Coumadin Loading: Saving Money or Costing Lives?

1. Coumadin Loading: Saving Money or Costing Lives? Eric J. Melvin, M.D. January 6, 2004

2. Introduction • Coumadin is the major oral anticoagulant used in the United States • The indications for anticoagulation with coumadin include atrial fibrillation, prosthethic heart valves, thromboembolic disease, hypercoaguable states, and depressed cardiac function

3. Introduction • The major risk associated with coumadin therapy is bleeding and approximately 10% of patients on coumadin for one year have a significant bleeding complication requiring medical therapy (Braundwald et al., 2001) • 0.5% to 1% of patients on coumadin for one year will have a fatal hemorrhage

4. Introduction • The risk of bleeding increases with increasing dosages of coumadin and the dosage needed to achieve a target INR must be individualized • A common problem in treating patients with coumadin is the delay in achieving the target INR and this results in increased LOS or outpatient Lovenox therapy

5. Introduction • In an attempt to shorten the time required for attaining the target INR after initiating coumadin therapy, many physicians are loading patients with high doses of coumadin • the goal of this coumadin loading is to shorten LOS and prevent the need for outpatient Lovenox therapy

6. The Coagulation Cascade

7. Monitoring Coumadin Therapy • Coumadin’s effect on the coagulation cascade is measured using the Prothrombin Time(PT) and International Normalized Rato(INR) • The major factor that determines the PT/INR is factor VII and it is the decrease in the plasma level of this factor which most affects the PT/INR (Ravel, 1989)

8. Monitoring Coumadin Therapy • It is important to note that the intrinsic and extrinsic pathways of the coagulation system have been documented in vitro and that in vivo the presence of two distinct pathways is not as distinct • Congenital deficiencies of factor VII often produce minimal bleeding tendencies indicating the extrinsic pathway in vivo may not be as dependent on factor VII

9. Standard Loading Dosage • The loading dose is more art than science as it is difficult to predict how a patient’s INR will respond to coumadin • Lexi-Comp currently recommends individualizing the initial loading dose with most patients receiving a 5 to 10 mg loading dose for two days

10. Standard Maintenance Dosage • The maintenance dose is dependent on the target INR and multiple patient variables including patient weight, age, hepatic function, nutritional status, and concurrent medications • Most individuals require between 2 and 10 mg of coumadin qd as a maintenance dose to maintain a therapeutic INR

11. Attaining a Therapeutic INR • Coumadin inhibits the formation of vitamin K-dependent clotting factors by hepatocytes but does not affect those factors already in circulation • Therapeutic doses of coumadin decrease the total amount of each vitamin-K dependent clotting factor made by the liver by 30 to 50% (Hardman and Limbird, 1996)

12. Attaining a Therapeutic INR • Increasing the loading dose of coumadin further suppresses hepatic synthesis of factors and shortens the time required for attaining a therapeutic INR (Katzung, 1995) • The amount of previously formed factors is highly variable and effected by nutrition, preexisting liver disease, patient weight, and other factors

13. Attaining a Therapeutic INR • The increase in the PT/INR is determined by the time required for the degradation of factors previously formed and the relative decrease in the hepatic synthesis of factors • Additionally, the 1/2 lives of each of the factors differs and these differences result in a delay in the attainment of the full antithrombotic effect of coumadin

14. Approximate Half-Lives of Vitamin K Dependent Factors and Anticoagulants

15. Effect of Coumadin on Clotting Factor Concentrations

16. Indications for Bridging Therapy • As the time required for attaining a therapeutic INR is on average 2-3 days, patients remain at risk for continued thromboembolic events during this time • The risk of coumadin-induced skin necrosis may be increased when coumadin therapy is first initiated without heparin bridging

17. What Does This Delay Cost? • At NCBH the cost/day for a general hospital bed is $365 with a total cost of $1095 for the three day increase in LOS required while attaining a therapeutic INR • The average cost/day for outpatient Lovenox is $99 with a total cost of $297 for three days of bridging therapy while attaining a therapeutic INR

18. Adverse Effects of Coumadin • Coumadin increases bleeding risk via its antithrombotic effects and this bleeding risk increases as the INR increases (Landerfield et al., 1993) • Coumadin also inhibits the synthesis of the vitamin-K dependent proteins C and S and these proteins serve as inhibitors of the activated coagulation cascade

