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Clinical Controversies Activity Number: 0217-0000-16-134-L01-P, 1.50 hours of CPE credit; Activity Type: A Knowledge-Based Activity
Tuesday, October 25, 2016 10:15 a.m. to 11:45 a.m. Great Hall 4
Moderator: Douglas L. Jennings, Pharm. D., FCCP, FAHA, AACC, BCPS, AQ-Cardiology Clinical Pharmacy Manager-Heart Transplant and Mechanical Circulatory Support, New York Presbyterian Columbia University Medical Center, New York, New York
Agenda
10:15 a.m. Ivabradine For Heart Failure: A “Funny” Alternative or Serious Drug Therapy? Sheryl L. Chow, Pharm. D., FCCP, BCPS, AQ-Cardiology Associate Professor, Western University of Health Sciences, Los Angeles, California
10:35 a.m. Digoxin and Heart Failure: The End of an Era? Steven P. Dunn, Pharm. D., BCPS Pharmacy Clinical Coordinator, Cardiology, University of Virginia Health System, Charlottesville, Virginia
10:55 a.m. Emerging Concepts in the Management of Clostridium difficile-Associated Diarrhea P. Brandon Bookstaver, Pharm. D., BCPS, AQ-IDAssociate Professor and Vice Chair, South Carolina College of Pharmacy, University ofSouth Carolina, Columbia, South Carolina
11:15 a.m. Short-Course Antimicrobials for Systemic Infections: How Low Can We Go? David T. Bearden, Pharm. D. Clinical Professor and Chair, Department of Pharmacy Practice; Clinical Assistant Director, Department of Pharmacy Services, Oregon State University/Oregon Health and Science University College of Pharmacy, Portland, Oregon
11:35 a.m. Question and Answer Session
Conflict of Interest Disclosures David T. Bearden: no conflicts to disclose P. Brandon Bookstaver: Speaker’s Bureau: (Rockpointe, FeeCe.com), Grants: (Allergan, Plc) Sheryl L. Chow: Consultancies: (Relypsa), Speaker’s Bureau: (Amgen, Novartis)Steven P. Dunn: no conflicts to discloseDouglas L. Jennings: no conflicts to disclose
Learning Objectives 1. Explain how I-f,or “funny” channel inhibition relates to heart failure symptoms and outcomes.2. Evaluate the literature describing the use of ivabradine in patients with heart failure.
© American College of Clinical Pharmacy 1
3. Recommend a clinical role for ivabradine in the management of heart failure.4. Review the pitfalls of digoxin therapy in heart failure.5. Define the risk of mortality in digoxin-treated patients.6. Clarify the role for digoxin in the management of heart failure.7. Discuss the clinical utility of C. difficile ribotyping.8. Define the role of metronidazole as a first-line therapy.9. Outline the role of pharmacists in fecal bacteriotherapy.10. Analyze the evidence base for shortening antimicrobial courses11. Outline the benefits/risks of short course antibiotic therapy.12. Define the role of antimicrobial stewardship in the implementation of abbreviated antibiotic course.
Self-Assessment Questions
Self-assessment questions are available online at www.accp.com/am
© American College of Clinical Pharmacy 2
Ivabradine for Heart Failure: A “funny” alternative or a serious drug therapy?
American College of Clinical PharmacyHollywood, FL
October 25, 2016
Sheryl L. Chow, PharmD, FCCP, FAHA, FHFSA, BCPS AQ‐CardiologyAssociate ProfessorCollege of Pharmacy
Western University of Health Sciences
Conflict of Interest
• Speakers Bureau: Novartis, Amgen, and American Heart Association
• Consultant: Relypsa
Objectives
• Explain how If channel inhibition relates to heart failure symptomsand outcomes
• Evaluate the literature describing use of ivabradine in patients with heart failure
• Recommend a clinical role for ivabradine in the management of heartfailure
Ivabradine Mechanism of Action
Ivabradine Pivotal Study –SHIFT
Systolic Heart failure treatment with the If inhibitor ivabradine Trial
SHIFT Study
Ivabradine 5 mg twice daily for 2 weeks (n = 3,268)
Ivabradine 7.5/5.0/2.5 mg twice daily according to HR and tolerability*
Placebo twice daily (n = 3,290)
Median follow‐up duration: 22.9 months (interquartile range = 18 to 28 months)
14 day run‐in
SHIFT Study Design
Ran
domization
HF, heart failure; HR, heart rate; LVEF, left ventricular ejection fraction.Swedberg K, et al. Lancet. 2010;376:875‐885.
SHIFT Study
Randomized, double‐blind, parallel‐group study to assess the effect of ivabradine in addition to guidelines‐based treatment in 6,558 patients with HF, conducted from October 2006 throughMarch 2010.
• Subjects ≥ 18 years
• In sinus rhythm and had a resting HR ≥ 70 bpm
• NYHA Class II, III, or IV and in stable condition for≥ 4 weeks
• LVEF ≤ 35%
• Optimal stable Standard of Care (SOC) therapy,including maximallytolerated doses of beta‐blockers
• Hospitalization for worsening HF within ≤ 12 months
© American College of Clinical Pharmacy 3
Primary and Secondary Endpoints
CV, cardiovascular.Swedberg K, et al. Lancet. 2010;376:875‐885.Corlanor® (ivabradine) Prescribing Information, Amgen.
SHIFT Study
• Composite of the first occurrence of either CV death or hospital admissionfor worsening HF
•Primary Endpoint
• CV death (component of the primary composite endpoint)
• Hospitalization for worsening HF (component of the primary composite endpoint)
•Secondary Endpoints
Key Inclusion and Exclusion Criteria
MI, myocardial infarction; NYHA, New York Heart Association.Swedberg K, et al. Lancet. 2010;376:875-885. Swedberg K, et al. Eur J Heart Fail. 2010;12:75‐81.
SHIFT Study
• Male/female ≥ 18 years
• NYHA Class II, III, or IV and instable condition for ≥ 4 weeks
• LVEF ≤ 35%
• Sinus rhythm with resting HR ≥ 70 bpm (resting EKG)
• Hospital admission for worsening HF within previous 12 months
Key Inclusion Criteria
• Recent MI (< 2 months)
• Ventricular or atrioventricular pacing operative for 40% or more of the day
• Permanent atrial fibrillation or flutter
• Sick sinus syndrome, sino‐atrial block,second and third degree atrioventricular block
• Symptomatic hypotension
• Severe or uncontrolled hypertension
Key Exclusion Criteria
Patient Baseline Characteristics
eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure.Swedberg K, et al. Lancet. 2010;376:875-885.
SHIFT Study
IvabradineN = 3,241
PlaceboN = 3,264
Age (mean years, SD) 61 (11) 60 (12)
Male, % 76 77
NYHA II, % 49 49
NYHA III, % 50 50
NYHA IV, % 2 2
HR (mean bpm, SD) 80 (10) 80 (10)
LVEF (mean %, SD) 29 (5) 29 (5)
SBP (mean mmHg, SD) 122 (16) 121 (16)
eGFR (mean mL/min/1.73 m2, SD) 75 (23) 75 (23)
Patient Baseline Characteristics (continued)
ACE, angiotensin converting enzyme; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; SD, standard deviation.Swedberg K, et al. Lancet. 2010;376:875-885.
