Reviewing the reality: why we need to change * Peter J. Lin Introduction

European Heart Journal Supplements (2005) 7 (Supplement E), E15–E20
doi:10.1093/eurheartj/sui031
Reviewing the reality: why we need to change
Peter J. Lin*
Director of Primary Care Initiatives, Canadian Heart Research Centre, Toronto, Canada
Introduction
A brief history of warfarin
More than 80 years ago, livestock farmers in North
Dakota, United States, observed severe, unexplained
* Corresponding author. Tel: þ1 416 467 5787.
E-mail address: peterlin1@rogers.com
The coagulation system and the site
of action of warfarin
To understand the limitations of warfarin, we need first
to appreciate the coagulation system and the sites of
action of warfarin. The coagulation system is designed
to prevent bleeding at the site of vessel injury through
the formation of a blood clot. Clot formation occurs as
a result of interactions between three components: the
blood vessel wall, cellular components within the blood
(predominantly platelets in the arterial circulation and
red cells in the venous circulation), and plasma clotting
factors. A detailed review of the blood clotting process
is beyond the scope of the present article, and readers
are referred to some reviews for further information.6–9
Focusing briefly on the plasma clotting factors, these
factors are involved in a proteolytic ‘cascade’ activation
pathway that ultimately results in the production of
thrombin, via the intrinsic and extrinsic pathways
(Figure 1 ). Thrombin then converts soluble fibrinogen
into insoluble fibrin, forming a clot. Under normal haemostatic conditions, excessive clotting is prevented by
several mechanisms, including the following: antithrombin III, which inhibits factors IX, X, XI, and XII
and thrombin; tissue factor pathway inhibitor, which
inhibits active factor X; the protein C, protein S, and
& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Downloaded from by guest on October 28, 2014
For nearly 60 years, vitamin K antagonists (VKAs) such as
warfarin have been the mainstay of oral anticoagulation
in a range of thromboembolic disorders, ranging from
stroke prevention in atrial fibrillation (AF) to the treatment and secondary prevention of venous thromboembolism. Although highly effective, warfarin has numerous
limitations that have resulted in its underuse and the
imposition of considerable burdens on both patients and
healthcare systems. In the case of stroke prevention in
AF, the argument has been made that warfarin use can
be maximized and its limitations minimized by using
several strategies, such as improving international normalized ratio (INR) control through greater use of anticoagulation clinics or patient self-management, and
greater adherence to relevant treatment guidelines.1
But is this realistic? Can the limitations of VKAs such as
warfarin really be effectively and properly minimized in
everyday clinical practice? In this article, the author
provides a counter-argument that warfarin is difficult to
use in clinical practice, that its limitations make it difficult to manage, and that we need new oral agents with
improved benefit–risk profiles and increased consistency
and predictability when compared with warfarin. To
understand the need for new agents, one must first
understand how warfarin works. To this end, it is necessary to review the history of warfarin, and its pharmacodynamic and pharmacokinetic profiles, so that it
becomes clear that the concerns and challenges that
face physicians and patients are very real and are
a direct result of the characteristics of warfarin.
bleeding in cattle, which was later linked to their diet
of fermented hay or silage made from sweet clover,
grown as a substitute for corn at this time.2 In 1939,
the coumarin dicoumarol was identified as the active
agent in sweet clover responsible for the bleeding disorder.3 Several coumarin derivatives have since been synthesized, the most potent being warfarin (derived from
the acronym for Wisconsin Alumni Research Foundation,
WARF).4 It was initially used as a rat and mouse poison,
but the survival of a man after an attempted suicide by
the use of a large amount of warfarin-based rodenticide
led to clinical trials of warfarin as an anticoagulant in
humans.5
E16
P.J. Lin
Disruption of the coagulation cascade by warfarin.
thrombomodulin complex, which inhibits factors VIII
and V; and of course the fibrinolytic system. However,
in a condition such as AF, the haemostatic balance is
disrupted as a result of stasis within the fibrillating
left atrial appendix, leading to inappropriate clot formation.10,11 Effectively, the balance has been tipped in
favour of forming blood clots. Hence, our role is to
restore that balance by using anticoagulants.
What anticoagulant strategies are available to prevent
clot formation and to restore the haemostatic balance?