19. Protein C and Protein S in the Coagulation Cascade

20. Coumadin-Induced Skin Necrosis • Coumadin-induced skin necrosis is a rare complication of coumadin therapy and usually develops soon after initiation of therapy • It is thought to develop secondary to the decrease in Protein C concentrations induced by coumadin as protein C has a very short 1/2 life and concentrations decrease soon after initiation of coumadin

21. Objective • To review studies examining the use of coumadin-loading vs. non-loading with regards to: 1) time needed to attain a therapeutic INR 2) number of supratherapeutic INRs 3) decline in levels of factor II 4) levels of protein C

22. Harrison et al., 1997 • Harrison et al. performed a RCT comparing the effects of loading patients with 10 mg or 5 mg of warfarin for 1 day on: 1) time to therapeutic INR(2-3) 2) proportion of supratherapeutic INRs(>3) 3) decline in the levels of factor II, factor VII, and protein C at 12, 36, 60, 84, and 108 hours after initiation of therapy

23. Harrison et al., 1997 • 51 patients requiring anticoagulation were randomly assigned to receive a 10 mg or 5 mg loading dose of warfarin • It is unclear in the study if patients were bridged with heparin therapy during treatment with warfarin over the 7 days of the study

24. Harrison et al., 1997 • 25 patients received a 10 mg loading dose of warfarin and 24 patients received a 5 mg loading dose of warfarin • The two groups did not significantly differ in age, weight, or frequency of acute thromboembolism, cancer, or surgery prior to or during the study

25. Harrison et al., 1997 • Starting on day 2 the dose of warfarin was individualized based on the INR using a nomogram and warfarin doses in the two groups were similar except on days 1 and 2 • Treatment of supratherapeutic INRs with vitamin K was left to the discretion of the attending physician treating the patient

26. Harrison et al., 1997 • The 10 mg group achieved an INR > 2 significantly sooner than the 5 mg group at 36 hours (44% and 8%, respectively) but many of these patients had INRs > 3(20% and 4%, respectively) • Factor VII levels were significantly less in the 10 mg group compared with the 5 mg group at 36 and 60 hours

27. Harrison et al., 1997 • There was no difference in the number of patients with a therapeutic INR in the 10 mg and 5 mg group at 60 hours(36% and 42%, respectively) • There were significantly greater numbers of supratherapeutic INRs in the 10 mg group compared with the 5 mg group at 36 hours (20% and 4%, respectively) and at 60 hours (36% and 0%, respectively)

28. Harrison et al., 1997 • Protein C levels were significantly lower in the 10 mg group compared with the 5 mg group at 36 and 60 hours but not at 0, 12, 84, and 108 hours • Factor II levels were not significantly different in the two groups at any time(0, 12, 26, 60, 84, and 108 hours)

29. Harrison et al., 1997 • Loading with 10 mg of warfarin compared with 5 mg resulted in an earlier increase in the INR to >2 but there was no difference in the number of patients with a therapeutic INR at 60 hours of therapy • Loading with 10 mg of warfarin significantly increased the risk of supratherapeutic INRs and thus may increase the risk of bleeding

30. Harrison et al., 1997 • Protein C levels were decreased at 36 and 60 hours after loading with 10 mg of warfarin compared with 5 mg and this may increase the risk of creating a hypercoaguable state • Factor II levels were not different in the two groups and thus the antithrombotic effect may not differ between the two groups

31. Conclusions • The authors concluded that loading with 10 mg of warfarin compared with 5 mg resulted in: 1) a more rapid increase in the INR in the 10 mg group but no difference in the number of therapeutic INRs at day 5 2) an increase in the number of supratherapeutic INRs in the 10 mg group

32. Conclusions • 3) a more rapid decline in the levels of protein C in the 10 mg group 4) no difference in the rate of decline in factor II levels by day 5 of therapy

33. Strengths • 1) measured the effect of warfarin loading on factor II levels and protein C levels in addition to factor VII levels and INR 2) a primary endpoint was the number of patients with a therapeutic range INR at days 5, 6, and 7

34. Weaknesses • 1) a smaller number of patients 2)assessed values whose clinical relevance is not known (ex. protein C) 3) defined supratherapeutic INR as > 3 4) did not follow patients past 7 days of therapy 5) patients included in the study were requiring anticoagulation for unspecified reasons