SHIFT Study
IvabradineN = 3,241
PlaceboN = 3,264
Medical History
Duration of heart failure (years, SD) 4 (4) 4 (4)
Ischemic etiology 68% 67%
Myocardial infarction 56% 56%
Hypertension 67% 66%
Diabetes 30% 31%
Previous stroke 7% 9%
History of atrial fibrillation/flutter 8% 8%
Treatment at Randomization
beta-blocker 89% 90%
ACE inhibitor 79% 78%
Diuretic (excluding antialdosterone agents) 84% 83%
Antialdosterone agents 61% 59%
Cardiac glycosides 22% 22%
Devices 3% 4%
CRT 1% 1%
ICD 3% 4%
Reasons for Failure to Reach Beta‐Blocker Target Dose or Not Receiving Beta‐Blocker
IvabradineN = 3,241
PlaceboN = 3,264
Patient at target dose of beta‐blocker 26% 26%
Patients at ≥ 50% target dose of beta-blocker 56% 56%
Reasons for not reaching beta-blocker target dose
Hypotension 44% 45%
Fatigue 32% 32%
Dyspnea 14% 14%
Dizziness 13% 12%
Bradycardia 6% 6%
Patients not receiving beta‐blocker 11% 10%
Reasons not prescribed betablocker*
COPD 37% 32%
Hypotension 17% 20%
Asthma 10% 11%
Cardiac decompensation 7% 9%
Dizziness or bradycardia 7% 5%
Fatigue 5% 6%
Raynaud or PAD 5% 6%
*More than one reason could be reported.COPD, chronic obstructive lung disease; PAD, peripheral arterial disease.Swedberg K, et al. Lancet. 2010;376:875-885.
SHIFT Study
6,558 randomized
7,411 screened
3,241 analyzed2 (<1%) lost to follow-up73 (2%) consent withdrawals
3,264 analyzed1 (<1%) lost to follow-up58 (2%) consent withdrawals
Excluded patients: 2725 Patients from removed centers2 Study drug not dispensed
Patient Disposition
Excluded patients: 2621 Patients from removed centers5 Study drug not dispensed
Swedberg K, et al. Lancet. 2010;376:875-885.
SHIFT Study
3,290 placebo3,268 ivabradine
Median follow-up duration: 22.9 months
© American College of Clinical Pharmacy 4
Ivabradine TitrationStarting dose
Titration Period: D14 & D28Follow-up Period: Every 4 months
< 50 bpm or patient experiencing signs or symptoms related to
bradycardia
5 mg twice daily
2.5 mg twice daily
50 to 60 bpm > 60 bpm
5 mg twice daily 7.5 mg twice daily
Treatment was discontinued if heart rate remained below 50 bpm or symptoms of bradycardia persisted after dose reduction.
SHIFT Study
D, day.Swedberg K, et al. Lancet. 2010;376:875-885.Corlanor® (ivabradine) Prescribing Information, Amgen.
Difference in Heart Rate Reduction Between Groups Was Early and Sustained Throughout Study
Swedberg K, et al. Lancet. 2010;376:875-885.Data on file, Amgen.
90
80
70
60
50
00 2 weeks 1 4 8 12 16 20 24 28 32
Follow-up (months)
64
7580
75
67
Placebo
Ivabradine
Beta-blocker dose remained stable in 86% of the ivabradinegroup and 82% of the placebo group throughout the study
MeanHeartRate (bpm)
SHIFT Study
Time to First Event of Hospitalization for Worsening HF or CV Death
Primary Composite Endpoint: Time to CV Death or First Hospitalization for Worsening HF.ARR, absolute risk reduction; CI, confidence interval; SOC, standard of care.Corlanor® (ivabradine) Prescribing Information, Amgen.Swedberg K, et al. Lancet. 2010;376:875-885
Time (months)
40
30
20
10
00 6 18 24 3012
Placebo + SOC(937 events)
Ivabradine + SOC(793 events)
18% Relative Risk Reduction
Hazard Ratio 0.82 95% CI (0.75–0.90)ARR = 4.2%P < 0.0001
Patients W
ithPrimary
Composite Endpoint(%
)
36
Primary Composite Endpoint
The treatment effect reflected only a reduction in the risk of hospitalization for worsening HF; there was no favorable effect on the mortality component of the primary endpoint.
Hospitalization for Worsening HF at Any Time
Swedberg K, et al. Lancet. 2010;376:875-885.
Hazard Ratio 0.7495% CI (0.66–0.83)ARR = 4.7%
26% Relative Risk Reduction
Placebo + SOC(672 events)
Ivabradine + SOC(514 events)
40
30
20
10
00 6 18 24 3012
Time (months)
Patients W
ith First Hospitalization
For Worsen
ingHF (%
)
Secondary Endpoint
CV Death at Any Time
CI, confidence interval; CV, cardiovascular; SOC, standard of care.Swedberg K, et al. Lancet. 2010;376:875-885.
9% Relative Risk Reduction
Placebo + SOC(491 events)
Ivabradine + SOC(449 events)
40
30
20
10
00 6 18 24 3012
Hazard Ratio 0.9195% CI (0.80–1.03)ARR = 1.1%
Time (months)
Patients W
ithCV Death (%)
Secondary Endpoint
In the overall treatment population, ivabradinehad no statistically significant benefit on cardiovascular death
Ivabradine(n = 3,241)
Placebo(n = 3,264)
HR(95% CI)
Interaction Test P Value
Primary composite endpoint1
< 77 bpm (N = 3,144) 21% 23%0.029
77 bpm (N = 3,357) 27% 34%
CV death2
< 77 bpm (N = 3,144) 12% 11%0.038
77 bpm (N = 3,357) 15% 18%
Hospitalization for WHF2
< 77 bpm (N = 3,144) 14% 16%0.107
77 bpm (N = 3,357) 18% 25%
Effect of Ivabradine on Outcomes in Patients by Baseline Heart Rate (median 77 bpm)
• The median heart rate in SHIFT (77 bpm) was a pre‐specified cut point of the randomized set
Favors Ivabradine Favors Placebo
2.00 1.0
1. Swedberg K, KomajdaM, BohmM, et al. Lancet. 2010;376:875‐885. 2. Data on file, Amgen.
© American College of Clinical Pharmacy 5
Favors ivabradine Favors placebo
% of TotalPopulation
Corlanorn (%)
Placebon (%)
Hazard Ratio (95% CI)
Hazard Ratio (95% CI)
Age≥ 65 years 38.0% 386 (30.5%) 410 (33.9%) 0.89 (0.77, 1.02)≥ 75 years 11.1% 125 (33.9%) 133 (37.7%) 0.89 (0.70, 1.14)
Age quartile19 to ≤ 53 26.6% 145 (17.4%) 227 (25.4%) 0.64 (0.52, 0.79)53 to ≤ 60 23.9% 175 (23.0%) 195 (24.7%) 0.90 (0.74, 1.11)60 to ≤ 69 26.5% 241 (27.7%) 261 (30.6%) 0.89 (0.74, 1.05)≥ 69 years 23.1% 232 (29.9%) 254 (35.1%) 0.84 (0.70, 1.00)
SexMale 76.4% 624 (25.3%) 725 (28.9%) 0.84 (0.76, 0.94)Female 23.6% 169 (21.7%) 212 (28.0%) 0.74 (0.60, 0.91)
RaceCaucasian 88.7% 722 (25.1%) 835 (28.9%) 0.84 (0.76, 0.93)Black 1.2% 9 (28.1%) 15 (34.9%) 0.62 (0.27, 1.45)Asian 8.2% 47 (17.5%) 68 (25.8%) 0.64 (0.44, 0.93)Other/unknown 2.0% 15 (24.2%) 19 (29.2%) 0.74 (0.37, 1.47)
Cause of heart failureNon‐ischemic 32.1% 218 (21.2%) 296 (27.9%) 0.72 (0.60, 0.85)Ischemic 67.9% 575 (26.0%) 641 (29.1%) 0.87 (0.78, 0.97)
Weight Quartile≤ 69.4 25.0% 224 (27.8%) 290 (35.2%) 0.74 (0.62, 0.89)> 69.4 to ≤ 79.6 25.0% 196 (24.9%) 234 (28.0%) 0.88 (0.72, 1.06)> 79.6 to ≤ 91 25.7% 191 (22.6%) 203 (24.6%) 0.88 (0.72, 1.07)> 91 24.3% 182 (22.7%) 210 (27.0%) 0.81 (0.66, 0.99)
Baseline heart rate quartile≤ 73 30.1% 199 (20.1%) 211 (21.8%) 0.91 (0.75, 1.11)> 73 to ≤ 77 22.2% 169 (23.4%) 181 (25.0%) 0.92 (0.74, 1.13)> 77 to ≤ 84 23.1% 197 (25.9%) 202 (27.2%) 0.94 (0.77, 1.14)> 84 24.4% 228 (29.8%) 343 (41.6%) 0.64 (0.54, 0.76)
0.25 0.50 0.75 1.00 1.25 1.50
Corlanor® (ivabradine) Prescribing Information, Amgen.