One approach has been the use of heparins (unfractionated and low-molecular-weight heparins), which
indirectly act to enhance the activity of antithrombin
III.12 However, the need for parenteral administration
has limited their use, particularly in the chronic/outpatient setting.13,14 Another strategy uses warfarin and other
VKAs. Warfarin exerts its anticoagulant effect by inhibition of the synthesis of several vitamin K-dependent
proteins—the coagulation factors VII, IX, and X, thrombin
(factor II) and the anticoagulation proteins C and S.15 The
mechanism of action of warfarin and how this leads
to several of the complications seen with this agent is
discussed subsequently.
Mechanism of action of warfarin
Vitamin K-dependent proteins require g-carboxylation to
be fully active, and this process is coupled with oxidization of vitamin K (Figure 2 ). Oxidized vitamin K cannot
be used again; therefore, the body recycles it by reducing the vitamin K to its natural state. VKAs prevent
the recycling of vitamin K by blocking this conversion of
oxidized vitamin K back to the reduced form. This in turn
blocks g-carboxylation of vitamin K-dependent proteins,
resulting in the synthesis of proteins that have reduced
activity.16
This mechanism of action means that warfarin has a
delayed onset of action, as the complete effect of
warfarin is only achieved after clearance of currently
active vitamin K-dependent coagulation factors has
taken place. It can take several days for the maximal
effect of warfarin to be achieved owing to the long
half-lives of some vitamin K-dependent coagulation
factors (Table 1 ).The half-lives vary for the different
coagulation factors, e.g. factor VII has the shortest
half-life (4–6 h), and hence it will be depleted first, but
others have longer half-lives (up to 72 h). Therefore,
the full effect is not achieved for several days. Another
complicating factor is that proteins C and S, which are
also inhibited by warfarin, are endogenous anticoagulants that reduce thrombin generation. Protein C
has a short half-life (only 8 h), which means that warfarin
therapy may produce a hypercoagulable state initially
until more coagulation factors are metabolized and
removed from the system.16 Owing to this delayed
onset of action and also the potential hypercoagulable
state, overlap with heparin is required, typically for
3–5 days, to protect patients until the full effect of
warfarin is realized.16
Downloaded from by guest on October 28, 2014
Figure 1
Reviewing the reality: why we need to change
E17
Table 1
factors
The variable half-lives of vitamin K-dependent
Coagulation factor
Half-life (h)
II
VII
IX
X
Protein C
Protein S
60
4–6
24
48–72
8
30
can create significant fluctuations in the anticoagulation
effects despite the same dose of warfarin.
Warfarin–drug interactions
Figure 2 The vitamin K cycle and its link to carboxylation of coagulation
factors. Vit, vitamin. Reproduced with permission from Hirsh J. et al. 44
American Heart Association/American College of Cardiology Foundation
guide to Warfarin therapy. Circulation 2003;107:1692–1711.
Once an anticoagulant effect is established, the main
complication of warfarin therapy is bleeding, with the
bleeding risk increasing substantially with the intensity
of anticoagulation.16 A narrow optimal INR range of
2.0–3.0 has been identified as providing effective anticoagulation at the lowest risk of bleeding.1,16 Patients
therefore require regular coagulation monitoring and frequent dose adjustments to get the level of anticoagulation to within the therapeutic range. Bleeding risk is
particularly increased in patients receiving concomitant
antiplatelet drugs,17 those aged .65 or those with prior
stroke, renal impairment, or anaemia.18,19
Variability in response
Warfarin–food interactions
A major drawback to the VKA mode of action is that subjects receiving long-term therapy will be sensitive to
fluctuating dietary vitamin K. Vitamin K in the diet is
derived predominantly from phylloquinones in plant
material,20 which are found in a variety of foods including
cauliflower, green cabbage, seaweed, broccoli, and
spinach.21 Dietary vitamin K is converted in the liver to
a reduced form by a warfarin-insensitive system that
allows the synthesis of fully active vitamin K-dependent
coagulation factors, thereby counteracting the anticoagulant effect of warfarin. This can lead to intra-individual
inconsistency in the dose–response relationship of warfarin. Therefore, variable intakes of dietary vitamin K
Downloaded from by guest on October 28, 2014
Bleeding complications
Warfarin is a racaemic mixture of two enantiomers,
R- and S-warfarin, the S-form being three to five times
more potent than the R-form.22,23 The two forms are
present in roughly equal proportions, have half-lives
of 36–42 h, circulate bound to plasma albumin, and
ultimately accumulate in the liver where they are
metabolized.16 Warfarin is differentially metabolized by
a variety of cytochrome P450 (CYP) enzymes, depending
on the enantiomer being metabolized (stereoselective
metabolism) and the site of metabolism (regioselective metabolism) (Figure 3 ).24 In vitro studies have
shown that S-warfarin is metabolized predominantly
by CYP2C9 and to a lesser extent through CYP3A4.24
R-warfarin, on the other hand, is metabolized predominantly through CYP1A2 but also through CYP3A4 and
CYP2C19. Therefore, metabolism of warfarin involves
multiple cytochromes and, as a consequence, is particularly prone to pharmacokinetic drug interactions.
