherapy
Cryosurgery ADT
Metastatic Hormone-naïve
Orchiectomy ADT
Castration-Resistant
Non-Metastatic
No standard 2nd-line hormonal
agents
Asymptomatic Metastatic
(chemo-naïve)
2nd-line ADT Docetaxela,b
Symptomatic Metastatic
(chemo-naïve)
Docetaxelb
Mitoxantrone
Palliative Radiation
89Strontium 153Samariuma,b
Metastatic Post-docetaxel
Mitoxantrone Docetaxel
rechallenge Other chemo a Selected patients
b Category 1 evidence
Adapted from: Higano CS, et al. Urol Oncol 2011;29(6 Suppl):S1-S8.
7
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Treatment Paradigm by Disease State: 2013
a Selected patients b Category 1 evidence
Adapted from: Higano CS, et al. Urol Oncol 2011;29(6 Suppl):S1-S8.
Castration-Resistant
Asymptomatic Metastatic
(chemo-naïve)
Sipuleucel-Tb
Abirateroneb
Enzalutamide (off-label) 2nd-line ADT
Docetaxela,b
Symptomatic Metastatic
(chemo-naïve)
Abiraterone Enzalutamide (off-label)
Docetaxelb
Mitoxantrone
Palliative Radiation 89Strontium
153Samariuma,b
Metastatic Post-docetaxel
Cabazitaxelb
Sipuleucel-T
Abirateroneb
Enzalutamideb
Radium-223 Mitoxantrone
Docetaxel rechallenge
Other chemo
Bone Health in Metastatic Disease: Denosumabb or Zoledronic acidb
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Androgen and the
Androgen Receptor (AR):
Targeting the Androgen Pathway
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Model of the Evolution of CRPC
CRPC
Androgen-dependent cell CRPC, Castration Resistant Prostate Cancer
ADPC, Androgen-Dependent Prostate Cancer
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Androgen and AR-defined
Prostate Cancer Cell States
Nelson PS. J Clin Oncol 2012;30:644-646.
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Mechanisms of CRPC:
Persistent AR Pathway Signaling
• Hyperactive AR
– Amplification of the AR gene or increased protein expression
– AR point mutations
• Increased AR expression and expression of androgen-regulated genes (such as PSA)
– Increase in PSA = indicative of AR transcriptional activity reactivation
• Persistent intratumoral ligand: testosterone or precursors
– Intratumoral conversion
Taplin ME, Balk SP. J Cell Biochem 2004;91:483-490.
Stanbrough M, et al. Cancer Res 2006;66:2815-2825.
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Higher AR Levels in CRPC Tumors AR expression in
bone marrow mets
Stanbrough M, et al. Cancer
Res. 2006;66:2815-2825.
At autopsy – 73% of 15
samples exhibit AR
amplification Friedlander TW, et al. Cancer Res
2012;72:616-625.
Increased AR mRNA
in CRPC tested
Holzbeierlein J, et al. Am J
Pathol 2004;164:217-227.
8
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Drug Targets
Involving the
Androgen-Receptor
Pathway
Schweizer MT, Antonarakis ES. Ther Adv Urol 2012;4:167-178.
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AR Signaling: Matching Biology to Therapy
Androgen
Production
AR
Binding
Signaling Event Intervention
Conversion
to DHT
Androgen
Transport/
Circulation/
Uptake
SCC Inhibitors CYP 17
Inihibitors
Block Transport
5-Alpha Reductase inhibitors
Ketoconazole Abiraterone Tak-700 Tok-001
Drugs
Dutasteride
Enzalutamide ARN-509 Tok-001
Novel AR Inhibitors
Pre
-R
ecep
tor
Rec
epto
r
Intracrine Production
Polymorphisms
Amplified 5 Alpha Reductase
Amplified AR Splice Variant AR
Aberration
None
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Steroid / Androgen Synthesis Pathway
45
Schweizer MT, Antonarakis ES. Ther Adv Urol 2012;4:167-178.
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CALGB 9583 (Phase III Trial)
• Antiandrogen withdrawal (AAWD) alone vs. simultaneous
AAWD and Ketoconazole
Observations With Ketoconazole
Small EJ, et al. J Clin Oncol 2004;22:1025-1033.
Ryan CJ, et al. Clin Cancer Res 2007;13:2030-2037.
3. Androgens rise at time
of disease progression
1. Approximately 30% are
progression free at 2 years 2. Higher baseline androgens
= better survival
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Abiraterone: A CYP17 Inhibitor
Low-dose steroid replacement reduces mineralocorticoid-related toxicity
Attad G, et al. J Clin Oncol 2008;26:4563-4571.
Ryan CJ, et al. J Clin Oncol 2010;28:1481-1488.
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Abiraterone Acetate (Zytiga)
• FDA-approved: April 28, 2011
– Metastatic CRPC in combination with prednisone
• Pharmacology
– Inhibits 17 alpha-hydroxylase/C17,20-lyase (CYP17), enzyme required for androgen biosynthesis
• Dosing
– 1,000 mg (250 mg tablet x 4) PO daily + Prednisone 5 mg PO bid
– Empty stomach (no food 2 hours before and at least 1 hour after the dose) • Increased absorption with food
• Adverse effects:
– Hot flushes, diarrhea, fatigue, muscle weakness, joint swelling/discomfort, HTN, hypo-K, fluid retention
48
Abiraterone Acetate. Facts and Comparisons. www.factsandcomparisons.com. [Accessed: 10/31/12].
9
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Abiraterone Acetate (Zytiga)
COU-AA-301 Study
• Phase III, multicenter, randomized, double-blind,
placebo-controlled trial
– Metastatic, castration-resistant prostate cancer
• Primary endpoint = overall survival
49
Abiraterone acetate 1000 mg PO
daily on empty stomach +
Prednisone 5 mg PO bid (n=797)
Metastatic
CRPC,
previously
treated with
docetaxel
(N=1195) Placebo + Prednisone 5 mg PO
bid (n=398)
R
A
N
D
O
M
I
Z
E
D
de Bono JS, et al. N Engl J Med 2011;364:1995-2005.
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COU-AA-301 Study: Overall Survival
de Bono JS, et al. N Engl J Med 2011;364:1995-2005.
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Abiraterone Acetate (Zytiga)
COU-AA-302 Study
• Phase 3, multinational, randomized, double-blind,
placebo-controlled trial
– Chemotherapy naive patients with mCRPC AA 1000 mg daily
Prednisone 5 mg BID
(n = 546)
Co-Primary:
• rPFS by central review
• OS
Secondary:
• Time to opiate use
(cancer-related pain)
• Time to initiation of
chemotherapy
• Time to ECOG-PS
deterioration
• TTPP
Efficacy endpoints
Placebo daily
Prednisone 5 mg BID
(n = 542)
R A N D O M I Z E D
1:1
• Progressive chemo-
naïve mCRPC
patients
• Asymptomatic or
mildly symptomatic
Patients (N=1088)
Ryan CJ, et al. N Engl J Med 2013;368:138-148.
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COU-AA-302 Study: rPFS
Primary End Point
Ryan CJ, et al. N Engl J Med 2013;368:138-148.
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COU-AA-302 Study: Overall Survival
Strong Trend
53
Note: Prespecified boundary for significance (P≤0.001) not reached at the
observed number of events Ryan CJ, et al. N Engl J Med 2013;368:138-148.