Effect of Treatment on Primary CompositeEndpoint in Subgroups (1/2)
SHIFT Study
Effect of Treatment on Primary CompositeEndpoint in Subgroups (2/2)
Corlanor® (ivabradine) Prescribing Information, Amgen.
% of TotalPopulation
Corlanor®
n (%)Placebon (%)
Hazard Ratio (95% CI)
Hazard Ratio (95% CI)
NYHA class
NYHA class II 48.7% 300 (18.9%) 356 (22.5%) 0.81 (0.69, 0.94)
NYHA class III 49.5% 470 (29.3%) 542 (33.5%) 0.84 (0.75, 0.95)
NYHA class IV 1.7% 23 (46.0%) 38 (62.3%) 0.71 (0.42, 1.19)
Baseline LV ejection fraction quartile
≤ 26 27.6% 303 (33.9%) 335 (37.1%) 0.87 (0.75, 1.02)
> 26 to ≤ 30 25.3% 194 (23.9%) 252 (30.2%) 0.76 (0.63, 0.91)
> 30 to ≤ 33 26.0% 168 (20.3%) 224 (25.9%) 0.75 (0.62, 0.92)
> 33 21.1% 128 (18.1%) 126 (19.0%) 0.93 (0.73, 1.19)
Baseline beta blocker use quartile
None 10.5% 101 (29.4%) 134 (39.3%) 0.72 (0.55, 0.93)
> 0 to < 25 14.0% 148 (30.8%) 171 (40.0%) 0.74 (0.59, 0.92)
≥ 25 to < 50 25.0% 204 (26.2%) 260 (30.8%) 0.81 (0.68, 0.98)
≥ 50 to < 100 26.0% 181 (21.6%) 212 (24.8%) 0.88 (0.72, 1.07)
≥ 100 22.9% 149 (20.1%) 150 (20.1%) 0.99 (0.79, 1.24)
Baseline aldosterone antagonist useYes 60.3% 556 (28.1%) 632 (32.6%) 0.81 (0.73, 0.91)
No 39.7% 237 (18.8%) 305 (23.1%) 0.80 (0.68, 0.95)
DiabetesNo history of diabetes 69.6% 525 (23.1%) 611 (27.1%) 0.83 (0.74, 0.93)
History of diabetes 30.4% 268 (27.5%) 326 (32.4%) 0.81 (0.69, 0.95)
HypertensionNo history of hypertension 33.7% 274 (25.4%) 330 (29.7%) 0.81 (0.69, 0.95)
History of hypertension 66.3% 519 (24.0%) 607 (28.2%) 0.83 (0.74, 0.93)
All 100.0% 793 (24.5%) 937 (28.7%) 0.82 (0.75, 0.90)
0.25 0.50 0.75 1.00 1.25 1.50Favors corlanor Favors placebo
SHIFT Study
Improvement (%) Ivabradine Placebo
Treatment ComparisonP Value
NYHA classificationIvabradine, n = 887; Placebo, n = 776
28% 24% 0.001
Patient assessment of HF symptomsIvabradine, n = 2,118; Placebo, n = 2,017
72% 68% 0.0005
Physician assessment of HF symptomsIvabradine, n = 1,888; Placebo, n = 1,772
61% 57% 0.0011
Effects of ivabradine in NYHA Class or Heart Failure Symptoms in SHIFT
HF = heart failure; NYHA = New York Heart Association; SHIFT = Systolic Heart failure treatment with the If inhibitor ivabradine Trial
Swedberg K, et al. Lancet. 2010;376:875‐885.
• Small but significant improvements were observed in NYHA functionalclass and patient‐ and physician‐assessed change in heart failure symptoms
Adverse Drug Reactions with Rates ≥ 1.0% Higher on Ivabradine than Placebo
Adverse Events IvabradineN = 3,260
PlaceboN = 3,278
Bradycardia 10% 2.2%
Hypertension (Blood pressure increased)
8.9% 7.8%
Atrial Fibrillation 8.3% 6.6%
Phosphenes (Visual brightness) 2.8% 0.5%
Corlanor® (ivabradine) Prescribing Information, Amgen.
Adverse Events
Ivabradine Event (%)
PlaceboEvent (%) HR (95% CI) P Value
Primary composite endpointCV death or hospitalization for WHF
< 75 bpm (N = 2,351) 21% 21% 0.77
< 0.0001 75 bpm (N = 4,150) 27% 33%
CV death
< 75 bpm (N = 2,351) 12% 11% 0.34
0.02 75 bpm (N = 4,150) 15% 17%
Hospitalization for WHF
< 75 bpm (N = 2,351) 13% 15% 0.23
< 0.0001 75 bpm (N = 4,150) 18% 24%
Favors Ivabradine Favors Placebo0.5 1.0 2.0
Efficacy Endpoints in Patients With a Baseline Heart Rate < 75 or 75 bpm (Post‐Hoc Analysis)
CV = cardiovascular; WHF = worsening heart failure; CI = confidence interval.BohmM, et al. Clin Res Cardiol. 2013;102:11‐22.
Primary Endpoint:
• Change in LVESVI from baseline to 8 months
Placebo (n = 203)Ivabradine (n = 208)
Included set (n = 611)89 centers, 21 countriesIncluded set (n = 611)89 centers, 21 countries
Placebo (n = 307)Ivabradine (n = 304)
What Was the Effect of Ivabradine on Left Ventricular End‐Systolic Volume Index?
LVESVI = left ventricular end‐systolic volume index
Tardif J‐C, et al. Eur Heart J. 2011;32:2507‐2515.
Excluded (n = 104)
68 echocardiography issues
23 withdrawn due to death
13 consent withdrawn
Excluded (n = 96)
79 echocardiography issues
13 withdrawn due to death
4 consent withdrawn
© American College of Clinical Pharmacy 6
Heart Rate Change in the Echo Substudy
0
25
50
75
100
Mean Heart Rate
(bpm)
Ivabradine(N = 208)
Baseline Month 8
Placebo(N = 203)
Baseline Month 8
78.4
63.5
78.872.2
Tardif J‐C, et al. Eur Heart J. 2011;32:2507‐2515.
Prespecified SHIFT echocardiographic substudy (N = 411) evaluated the effect of heart rate reduction with ivabradine on hemodynamic parameters after 8 months of treatment compared with placebo. Mean dosage of ivabradine during the substudy was 6.0 +1.6 mg bid.
bid = twice daily; bpm = beat per minute.
Effect of Ivabradine on LV Ejection Fraction
a∆ = estimate of ivabradine minus placebo based on a parametric covariance analysis adjusted for country, beta‐blocker intake at randomization, and baseline value. The 95% CI is from the same estimate (two‐sided).CI = confidence interval; LV = left ventricular; LVEF = LV ejection fraction.
Tardif J‐C, et al. Eur Heart J. 2011;32:2507‐2515.
