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

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)

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) 963-968 del Campo, Ann. Pharmacother. 2015

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

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

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

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

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

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

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

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%)

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

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

Results: Comorbidities p = 0.11

Results: Comorbidities

Results: Comorbidities p = 0.887

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

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

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)

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.

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

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

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.

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

Questions?

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) 962-968

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