The drugs most likely to interact are those that are
also metabolized by the CYP system. Some of these
drugs are CYP inhibitors, resulting in decreased warfarin
metabolism and therefore higher serum concentrations
of warfarin. Inhibition of S-warfarin metabolism is more
important clinically, owing to the increased pharmacological potency compared with the R-form. Other drugs
induce (accelerate) the CYP system, causing warfarin to
pass through the body faster, resulting in lower serum
levels of warfarin. With all these multiple points of
interaction, drugs from many different classes can alter
warfarin metabolism. For example, phenylbutazone (a
non-steroidal anti-inflammatory drug), sulfinpyrazone
(used for the treatment of hyperuricaemia), and the antibiotics metronidazole and trimethoprim each potentiate
the anticoagulant effect of warfarin through inhibition of
S-warfarin metabolism.16,25–27 In contrast, drugs such as
the barbiturate depressants, the antibiotic rifampicin,
and the anticonvulsant carbamazepine inhibit the anticoagulant effect of warfarin through increased hepatic
clearance.16
The list of potential drug interactions is extensive;28
in fact, warfarin interacts with almost every class of
drug known. This is an important consideration for
treating conditions such as stroke prophylaxis in AF,
E18
P.J. Lin
carefully monitored
accordingly.37
and
warfarin
doses
reduced
Why we need to change
Limitations of warfarin therapy
Figure 3 R- and S-warfarin and the major CYP enzymes responsible for
their metabolism.
where patients at the highest risk tend to be elderly and
are more likely to have co-morbidities requiring
polypharmacy.
Genetic and environmental variability
Downloaded from by guest on October 28, 2014
Warfarin therapy is further complicated by genetic and
environmental factors. Genetic polymorphisms resulting
from single amino acid substitutions can reduce the metabolic activity of CYP2C9, leading to an increased level of
S-warfarin and an increased frequency of bleeding.29
Wild-type CYP2C9 (CYP2C9 1) has at least five allelic variants (CYP2C9 2–CYP2C9 6) that underlie inter-individual
and ethnic differences. For example, CYP2C9 2 and
CYP2C9 3 are significant among white populations,
CYP2C9 4 has been exclusively identified in Japanese
individuals, and CYP2C9 5 and CYP2C9 6 are found
among African-Americans.30 Carriers of such variant
alleles are at particular risk of adverse events when a
drug has a narrow separation of antithrombotic and
haemorrhagic effects, as is the case with warfarin. This
was demonstrated by a case of a 90-year-old patient
treated with 5 mg of warfarin per day, who was hospitalized for gastro-intestinal bleeding with an INR of 66.31
Warfarin could still be detected in this individual 11
days after the last dose, suggesting reduced clearance
of the drug. Genetic analysis revealed that this patient
was a carrier of the two variant alleles CYP2C9 2 and
CYP2C9 3.31 There is also reduced warfarin clearance
with age, which is reflected in exaggerated anticoagulant
responses, a further complication for warfarin use in the
elderly.32,33
Hereditary resistance to warfarin has also been demonstrated,34–36 where patients require much larger doses
(five- to 20-fold higher) of warfarin to achieve an anticoagulant effect.16 This warfarin resistance is attributed
to a reduced affinity of warfarin for its hepatic receptor.
