Case Objectives

• Appreciate the challenges of initiating warfarin therapy in the hospitalized patient
• 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 & Commentary: Part 1

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

Warfarin is among the most commonly prescribed drugs. Because excessive dosing can lead to major bleeding, it is also near the top of the list of drugs that lead to serious adverse events in elderly patients.(1) Physicians who use warfarin must know its fundamental pharmacology in order to properly initiate therapy and thereby ensure patient safety.(2)

Pharmacology of Warfarin

First, warfarin acts by inhibiting the action of vitamin K, which is required to carboxylate and thereby activate four clotting factors (II, VII, IX, and X).(3) This inhibition translates to prolongation of blood clotting times, measured using the prothrombin time or the international normalized ratio (INR). Because warfarin inhibits the action of vitamin K, exogenously administered vitamin K can overcome the effect of warfarin, leading to synthesis of normal clotting factors with normalization of clotting.

Second, warfarin is metabolized in the liver by the P450 cytochrome CYP2C9. It has a half-life of degradation of approximately 35 hours, which means that when a fixed dose is administered orally, it takes approximately 7 to 9 days before the warfarin level or INR reaches a steady state.(4) Patients with liver disease or patients who take medications that inhibit CYP2C9 require less warfarin.

Third, warfarin is highly protein bound to albumin, and it is the free or unbound warfarin level that interferes with activation of the clotting factors.(5) This means that hospitalized patients who have a low level of albumin are much more sensitive to warfarin because there is less protein binding and thus a higher level of free warfarin.(6) Patients in the hospital are often very sick, and those with an albumin level less than 1.8 can be expected to be very sensitive to warfarin. As patients recover out of the hospital, they generally require a higher dose of warfarin.

Fourth, there is wide inter-subject variation in the dose of warfarin required to raise the INR to a therapeutic level, eg, an INR of 2.5. The average dose is approximately 4.3 mg, but the range is from 0.5 to 15 mg/day.(7) Older patients require less warfarin (1% reduction in clearance per year after age 55), men generally require more than women, and heavier patients require a higher dose.(8,9)

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

To summarize, in the elderly patient in this case, when we initiate warfarin therapy we should expect: (i) a low maintenance dose of warfarin, perhaps 3 mg/day, and (ii) a 7- to 9-day time lag before the INR reaches steady state. After the first dose of warfarin, it will take approximately 20 hours before there is any significant change in the INR (because factor VII levels first have to fall), so that the INR value measured just 10-12 hours after the first dose is of little clinical use. In the average person, the INR value measured the morning after a 5 mg dose (given at 17:00 pm) is usually normal or less than 1.1. A very sensitive individual will have an INR of greater than 1.3, indicating that a maintenance dose of approximately 1 mg will be needed to achieve the usual therapeutic INR of 2-3.

Clinical Rules for Initial Dosing of Warfarin

Among hospitalized patients, particularly elderly patients, start with 5 mg of warfarin. Other factors associated with lower warfarin requirements include a body mass index (BMI) less than 20, liver disease (including passive congestion from congestive heart failure), and being treated with a drug that inhibits warfarin metabolism (eg, metronidazole, trimethoprim-sulfamethoxazole, erythromycin, fluconazole, amiodarone, and others [Table 1]).(10)

Give the first dose of warfarin as early in the day as possible, not at 5:00 in the evening. The longer the time interval between the first dose and the initial INR measurement, the more the INR will truly reflect the sensitivity to warfarin. If the time interval is too short, the physician should order another INR later in the day (at about 3:00 pm) and use this result to judge the best next dose of warfarin. Optimally, the amount of time between the first warfarin dose and the INR measurement should be as close to 20 hours as possible; 12 hours is too short.

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 the patient is young and if the INR on day 2 is less than 1.1 twenty or more hours after the first dose, 10 mg can be given.

Case & Commentary: Part 2

The intern checked the INR the next day and noted it was 1.0. He increased the warfarin order to 10 mg at bedtime. The following day, the INR was 1.2. In response, he increased the warfarin dose again 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.