0
10
20
30
40
50
LVEF (%)
Adjusted Change From Baseline in LVEF∆ +2.7% (95% CI: 1.3, 4.2)a
P < 0.001
Ivabradine(N = 204)
Baseline Month 8
Placebo(N = 199)
Baseline Month 8
32 ± 935 ± 10
32 ± 9 32 ± 10
Effect of Ivabradine on LV Remodeling
0
25
50
75
100
LVESVI (mL/m
2 )
Adjusted Change From Baseline in LVESVIa
∆ –5.8 mL/m2 (95% CI: –8.8, –2.7)b
P < 0.001
Ivabradine(N = 208)
Baseline Month 8
Placebo(N = 203)
Baseline Month 8
65 ± 2958 ± 28
64 ± 30 63 ± 29
aLVESVI = LV end‐systolic volume; b∆ = estimate of ivabradine minus placebo based on a parametric covariance analysis adjusted for country, beta‐blocker intake at randomization, and baseline value. The 95% CI is from the same estimate (two‐sided).
CI = confidence interval; LV = left ventricular; LVESVI = LV end‐systolic volume index.
Tardif J‐C, et al. Eur Heart J. 2011;32:2507‐2515.
5
6.7
3.3
4.3
0
2
4
6
8
10KCCQ‐CSS KCCQ‐OSS
Ivabradine (n = 842) Placebo (n = 839)
Δ, 1.8 (0.30–3.24)*P = 0.018
Δ, 2.4 (0.91–3.85)*P < 0.001
Chan
ge at 12
months
Between‐group difference for change in KCCQ‐CSS and KCCQ‐OSS at 12 months
Effects of ivabradine in Health‐Related Quality of Life in SHIFT
* The treatment effect on the change from baseline in KCCQ scores at 12 months was assessed, using a covariance analysis adjusted for baseline KCCQ, beta‐blocker intake at randomization, and country.
CSS = clinical summary score ; KCCQ = Kansas City Cardiomyopathy Questionnaire; OSS = overall summary score; SHIFT = Systolic Heart failure treatment with the If inhibitor ivabradine Trial
Ekman I, et al. Eur Heart J. 2011;32:2395‐2404.
How treatments are evaluated for ACC/AHA/HFSA Guidelines
Class (Strength) of Recommendation (COR)
Class I (benefit >>> risk)Strong recommendation. A Class I treatment is recommended, useful, effective, and beneficial
Class IIa (benefit >> risk)Moderate recommendation. A Class IIarecommendation is reasonable, can be useful, effective, and beneficial
Class IIb (benefit ≥ risk)Weaker recommendation. A Class IIb treatment may be reasonable and might be considered.
Class III Harm (risk> benefit)A class III treatment is potentially harmful and associated with excess morbidity/mortality
Level (Quality) of Evidence (LOE)
Level AEvidence from more than 1 randomized clinical trial or meta‐analyses of high‐quality randomized clinical trials, or 1 or more randomized clinical trials corroborated by high‐quality registry studies
Level B‐R (NEW)Evidence form 1 or more randomized clinical trials or meta‐analyses of moderate quality randomized clinical trials
Level B‐NR (NEW)Evidence from 1 or more well‐designed non‐randomized studies, observational studies, or registry studies, or meta‐analyses of such studies
Level C‐EOConsensus of expert opinion based on clinical experience
Yancy et al. Circulation. 2016;134:[ePub ahead of print]
Potential Candidates for Ivabradine Therapy
Taking maximally tolerated doses of beta‐blockers
• Common reasons for not takingmaximally tolerated dose
• Hypotension
• Fatigue
• Dizziness
Contraindicated to beta‐blocker use
• Common reasons for not receiving any dose
• COPD
• Hypotension
• Severe Asthma
Patients with stable symptomatic chronic heart failure with LVEF ≤ 35% in sinus rhythm receiving standard therapy with resting heart rate ≥ 70 bpm.
Corlanor Prescribing Information, Amgen
© American College of Clinical Pharmacy 7
Summary
• Ivabradine is the first‐in‐class, HCN channel blocker that lowers heartrate.
• Indicated to reduce risk of hospitalization for worsening HF in patientswith stable symptomatic CHF with LVEF ≤ 35%, who are in sinus rhythm with resting HR ≥ 70 bpm.
• Maximally tolerated beta‐blockers
• Contraindication to beta‐blockers
• Current guideline updates provide a moderate recommendation(Class IIA; LOE B‐R) based on SHIFT data.
• Further study needed in other populations?
© American College of Clinical Pharmacy 8
2016 ACCP Annual Meeting
Digoxin and Heart Failure: The End of an Era?
Steven P. Dunn, PharmD, BCPS (AQ Cardiology), FAHA
Pharmacy Clinical Coordinator, Heart & Vascular
University of Virginia Health System
Assistant Professor of Medicine, UVA School of Medicine
Charlottesville, Virginia
October 2016
2016 ACCP Annual Meeting
Conflict of Interests
• No relevant conflicts
• I do have foxglove in my garden
2016 ACCP Annual Meeting
Learning Objectives
• Review the pitfalls of digoxin therapy in heart failure.
• Define the risk of mortality in digoxin‐treated patients.
• Clarify the role for digoxin in the management of heart failure.
2016 ACCP Annual Meeting
The Digoxin Era• Digoxin has been in use for cardiac disease for more than 200 years
• Medical utility of foxglove first identified by Withering
“It was decided to proceed with the proposal for digitalization.. There was no dyspnea on lying flat.. The lungs were entirely clear.”‐‐Dr. Howard G. Bruenn on treating President Franklin D. Roosevelt
2016 ACCP Annual Meeting
Digoxin – Mechanism of Action
• Dual cardiac mechanisms:• Positive inotropic effect due to inhibition of Na/K/ATPase channel resulting inpreferential use of Na/Ca channel, increasing intramyocitic calcium concentration
• Increase in parasympathetic activity via vagal nerve stimulation• Compensatory neurohormonal action – decreased norepinephrine
• Slows heart rate
• Net effects: increased inotropy, lowered HR, and decreased norepinephrine concentration
2016 ACCP Annual Meeting
Lower serum digoxin
concentration associated with
improved mortality
Withering describes the
use of foxglove in heart failure
DIGNo mortality
benefit to digoxin in HF; reduces
rehospitalization
Digoxin analyses in atrial fibrillation
2014200319971970’s1785
Retrospective observational
studies suggest association of
digoxin use with mortality in HF
patients
© American College of Clinical Pharmacy 9
2016 ACCP Annual Meeting
Guideline Recommendations• 2013 ACC/AHA: Class IIa, LOE C: “Digoxin can be beneficial in patients with HFrEF, unless contraindicated, to decrease hospitalizations for HF”
• 2010 HFSA: “Digoxin may be considered to improve symptoms in patientswith reduced LVEF who have signs and symptoms of HF and are receivingstandard therapy” (SOE B/C)
• 2016 ESC: “Digoxin may be considered in patients in sinus rhythm with symptomatic HFrEF to reduce the risk of hospitalization …”
• 2013 CCS: “We recommend digoxin in patients in sinus rhythm who continue to have moderate to severe symptoms, despite optimized HFtherapy to relieve symptoms and reduce hospitalizations” (StrongRecommendation)
J Am Coll Cardiol. 2013;62:e147‐239J Card Fail 2010;16:475‐539
Eur Heart J (2016) 37, 2129–2200Can J Cardiol 29 (2013) 168–181
2016 ACCP Annual Meeting
Digoxin Headwinds
• (Un)ease of use; potential for toxicity
• Lack of overall survival benefit in heart failure patients
• Increase in mortality in digoxin treated patients with atrial fibrillation?