Cigarette smoking can induce CYP1A2 activity, the
major cytochrome responsible for R-warfarin metabolism. With increased smoking, the CYP1A2 increases
its metabolism of R-warfarin, which translates into a
need for higher dosages. During longer non-smoking
periods, the enzyme activity slows down and thus less
warfarin is needed. Therefore, a change in smoking
habit may affect warfarin coagulation response. After
smoking cessation, for example, patients need to be
A detailed look at the characteristics of warfarin and its
pharmacological profile has highlighted its unpredictable
anticoagulant response and the underlying reasons for it.
The close coagulation monitoring required to maintain
the level of anticoagulation within the narrow therapeutic range can cause inconvenience to the patient
and required the infrastructure to deal efficiently with
such intense patient management. In fact, even with
weekly monitoring, it is still possible for the INR to be
out of range because of changes in diet or in intermittent
use of other medications that affect warfarin levels.
Therefore, even more frequent testing may not eliminate
the difficulties that warfarin poses.
The limitations associated with warfarin therapy have
resulted in the global problem of under-treatment with
anticoagulants for the prevention of strokes in AF. In
Italy, for example, only about one in five hospitalized
patients with AF will receive oral anticoagulation and
only 25% of chronic AF patients receive a VKA.38 The
United States has the best rate of VKA use in AF, but
this still only amounts to 40% of patients with AF receiving oral anticoagulation.39 Physician surveys suggest that
fear of bleeding complications is the major factor responsible for under-prescription.40,41 Given that warfarin
therapy is proved to be effective and safe if maintained
within an INR range of 2.0–3.0, is this fear of bleeding
complications unwarranted?
The unpredictable nature of warfarin means it is difficult to monitor and the therapeutic range is difficult to
achieve, even in controlled trial settings. For example,
the SPORTIF II trial was a small study involving approximately 50–100 warfarin-treated patients with AF.42 The
study protocol and controlled trial conditions meant
that experienced nursing staff carried out regular monitoring and dose adjustments, in order to maintain an
INR within the target range. Since the trial involves a
relatively small number of individuals, control of INR
would be expected to be better than that generally
achieved in clinical practice. Despite this, an INR of
2.0–3.0 was only achieved 44% of the time (Figure 4 ).
Patients received sub-therapeutic levels 38% of the
time, and 18% of the time the INR was above 3.0, increasing the risk of major haemorrhage.
This difficulty in achieving INR is reflected in the frequency of major bleeding observed with warfarin at the
start of outpatient therapy. Follow-up information for
562 patients initiating warfarin therapy revealed a cumulative incidence of 11% for major bleeding in the first
12 months.19
Furthermore, a recent prospective analysis of more
than 18 820 patients admitted to two hospitals in the
UK over a 6-month period found that in 80% of cases
hospitalization was due to adverse drug reactions43 and
Reviewing the reality: why we need to change
E19
that warfarin alone was responsible for 10.5% of cases,
with adverse reactions including gastro-intestinal
bleeding and haematoma. Despite the proven benefit of
warfarin, this level of morbidity and the associated
costs explains the reluctance of physicians to start
therapy and highlights the need for drugs with improved
benefit–risk ratios.
the development of the direct thrombin inhibitor class
of anticoagulant. The first oral agent in this class, ximelagatran, represents the first-ever alternative to VKAs for
oral anticoagulation. Ximelagatran was developed to
overcome many of the limitations of warfarin and other
VKAs and has the potential to maximize anticoagulation
use in patients with AF, including better adherence to
established treatment guidelines.
Need for safer and more practical agents
Warfarin therapy has been invaluable as an oral anticoagulant over the past 60 years; however, its limitations
have provided the stimulus for the development of new
oral anticoagulants that will overcome the drawbacks
of VKA therapy. These agents are being developed to
have limited or no dietary interactions and a low
potential for drug interactions, with a predictable pharmacokinetic profile. The consistent anticoagulant
response would allow fixed dosing without coagulation
monitoring. Furthermore, a fast onset of action and
oral administration would allow utility in both acute
and chronic settings.