The day 3 morning INR was 1.2 following a 5-mg dose on day 1 and a 10-mg dose on day 2. This INR value should be interpreted as reflecting the effect of the initial 5-mg dose. Using a personal digital assistant (PDA)-based computer-dosing tool called WARFDOCs, which is based on a previous DOS-based Bayesian Forecasting program called DrugCalc®(11), the estimated steady-state dose of warfarin is 3.54 mg, assuming the patient is 80 years old and weighs 170 pounds. The computer modeling predicts that if 10 mg is given on each of the next 2 days, the INR value will be 4.0 on day 5, a potentially dangerous level. Giving even higher doses will lead to an even faster rise in the INR. WARFDOCs was developed as part of an AHRQ-funded patient-safety project. The PDA version will be publicly available soon.

The morning after a 15-mg dose of warfarin was given on day 3, the day 4 INR was 1.8. The WARFDOCs program projects that the steady-state dose is still 3.55 mg, and it predicts that giving just 10 mg on day 4 will result in a supratherapeutic INR of 3.3 on day 5, rising to an INR of over 7 on day 6. Because the intern did not have any first-hand experience dosing warfarin, an even higher dose of 20 mg was administered on day 4 and, not surprisingly, the day 6 INR was greater than 9.0, a level at which spontaneous bleeding can occur.

Using the WARFDOCs dosing program (Table 2) 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; it would take approximately 12 days to attain the predicted steady-state INR of 4.7.

If one wanted to shorten the time required to achieve a therapeutic INR of 2.5, one could give a modestly higher dose of 7.5 mg on days 4 and 5 and then drop the dose to 3.5 mg thereafter. This requires considerable experience or use of the computer software. A better plan would be to exercise patience and just 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 the warfarin dose to 3 or 4 mg, testing the INR every few days.

Case & Commentary: Part 3

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

This serious dosing error could have been prevented in three ways. First, someone experienced in dosing warfarin should have been supervising this intern. This could have been a nurse, a hospital pharmacist, the attending physician, or an anticoagulation nurse/pharmacist specialist.(12,13) Second, the intern could have used computer modeling.(11,14-16) Third, the intern could have used a validated nomogram.(17,18) Several publications have shown that computer modeling of warfarin leads to more accurate dosing than routine dosing by physicians.(11,19,20) Finally, data also suggest that a pharmacist’s overview of anticoagulant care reduces the incidence of adverse outcomes.(21) Supervision or primary management of warfarin by a dedicated anticoagulation pharmacist probably would have prevented this error entirely.

In summary, warfarin dosing is a potentially dangerous process, particularly in the hospitalized patient. In the absence of clinical experience, a provider should take advantage of the expertise of pharmacists or specialized anticoagulation personnel to aid in dosing decisions. In the near future, this process will be simplified and made safer with computer-based management tools. For now, many clinicians will use such tools as stand-along adjuncts, accessed either through their computers or hand-held PDAs. Ideally, the WARFDOCs calculator will be integrated into the hospital or outpatient clinic’s electronic medical record (EMR) system. When a first-time warfarin dose is ordered, the computer would capture the demographic data (age, height, weight, etc.) along with all INR levels and warfarin doses. Subsequently, each time an INR is measured after warfarin is administered, the engine would show a steady-state dose prediction and the expected value of the INR over the next 2 days if the steady-state dose is given. This would require no work by the physician, and the program would seamlessly provide data upon which the doctor could base the next dosing decision. Such a vision may be realized in many health care organizations in the next few years.

Richard H. White, MD Director, Anticoagulation Service University of California, Davis

Faculty Disclosure: Dr. White has declared that neither he, nor any immediate member of his family, has a financial arrangement or other relationship with the manufacturers of any commercial products discussed in this continuing medical education activity. In addition, his commentary does not include information regarding investigational or off-label use of pharmaceutical products or medical devices.