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Abiraterone Monitoring and Safety
• May cause HTN, hypo-K, fluid retention, and increases in AST/ALT
– Monitor BP, serum potassium, LFTs, and symptoms of fluid retention at least monthly
• Use with caution in patients with a history of cardiovascular disease
• Co-administer with a corticosteroid to suppress adrenocorticotropic hormone (ACTH) drive
• Drug interactions:
– Avoid (or caution) with CYP3A4 strong inhibitors and inducers
– Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index
• Pricing
– 250 mg (120): $7,674.37
54
Abiraterone Acetate. Lexi-comp. www.lexi-comp.com. [Accessed: 5/15/13].
10
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Potential New CYP17 Inhibitors
• Orteronel (TAK-700)
– Higher specificity for C17-20 lyase inhibition vs. 17α-hydroxylase inhibition • May not require concomitant prednisone
– Currently in several phase III trials • Several of these do not include prednisone
• Galeterone (TOK-001)
– Disrupts multiple androgen signaling pathways simultaneously • Downregulation of the AR and competitive inhibition of
androgen binding and AR translocation into the nucleus
– Currently in phase I and phase II trials
Schweizer MT, et al. Ther Adv Urol 2012;4:167-178.
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www.clinicaltrials.gov. [Accessed: 5/15/13].
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AR Signaling: Matching Biology to Therapy
Androgen
Production
AR
Binding
Signaling Event Intervention
Conversion
to DHT
Androgen
Transport/
Circulation/
Uptake
SCC Inhibitors CYP 17
Inihibitors
Block Transport
5-Alpha Reductase inhibitors
Ketoconazole - Abiraterone Tak-700 Tok-001
Drugs
Dutasteride
Enzalutamide ARN-509 Tok-001
Novel AR Inhibitors
Pre
-R
ecep
tor
Rec
epto
r
Intracrine Production
Polymorphisms
Amplified 5 Alpha Reductase
Amplified AR Splice Variant AR
Aberration
None
All Rights Reserved, Duke Medicine 2007
Enzalutamide (Xtandi)
• FDA-approved: August 31, 2012
– Metastatic CRPC after docetaxel
• Pharmacology
– Competitively inhibits androgen binding to receptor and inhibits androgen receptor nuclear translocation and interaction with DNA
• Dosing
– 160 mg (40 mg capsule x 4) PO daily
– With or without food
• Adverse events
– Hot flushes, muscular weakness, fatigue, cardiovascular risks, weight gain, hyperlipidemia, muscle wasting, seizure (0.9%)
Enzalutamide. Facts and Comparisons. www.factsandcomparisons.com. [Accessed: 10/31/12].
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59
AR Inhibition: Proposed Mechanism of Action
Scher, ASCO GU 2012
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Enzalutamide (Xtandi)
AFFIRM Trial • Phase 3, randomized, international, double-blind, placebo-
controlled trial
– CRPC previously treated with one or two chemotherapy regimens, at least one of which contained docetaxel
– Primary endpoint = overall survival
Enzalutamide 160 mg PO daily (n=800) Metastatic
CRPC,
previously
treated with
docetaxel
(N=1199) Matching Placebo PO daily (n=399)
R
A
N
D
O
M
I
Z
E
D
Scher HI, et al. N Engl J Med 2012;367:1187-1197.
11
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Enzalutamide: AFFIRM Trial
Overall Survival
Median OS:
Enzalutamide: 18.4 mo
Placebo: 13.6 mo
37% reduction in risk of
death vs. placebo
Study halted and
unblinded at interim
analysis
Scher HI, et al. N Engl J Med 2012;367:1187-1197.
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Enzalutamide: AFFIRM Trial
Secondary Endpoints
62
Scher HI, et al. N Engl J Med 2012;367:1187-1197.
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Enzalutamide (Xtandi)
PREVAIL Trial • Phase 3, multinational, randomized, double-blind,
placebo-controlled trial
– Chemotherapy-naïve patients with progressive metastatic castration-resistant prostate cancer
– Asymptomatic or mildly symptomatic
• Primary endpoints:
– Overall survival and progression-free survival
• Secondary endpoints:
– Time to first skeletal-related event
– Time to initiation of cytotoxic chemotherapy
• Estimated primary completion date: September 2014
– Interim analysis planned in 2013
63
www.clinicaltrials.gov. [Accessed: 5/1/13].
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Enzalutamide Monitoring and Safety
• Seizure history or other predisposing factors
– Use with caution
• Drug interactions
– Strong CYP3A4 and moderate CYP2C9 and
2C19 inducer
– CYP3A4 and CYP2C8 substrate
• Pricing
– 40 mg (120): $8,940.00
Enzalutamide. Lexi-comp. www.lexi-comp.com. [Accessed: 5/15/13].
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Potential New AR Inhibitors
• ARN-509
– Competitive AR inhibitor
– Purely antagonistic
– Reduce efficiency of nuclear translocation of the AR and impair AR binding to androgen-response elements of DNA
– Less effective blood-brain barrier penetration vs. enzalutamide • Possibly less off-target inhibitory effects on gamma
aminobutyric acid (GABA) type A = less seizure risk
– Currently in phase I and II clinical trials • NCT01790126, NCT01792687
Schweizer MT, et al. Ther Adv Urol 2012;4:167-178.
All Rights Reserved, Duke Medicine 2007
Emerging Agents for Advanced
Prostate Cancer
Androgen-Independent Pathway
66
12
All Rights Reserved, Duke Medicine 2007 All Rights Reserved, Duke Medicine 2007 www.clinicaltrials.gov. [Accessed: 5/15/13].
All Rights Reserved, Duke Medicine 2007
Radium-223 Chloride (Xofigo) (formerly known as Alpharadin) • Intravenous radioisotope
– FDA-approved: 5/15/13
• Alpha-particle emitter (first-in-class)
– High energy and short radius of activity
– Double-strand DNA breaks
– Lower penetration to surrounding tissues compared with beta-emitting radiopharmaceuticals
• Beta-particle emitters (available radioisotopes)
– Strontium-89 (Metastron) and Samarium-153 (Quadramet)
– Longer radius of activity
– Single-strand DNA breaks
– Approved for pain palliation due to skeletal metastases
Higano CS, Crawford ED. Urol Oncol 2011;29(6 Suppl):S1-S8.
Shore N, et al. BJU Int 2012;109(Suppl 6):22-32.
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Radium-223 Targets Bone Metastases
Bone surface
Range of alpha-particle
Radium-223 Perez et al. Principles and Practice of Radiation Oncology. 5th ed.
Lippincott Williams & Wilkins;2007:103.
Cheetham PJ, et al. Oncology (Williston Park) 2012;26:330-337,341.
• Calcium mimetic natural bone-
targeting agent
• Preferential uptake in areas of
new bone formation
• Incorporated into bony matrix
• Excreted into small intestine
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Radium-223 (Xofigo)
ALSYMPCA: Phase 3 Randomized Trial
71
Parker C, et al. European Multidisciplinary Cancer Congress. 2011; Abstract no. 1LBA
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Month 0 3 6 9 12 15 18 21 24 27
Radium- 223 541 450 330 213 120 72 30 15 3 0
Placebo 268 218 147 89 49 28 15 7 3 0
ALSYMPCA: Overall Survival
0
10
20
30
40
50
60
70
80
90
100
%
Radium-223, n = 541
Median OS: 14.014.9 months
Placebo, n = 268
Median OS: 11.211.3 months
HR 0.695; 95% CI, 0.581-0.832
P = 0.00007
Adverse events: slightly worse with placebo Parker C, et al. ASCO 2012. Abstract LBA4512.
13
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ALSYMPCA: Updated Analysis
Adverse Events of Interest
Parker C, et al. ASCO 2012. Abstract LBA4512.
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Summary
• Compelling survival with abiraterone and enzalutamide in patients with heavily pretreated CRPC has reinforced the value of inhibiting the androgen receptor axis
• Need to further define the optimal application and timing of prostate cancer therapies
• Monotherapy vs. combination therapy and clinical efficacy?
