moderator: douglas l. jennings, pharm. d., fccp, faha ......douglas l. jennings: no conflicts to...

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


http://www.accp.com/am

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


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


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%




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.




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.


Favors ivabradine Favors placebo

% of TotalPopulation

Corlanorn (%)

Placebon (%)

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)


% of TotalPopulation

Corlanor®

n (%)Placebon (%)



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%


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


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


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.


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.


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


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?


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


Conflict of Interests

• No relevant conflicts

• I do have foxglove in my garden


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.


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


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


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



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


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


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


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


Digoxin Headwinds






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



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 ? ?


Digoxin Headwinds






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


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


Digoxin Headwinds






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



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


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


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)


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


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



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


Conflicts of Interest

• Clostridium difficile infection Speaker forRockpointe Inc. on educational grant funded by Merck & Co., Inc.


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


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?


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


Ribotype027

Global Outbreaks

Impact on clinical

outcomes

Antibiotic resistance

Severity of disease

Impact on recurrence rates



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.


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


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.


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.


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


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!



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.


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.


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.


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.


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.


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



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.


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


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)


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


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.


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



Commercial Product vs. Local Prep


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


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.


Get your hands dirty


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


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



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


Conflict of Interests

• None


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


Duration of Therapy

Limited science behind the numbers…

… GAβHS pharyngitis…

FreeImages.com/Paige Foster


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


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.



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.


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


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


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%


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


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



Current State of Short Durations

• IAI – 4d post source control

• VAP – 7‐8d (more for Pseudomonas controversial)

• Hospitalized CAP – 5d

• Bacteremia & Sepsis?


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


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


moderator: douglas l. jennings, pharm. d., fccp, faha ......douglas l. jennings: no conflicts to...

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