• Alternatives to digoxin in selected patients
2016 ACCP Annual Meeting
Digoxin Toxicity in Heart Failure
• Digoxin toxicity characterized by nausea, vomiting, visual disturbance, bradyarrhythmia, and potentially ventricular tachycardia
• Generally requires hospitalization and potential reversal of digoxin effect via antidote
• Highly cleared by the kidneys (50‐70% unchanged)• Heart failure patients are at higher risk of acute kidney injury via cardiorenalmechanisms of decompensation
• Distributes mainly to lean body tissue• Heart failure is linked to lean body wasting via cardiac cachectic mechanisms
• Inotropic effect likely increases arrhythmogenicity• Heart failure patients are at high risk of sudden cardiac death
2016 ACCP Annual Meeting
Is Digoxin Toxicity Such a Big Deal?
• Premier database analysis of 19,543 cases of digoxin toxicity from 2007‐2011
• Only 5,004 patients received digoxin immune fab (25.6%)
• Patients receiving immune fab on hospital Day 1 or 2 did not experience increased mortality or length of stay compared to patientsnot receiving immune fab
• Take home: digoxin toxicity may result in hospitalization but appearsto not significantly increase mortality
J Am Coll Cardiol HF. 2016;4:357‐64
2016 ACCP Annual Meeting
Digoxin Headwinds
• (Un)ease of use; potential for toxicity
• Lack of overall survival benefit in heart failure patients
• Increase in mortality in digoxin treated patients with atrial fibrillation?
• Alternatives to digoxin in selected patients
2016 ACCP Annual Meeting
Notable DIG trial secondary analyses
J Am Coll Cardiol. 2005;46:497‐504J Card Fail. 2013;19:295‐302
Eur J Heart Fail. 2013;15:551‐9
• Increased mortality in women?
• Lower SDC association with improved mortality
• Digoxin use associated with improved renal function(>20% increase in GFR)
• “Sicker” HF patients (NYHA III/IV, LVEF <25%, cardiothoracic ratio >55%) demonstrated improvements in 2‐year HF‐related mortality, all‐cause mortality, and hospitalizations
© American College of Clinical Pharmacy 10
2016 ACCP Annual Meeting
The DIG Trial
Digoxin (n=3397) Placebo (n=3403)
Concomitant Therapies (%)
Diuretics 81.2 82.2
ACE Inhibitors 94.1 94.8
Nitrates 42.1 43.1
Other vasodilators 5.4 6.0
Beta Blockers ? ?
MRA’s ? ?
Bi‐ventricular pacing/ICD ? ?
2016 ACCP Annual Meeting
Digoxin Headwinds
• (Un)ease of use; potential for toxicity
• Lack of overall survival benefit in heart failure patients
• Increase in mortality in digoxin treated patients with atrial fibrillation?
• Alternatives to digoxin in selected patients
2016 ACCP Annual Meeting
Digoxin in Atrial FibrillationAFFIRM Trial – A Tale of Two Analyses
• Whitbeck et al.• Analyzed digoxin use inmultivariate Cox proportional hazard ratio
• All‐cause mortality: HR 1.41, 95% CI 1.19‐1.64
• CHF patients only: HR 1.41, 95% CI 1.09‐1.84
• Gheorghiade et al.• Analyzed digoxin use inpropensity matched cohorts
• Digoxin not associated with all‐cause mortality (HR 1.06, 95% CI 0.83‐1.37) or cardiovascular mortality (HR 1.13, 95% CI 0.79‐1.63)
Eur Heart J. 2013;34:1481–1488Eur Heart J. 2013;34:1489‐97
2016 ACCP Annual Meeting
Digoxin in Atrial Fibrillation
• TREAT‐AF – VA healthcare system• 122,465 patients with atrial fibrillation – 28,679 patients receiving digoxin
J Am Coll Cardiol 2014;64:660–8
2016 ACCP Annual Meeting
Digoxin Headwinds
• (Un)ease of use; potential for toxicity
• Lack of overall survival benefit in heart failure patients
• Increase in mortality in digoxin treated patients with atrial fibrillation?
• Alternatives to digoxin in selected patients
2016 ACCP Annual Meeting
Alternatives to Digoxin• The DIG trial was conducted prior to modern‐day HF therapies:
• Beta‐blockers, MRA’s, device therapy
• Ivabradine was FDA approved in 2015 and has been in use in Europesince 2005
• Slows If current in the SA node, reducing sinus heart rate
© American College of Clinical Pharmacy 11
2016 ACCP Annual Meeting
Ivabradine – SHIFT trial
Outcomes IVA (%)
(n=3241)
PLB (%) (n=3264)
HR
(95% CI)
p value
CV death or HF hospitalization 24 29 0.82
(0.75–0.90)<0.0001
HF death 3 5 0.74
(0.58–0.94)0.014
HF hospitalization 16 21 0.74
(0.66–0.83)<0.0001
CV death, HF hospitalization, or admission for nonfatal MI
25 30 0.82
(0.74‐0.89)<0.0001
Lancet. 2010; 376:875‐885
2016 ACCP Annual Meeting
89 91
84
61
22
3
90 91
83
59
22
4
0
10
20
30
40
50
60
70
80
90
100
Beta‐blockers ACEIs and/orARBs
Diuretics Aldosteroneantagonists
Digitalis ICD/CRT
Patients (%)
Ivabradine
Placebo
Lancet. 2010; 376:875‐885
Ivabradine – SHIFT trial
2016 ACCP Annual Meeting
Role of Digoxin in Heart Failure• Digoxin is no longer first‐line therapy in patients with heart failure
• Digoxin use should likely be relegated to specialized HF or EP clinics
• Digoxin may be useful as secondary therapy in patients with continued symptoms or intolerant/contraindicated for first‐line therapy (especially beta‐blockers)
• Ivabradine may be a better choice but potentially unaffordable for many
• Digoxin as add‐on therapy for atrial fibrillation and normal LVEF is in question
• Digoxin still has a role in heart failure patients with atrial fibrillation• Ivabradine will NOT slow RVR from atrial dysrhythmia
• Other cardiac indications:• Congenital• RV inotropic support (patients with LVADs, pulmonary hypertension)
2016 ACCP Annual Meeting
Digoxin ‐ Pearls for Use• Excellent role for pharmacists in heart failure clinics
• Screen for renal function• Examine drug‐drug interactions carefully involving p‐glycoprotein(amiodarone)
• Use a nomogram (Bauman‐DiDomenico Nomogram ‐ Arch Intern Med. 2006 Dec 11‐25;166(22):2539‐45) or calculator (DigCalc –available on Apple App Store and Google Play)
• Most HF patients will require 125 mcg/day or less – maintain digoxintrough concentration of 0.5‐1 ng/ml
• Don’t check concentrations within 4‐6 hours after taking a dose
2016 ACCP Annual Meeting
Digoxin – Future Directions?
• Don’t count out a drug that’s been in use for over 200 years!
• DIGIT‐HF:• HFrEF III/IV or HFrEF II and EF <20% with or without AF
• Primary endpoint: Composite of mortality and HF hospitalization
• RATE‐AF:• HFrEF NYHA II or greater and permanent AF
• Primary endpoint: Patient reported Quality of Life
EudraCT: 2013‐005326‐38ClinicalTrials.gov ID: NCT02391337
© American College of Clinical Pharmacy 12
2016 ACCP Annual Meeting
P. Brandon Bookstaver, PharmD, FCCP, FIDSA, BCPS, AAHIVPAssociate Professor & Director of Residency Training
Infectious Diseases Pharmacist
College of Pharmacy, University of South Carolina & Palmetto Health Richland
Columbia, SC
October 25, 2016
Emerging Concepts in the Management of Clostridium difficile‐Associated Diarrhea
2016 ACCP Annual Meeting
Conflicts of Interest
• Clostridium difficile infection Speaker forRockpointe Inc. on educational grant funded by Merck & Co., Inc.
