1. Impact Of Comorbidities and Concomitant Medication Administration On Inpatient Management Of Warfarin Therapy
William Wheeler, PharmD
PGY1 Pharmacy Resident
Baptist Health Lexington
Lexington, KY

2. Disclosure Statement
Disclosure statement: these individuals have the following to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation.
Resident: William Wheeler, PharmD (nothing to disclose)
Co-Investigator: Whitney Thomas, PharmD, BCPS (nothing to disclose)

3. del Campo, Ann. Pharmacother. 2015
Background
The oral anticoagulant warfarin requires close management due to labile INR levels
There is a paucity of evidence regarding inpatient management of warfarin
Study by del Campo, et al revealed potential influence of comorbidities on therapy
Michaela del Campo, BPHARm and Greg Roberts, Bpharm. Changes in Warfarin Sensitivity During Decompensated Heart Failure and Chronic Obstructive Pulmonary Disease. Annals of Pharmacotherapy 2015, Vol. 49(9)
del Campo, Ann. Pharmacother. 2015

4. Background 383-bed tertiary care facility
Specialized cardiac and cancer services
Pharmacists in our hospital manage the majority of inpatient warfarin therapy
5,800 doses in 2015
Observations that comorbidities and concomitant medications influence INR levels

5. Purpose
Examine the extent to which various comorbidities and concomitant medications influence inpatient warfarin sensitivity to better guide dosing by clinical pharmacists

6. Objectives
Primary Objective: Determine the change in warfarin sensitivity from admission to discharge for patients that received in-patient warfarin therapy
Secondary Objective: Determine the extent to which comorbidities and medications may influence warfarin sensitivity

7. Methodology
Single-center, IRB-approved, retrospective analysis of electronic medical records
Adult medical/surgical, telemetry, and ICU patients
Inclusion criteria:
Admitted on warfarin therapy, continued for at least 4 days, and discharged on warfarin therapy
Exclusion criteria:
Warfarin held, discontinued, or reversed with phytonadione

8. Methodology
Patients were identified with medication-specific codes (SIM codes)
All warfarin patients that did not receive phytonadione
Fluconazole, levofloxacin, amiodarone, metronidazole, erythromycin, sulfamethoxazole/trimethoprim
ICD-9 codes:
To determine comorbidities
To exclude those without long-term anticoagulation

9. del Campo, Ann. Pharmacother. 2015
Methodology
Data collected:
INR and average daily dose on admission and discharge
Warfarin sensitivity: the ratio of INR to average daily dose
Therapeutic on admission and discharge for warfarin indication (yes/no)
Demographic data and Charlson comorbidities
Statistical Analysis
Mean and standard deviation with paired t-test
Fischer’s Exact test for categorical data
del Campo, Ann. Pharmacother. 2015

10. 175 patients enrolled in study
Results
921 patients evaluated
605 initially excluded
283: not on long-term anticoagulation
322: length of stay 3 days or less
141 further excluded
67 held during stay
37 warfarin discontinued
11 not on warfarin on admission
7 expired
19 other
175 patients enrolled in study
Flow chart (reasons for exclusion either ennumerated or on hand)
Warfarin hold reasons: surgery, procedure, supratherapeutic INR, bleed
Warfarin discontinue reasons: comfort measures, change to alternative agent, permanent discontinuation of therapy,
Other Exlclusions: no labs available, no records available, patient left AMA, given blood, NPO status, noncompliance on admission

11. Demographics Descriptor n = 175 Age 76 (68, 84) Gender, Male
90 (51.4%)
Obesity or Morbid Obesity
46 (26.3%)
Charlson Comorbidity Index
6 (4, 7)
Therapeutic INR on Admission
66 (37.7%)

12. Results: Total Population
Admission
Discharge p
INR
2.37 ± 1.08
2.37 ± 0.759
0.97
Daily dose (mg)
4.17 ± 1.86
4.02 ± 2.02
0.17
Warfarin Sensitivity
0.689 ± 0.428
0.77 ± 0.558
0.03
Therapeutic INR
66 (37.7%)
91 (52%)
0.01

13. Results: Comorbidities
p = 0.77
p = 0.89
p = 0.97

14. Results: Comorbidities
p = 0.11

15. Results: Comorbidities

16. Results: Comorbidities
p = 0.887

17. Results: Comorbidities
p = 0.89
p = 0.11
p = 0.35
p = 0.26

18. Results: Medication
Should I put n values for the medications?

19. Discussion
Primary Objective: Patients admitted on warfarin therapy showed increased warfarin sensitivity at discharge
More patients were therapeutic at discharge
52% v. 37.7% (p = 0.01)
Patients were more sensitive to warfarin therapy on discharge than admission (p = 0.03)

20. Discussion Secondary Objective: Comorbidity Influence
In contrast to study by del Campo, Congestive Heart Failure did not demonstrate a decrease in sensitivity at discharge (p = 0.97)
Acute Kidney Injury demonstrated absolute decrease in sensitivity at discharge(p = 0.26)
Acute Respiratory Failure demonstrated absolute increase in sensitivity at discharge (p = 0.11)
Myocardial Infarction demonstrated a nonsignificant trend towards increased sensitivity at discharge.

21. Discussion Secondary Objective: Medication Influence
All medications demonstrated increased warfarin sensitivity on discharge
Levofloxacin numerically increased warfarin sensitivity (p = 0.07)
Metronidazole nearly doubled warfarin sensitivity (p = 0.06)
Too few patients received erythro and sulfa (2 & 1 respectively)
No differentiation between IV and oral formulations of medications – could be very clinically important for metronidazole which undergoes enterohepatic recycling

22. Discussion Limitations
Study not designed to examine overlap between comorbidities and medications
Erythromycin and sulfamethoxazole/trimethoprim excluded
No accounting for peak INR during stay
No differentiation between oral and intravenous medications
This was a retrospective sample and I selected a convenience sample
Did not scrutinize indication for anticoagulation but instead just looked at whether or not they were therapeutic for that indication; sub-analysis of each disease state may have been useful
Additionally, since these medications were collected by dispensation data, this does not actually indicate whether the drugs were administered – I did not do a chart review to ensure administration

23. Conclusions
Patients demonstrate a statistically significant increase in warfarin sensitivity upon discharge
More patients were therapeutic on discharge
Potential for staff education
Acute kidney injury demonstrated absolute decrease in warfarin sensitivity
Acute respiratory failure demonstrated absolute increase in warfarin sensitivity
Absolute increase in sensitivity when on levofloxacin and metronidazole
Warfarin is extensively metabolised via CYP2C9 as well as other isoenzymes; it may be that in acute respiratory failure there is simply a diminished metabolism of warfarin due to hypoperfusion, thereby making these patients less sensitive until they are better perfusing and metabolising.
On the other hand, warfarin is 92% renally eliminated, so it would appear reasonable that patients presenting with an AKI would be retaining more active metabolites and therefore become less sensitive once their renal function improves towards discharge.

24. Self-Assessment Question
Of the medications reviewed for concomitant administration with inpatient warfarin therapy, which had the correlation for the most influence on warfarin sensitivity?
Answer: Metronidazole

25. Questions?

26. References
del Campo, et al. “Changes in Warfarin Sensitivity During Decompensated Heart Failure and Chronic Obstructive Pulmonary Disease.” Annals of Pharmacotherapy. 2015, Vol. 49(9)

27. Impact Of Comorbidities and Concomitant Medication Administration On Inpatient Management Of Warfarin Therapy
William Wheeler, PharmD
PGY1 Pharmacy Resident
Baptist Health Lexington
Lexington, KY