# Presentation: 056438

## Spotlight Case July 2005

**Impatient Inpatient Dosing**

## Source and Credits

- This presentation is based on the July 2005 AHRQ WebM&M Spotlight Case in Medicine
- See the full article at _[http://webmm.ahrq.gov](http://webmm.ahrq.gov/)__  _
- CME credit is available through the Web site
- Commentary by: **Richard H. White**, **MD**, University of California, Davis
- Editor, AHRQ WebM&M: Robert Wachter, MD
- Spotlight Editor: Tracy Minichiello, MD
- Managing Editor: Erin Hartman, MS

## Objectives

*	**At the conclusion of this educational activity, participants should be able to:*
- Appreciate the challenges of initiating warfarin therapy in hospitalized patients
- Understand the fundamental pharmacology of warfarin
- List the clinical rules for initial dosing of warfarin
- Access resources available to aid providers in warfarin dosing

## Case: Impatient Inpatient Dosing

*	**An elderly man with a diagnosis of acute deep venous thrombosis (DVT) during hospital stay was started on warfarin 5 mg at bedtime and enoxaparin (a low-molecular-weight heparin). *

## Warfarin

- Warfarin is among the most commonly prescribed drugs
- Near the top of list of drugs that lead to serious adverse events in elderly patients
- Physicians who use warfarin must know its pharmacology in order to safely initiate therapy

*Gurwitz JH, et al. JAMA. 2003;289:1107-1116.**Gage B, et al. Am J Med. 2000;109:481-488.  *

## Pharmacology of Warfarin

- Vitamin K carboxylates and thus activates four clotting factors
- Warfarin inhibits action of vitamin K, preventing activation of factors II, VII, IX, and X
- This relative factor deficiency leads to prolongation of clotting times, the prothrombin time, and the international normalized ratio (INR)
- Exogenous vitamin K can overcome warfarin effect, leading to synthesis of normal clotting factors with normalization of clotting

*Holford NH. Clin Pharmacokinet. 1986;11:483-504.*

## Pharmacology of Warfarin

- Warfarin is metabolized in the liver by the P450 cytochrome CYP2C9
- Half life is 35 hours—takes approximately 7-9 days before warfarin level or INR reaches a steady state
- Patients with liver disease or those taking medications that inhibit CYP2C9 require less warfarin

*Vadher B, et al. BMJ. 1997;314:1252-1256. *

## Pharmacology of Warfarin

- Warfarin is highly protein bound to albumin
- Only free or unbound warfarin interferes with activation of the clotting factors
- Hospitalized patients with low serum albumin are much more sensitive to warfarin due to less protein binding and higher level of free warfarin
- If albumin less than 1.8, patient will be sensitive to warfarin
- As patients recover out of the hospital, warfarin requirements will increase

*Palareti G, et al. Clin Pharmacokinet. 1996;30:300-313.**Ageno W, et al. Am J Cardiol. 1999;84:905-908.  *

## Pharmacology of Warfarin

- Wide intersubject variation in dose of warfarin required to raise INR to therapeutic level
- Average dose is about 4.3 mg, but range is 0.5-15 mg/day
- Older patients require less warfarin (1% reduction in clearance/year after age 55)
- Men generally require more than women; heavier patients require a higher dose

*Jupe DM, et al. **Br J Clin Pharmacol. 1988;25:607-610. **Wynne HA, et al. Age Ageing. 1996;25:429-431. **Dobrzanski S, et al. J Clin Hosp Pharm. 1983;8:75-77. *

## Pharmacology of Warfarin

- Anticoagulant response to warfarin, measured using the prothrombin time or INR, is used to determine the correct dose
- Initial INR response to warfarin depends not only on the serum level of free warfarin but also the rate of degradation of normal clotting factors, particularly factor VII (half life 6 hours)

*Jupe DM, et al. **Br J Clin Pharmacol. 1988;25:607-610. **Wynne HA, et al. Age Ageing. 1996;25:429-431. **Dobrzanski S, et al. J Clin Hosp Pharm. 1983;8:75-77. *

## What to Expect When Starting this Patient on Warfarin

- A low maintenance dose of warfarin, perhaps 3 mg/day, given patient is elderly
- A 7- to 9-day time lag before the INR reaches steady state due to half life of warfarin

## Timing of INR Measurement

- After initial dose, it takes about **20 hours** before any significant change in INR because factor VII levels have to fall first
- INR measured 10-12 hours after first dose is of little clinical use
- The morning after a 5 mg dose (given at 17:00), INR is usually normal or less than 1.1
- Only a sensitive individual will have an INR greater than 1.3, indicating that a maintenance dose of approximately 1 mg will be needed

## Clinical Rules for Initiating Warfarin

- Among hospitalized patients, particularly elderly patients, start with 5 mg of warfarin
- Other factors associated with lower warfarin requirements include
- Body Mass Index less than 20
- Liver disease
- Concomitant use of drug that inhibits warfarin metabolism

*Buckley NA, Dawson AH. Med J Aust. 1992;157:479-483. *

## Drugs that Decrease Warfarin Metabolism and Increase INR

*UCSF Medical Center. March 2005.**Holbrook AM, et al. Arch Intern Med. 2005;165:1095-106. *

| Erythromycin†
Metronidazole†
Fluconazole†
Itraconazole†
Ketoconazole†
SMX/TMP† | Amiodarone†
Cimetidine†
Phenytoin*
Dong quai*
Statins*
Alcohol‡ |
| --- | --- |

- List is not all-inclusive; INR should be monitored after initiating or modifying any drug therapy.