2016 ACCP Annual Meeting
Learning Objectives
• Discuss the clinical utility of C. difficile ribotyping
• Define the role of metronidazole as a first‐linetherapy
• Outline the role of pharmacists in fecal bacteriotherapy
2016 ACCP Annual Meeting
Audience Question
How many of your institutions are doing C. difficileribotyping?
• A) On all positive CDI tests
• B) By request only
• C) Not available at my institution
• D) Ribo who?
2016 ACCP Annual Meeting
Clostridium difficile: Pathogenicity Locus & Typing Methods
• Restriction endonuclease analysis (eg BI)
• Pulsed‐ field gel electrophoresis (eg North American pulsed‐field type 1, NAP1)
• Toxinotyping – Toxin type I to XXXIV
• Ribotyping – >200 ribotypes identified
RupnikM, et al. J Clin Micro 2016;54:13‐8. Valiente E, et al. J Med Microbiol 2012;61:49‐56.Tenover F, et al. J Clin Micro 2011;49:1831‐7.
B1/NAP1/027 ‐‐‐ aka Ribotype 027
tcdR tcdB tcdE tcdA tcdC
PaLoc
cdtA cdtB
2016 ACCP Annual Meeting
Ribotype027
Global Outbreaks
Impact on clinical
outcomes
Antibiotic resistance
Severity of disease
Impact on recurrence rates
© American College of Clinical Pharmacy 13
2016 ACCP Annual Meeting
Antibiotic Resistance in RT027PCR Ribotype Measure Clindamycin Moxifloxacin Rifampin
027
MIC50 4 >32 <0.002
MIC90 >256 >32 >32
No. (%) Resistant
38 (47.5) 78 (97.5) 22 (27.5)
MDRO 22 (27.5)
He M, et al. Nat Genet 2013;45:109‐13. Tenover FC, et al. Antimicrob Agents Chemother 2012;56:2929‐2.
What about metronidazole or vancomycin resistance?
MIC50 and MIC90 values reportedly higher for metronidazole in RT‐027, but limited resistance (MIC>8mcg/mL) reportedglobally
Permission for figure above received from Publisher of Nature Genetics.
2016 ACCP Annual Meeting
Severity of Disease & Severe Clinical Outcomes Association with RT‐027
Study Population RT027 Associated Outcomes
Walk S, et al. ClinInfect Dis 2012
N=310 cases14% RT‐027 (U of Michigan)
Severe disease: 1.92 (0.83 – 4.32) & 1.73 (0.83 – 3.48) in derivation & validation data sets, respectively
Walker AS, et al. Clin Infect Dis 2013
N=2745 cases20% RT‐027 (UK) 14‐day mortality: 3.40 (2.45‐4.68)
See I, et al. ClinInfect Dis 2014
N=2,057 cases28.4% RT‐027 (CDC EIP)
Severe disease: 1.74 (1.36‐2.22)Severe outcomes: 1.66 (1.09‐2.54)Increased 14‐day mortality
Rao et al. ClinInfect Dis 2015
N=1144 cases16.2% RT‐027 (U of Michigan)
Severe disease: 2.21 (1.35‐3.62)30‐d mortality: 2.55 (1.57 – 4.13)
Aitken SL, et al. ICHE 2015
N=715 cases24% RT‐027 (Houston)
Severe disease: 1.89 (1.14‐3.10)Severe outcomes: No significant association
2016 ACCP Annual Meeting
Recurrence & RT‐027• Figueroa I, et al. used strains from patients included inoriginal Phase 3 RCT for fidaxomicin vs. vancomycin
• Higher rate of recurrence with RT‐027 with same strain (relapse) ‐‐‐
• Advantages of fidaxomicin for reduced recurrence rates compared to vancomycin was mitigated in RT‐027 strains
• Richardson C, et al. in a Canadian population, RT‐027 appeared significantly associated with recurrencecompared to other RTs
• One limitation to interpretation is that spore burden appears higher in hospital acquired cases in epidemics, which are both associated with RT‐027
• Other strong predictors such as concurrent antibiotics too
Figueroa I, et al. Clin Infect Dis 2012; S104‐9. Richardson C, et al. Anaerobe 2014;33:105‐8.Louie TJ, et al. NEJM 20011;364:422‐31.
2016 ACCP Annual Meeting
Summary Assessment of Outcomes & Ribotyping
• RT‐027 consistently associated with the following:
‐ Disease in older patients
‐ Hospital acquired infections/outbreaks
‐ In epidemics/clusters, RT‐027 associated with severe diseases/outcomes
• Other RTs (eg RT‐078) equally virulent
• Some RTs (014‐020) significantly less virulent
• Clinical outcomes such as concurrent antibiotics & organ dysfunction consistent correlation with negative outcomes
Goorhuis A. Clin Infect Dis 2015. Walk ST, et al. Clin Infect Dis 2012;55:1661‐8. Walker AS, et al. Clin Infect Dis 2013;56:1589‐600.
See I, et al. Clin Infect Dis 2014;58:1394‐400. Rao K, et al. Clin Infect Dis 2015. Aitken SL, et al. ICHE 2015.
2016 ACCP Annual Meeting
Ribotyping Options• Fluorescent ribotyping, modified capillary gel electrophoresis, multilocus variable‐number tandem‐repeat analysis
• Commercial product: Cepheid Xpert C. difficile Epiassay
• tcdB, cdt, and single‐base deletion in tcdC
• Sensitivity: 96‐99.7% and specificity: 93‐98.6%
Babady NE, et al. J Clin Microbiol 2010;48:4519‐24. Kok J, et al. J Clin Microbiol 2011;49:3719‐21.Available at: https://www.gov.uk/government/collections/clostridium‐difficile‐ribotyping‐network‐cdrn‐service Accessed 15 August 2016
Health protection‐collection
Clostridium difficile ribotypingnetwork (CDRN) service
Government of the United Kingdom
2016 ACCP Annual Meeting
So, what should we do?• Ribotyping as a rapid diagnostic test directly from stool is limited to a single test currently
• Advantages:• Infection control & hospital epidemiology (outbreaks?)
• Research purposes
• Questions:• Would this impact treatment decisions? Would you utilize vancomycin?
• Would you treat a recurrent episode differently? Or utilize concurrent antibioticsdifferently?
• My perspective: Clinical and host factors are more consistently predictive of negative outcomes in CDI; thus ribotyping at your institution should not be a (the) priority diagnostic tool. If using or plan to obtain, please collaborate/engage in epidemiologic, clinical and outcomes research – it’s still needed!
© American College of Clinical Pharmacy 14
2016 ACCP Annual Meeting
Audience responseWhere does metronidazole fit in your CDI protocol at your institution?
• A) First‐line therapy for majority of patients regardless of severity of illness
• B) First‐line therapy for majority of patients outside the ICU
• C) First‐line therapy only in those with mild‐to‐moderate disease.
• C) One of the above options plus typical first recurrence.
• D) Infrequently used at my institution except in specific instances.
2016 ACCP Annual Meeting
Clostridium difficile InfectionUnited States Guideline Comparison
Variables IDSA/SHEA GuidelinesAmerican College of Gastroenterology
Treatment Mild/Moderate
Metronidazole (MTR) 500mg TID PO x 10‐14 days
MTR 500mg PO TID x 10 days
Treatment Severe
Vancomycin (Vanc) 125mg PO QID x 10‐14 days
Vanc 125mg PO QID x 10 days
Treatment of Complicated
Vanc 500mg PO QID + MTR 500mg Q8 hours IV; (Vanc PR if complete ileus)
Vanc 500mg PO QID PLUS MTR 500mg Q8 hours IV PLUS Vanc 500mg PR in 500 cc QID
Treatment of Recurrence
Initial – repeat courseMultiple – Vanc taper
Initial – repeat course; 2nd – Vanc taper; 3rd – Fecal microbiota transplant (FMT)
IDSA/SHEA Practice Guidelines for CDI. ICHE. 2010;31:431‐435.