• Financial implications of new agents
• New targeted therapies will need to be developed in conjunction with biomarkers that predict response (i.e., Her-2 trastuzumab in breast cancer)
74
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Self-Assessment Question
• Which of the following agent(s) is/are approved for
the treatment of metastatic castration resistant
prostate cancer (mCRPC) pre-chemotherapy?
A. Ketoconazole
B. Enzalutamide (Xtandi)
C. Abiraterone (Zytiga)
D. Radium-223 (Xofigo)
E. B and C
F. All of the above
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Implementation of Transitions of Care at
the Duke Outpatient Clinic June 10, 2013
Ben Smith PharmD, BCACP
Holly Causey PharmD, BCACP, CPP, CDE
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The authors of this presentation have the following to
disclose concerning financial or personal relationships
with commercial entities that may have a direct or
indirect interest in the subject matter of this
presentation:
Ben Smith: nothing to disclose
Holly Causey: nothing to disclose
Disclosures
All Rights Reserved, Duke Medicine 2007
Objectives
Upon completion of this knowledge based program, the
participant should be able to:
– Describe current practices to reduce
hospitalization, including post-hospital follow-
up visits
– Review current transitional care programs
– Explain roles for pharmacists in transitions of
care
– Discuss implementation of transitions of care
at the Duke Outpatient Clinic
14
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National Models of Care Transitions
• Project Red
– RN discharge advocate coordinated discharge
plan with hospital team/educated patient
– RN created after-hospital care plan
– Pharmacist contacted patient 2-4 days after
discharge
– Decreased hospital utilization for intervention
group (0.314 vs. 0.451 visit per person per
month; p=0.009)
Ann Intern Med. 2009;150:178-187
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ASHP-APhA Medication Management in
Care Transitions Best Practices
• Einstein Healthcare Network
• Froedtert Hospital
• Hennepin County Medical Center
• Johns Hopkins Medicine
• Mission Hospital
• Sharp HealthCare
• University of Pittsburgh Medical Center
• University of Utah Hospitals and Clinics
http://www.pharmacist.com/medication-management-care-transitions-best-practices
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National Models of Care Transitions
• Einstein Healthcare Network
– Pharmacist med rec and patient consult upon
discharge
– Address medication access barriers
– Scripted pharmacist post-discharge phone call
– 30-day readmission rate 10.6% vs. 21.4% in
controls
http://www.pharmacist.com/medication-management-care-transitions-best-practices
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National Models of Care Transitions
• Froedtert Hospital
– Pharmacist completes med rec at admission,
transfers, and discharge
– High risk patients receive pharmacist follow-up
call 2-3 days post discharge
– Option to schedule for pharmacy visit
– HF readmissions decreased from 30.37% to
20.13%
http://www.pharmacist.com/medication-management-care-transitions-best-practices
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National Models of Care Transitions
• Hennepin County Medical Center
– Re-engineered discharge plan by care
coordinator
– Pharmacist completes med rec at discharge
– Follow-up phone call
– Patients without follow-up at discharge: Visit
with pharmacist and nurse practitioner within 7
days of discharge
– 30-day readmission rate 8% vs. 23%
http://www.pharmacist.com/medication-management-care-transitions-best-practices
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National Models of Care Transitions
• John Hopkins Medicine
– Screening criteria to determine population of
focus
– Post-discharge phone call completed by
inpatient pharmacist within 72 hrs of discharge
– Home-based med rec by inpatient or outpatient
pharmacist for select patients
http://www.pharmacist.com/medication-management-care-transitions-best-practices
15
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National Models of Care Transitions
• Mission Hospital
– Medication Access/education for uninsured
– Pharmacy technician performs up to 3 follow-
up calls following discharge within 72 hours,
within first week of refill, after first PCP visit
– Pharmacist clinic visits scheduled if needed
– Engagement with community partners
– $210,000 estimated cost avoidance in year 1
http://www.pharmacist.com/medication-management-care-transitions-best-practices
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National Models of Care Transitions
• Sharp HealthCare
– Pharmacy technicians interview patients
admitted > 24 hours
– Pharmacist review focuses on HF or
hospitalist referred patients
– Discharge med education and access focus
– Pharmacy resident f/u phone call or home visit
within 5 days
– HF readmissions decreased from 20% to 13%
http://www.pharmacist.com/medication-management-care-transitions-best-practices
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National Models of Care Transitions
• University of Pittsburgh School of Pharmacy and
Medical Center
– Screening questionnaire identifies patients
– Pharmacist performs med rec/education
during admission
– Inpatient pharmacist performs f/u call within 72
hours of discharge
– Two HCAHPS med questions improved from
22% and 27% to 75%
– 30-day readmissions 10.5% vs. 23.7%
http://www.pharmacist.com/medication-management-care-transitions-best-practices
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National Models of Care Transitions
• University of Utah Hospitals and Clinics
– Service covers 90% of discharges
– Med rec at admission, during hospitalization,
and at discharge
– Discharge pharmacist places note in EMR
– Clinic pharmacists perform f/u calls
– Clinic pharmacist visit scheduled if high risk
– Decreased HF readmissions: 20.5-22.1% to 16%
http://www.pharmacist.com/medication-management-care-transitions-best-practices
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Implementation at the Duke
Outpatient Clinic
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Phase 1
• Target: Duke Outpatient Clinic patients with Medicaid
and Aging/Blind/Disabled
• Implementation: late October 2012
• Documentation: CMIS, Maestro Care
• Involvement:
– CCNC
– DOC clinical pharmacists
– PCP
16
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Phase 1 Process
Daily list of Medicaid ABD
patients hospitalized
and seen in ED
Contacted patient via phone for
comprehensive medication
review
Communicated with CCNC
care manager
PCP visit within 7-14 days
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Phase 2
• Target: all Duke Outpatient Clinic patients
• Incorporation of Medicare transitional billing codes
• Implementation: February 2013
• Documentation: CMIS if applicable, Maestro Care,
PCP sent reminder email
• Involvement: interdisciplinary
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Phase 2 Process
Hospital D/C list sent daily to front
desk staff
Phone call w/in 48 hours of discharge
PharmD call patient for medication review and follow up of other issues
Provider sees patient within
7-14 days post
discharge
Telephone note routed to Holly/Ben in Maestro Care
Telephone note routed to provider in Maestro Care
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Front Desk Follow-Up Call
• Follow-up visit scheduled or patient reminded of
appointment time/date
• Medication access addressed
• Transportation availability addressed
• Telephone note CC’d to Holly/Ben in Maestro Care
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Front Desk Follow-Up Call
• Contacted patient to remind and/or schedule patient for Duke
Outpatient Clinic hospital follow-up visit with physician. Patient
or caregiver asked to bring all medications, blood glucose
log/meter, and blood pressure log (as applicable).
• Patient or caregiver voiced understanding of appointment
date/time and informed that clinical pharmacist may contact
patient to discuss medications prior to visit.
Follow Up Appointment
1. The patient does have an appointment for follow up at Duke
Outpatient Clinic.
2. The patient believes that she can attend this appointment and
has transportation.
3. The patient verbalized that she was able to pick-up
medications prescribed at hospital discharge.