Thrombin inhibition: a promising new
concept
As described earlier, the coagulation cascade ultimately
leads to thrombin generation, which in turn leads to
platelet activation and fibrin formation. The key role of
thrombin in the coagulation process meant that it was
identified as a promising therapeutic target and led to
References
1. Vo
¨ller H. In defence of current treatment options: where are we now?
Eur Heart J Suppl 2005;7:E4–E9.
2. Gustafsson D, Bylund R, Antonsson T et al. A new oral anticoagulant:
the 50-year challenge. Nat Rev Drug Discov 2004;3:649–659.
3. Campbell HA, Link KP. Studies on the hemorrhagic sweet clover
disease. IV. The isolation and crystallization of the hemorrhagic
agent. J Biol Chem 1941;138:21–33.
4. Allen EV, Baker NW, Waugh JM. A preparation from spoiled sweet
clover [3,30 -methylene-bis-(4-hydroxy-coumarin)] which prolongs
coagulation and prothrombin time of the blood: A clinical study.
JAMA 1942;120:1009–1015.
5. Link KP. The discovery of dicumarol and its sequels. Circulation
1959;19:97–107.
6. Schenone M, Furie BC, Furie B. The blood coagulation cascade. Curr
Opin Hematol 2004;11:272–277.
7. Davie EW. A brief historical review of the waterfall/cascade of blood
coagulation. J Biol Chem 2003;278:50819–50832.
8. Davie EW. Biochemical and molecular aspects of the coagulation
cascade. Thromb Haemost 1995;74:1–6.
9. Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation,
maintenance, and regulation. Biochemistry 1991;30:10363–10370.
10. Abusaada K, Sharma SB, Jaladi R et al. Epidemiology and management of new-onset atrial fibrillation. Am J Manag Care 2004;10:
S50–S57.
Downloaded from by guest on October 28, 2014
Figure 4 The SPORTIF II trial: proportion of patients within target INR range. Reprinted from J Am Coll Cardiol, Vol 41, Peterson P. et al. Ximelagatran
versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: A dose guiding tolerability and safety study, pp.
1445–1451. & (2003), with permission from the American College of Cardiology foundation.
E20
28. Cropp JS, Bussey HI. A review of enzyme induction of warfarin
metabolism with recommendations for patient management.
Pharmacotherapy 1997;17:917–928.
29. Redman AR. Implications of cytochrome P450 2C9 polymorphism
on warfarin metabolism and dosing. Pharmacotherapy 2001;21:
235–242.
30. Schwarz UI. Clinical relevance of genetic polymorphisms in the
human CYP2C9 gene. Eur J Clin Invest 2003;33(Suppl. 2):23–30.
31. Bloch A, Ben Chetrit E, Muszkat M et al. Major bleeding caused by
warfarin in a genetically susceptible patient. Pharmacotherapy
2002;22:97–101.
32. Gurwitz JH, Avorn J, Ross-Degnan D et al. Aging and the anticoagulant
response to warfarin therapy. Ann Intern Med 1992;116:901–904.
33. Mungall D, White R. Aging and warfarin therapy. Ann Intern Med
1992;117:878–879.
34. O’Reilly RA, Pool JG, Aggeler PM. Hereditary resistance to coumarin
anticoagulant drugs in man and rat. Ann N Y Acad Sci 1968;151:
913–931.
35. Holt RJ, Freytes CO. Familial warfarin resistance. Drug Intell Clin
Pharm 1983;17:281–283.
36. Alving BM, Strickler MP, Knight RD et al. Hereditary warfarin resistance. Investigation of a rare phenomenon. Arch Intern Med 1985;
145:499–501.
37. Faber MS, Fuhr U. Time response of cytochrome P450 1A2 activity on
cessation of heavy smoking. Clin Pharmacol Ther 2004;76:178–184.
38. Ageno W, Ambrosini F, Nardo B et al. Atrial fibrillation and antithrombotic treatment in Italian hospitalized patients: a prospective,
observational study. J Thromb Thrombolysis 2001;12:225–230.
39. Stafford RS, Singer DE. Recent national patterns of warfarin use in
atrial fibrillation. Circulation 1998;97:1231–1233.