- *Moderate interaction; †Severe interaction; ‡Effect of alcohol on INR is unpredictable, may increase or decrease INR.

## Drugs that Increase Warfarin Metabolism and Decrease INR

| Phenobarbital†
Rifampin/Rifabutin†
Carbamazepine*
Vitamin K†
Phenytoin* (chronic use) | Sucralfate*
Ginseng*
Alcohol‡
 |
| --- | --- |

- *Moderate interaction; †Severe interaction; ‡Effect of alcohol on INR is unpredictable, may increase or decrease INR.

- List is not all-inclusive; INR should be monitored after initiating or modifying any drug therapy.

*UCSF Medical Center. March 2005.**Holbrook AM, et al. Arch Intern Med. 2005;165:1095-106. *

## Clinical Rules for Initiating Warfarin

- Give first dose of warfarin as early in the day as possible, not at 5:00 PM
- If the time interval between warfarin dose and INR is too short, physician should order another INR later in the day (about 3:00 pm) and use this result to determine the best next dose of warfarin

## Clinical Rules for Initiating Warfarin

- In elderly patients, even if the INR on Day 2 is less than 1.1, it is prudent to administer a second dose of 5 mg
- If patient is young and if INR on Day 2 is less than 1.1 twenty or more hours after the first dose, 10 mg can be given

## Case (cont.): Impatient Inpatient Dosing

*The intern checked the INR the next day and noted it was still 1.0. He increased the warfarin order to 10 mg at bedtime. The following day the INR was 1.2. In response, he again increased the warfarin dose to 15 mg at bedtime. On the fourth day of warfarin therapy, the INR was 1.8. The intern then wrote an order for 20 mg at bedtime.*

## Warfarin Dosing the Right Way

- PDA-based computer-dosing tool called WARFDOCs, based on a previous Bayesian forecasting program called DrugCalc®
- For 80-year-old, 170 lb male, WARFDOCs estimates warfarin requirement of 3.54 mg
- The computer model predicts that if 10 mg is given on each of the next two days, the INR value will be 4.0 on Day 5 (goal is 2-3)

## Computer-predicted INR response if this patient were given a daily dose of 5 mg of warfarin

| Day | AM INR | PM Dose (mg) | Predicted Steady-State Dose (mg) |
| --- | --- | --- | --- |
| 1 | 1.0 | 5.0 | — |
| 2 | 1.05 | 5.0 | 3.6 |
| 3 | 1.28 | 5.0 | 3.6 |
| 4 | 1.46 | 5.0 | 3.6 |
| 5 | 1.75 | 5.0 | 3.6 |
| 6 | 2.03 | 5.0 | 3.6 |
| 7 | 2.32 | 5.0 | 3.6 |
| 8 | 2.61 | 5.0 | 3.6 |

**Notes:**
Using the WARFDOCs dosing program (Table) to model this patient’s expected response to a daily dose of 5 mg, we see that the INR is expected to rise slowly but steadily. The model predicts that it takes 5 days to achieve an INR of just over 2.0 and approximately 12 days to attain the predicted steady-state INR of 4.7. 

## In a Hurry?

- To shorten time required to achieve INR of 2.5, could give a modestly higher dose of 7.5 mg on days 4 and 5 and then lower dose to 3.5 mg
- Requires considerable clinical experience or use of the computer software
- Ideally, be patient and use low-molecular-weight heparin (LMWH) as a “bridge” for 7 days while the INR rises slowly to 2.32, then stop the LMWH and reduce warfarin dose to 3 or 4 mg, testing INR every few days

## Case (cont.): Impatient Inpatient Dosing

*On day number 6, the patient’s INR was over 9.0, a dangerous level. The patient developed an acute episode of bleeding that required transfusion. Anticoagulation was stopped and vitamin K was given.*

## Reducing Dosing Errors with Warfarin

- Consult experienced providers
- Pharmacist overview of anticoagulant care reduces the incidence of adverse outcomes
- Or use computer modeling
- Shown to be more accurate than routine dosing by physicians
- Or use a validated nomogram

*(See notes section for list of references.)*

## Take-Home Points

- Hospitalized patients generally require lower doses of warfarin due to hypoalbuminemia, advanced age, concomitant medications
- Warfarin takes 7-9 days to reach steady state; patience should be exercised with initial dosing
- INR levels should be drawn long enough after warfarin dose given to allow level to reflect drug’s effect
- In absence of clinical experience, providers should use computer modeling, validated nomograms, or consult an anticoagulation expert