Guidelines for diagnosis, treatment and prevention of CDI. Am J Gastroenterol. 2013;108:478‐498.
2016 ACCP Annual Meeting
Examining Clinical Cure Rates: Vancomycin vs. Metronidazole
Odds Ratio Odds Ratio
M‐H Fixed 95% CI M‐H Fixed 95% CI ___ 0.89 [0.36, 2.25] 0.48 [0.03, 9.10] 0.53 [0.16, 1.72] 0.35 [0.02, 6.70] 0.67 [0.41, 1.10]
0.67 [0.45, 1.00]
0.001 0.1 1 10 1000Favors Vancomycin Favors Metronidazole
N=288 N=415
Odds Ratio Odds RatioM‐H Fixed 95% CI M‐H Fixed 95% CI ___ 0.31 [0.01, 6.88]0.10 [0.01, 1.79]0.52 [0.19, 1.40] 0.54 [0.26, 1.12]
0.46 [0.26, 0.80]
0.001 0.1 1 10 1000Favors Vancomycin Favors Metronidazole
N=118 N=206
Mild/Moderate Disease
• Meta-analysis of 9 studies examining metronidazole versus vancomycin
• Quality of evidence• 3 High quality • 6 Moderate
qualitySevere Disease
Li R, et al. PLoS ONE 2015; 10(10): e0137252 Johnson S, et al. Clin Infect Dis 2014;59(3):345-54.
2016 ACCP Annual Meeting
Examining Clinical Cure Rates: Vancomycin vs. Metronidazole
Odds Ratio Odds Ratio
M.H. Fixed 95% CI M.H. Fixed 95% __________ 0.31 [0.06, 1.48]
1.63 [0.26, 10.37]
3.57 [0.19, 67.81]
1.07 [0.16, 6.47]
0.99 [0.40, 2.45]
0.002 0.1 1 10 500
Favors Metronidazole Favors Vancomycin
• Meta-analysis (described previously)
No difference between metronidazole and vancomycin in recurrence rates regardless of initial severity of disease ***
• Retrospective cohort of VAMC 2005 – 2012 of + CDI (any severity)• Vancomycin (n=2,104) vs. metronidazole (n=8,014)• 8 week recurrence rates: V: 15.8% vs. M: 16.7%, p=0.32• 30-d mortality: V:8.6% vs. M:12.4%, RR=0.69 (0.59-0.80)
Li R, et al. PLoS ONE 2015; 10(10): e0137252Stevens V, et al. Antimicrobial Resistance and Infection Control 2015 4/Suppl1:038.
2016 ACCP Annual Meeting
Metronidazole PK Concerns• Average fecal concentrations following metronidazole 400mg PO q8 hours (or 500mg IV q8) in earlydisease/watery stools = 9mcg/g
• Hydroxymetabolite ~12mcg/g
• As stool becomes more formed what happens to metronidazole fecal concentrations?
• Confirmed in healthy volunteers
• Majority of metronidazole absorbed in upper GI tract; as inflammation decreases, movement into gut lumenis reduced
Bolton RP, Gut 1986;27:1169‐72. Arabi Y, et al. J Antimicrob Chemother 1979;5:521‐7.
2016 ACCP Annual Meeting
Resistance concerns w/ Metronidazole?
Agent Sensitive Intermediate Resistance
Metronidazole(CLSI)
< 8 mcg/mL 16 mcg/mL> 32
mcg/mL
Metronidazole (EUCAST)
<2 mcg/mL ‐ >2 mcg/mL
Vancomycin (EUCAST)
<2 mcg/mL ‐ >2 mcg/mL
• Resistance / reduced susceptibility (MIC>4mcg/mL) to metronidazole has sporadically been reported
**Testing methods create significant variation in susceptibility testing results
Ex: E‐test tend to underestimate MIC values for metronidazole and C. difficile
Baines SD, et al. Antibiotics 2015;4:267‐98.
No correlation between resistance/reduced susceptibility and outcomes
© American College of Clinical Pharmacy 15
2016 ACCP Annual Meeting
Other potential concerns of metronidazole therapy: ADEs, DDIs and VRE
• CNS toxicity – overall rare; primarily manifesting as cerebellar dysfunction (77%) or altered mental status (33%)
• Median duration 54 days; 11% among those <72 hours of tx.
• Drug‐drug interactions• EtOH‐based solutions• Warfarin
• VRE colonization associated with up to 50% of CDI cases• Lack of correlation with drug therapy• Increases during therapy, reduced by 2 weeks post‐completion
Kuriyama A, et al. Clin Neuropharmacol 2011;34:241‐7. Fujitani S, et al. Am J Infect Control 2011;39:188‐93. Holt RK, et al. Drug Metabol Drug Interact 2010;24:35‐9. Al‐Nassir WN, et al. Antimicrob Agents Chemother 2008;52:2403‐6.
2016 ACCP Annual Meeting
Summary Comparison: Metronidazole vs. Vancomycin
Variable Metronidazole Vancomycin
Mild‐Moderate Disease
Guideline recommended; supported by evidence
Supported by evidence; recent RCT, VA cohort and meta‐analysis suggesting superiority in all cases
Severe DiseaseInferior to vancomycin
Superior to metronidazole; Supported by evidence as 1st line
Recurrence rates No difference
VRE colonization /impact gut
No substantial differences
DDI/ADE Infrequent ADE (CNS); warfarin, EtOH DDIs
Rare
Pharmacokinetics Fecal conc.=9mcg/kg; reduced fecal concentrations as disease improves; no direct clinical link to failure
Fecal conc. >500‐1000 times MIC90; no direct clinical link to success/failure
Resistance Sporadic; no direct link to clinical failures
Rare; highly dependent on testing methods
Cost$$
$ (if using IV formulation); $$$ if using capsules
2016 ACCP Annual Meeting
Audience ResponseHow many of your institutions are actively doing fecal microbiota transplants?
What is your current role in FMT at your institution?• A) None, but I think they’re cool
• B) None, and I think they’re grosssss
• C) Significant involvement – I assisted in protocol development
• D) Very significant involvement – I assisted in protocol development and assist with performing the FMT (egscreening, packaging, etc)
2016 ACCP Annual Meeting
ID MD: can you help me with tx?
BB: sure, what do you need specifically?
ID MD: protocol? Donor? Screening? Best route?
That’s all
2016 ACCP Annual Meeting
Fecal Microbiota Transplant‐ The ultimate “probiotic” since 1958 ‐
• Healthy related or unrelated donor stool transplantedvia ND/enema/colonoscope to patient with recurrent/relapsing CDI
• What is required?• Hospital protocol
• IND not required if used for CDI
• Resource page: https://www.idsociety.org/FMT/Moore T, et al. Clin Infect Dis 2014;58:541‐5.
2016 ACCP Annual Meeting
Fecal Microbiota Transplant: Rates of cure without relapse at 10 weeks
0
10
20
30
40
50
60
70
80
90
100
First Infusion ofDonor Feces (N=16)
Infusion of DonorFeces Overall (N=16)
Vancomycin (N=13) Vancomycin withBowel Lavage
(N=13)
93.8
23.1
FMT-related ADE:Belching: (3/16), 19%
N Engl J Med 2013;368:407-15.
Percentage Cured without relapse
81.3
30.8
© American College of Clinical Pharmacy 16
2016 ACCP Annual Meeting
Commercial Product vs. Local Prep
2016 ACCP Annual Meeting
Screening of potential donor…or the donor could be you?