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PharmD Follow-Up Call Assessment
• New medications and knowledge of medications
• Knowledge of reason for hospitalization
• Knowledge of current self-care needs
• Documentation of educational needs
• Home health utilization
• Ability of patient to attend scheduled appointment
• Request medications and/or medication list brought to
follow-up visit
• At the conclusion of our call, the telephone note was CC’d
to patient’s PCP along with an email reminder
17
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Coordination of Care
• Avoid PharmD calls to patients targeted by other
services
– Community Care of NC
– Heart Failure follow-up team
– Stroke follow-up team
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Interdisciplinary Effort
• Patient Service Associates (PSA)
• Licensed Clinical Social Worker (LCSW)
• MD
• PharmD
• RN
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Hospital Follow-Up Visit
• RN assessment included in visit
• PCP Hospital Follow-Up Template Addresses:
– Medications
– Consultations/diagnostic tests
– Patient empowerment/education
– Home status/level of function
– Communication with providers/pharmacy
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Metrics – Discharge Phone Calls
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Metrics –Follow Up Scheduling
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Areas for Improvement
• Telephone documentation by PSA to include:
– Patient has an alternate PCP
– If appointment was scheduled
– If patient to reschedule later
• Scheduling patients in < 14 days of discharge if
appointment set > 14 days
– If patient refuses, this should be documented
in the initial telephone note
18
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Future of DOC Transitions
• Progress towards creating a transitions of care model
for all Duke ambulatory clinics
• Evaluate potential reduction of 30-day readmissions
• Evaluate increased primary care revenue capture
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Acknowledgements
• Community Care of North Carolina
• DOC Discharge Clinic Committee
• DOC staff
• Matthew Ransom PharmD, BCACP
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Self Assessment Question 1
• Question
– What are two tasks that health system
pharmacists can complete to facilitate care
transitions?
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Health Literacy SAY WHAT?!?
Evan Frasure, PharmD
Continuity of Care Coordinator
Department of Pharmacy
Duke University Hospital
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Disclosures
• The author of this presentation has nothing to
disclose concerning possible financial or personal
relationships with commercial entities that may have
a direct or indirect interest in the subject matter of this
presentation
All Rights Reserved, Duke Medicine 2007
Objectives
• Define health literacy and its prevalence in the U.S.
population
• Describe the impact of health literacy on pharmacy
practice
• Identify strategies for counseling patients with low
health literacy, including the use of “universal
precautions’
19
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“The single biggest problem in
communication is the illusion
that it has taken place”
-George Bernard Shaw
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“It is not just, nor fair, to expect a
patient to make appropriate health
decisions and safely manage
his/her care without first
understanding the information
needed to do so.”
Reducing the Risk by Designing a Safer, Shame-Free
Health Care Environment. AMA, 2007
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What is Health Literacy Anyway?
“The ability to obtain, process,
and understand health
information to make informed
decisions about health care.”
AHRQ Health Literacy Universal
Precautions Toolkit
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How Common is it?
• 36% of the U.S. adult population has limited health
literacy
• Only 12% achieve the proficient level
• Varies by race, age, ethnicity, education, and
socioeconomics
• Low health literacy may be present regardless of the
above demographics
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National Center for Education
Statistics
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National Center for
Education Statistics
20
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National Center for
Education Statistics
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Low Health Literacy is associated with . . .
• Less knowledge about disease
• More healthcare utilization/cost
– Hospital admissions
– ED visits
• Decreased medication adherence
• Poorer health status in the elderly
• Increased mortality rate in the elderly
Berkman et al, Anal Intern Med.
2011;155:97-107
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PHARMACY SPECIFIC
IMPLICATIONS
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Take 1 pill by mouth once
daily.
Health literacy level
Adequate – 84%
Marginal – 78%
Low – 74%
Davis TC et al. JGIM 2008;24
(1):57-62.
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Take 1 pill by mouth every 12 hours
Health literacy level
Adequate – 61%
Marginal – 51%
Low – 30%
Davis TC et al. JGIM 2008;24
(1):57-62.
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Take two tablets by mouth twice daily
Health literacy level
Adequate – 71%
Marginal – 57%
Low – 33%
Davis TC et al. JGIM 2008;24
(1):57-62.
21
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Davis et al 2006. Adapted from
Table 3.
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WHAT CAN I DO ABOUT IT?
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Health Literacy Universal
Precautions Toolkit AHRQ
Pub. No. 10-0046-EF
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Universal precautions
• You cannot tell by looking
• Higher literacy skills does not equal understanding
• Health literacy is not a state but rather a trait
• Everyone benefits from clear communication
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Tool #3 - Raise awareness
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Tool #5 - Teach-Back method
• A way to confirm understanding
• NOT A TEST
• Helps create dialogue between the patient and
provider
• Once part of a routine, it does not take longer to
perform
22
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How do I get started?
• Start slowly
• Plan your approach
• Clarify
– As often as necessary
– Patient’s own words
• Practice, practice, practice
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EXAMPLES OF TEACH-BACK
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“Do you understand everything I told you today
about your diabetes?”
“We covered a lot today about your diabetes,
and I want to make sure that I explained things
clearly. So let’s review what I have discussed.
What are 3 things you can do that will help you
control your diabetes?”
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“To be sure you understand what I just said,
please tell me how you will take this new
medication.”
“I want to be sure I explained your new
medication correctly. Will you tell me how you
are going to use this medication?”
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Summary
• Health literacy is a major concern in today’s
healthcare environment
• Health literacy can greatly impact the proper use of
medications
• Using universal precautions including the teach-back
method can have significant impact
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Self-assessment question
What factor(s) determine a patient’s
health literacy?
a) Formal education
b) Ethnicity
c) Age
d) None of the above
e) All of the above
23
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BREAK TIME!
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Incidence of Vancomycin-Induced
Nephrotoxicity in Patients with and without
Concomitant Piperacillin-Tazobactam
Lindsey D. Burgess, PharmD
PGY1 Pharmacy Resident
Duke University Hospital
Durham, NC Co-investigator:
Richard H. Drew, PharmD, MS, BCPS, FCCP
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Disclosure Statement
These individuals have the following to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation:
– Resident: Lindsey D. Burgess, PharmD: Nothing to disclose
– Co-Investigator: Richard H. Drew, PharmD, MS, BCPS, FCCP: Nothing to disclose
All Rights Reserved, Duke Medicine 2007
Objective
• Describe the relative incidence of nephrotoxicity
between vancomycin monotherapy and in
combination with piperacillin-tazobactam, and state
possible confounding factors
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Background
• Acute kidney injury (AKI) is a complication of many
illnesses and pharmaceutical agents
• Development of AKI in hospitalized patients increases
morbidity and mortality
• Drug-induced mechanisms
– Hypoperfusion
• Angiotensin converting enzyme inhibitors or nonsteroidal anti-
inflammatory drugs
– Renal tubular necrosis
• Aminoglycoside antibiotics
– Interstitial nephritis
• Penicillin antibiotics
Pannu, N et al. Crit Care Med. 2008;36:S216-23.
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Vancomycin
• Glycopeptide antibiotic used for the treatment of drug-
resistant gram positive organisms
– Methicillin-resistant S.aureus (MRSA)
• Associated with nephrotoxicity
– Incidence 5-35%
– Usually reversible
– Risk factors: advanced age, concomitant nephrotoxins,
pre-existing renal dysfunction, high trough
concentrations
• Requires careful monitoring of renal function and dose
adjustment when necessary Elyasi, S et al. Eur J Clin Pharmacol. 2012 Sep;68(9):1243-55.
24
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Piperacillin-Tazobactam (PT)
• Ureidopenicillin and beta-lactamase inhibitor
• Frequently used in combination with vancomycin
– Adds gram-negative and anaerobic activity
• Infrequently associated with nephrotoxicity
– Rare published reports
– Incidence <1% Zosyn package insert. Pfizer, May 2012.
http://labeling.pfizer.com/ShowLabeling.aspx?id=416
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Combination Vancomycin and PT:
Nephrotoxicity
• Combination reported to exhibit increased nephrotoxicity
compared to vancomycin monotherapy
– Incidence with combination 49.3% compared to 8.9%
with vancomycin monotherapy
• OR=9.95, p<0.001
• Based on the high frequency of co-administration,
confirmation of these findings would have significant
implications on empiric antimicrobial therapy
Min E, Box K, Lane J et al. Crit Care Med. 2011; 39(Suppl.):200.