35. Kovacs et al., 2003 • Kovacs et al. performed a RCT comparing the effects of loading patients with 10 mg or 5 mg of warfarin for two days on: 1) time to therapeutic INR > 1.9 2) proportion of patients with a therapeutic range INR (2-3) at day 5 3) proportion of supratherapeutic INRs (>5) 4) number of significant bleeds 5) number of INR measurements

36. Kovacs et al., 2003 • 201 patients requiring anticoagulation for treatment of objectively confirmed acute venous thromboembolism were randomzied to receive 10 mg or 5 mg loading dosages of warfarin • The patients were to be treated as outpatients and after receiving the loading doses for warfarin were treated using nomograms

37. Kovacs et al., 2003 • 104 patients received a 10 mg loading dose of warfarin and 97 patients received a 5 mg loading dose of warfarin on days 1 and 2 as outpatients • The two groups did not significantly differ in age, weight, or frequency of cancer prior to initiation of the study

38. Kovacs et al., 2003 • Patients were treated with at least 5 injections of LMWH until the INR was > 1.9 • The number of new thromboembolic events and major bleeding episodes were documented over the next 90 days and 28 days, respectively

39. Kovacs et al., 2003 • INR measurements were recorded for both groups on days 3, 4, and 5 and then individually measured as needed based on each patients INR • The number of INR measurements and supratherapeutic INRs > 6 were recorded over 28 days for the two groups

40. Kovacs et al., 2003 • Patients treated with with 10 mg achieved a therapeutic INR (>1.9) significantly sooner than patients treated with 5 mg (4.2 days and 5.4 days, respectively) • A significantly greater number of patients in the 10 mg group compared with the 5 mg group achieved a therapeutic range INR by day 5 (83% and 46%, respectively)

41. Kovacs et al., 2003 • The rates of significant bleeding were not different between the 10 mg group and the 5 mg group (1% in each group) • The number of supratherapeutic INRs > 5 during 28 days of therapy was not different between the 10 mg group and the 5 mg group (9% and 11%, respectively)

42. Kovacs et al., 2003 • The rate of recurrence of venous thromboembolism during the 4 weeks did not differ between the 10 mg and 5 mg groups (3% and 0%, respectively) • The number of INR assessments was significantly higher in the 5 mg compared with the 10 mg group (9.1 and 8.1, respectively)

43. Conclusions • The authors concluded that loading with 10 mg of warfarin compared with 5 mg resulted in: 1) the 10 mg group achieving a therapeutic INR 1.4 days earlier 2) the 10 mg group having a greater number of patients having a therapeutic range INR at day 5

44. Conclusions • 3) no difference in the risk of supratherapeutic INRs > 5 4) no difference in the incidence of major bleeding 5) no difference in the incidence of recurrence of venous thromboembolism 6) an increase in the number of INR measurements in the 5 mg group

45. Strengths • 1) a larger number of patients 2) followed patients for a greater period of time (28 days and 90 days) 3) measured clinically relevant values in the form of major bleeding events, number of INR measurements, and recurrent thromboembolism 4) defined a supratherapeutic INR as > 5

46. Weaknesses • 1) assumed that anticoagulation activity may reflect antithrombotic activity 2) primary endpoint was INR > 1.9 and not a therapeutic range INR (2-3) 3) assessed thromboembolic activity while not being able to assess coumadin-induced skin necrosis (do to low incidence)

47. Summary • It is important to note that anticoagulation activity does not necessarily correlate with antithrombotic activity, especially during initiation of coumadin therapy • Factor II levels most determine the antithrombotic activity and because of its long 1/2 life the decline in the levels of factor II is delayed when coumadin therapy is initiated

48. Summary • Loading with 10 mg of coumadin results in a more rapid decline in factor VII levels resulting in a more rapid increase in the INR but may be associated with a greater number of supratherapeutic INRs • It is not clear based upon the data if there is any difference in the number of patients therapeutic at day 5 of therapy with 10 mg and 5 mg loading doses

49. Summary • The more rapid decline in protein C levels induced by loading with 10 mg of coumadin may result in the production of a hypercoaguable state • This hypercoaguable state may increase the risk of producing coumadin-induced necrosis which, although rare, may have devastating effects on the patient

50. Summary • Given the conflicting data currently available, more studies are needed examining the risks and benefits of coumadin loading • Based on the current data, it appears coumadin loading has more potential risks than benefits