Serum Labs Stool SpecimenOther Donor Screening
HIV C. difficile toxin B (PCR) >18 y/o
HCV (anti‐HCV‐Ab) Cx for enteric pathogens No antibiotics for 3 months
HBV (sAg) O&P (if history suggests) No major GI illness/sx
HAV (IgM) MDRO GNR*No auto‐immune disease or DMARD tx.
RPR No chronic pain d/o
JC Virus* No malignancy
HTLV‐1* *Obesity
HPV* *Current PPI use
*Food intake/allergens
https://www.gastro.org/research/Joint_Society_FMT_Guidance.pdf
2016 ACCP Annual Meeting
Billing & Coding
• Commercial Payers• 44705, Preparation of fecal microbiota for instillation, including assessment of donor specimen
• CMS Beneficiaries• G0455, Preparation with instillation of fecal microbiota by any method,including assessment of donor specimen
• No payment available for screening labs
Available at: http://www.gastro.org/practice‐management/coding/fmt‐coding‐guidance Accessed 24 August 2016.
2016 ACCP Annual Meeting
Get your hands dirty
2016 ACCP Annual Meeting
Summary of Pharmacist’s Role in FMT• 1) Identifying potential patients for FMT
• Best achieved by knowing the evidence
• 2) Ensuring/helping to develop hospital protocol• Available routes to deliver FMT at your institution• Local prep versus commercial product• Donor bank versus individual related or unrelated donors (what to screen for)
• Billing codes
• 3) Prepping the product
• 4) Logging patient outcomes for future requirements from FDA or for scholarly purposes
2016 ACCP Annual Meeting
P. Brandon Bookstaver, PharmD, FCCP, FIDSA, BCPS, AAHIVPAssociate Professor & Director of Residency Training
Infectious Diseases Pharmacist
College of Pharmacy, University of South Carolina & Palmetto Health Richland
Columbia, SC
October 25, 2016
Emerging Concepts in the Management of Clostridium difficile‐Associated Diarrhea
© American College of Clinical Pharmacy 17
2016 ACCP Annual Meeting
Short‐Course Antimicrobials for Systemic Infections : How Low Can We Go?
David T. Bearden, Pharm.D.Clinical Professor and Chair, Department of Pharmacy Practice
Clinical Assistant Director, Department of Pharmacy Services
Oregon State University / Oregon Health & Science University, College of Pharmacy
Portland, Oregon
October 25, 2016
2016 ACCP Annual Meeting
Conflict of Interests
• None
2016 ACCP Annual Meeting
Learning Objectives
• Analyze the evidence base for shortening antimicrobial courses
• Outline the benefits/risks of short course antibiotic therapy
• Define the role of antimicrobial stewardship in the implementation of abbreviated antibiotic course
2016 ACCP Annual Meeting
Duration of Therapy
Limited science behind the numbers…
… GAβHS pharyngitis…
FreeImages.com/Paige Foster
2016 ACCP Annual Meeting
The Good… and Bad of Shortened Therapy
Potential Positives
• Less selective pressure
• Dead bugs don’t mutate – hithard, stop early
• Less cost
Potential Negatives
• Poorer clinical response
• Relapse/Reinfection
• Readmissions
2016 ACCP Annual Meeting
Does this translate to severe infections?
Comparison of 8 vs 15 days of antibiotic therapy for ventilator‐associated pneumonia in adults: a randomized trial
• 401 VAP patients• No mortality difference (18.8% short vs 17.2%)
• No LOS or ICU LOS difference
• Caution for non‐fermenting GNR (e.g., Pseudomonas sp)• 40.6% recurrence vs 25.4%
Reconfirmed in 2015 Cochrane Review
JAMA. 2003 Nov 19;290(19):2588‐98.
Cochrane Database Syst Rev. 2015 Aug 24;(8):CD007577.
© American College of Clinical Pharmacy 18
2016 ACCP Annual Meeting
Intraabdominal Infections
• Randomized 518 patients with adequate source control• Standard abx: 2d post clinical improvement (fever, WBC, ileus)
• Short course: 4 ± 1d
• No outcome differences• Surgical Site Infect (6.6% short vs 8.8%)
• Recurrence (15.6% short vs 13.8%)
• Death (1.2% short vs 0.8%)
• Secondary analysis with sepsis unchanged
J Am Coll Surg. 2016 Apr;222(4):440‐6.
N Engl J Med. 2015 May 21;372(21):1996‐2005.
2016 ACCP Annual Meeting
Bacteremia
• Difficult to compare sources• 24 trials examined
• No differences in• Clinical cure (86.5% vs. 95.9%)
• Microbiological cure (100% vs 93.8%)
• Survival (88.2% vs 89.6%)
Crit Care. 2011;15(6):R267.
neonates, 66 pts
IAI, 40 pts
pyelo, 9 pts
pneumonia, 40 pts
2016 ACCP Annual Meeting
Community Acquired Pneumonia
• Are the IDSA/ATS Guidelines Safe?
• Randomized Controlled Trial, 312 patients• Intervention at Day 5 to consider stopping per guidelines
JAMA Intern Med. 2016 Jul 25. doi: 10.1001
2016 ACCP Annual Meeting
How are we really doing?
• VA multicenter study, 1739 patients (CAP & HCAP)• Targets
• 5 ± 3d CAP with response
• 8d HCAP
J Hosp Med. 2016 Aug 16. doi: 10.1002
Appropriate14%
Excessive86%
2016 ACCP Annual Meeting
Antimicrobial Stewardship Implications
CDC Core Elements• “Antibiotic time‐out” at 48h, including duration if extended
• Audit and Feedback
• Automatic stop orders
Targeted duration reductions• Choose an indication with data
(e.g., Intraabdominal)
• Get baseline data
• Educate
• Audit and prepare for windows
(e.g., at d3 begin conversation)
• Follow up and report
http://www.cdc.gov/getsmart/healthcare/implementation/core‐elements.html
2016 ACCP Annual Meeting
Can Biomarkers Save Us?
• C‐reactive protein &
• Procalcitonin• Unclear utility
• Send out labs PCT
• Further data needed
Infected
PCT < 1.0 ng/mL and/or
CRP <100 mg/mL
Assess after 5d Abx
SOFA decreasing AND
PCT decrease ≥ 90% and/or CRP decrease ≥ 50%
STOP when
PCT decrease ≥ 90% and/or CRP decrease ≥ 50%
Or 7d Abx
Assess after 3d Abx
SOFA decreasing AND
PCT <0.1 ng/mL and/or CRP <30mg/mL
STOP therapy
STOP when
PCT <0.1 ng/mL and/or CRP <30mg/mL
Or 7d Abx
Intensive Care Med. 2015 Oct;41(10):1739‐51.
No
No No
Yes
Yes
© American College of Clinical Pharmacy 19
2016 ACCP Annual Meeting
Current State of Short Durations
• IAI – 4d post source control
• VAP – 7‐8d (more for Pseudomonas controversial)
• Hospitalized CAP – 5d
• Bacteremia & Sepsis?
2016 ACCP Annual Meeting
Stay tuned…
Short‐term late‐generation antibiotics versus longer term penicillin for acute streptococcal pharyngitis in children. Cochrane Database Syst Rev. 2012 Aug 15;(8):CD004872.
Continued questions
• Can we go <7 days?
• Biomarker improvement
• Clinical factors favoring shortening
• Differential antibiotic effects
2016 ACCP Annual Meeting
Short‐Course Antimicrobials for Systemic Infections : How Low Can We Go?
David T. Bearden, Pharm.D.Clinical Professor and Chair, Department of Pharmacy Practice
Clinical Assistant Director, Department of Pharmacy Services
Oregon State University / Oregon Health & Science University, College of Pharmacy
Portland, Oregon
October 25, 2016
© American College of Clinical Pharmacy 20