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Purpose of Study
• Investigate the incidence of nephrotoxicity in
hospitalized adult patients receiving
intravenous (IV) vancomycin monotherapy
compared to combination therapy with
vancomycin and PT
• Explore the effect of confounding variables on
the development of vancomycin-induced
nephrotoxicity
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Objectives
• Primary
– Compare the incidence of nephrotoxicity in hospitalized
adult patients receiving IV vancomycin with and without
the addition of IV PT
• Secondary
– Determine the impact of the following on incidence of
nephrotoxicity in patients receiving vancomycin therapy
• Concomitant nephrotoxic agents
• Age
• Vancomycin trough concentration >15 mcg/ml
• Charlson Co-morbidity Score
• Total vancomycin dose > 4gm/day at any point in therapy
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Primary Endpoint
• Incidence of nephrotoxicity
• Definition: Minimum 1.5 fold-increase in serum
creatinine
– Based on the maximum serum creatinine
value within the first 7 days of vancomycin
treatment from the serum creatinine
measured within 48 hours before initiating
vancomycin
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Study Design/Population
• Single-center, retrospective, IRB-approved cohort
study
Inclusion Criteria
• Male or females age >18 yrs
• Admitted to Duke University Hospital 7/1/09-7/1/12
• Minimum of 48 hours of vancomycin
• Minimum four days of measured serum creatinine concentrations
• For the cohort of patients on concomitant PT: >48 hours of PT concurrently with vancomycin and PT initiated within 48 hrs of initiation of vancomycin
25
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Population
• Serum creatinine >1.5 mg/dL or calculated creatinine
clearance <30 ml/min (based on Cockcroft-Gault
equation)
• Previous history of renal replacement therapy
• 1.5-fold increase in serum creatinine from that
measured at the time of hospital admission and
before the initiation of vancomycin
• Incomplete medical records
Exclusion Criteria
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Methods
• Subjects and data obtained from electronic records
from the Duke Enterprise Data Unified Content
Explorer (DEDUCE)
• Patients in each group were selected through random
number generation
• Data collection:
• Demographics
• Medication orders for vancomycin and PT
• Concomitant nephrotoxins
• Vancomycin trough concentrations
• ICD-9 codes for conditions to calculate Charlson score
• Serum creatinine concentrations
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Data Analysis
• Sample size
– 180 patients (90 in each group) for 80% power to detect the
minimal increase of 15%, assuming incidence of
nephrotoxicity in patients receiving vancomycin is 10%
• Statistical analysis
– Primary: chi-squared test with a one-sided p-value and
corresponding one-sided 95% confidence interval
– Secondary: univariate analysis to assess the effect of various
risk factors on the incidence of nephrotoxicity
– Multivariate logistic regression models were fitted to assess
the association of nephrotoxicity with the addition of PT
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Population
Vancomycin
198 patients screened
99 patients included*
Vancomycin + PT
176 patients screened
1 duplicate encounter excluded
92 patients included* •Selected by
•random assignment
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Results
Patient Demographics by Treatment Group
Description
Vancomycin
Monotherapy
n=99
Combination
Group
n=92 P=value
Male (%) / Female (%) 48 (47.1%) / 51
(57.3%)
54 (52.9%) / 38
(42.7%) 0.158
Age, yrs
Mean (SD)
Median (IQR)
56.3 (+15.9)
56.7 (46-68.8)
60.7 (+15.1)
62.0 (49-70.4)
0.054
Charlson Comorbidity Index
Median (IQR)
3 (2 – 5)
4 (2 – 5)
0.050
Concomitant nephrotoxins, n (%) 71 (77.8%) 74 (74.7%) 0.695
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Results
Characterization of Infection Site by Treatment Group
Infection Site(s)
Vancomycin
Monotherapy (%)
n=99
Combination
Group (%)
n=92 P=value
Bone and Joint
CNS
Respiratory
Urinary Tract
Blood
Intra-abdominal
Other
15 (17.1)
7 (8.0)
25 (28.4)
13 (14.8)
15 (17.1)
4 (4.6)
9 (10.2)
15 (14.0)
3 (2.8)
33 (30.8)
25 (23.4)
8 (7.5)
14 (13.1)
9 (8.4)
0.053
26
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Results
Diagnosis of Sepsis by Treatment Group
Sepsis Diagnosis
Vancomycin
Monotherapy
n=99
Combination
Group
n=92 P=value
None
Sepsis
Severe sepsis
Septic Shock
86.9
10.1
2.0
1.0
72.8
16.3
4.4
6.5
0.067
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Results: Primary Endpoint
Wald Χ2=3.04, one-sided p-value = 0.041
Nephrotoxicity by Treatment Group
Endpoint
Vancomycin
Monotherapy
(n=99)
Combination
Group
(n=92)
Nephrotoxic 8 (8.08%) 15 (16.3%)
Non-nephrotoxic 91 (91.92%) 77 (83.7%)
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Results: Secondary Endpoints
By univariate analysis
*All patients had vancomycin total daily dose ≤ 4gm/day
Risk of Nephrotoxicity in select subgroups
Description
Crude (Unadjusted)
Odds Ratio
95% CI
Age 0.98 0.95-1.01
Concomitant nephrotoxic agents 1.16 0.41-3.33
Vancomycin total dose ≥
4gm/day*
- -
Vancomycin trough ≥ 15 mcg/mL 3.67 1.07-3.02
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Multivariate Analysis
*Based on one-sided analysis of the hypothesis
Risk of Nephrotoxicity
Description
Adjusted
Odds Ratio
p-value*
Addition of PT 2.48 0.032
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Limitations
• Single center, retrospective cohort study
– Incomplete medical records
– Reliability of ICD-9 codes for Charlson score
• Lower incidence of nephrotoxicity than
postulated
– Vancomycin monotherapy: 8.08%
– Combination group: 16.30%
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Conclusions
• Significant increase in nephrotoxicity was observed in the
combination group compared to the vancomycin
monotherapy
– Study results confirmed previous findings
• Steady-state vancomycin trough concentration ≥15mcg/ml
was shown to increase the occurrence of nephrotoxicity
(similar to previous studies)
27
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Acknowledgements
• DUH Pharmacy Research Committee
• Statistical Support
– John Pura, MPH (Biostatistician)
• Residency Program Director
– Beth McLendon Arvik, PharmD
• Fellow Residents
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Self-Assessment Question
• What are potential confounding factors that may
contribute to the development of nephrotoxicity
during vancomycin therapy?
A. Use of concomitant nephrotoxic agents
B. Steady-state trough concentrations ≤15mcg/ml
C. Advanced age
D. A and B
E. A and C
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Co-Investigators:
Matthew Harris, PharmD, BCPS
Debra Sudan, MD
Matthew Ellis, MD
Tacrolimus Dose Requirements in African-
American and Caucasian Kidney Transplant
Recipients on Mycophenolate and Prednisone
Kristi J. Beermann, PharmD
PGY1 Pharmacy Practice Resident
All Rights Reserved, Duke Medicine 2007
Disclosure Statement
• These individuals have the following to disclose
concerning possible financial or personal relationships
with commercial entities (or their competitors) that may be
referenced in this presentation:
– Resident: Kristi J. Beermann, PharmD: Nothing to Disclose
– Co-Investigator: Matthew Harris, PharmD, BCPS: Nothing to
Disclose
– Co-Investigator: Debra Sudan, MD: Nothing to Disclose
– Co-Investigator: Matthew Ellis, MD: Nothing to Disclose
All Rights Reserved, Duke Medicine 2007
Objective
• Identify tacrolimus doses needed to achieve
therapeutic tacrolimus concentrations in African-
American versus Caucasian patients
All Rights Reserved, Duke Medicine 2007
Background-Kidney Transplant
• In patients with end-stage renal disease, kidney
transplant is the preferred management approach
• Immunosuppression is necessary to prevent rejection
following kidney transplantation
– Tacrolimus, mycophenolate, and prednisone are commonly
used in combination
• The risk of kidney rejection is highest during the first
30 days following transplantation
N Engl J Med 1999 Dec 2;341(23):1725-30.