References

1. Gurwitz JH, Field TS, Harrold LR, et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA. 2003;289:1107-1116. [ go to PubMed ]

2. Gage B, Fihn S, White R. Management and dosing of warfarin therapy. Am J Med. 2000;109:481-488. [ go to PubMed ]

3. Holford NH. Clinical pharmacokinetics and pharmacodynamics of warfarin. Understanding the dose-effect relationship. Clin Pharmacokinet. 1986;11:483-504. [ go to PubMed ]

4. Vadher B, Patterson DL, Leaning M. Evaluation of a decision support system for initiation and control of oral anticoagulation in a randomised trial. BMJ. 1997;314:1252-1256. [ go to PubMed ]

5. Palareti G, Legnani C. Warfarin withdrawal. Pharmacokinetic-pharmacodynamic considerations. Clin Pharmacokinet. 1996;30:300-313. [ go to PubMed ]

6. Ageno W, Turpie AG. Exaggerated initial response to warfarin following heart valve replacement. Am J Cardiol. 1999;84:905-908. [ go to PubMed ]

7. Jupe DM, Peterson GM, Coleman RL, McLean S. Warfarin dosage requirements: prospective clinical trial of a method for prediction from the response to a single dose. Br J Clin Pharmacol. 1988;25:607-610. [ go to PubMed ]

8. Wynne HA, Kamali F, Edwards C, Long A, Kelly P. Effect of ageing upon warfarin dose requirements: a longitudinal study. Age Ageing. 1996;25:429-431. [ go to PubMed ]

9. Dobrzanski S, Duncan SE, Harkiss A, Wardlaw A. Age and weight as determinants of warfarin requirements. J Clin Hosp Pharm. 1983;8:75-77. [ go to PubMed ]

10. Buckley NA, Dawson AH. Drug interactions with warfarin. Med J Aust. 1992;157:479-483. [ go to PubMed ]

11. White RH, Hong R, Venook AP, et al. Initiation of warfarin therapy: comparison of physician dosing with computer-assisted dosing. J Gen Intern Med. 1987;2:141-148. [ go to PubMed ]

12. Ellis RF, Stephens MA, Sharp GB. Evaluation of a pharmacy-managed warfarin-monitoring service to coordinate inpatient and outpatient therapy. Am J Hosp Pharm. 1992;49:387-394. [ go to PubMed ]

13. Landefeld CS, Anderson PA. Guideline-based consultation to prevent anticoagulant-related bleeding. A randomized, controlled trial in a teaching hospital. Ann Intern Med. 1992;116:829-837. [ go to PubMed ]

14. Poller L, Wright D, Rowlands M. Prospective comparative study of computer programs used for management of warfarin. J Clin Pathol. 1993;46:299-303. [ go to PubMed ]

15. Motykie GD, Mokhtee D, Zebala LP, Caprini JA, Kudrna JC, Mungall DR. The use of a Bayesian forecasting model in the management of warfarin therapy after total hip arthroplasty. J Arthroplasty. 1999;14:988-993. [ go to PubMed ]

16. Sun J, Chang MW. Initialization of warfarin dosages using computer modeling. Arch Phys Med Rehabil. 1995;76:453-456. [ go to PubMed ]

17. Fennerty A, Dolben J, Thomas P, et al. Flexible induction dose regimen for warfarin and prediction of maintenance dose. Br Med J (Clin Res Ed). 1984;288:1268-1270. [ go to PubMed ]

18. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5-mg and 10-mg warfarin loading doses. Arch Intern Med. 1999;159:46-48. [ go to PubMed ]

19. Chatellier G, Colombet I, Degoulet P. An overview of the effect of computer-assisted management of anticoagulant therapy on the quality of anticoagulation. Int J Med Inf. 1998;49:311-320. [ go to PubMed ]

20. Chatellier G, Colombet I, Degoulet P. Computer-adjusted dosage of anticoagulant therapy improves the quality of anticoagulation. Medinfo. 1998;9(pt 2):819-823. [ go to PubMed ]

21. Bond CA, Raehl CL. Pharmacist-provided anticoagulation management in United States hospitals: death rates, length of stay, Medicare charges, bleeding complications, and transfusions. Pharmacotherapy. 2004;24:953-963. [ go to PubMed ]

22. Tong L, Kayser S, Minichiello T. Oral Anticoagulation with Warfarin. UCSF Medical Center. Comprehensive Hemostasis and Antithrombotic Service (CHAS). March 2005.

23. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165:1095-1106. [ go to PubMed ]

Tables

Table 1. Drugs That Alter Response to Warfarin (22)

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

Table 2. Computer-Predicted INR Response if This Patient Were Given a Daily Dose of 5 mg of Warfarin