40. Gross CP, Vogel EW, Dhond AJ et al. Factors influencing physicians’ reported use of anticoagulation therapy in nonvalvular
atrial fibrillation: a cross-sectional survey. Clin Ther 2003;25:
1750–1764.
41. Pradhan AA, Levine MA. Warfarin use in atrial fibrillation: A random
sample survey of family physician beliefs and preferences. Can J
Clin Pharmacol 2002;9:199–202.
42. Petersen P, Grind M, Adler J. Ximelagatran versus warfarin for stroke
prevention in patients with nonvalvular atrial fibrillation. SPORTIF II:
a dose-guiding, tolerability, and safety study. J Am Coll Cardiol
2003;41:1445–1451.
43. Pirmohamed M, James S, Meakin S et al. Adverse drug reactions
as cause of admission to hospital: prospective analysis of 18 820
patients. BMJ 2004;329:15–19.
44. Hirsh J, Valentin F, Ansell J et al. American Heart Association/
American College of Cardiology Foundation guide to warfarin
therapy. Circulation 2003;107:1692–1711.
Downloaded from by guest on October 28, 2014
11. The Stroke Prevention in Atrial Fibrillation Investigators. Predictors
of thromboembolism in atrial fibrillation: II. Echocardiographic features of patients at risk. Ann Intern Med 1992;116:6–12.
12. Hirsh J, Warkentin TE, Shaughnessy SG et al. Heparin and lowmolecular-weight heparin: mechanisms of action, pharmacokinetics,
dosing, monitoring, efficacy, and safety. Chest 2001;119:64S–94S.
13. Hirsh J, Anand SS, Halperin JL et al. AHA Scientific Statement: Guide
to anticoagulant therapy: heparin: a statement for healthcare professionals from the American Heart Association. Arterioscler Thromb
Vasc Biol 2001;21:E9.
14. Wawrzynska L, Tomkowski WZ, Przedlacki J et al. Changes in bone
density during long-term administration of low-molecular-weight
heparins or acenocoumarol for secondary prophylaxis of venous
thromboembolism. Pathophysiol Haemost Thromb 2003;33:64–67.
15. Prydz H. Vitamin K–dependent clotting factors. Semin Thromb
Hemost 1977;4:1–14.
16. Hirsh J, Fuster V, Ansell J et al. American Heart Association/American
College of Cardiology Foundation guide to warfarin therapy. J Am Coll
Cardiol 2003;41:1633–1652.
17. Dale J, Myhre E, Loew D. Bleeding during acetylsalicylic acid and
anticoagulant therapy in patients with reduced platelet reactivity
after aortic valve replacement. Am Heart J 1980;99:746–752.
18. Ansell J, Hirsh J, Dalen J et al. Managing oral anticoagulant therapy.
Chest 2001;119:22S–38S.
19. Landefeld CS, Goldman L. Major bleeding in outpatients treated with
warfarin: incidence and prediction by factors known at the start of
outpatient therapy. Am J Med 1989;87:144–152.
20. Suttie JW, Mummah-Schendel LL, Shah DV et al. Vitamin K deficiency
from dietary vitamin K restriction in humans. Am J Clin Nutr 1988;
47:475–480.
21. Bolton-Smith C, Price RJ, Fenton ST et al. Compilation of a provisional
UK database for the phylloquinone (vitamin K1) content of foods. Br J
Nutr 2000;83:389–399.
22. Breckenridge A, Orme M, Wesseling H, Lewis RJ, Gibbons R. Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in
man. Clin Pharmacol Ther 1974;15:424–430.
23. O’Reilly RA. Studies on the optical enantiomorphs of warfarin in man.
Clin Pharmacol Ther 1974;16:348–354.
24. Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin.
Pharmacol Ther 1997;73:67–74.
25. Toon S, Low LK, Gibaldi M et al. The warfarin-sulfinpyrazone interaction: stereochemical considerations. Clin Pharmacol Ther 1986;
39:15–24.
26. O’Reilly RA. The stereoselective interaction of warfarin and metronidazole in man. N Engl J Med 1976;295:354–357.
27. O’Reilly RA. Stereoselective interaction of trimethoprimsulfamethoxazole with the separated enantiomorphs of racemic
warfarin in man. N Engl J Med 1980;302:33–35.
P.J. Lin