Nephrol Dial Transplant 2001 Sep;16(9):1905-9.
28
All Rights Reserved, Duke Medicine 2007
Background-Tacrolimus
• Dosed at 0.1 mg/kg/day in two divided doses for
kidney transplant rejection prophylaxis
– Goal tacrolimus concentration may range from 5
to 20 ng/mL, depending on certain factors
• Patient-specific factors, immunosuppressive agents
chosen, transplant center preference
• Studies suggest that African Americans may require
higher tacrolimus doses compared to Caucasian
kidney transplant recipients
Transplantation 2013 Feb 27;95(4):566-72.
Transplantation 2007 Apr 15;83(7):997-9.
Lancet 1996 Nov 23;348(9039):1446
All Rights Reserved, Duke Medicine 2007
Purpose
• Evaluate tacrolimus doses required to achieve
therapeutic tacrolimus concentrations in African-
American versus Caucasian kidney transplant
recipients at day 30 after transplantation
All Rights Reserved, Duke Medicine 2007
Objectives
• Primary
– Compare tacrolimus dose requirements (mg/kg/day) needed
to achieve therapeutic tacrolimus concentrations (8-12
ng/mL) on day 30 after transplantation in African-American
and Caucasian patients
All Rights Reserved, Duke Medicine 2007
Objectives
• Secondary
– Describe tacrolimus dose requirements (mg/kg/day) at
hospital discharge (Day DC) and post-transplant days 60
and 90
– Describe renal function (MDRD) at Day DC, and post-
transplant days 30, 60, and 90
– Describe biopsy-proven acute rejection episodes throughout
the 90 days after transplantation
– Describe tacrolimus concentration-related adverse effects
between the two groups throughout the 90 days after kidney
transplantation
MDRD: Modification of Diet in Renal Disease
All Rights Reserved, Duke Medicine 2007
Study Design
• Single-center, retrospective cohort study of patients
admitted to Duke University Hospital for kidney
transplantation between January 1, 2008 and
June 30, 2012
• Subjects identified through the transplant allograft list
and electronic order entry records
• IRB approved
All Rights Reserved, Duke Medicine 2007
Study Population-Inclusion Criteria
• >18 years of age
• Maintained on standard immunosuppressive regimen
(tacrolimus, mycophenolate, and prednisone)
• Tacrolimus concentration between 8-12 ng/mL at day
30 following de novo kidney transplantation
29
All Rights Reserved, Duke Medicine 2007
Study Population-Exclusion Criteria
• Multi-organ transplant recipient
• Documentation of non-adherence
• Patient death or transplant nephrectomy
• Use of sublingual or buccal route of administration of tacrolimus
• Dialysis dependent
• Concomitant receipt of strong 3A4 inducer/inhibitor medications
or bile acid sequestrants
• Enrollment in interventional research studies
• Systemic infection
• Positive urine or blood cultures for polyomavirus
• Dose change within 5 days from day 30 transplant visit
All Rights Reserved, Duke Medicine 2007
Methods
• Experimental groups included African-American and
Caucasian kidney transplant recipients meeting the
inclusion criteria
• Sample size calculation
– 200 patients needed to detect a difference in the
total daily tacrolimus dose of 0.8 mg/day
• Assuming an alpha of 0.05 and 80% power
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Baseline Demographics
African American
(N=85)
Caucasian
(N=62)
P-value
Age, years (mean +/- SD) 50 (13) 54 (11) 0.034
Gender ( % male) 48 71 0.006
Height, cm (mean +/- SD) 169 (15) 174 (9) 0.013
Weight, kg (mean +/- SD)
Day 30
84 (18)
84 (17)
0.927
Donor Status (%)
Living
SCD
DCD
ECD
DCD/ECD
21
73
6
14
7
45
87
5
3
5
0.002
0.113
Delayed Graft Function (%) 19 10 0.144
Induction Agent Used (%)
Steroids
Basiliximab
Thymoglobulin
Daclizumab
8
41
25
26
48
29
11
11
<0.001
SCD: Standard criteria donor, DCD: Donation after cardiac death, ECD: Expanded criteria donor
All Rights Reserved, Duke Medicine 2007
Total Tacrolimus Daily Dose at Day 30
P=0.005
All Rights Reserved, Duke Medicine 2007
Total Tacrolimus Daily Dose and
Concentration at Days DC, 60, and 90
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Renal Function-MDRD
Day DC: P=0.05
Day 30: P=0.22
Day 60: P=0.098
Day 90: P=0.041
30
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Adverse Events
• Biopsy-proven acute rejection through day 90
– 4 Caucasian subjects
• Acute cellular rejection of Banff grades IA, IB, and IIB
(two subjects)
– 1 African-American subject
• Acute cellular rejection of Banff grade IIA
• Documented concentration-related side effects
– Tremors: 10 subjects
– Headaches: 2 subjects
– Nephrotoxicity: 1 subject
All Rights Reserved, Duke Medicine 2007
Limitations
• Single-center, retrospective cohort study
• Inability to control for factors that may affect
tacrolimus concentrations
– Interacting medications, diet, timing of blood draw,
adherence
• Presence of cytochrome P-450 polymorphisms are
unknown
– Data suggest the presence of polymorphisms
induce the metabolism of tacrolimus
All Rights Reserved, Duke Medicine 2007
Conclusion
• African Americans required significantly higher total daily
tacrolimus doses than Caucasians at day 30 after de novo
kidney transplant
• African Americans required higher daily tacrolimus doses
than Caucasians at days 60 and 90 following transplant
• Renal function improved in both groups throughout the
study period
• Overall incidences of rejection and concentration-related
side effects were low
All Rights Reserved, Duke Medicine 2007
Acknowledgements
• DUH Pharmacy Research Committee
• Statistical Support
– Lan Lan, PhD
– John Pura, MPH
• Residency Program Director
– Beth McLendon-Arvik, PharmD
• Fellow Residents
All Rights Reserved, Duke Medicine 2007
Self-Assessment Question
• What was the difference in dose needed to achieve
therapeutic tacrolimus concentrations in African-
American versus Caucasian patients in this cohort?
A) 0.03 mg/kg/day
B) 1 mg/kg/day
C) 0.1 mg/kg/day
D) There was no difference in total daily tacrolimus
doses between races
All Rights Reserved, Duke Medicine 2007
Association between Oversedation from Continuous
Intravenous Sedation and Extubation Failures in
Mechanically-Ventilated Patients in the Pediatric
Intensive Care Unit
Jennifer M. Cole, PharmD
PGY1 Pharmacy Resident
Duke University Hospital
Durham, NC
Co-investigators: Travis Heath, PharmD, BCPS
David Turner, MD
31
All Rights Reserved, Duke Medicine 2007
Disclosure Statement
These individuals have the following to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation:
• Jennifer Cole, PharmD: Nothing to Disclose
• Travis Heath, PharmD: Nothing to Disclose
• David Turner, MD: Nothing to Disclose
All Rights Reserved, Duke Medicine 2007
Objective
• Describe the relationship between oversedation and
extubation failure in critically-ill pediatric patients, and
state associated risk factors
All Rights Reserved, Duke Medicine 2007
Analgesia and Sedation in the Intensive Care Unit
Am J Health Syst Pharm. 2002 Jan 15;59(2):150-78.
