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

• Coumadins 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 patients 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(gt3) 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 gt 2 significantly
  sooner than the 5 mg group at 36 hours (44 and
  8, respectively) but many of these patients had
  INRs gt 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 gt2
  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
  gt 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 gt 1.9 2) proportion
  of patients with a therapeutic range INR (2-3) at
  day 5 3) proportion of
  supratherapeutic INRs (gt5)
  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 gt 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 gt 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 (gt1.9) 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 gt 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 gt 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 gt 5

46
Weaknesses

• 1) assumed that anticoagulation activity may
  reflect antithrombotic activity 2)
  primary endpoint was INR gt 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

51
Acknowledgements

• John Owen M.D.
• Vera Luther M.D.
• Chris Thomas M.D.
• Brent Powers M.D.
• Joshua Leonard M.D.

52
Bibliography

• Braunwald E, Fauci AS, Kasper DL, Hauser SL, Long
  DL, Jameson JL (eds) Harrisons Principles of
  Internal Medicine, ed 15. New York, McGraw-Hill,
  2001.
• Crowther MA, Ginsberg JB, Kearon C, Harrison L,
  Johnson J, Massicotte MP, Hirsch J. A randomized
  trial comparing 5-mg and 10-mg warfarin loading
  doses. Arch Intern Med. 199915946-48.

53
Bibliography

• Hardman JG, Limbird LE (eds) Goodman and
  Gillmans The Pharmacological Basis of
  Therapeutics, ed 9. New York, McGraw-Hill, 1996.
• Katzung BG Basic and Clinical Pharmacology, ed
  6. East Morwalk, Connecticut, Appleton Lange,
  1995

54
Bibliography

• Kovacs MJ, Rodger M, Anderson DR, Morrow B, Kells
  G, Kovacs J, Boyle E, Wells P. Comparison of
  10-mg and 5-mg warfarin initiation nomograms
  together with low-molecular heparin for
  outpatient treatment of acute venous
  thromboembolism. Ann Intern Med. 2003
  138714-719.

55
Bibliography

• Landerfield CS, Beyth RJ. Anticoagulant-related
  bleeding clinical epidemiliogy, prediction, and
  prevention. Am J Med. 199395315-328.
• Ravel R Clinical Laboratory Medicine, ed 6.
  Saint Louis, Missouri, Mosby-Year Book, 1989.