New Horiz 1994;2(1):.64–74.
Am J Respir Crit Care Med 1999 Jun;159(6):1742-6.
• Provides anxiolysis and amnesia
• Improves tolerance to
mechanical ventilation
• Reduces stress response
• Prolongation of mechanical
ventilation
• ↑ rates of extubation failure
• ↑ risk for the development of
ventilator-associated pneumonia
• ↑ intensive care unit and hospital
length of stay
All Rights Reserved, Duke Medicine 2007
State Behavioral Scale (SBS) Scores
• Most common, reliable tool used to assess level of
sedation in mechanically-ventilated pediatric patients
• Scoring system includes assessment of the following:
• Respiratory effort
• Coughing
• Response to external stimulus
• Attention to caregiver
• Ability to console
• Movement Pediatr Crit Care Med 2006 Mar;7(2):107-14.
All Rights Reserved, Duke Medicine 2007
Score Description
-3 Unresponsive
-2 Responsive to noxious stimuli
-1 Responsive to gentle touch or voice
0 Awake and able to calm
+1 Restless and difficult to calm
+2 Agitated
State Behavioral Scale (SBS) Scores
Pediatr Crit Care Med 2006 March ; 7(2): 107–114.
All Rights Reserved, Duke Medicine 2007
Extubation Failure
• Defined as the need for reintubation within 48-72
hours after extubation
• Pediatric Intensive Care Units (PICU) rates range from
2.7% to 22%
• Risk factors in adults include:
• Upper airway obstruction
• Pulmonary insufficiency
• Cardiac dysfunction
• Neurological impairment
• Poor muscle strength
• Excessive sedation Pediatr Crit Care Med 2005 May;6(3):312-8.
32
All Rights Reserved, Duke Medicine 2007
Purpose
• Evaluate current sedation practices and their impact
on extubation failure in critically-ill pediatric patients
All Rights Reserved, Duke Medicine 2007
Objectives
• Primary Objective
• Determine whether an association exists between
oversedation from continuous intravenous sedation
and extubation failures in mechanically-ventilated
patients in the PICU
• Secondary Objective
• Identify risk factors associated with oversedation and
with extubation failure
• Age, gender, weight, average daily doses, glasgow coma scale
(GCS) prior to intubation, duration of mechanical ventilation,
duration of continuous infusion, extubation readiness test
failures
All Rights Reserved, Duke Medicine 2007
Study Design
• Retrospective, single-center, cohort study
• Large academic medical center
• IRB approved
• Subjects identified utilizing Duke Enterprise Data
Unified Content Explorer (DEDUCE)
• On-line research tool providing Duke investigators with
access to clinical information collected during patient care
All Rights Reserved, Duke Medicine 2007
Study Population
• PICU admission between 1/1/09 -10/31/12
• Mechanical ventilation ≥ 48 hours
• Benzodiazepine and/or opioid infusion ≥ 24 hours
Inclusion Criteria
• Benzodiazepine or opioid tolerance
• Continuous infusion neuromuscular blockade 7 days preceding extubation
• Extracorporeal membrane oxygenation
• Neurologically-devastated patients
• Death during admission
• Incomplete medical records
Exclusion Criteria
All Rights Reserved, Duke Medicine 2007
Patient Screening
129 patients identified
62 patients oversedated
46 patients not oversedated
Excluded
Tracheostomy: 11
Death: 7
Duration of infusion < 24 hours: 2
Neurologically-devastated: 1
All Rights Reserved, Duke Medicine 2007
Patient Population
Demographic Oversedated
(n=62)
Not Oversedated
(n=46) p value
Male Gender , n (%) 39 (62.90) 29 (63.04) 1.00
Age, years, mean (SD) 6.64 (7.11) 4.73 (6.02) 0.093
Weight Percentile for Age,
mean (SD) 44.46 (33.27) 31.82 (30.86) 0.076
Weight Percentile for Age,
median (range) 50 (3-95) 17.5 (3-90) -
Initial GCS*, mean (SD) 8.18 (4.02) 9.48 (3.59) 0.071
ERT* Failure, n (%) 13 (20.97) 8 (17.39) 0.642
Duration of Mechanical Ventilation,
days, mean (SD) 6.64 (4.94) 6.76 (4.92) 0.998
Duration of Mechanical Ventilation,
days, median (range) 5 (2-28) 5 (2-22) -
*GCS: Glasgow Coma Scale
*ERT: Extubation readiness test
33
All Rights Reserved, Duke Medicine 2007
Primary Diagnosis
All Rights Reserved, Duke Medicine 2007
Results
p value = 0.339
22.6%
n=7
n=14
All Rights Reserved, Duke Medicine 2007
Risk Factors for Oversedation
*log-transformed
Weight Percentile
Initial GCS
Duration of Opioid Infusion
Maximum Opioid Daily Dose*,
mg/kg/day
Maximum Benzodiazepine Daily Dose*, mg/kg/day
0 0.5 1 1.5 2
Adjusted Odds Ratio
All Rights Reserved, Duke Medicine 2007
Risk Factors for Extubation Failure
Initial GCS
Duration of Mechanical Ventilation
Maximum Opioid Daily Dose*, mg/kg/day
Maximum Benzodiazepine Daily Dose*,mg/kg/day
*log-transformed
0 0.5 1 1.5 2
Adjusted Odds Ratio
All Rights Reserved, Duke Medicine 2007
Limitations
• Retrospective, single-center
• Small sample size
• Not adequately powered to detect a difference
• Inconsistent documentation of SBS scores
• Outliers influence odds ratio
All Rights Reserved, Duke Medicine 2007
Conclusions
• More patients who were oversedated failed extubation
• Absolute difference of 7.36%
• Reevaluation of dosing
• Children with a higher weight percentile for age
• Benzodiazepine continuous infusions
34
All Rights Reserved, Duke Medicine 2007
Acknowledgements
• DUH Pharmacy Research Committee
• Keliana O’Mara, PharmD, BCPS
• Statistical Support
• Lan Lan, PhD
• John Pura, MPH
• Residency Program Director
• Beth McLendon Arvik, PharmD
• Fellow Residents
All Rights Reserved, Duke Medicine 2007
Self-Assessment Question
Which of the following is NOT included in the State
Behavioral Scale (SBS) scoring system?
A. Ability to console
B. Coughing
C. Sneezing
D. Respiratory drive
All Rights Reserved, Duke Medicine 2007
Impact of Intra-operative Acetaminophen
Administration on Post-operative Opioid
Consumption in Patients Undergoing Hip or
Knee Replacement
Doug Raiff, PharmD, BCPS
Co-investigators:
Cathy Vaughan, PharmD
Amber Jones, PharmD
Ellen Flanagan, MD
All Rights Reserved, Duke Medicine 2007
These individuals have the following to disclose concerning possible
financial or personal relationships with commercial entities (or their
competitors) that may be referenced in this presentation:
-Resident: Robert D. Raiff, PharmD, BCPS: Nothing to Disclose
-Co-Investigator: Cathy A. Vaughan, PharmD: Nothing to Disclose
-Co-Investigator: Amber M. Jones, PharmD: Nothing to Disclose
-Co-Investigator: Ellen M. Flanagan, MD: Nothing to Disclose
Disclosure Statement
All Rights Reserved, Duke Medicine 2007
Presentation Objective
• State the potential benefit(s) of intravenous
acetaminophen use for surgical pain management in
hip and knee replacement patients
All Rights Reserved, Duke Medicine 2007
Background Information
• Acute post-operative pain is a major health issue
– Pain management is a focus of the recent Affordable Care Act
– 80% of surgical patients suffer from acute post-operative pain
• Opioids frequently utilized in this setting
– Associated with adverse events
• Pruritus, nausea/vomiting, constipation, respiratory depression
• Result in longer inpatient stays and increased cost
• Acute perioperative pain management guidelines
– Recently updated by American Society of Anesthesiologists
– Advocate use of multimodal approach to pain management
USDHHS, CMS. HCAHPS: Patients’ Perspectives of Care Survey. Available at:
http://www.cms.gov/HospitalQualityInits/30_HospitalHCAHPS.asp. Accessed April 2, 2013
Apfelbaum JL , et al. Anesth Analg 2003; 97:534-40
Oderda G. Pharmacotherapy 2012; 32(9 Pt 2):6S-11S
American Society of Anesthesiologists. Anesthesiology 2012; 116:248-73
35
All Rights Reserved, Duke Medicine 2007
Background: Intravenous (IV) Acetaminophen
• FDA-approval: November 2010
• Added to Duke University Hospital (DUH) formulary March 2011 with
restrictions for use
• Pharmacokinetics vs. oral acetaminophen (APAP)
– Cmax up to 70% higher with IV route
– Overall exposure (AUC) similar
• Two pivotal studies in post-operative pain patients
– Total hip or knee replacement and abdominal laparoscopic
– Both did not randomize patients until morning after surgery
Ofirmev [package insert]. Cadence Pharmaceuticals. San Diego, CA: Cadence Pharmaceuticals, Inc.; November 2010
Sinatra RS, et al. Anesthesiology 2005; 102:822-31
Wininger SJ, et al. Clin Ther 2010; 14:2348-69
All Rights Reserved, Duke Medicine 2007
Study Purpose
• Investigate the impact of IV APAP administered intra-
operatively on post-operative opioid consumption in
adult patients undergoing hip or knee replacement
All Rights Reserved, Duke Medicine 2007
Study Objectives
• Primary Objective
– Compare post-operative opioid consumption (in
oral morphine equivalents) during the 24 hours
following hip or knee replacement in adult patients
who received intra-operative IV acetaminophen
versus those that received no IV acetaminophen.
All Rights Reserved, Duke Medicine 2007
Study Objectives
• Secondary Objectives
– Report time (in minutes) spent in post-anesthesia
care unit (PACU) following hip or knee replacement
– Characterize use of adjunctive analgesics during
the 24 hours following hip or knee replacement
– Report incidence of oversedation (RASS score ≤ -
4) during the 24 hours following hip or knee
replacement
– Report incidence of need for opioid reversal
(naloxone bolus administration) during the 24
hours following hip or knee replacement
All Rights Reserved, Duke Medicine 2007
Study Design
• Single-center, retrospective cohort
• Adult patients at DUH who underwent hip or knee replacement
between July 1, 2010 and March 31, 2012
• Subjects identified via Duke Enterprise Data Unified Content
Explorer (DEDUCE) database query
– Search conducted using associated ICD-9 codes
• IRB approved: January 2013
All Rights Reserved, Duke Medicine 2007
Study Design
0-24 hours immediately after surgery completion
Opioid consumption documented in both patient groups
Time zero: Completion of hip or knee replacement
0-60 minutes prior to completion of procedure
Patient receives IV APAP Patient does not receive IV APAP
36
All Rights Reserved, Duke Medicine 2007
Study Population
Inclusion Criteria
• Patients ≥ 18 years old
• Underwent hip or knee replacement surgery at DUH from July 1, 2010 through March 31, 2012
• For the experimental group, patients received a 1 gram dose of IV APAP ≤ 1 hour prior to surgery completion
Exclusion Criteria
• Intra-operative IV ketamine
• Intra-operative IV non-steroidal anti-inflammatory drugs
• IV APAP dose other than 1 gram
• More than one IV APAP dose given during 24-hour study period
All Rights Reserved, Duke Medicine 2007
Methods
• IV APAP group: Patients receiving intra-operative IV APAP
meeting inclusion criteria
• Non-exposed group: Equal number of patients who did not
receive intra-operative IV APAP
• Random number generator applied to both groups
• Sample size calculation
– 87 patients per group needed to detect 30% difference in
24-hour oral morphine usage
• Assuming 80% power and 2-sided α level of 0.05
• Two-sided, unpaired t-test utilized
• All opioids converted to oral morphine equivalents
– Rounded to nearest 0.1 mg
All Rights Reserved, Duke Medicine 2007
Results
Screened for study eligibility (N = 431)
IV APAP
(N = 88)
Non-Exposed Group
(N = 88)
Excluded from study (N = 255)
Dose outside of time frame (N = 155)
Intra-operative ketamine (N = 67)
>1 dose during 24-hour study (N = 27)
Dose other than 1 gram given (N = 5)
Received intra-operative NSAID (N = 4)
All Rights Reserved, Duke Medicine 2007
Baseline Demographics
All Rights Reserved, Duke Medicine 2007
Primary Endpoint
Ora
l M
orp
hin
e E
qu
iva
len
ts (
mg
)
149.3 ± 98.7 147.2 ± 122.6
All Rights Reserved, Duke Medicine 2007
Length of PACU Stay
Le
ng
th o
f sta
y (
min
)
37
All Rights Reserved, Duke Medicine 2007
Utilization of Adjunctive Analgesics
*Gabapentin or pregabalin
All Rights Reserved, Duke Medicine 2007
Safety
Sessler CN, et al. Am J Respir Crit Care Med 2002; 166:1338-44
• No patients in the IV acetaminophen and non-
exposed groups experienced either of the following:
– RASS score of ≤ -4 during the 24 hours
immediately following surgery
• Scale ranges from +4 (combative) to -5 (unarousable)
• Score of -4 is associated with deep sedation
– Need for naloxone bolus administration for
opioid reversal
All Rights Reserved, Duke Medicine 2007
Study Limitations
• Single-center, retrospective cohort study
• Different percentages of hip and knee procedures
within each of the groups
• No control placed on adjunctive analgesia regimens
patients received during 24-hour post-operative
period
– Patients may have received different pain
medications based on health care provider
All Rights Reserved, Duke Medicine 2007
Conclusions
• No statistical difference in 24-hour opioid consumption in
adult hip and knee replacement patients who received
intra-operative IV APAP versus patients who received no
IV APAP
• No apparent difference in length of PACU stay
• No patients required naloxone boluses or met pre-
specified oversedation criteria
– Larger study needed to evaluate this endpoint
• Higher number of patients in non-exposed group used
adjunctive analgesics
– Possibly a reflection of differences in pain control
• Future directions……
All Rights Reserved, Duke Medicine 2007
Acknowledgements
• DUH Pharmacy Research Committee
– Beth McLendon-Arvik, PharmD
• Statistical Support
– John Pura, MPH
– Lan Lan, PhD
• Residency Program Director
– Ann Scates-McGee, PharmD
• Fellow Residents
All Rights Reserved, Duke Medicine 2007
Self-Assessment Question
• What was the difference in 24-hour post-operative
opioid consumption (oral morphine equivalents)
between patients who received intra-operative IV
APAP and those patients who received no IV APAP?
A. 100 mg
B. 50 mg
C. 20 mg
D. 2 mg
38
All Rights Reserved, Duke Medicine 2007
• Questions?
• Please complete the evaluations!
• Thank you for attending Spring
Symposium 2013!