**[Oral Anticoagulant Therapy and its Limitations]{.smallcaps}**

***[The Importance of Expert Management]{.smallcaps}***

Prepared for the Surgeon General's Workshop on Deep Vein Thrombosis

Bethesda, MD

May 8 -- 9, 2006

Jack Ansell, M.D.

Professor of Medicine

Vice Chair, Department of Medicine

Boston University School of Medicine

Boston, Massachusetts

Ph 617 638 7250

Fx 617 638 8728

The only oral anticoagulants available for clinical use are the coumarin
and indandedione derivatives, collectively referred to as the vitamin K
antagonists (VKA), since their mechanism of action is to interfere with
vitamin K which is necessary for the synthesis of specific coagulation
proteins (factors II, VII, IX, and X) (Figure 1).^1^ Warfarin is the
most common VKA used in North America and world-wide, but other
longer-acting and shorter-acting variants are popular in selected
countries. Table 1 summarizes the current FDA approved indications for
warfarin therapy. The major change in the indications for the VKAs in
the last several decades has been the indication for stroke prevention
in atrial fibrillation (AF), a cardiac rhythm disturbance. However, the
use of warfarin has grown as more physicians have become aware of its
effectiveness, as recommended duration of treatment has increased for
patients with venous thromboembolism (VTE),^2^ as efforts have been
applied to treat more patients with AF, as well as the increasing
prevalence of AF,^3^ and as dose management of a difficult drug has
improved. Currently, estimates suggest that approximately 1% of the
populations of developed countries are receiving a VKA.^4^

Warfarin therapy interferes with blood coagulation so as to reduce the
ability of the blood to form a clot (thrombus) sometimes referred to as
"thinning of the blood."^1^ The optimal degree of interference, referred
to as the therapeutic range as measured by a coagulation test called the
prothrombin time (PT), is sufficient inhibition so as to limit blood
clotting, but not so much as to significantly enhance the risk of
spontaneous bleeding. The PT result is reported as an INR (International
Normalized Ratio), a calculation designed to reduce differences in
results due to different laboratory reagents for the PT test.^5^

Because the anticoagulant effect of warfarin does not correlate directly
with dose and because many factors will influence the dose required to
produce and maintain a therapeutic range, warfarin therapy requires
expert dose management with frequent PT tests. Testing may be required
weekly or every other week in unstable patients, and every four weeks in
stable patients. Fluctuations in dose response may be due to a number of
variables including changes in vitamin K~1~ intake (increased or
decreased vitamin K~1~ in the diet) or vitamin K~1~ or warfarin
absorption (gastrointestinal factors or drug effects), changes in
warfarin metabolism (often due to the effects of other drugs), changes
in vitamin K~1~ dependent coagulation factor synthesis or metabolism
(often due to liver disease), inaccuracy in PT testing, and problems
with patient compliance.^1^ The consequence of unrecognized changes or
incorrect dosing is a super or sub-therapeutic INR significantly
enhancing the risk of spontaneous bleeding with high INRs or recurrent
thrombosis or embolism with low INRs. Warfarin therapy requires
systematic and conscientious INR monitoring and dose management to
optimize therapy and avoid these adverse events. Finally, the
pharmacology of warfarin makes it less than an ideal oral anticoagulant
because of its slow onset of action, difficult reversibility, and mode
of metabolism in the liver. Table 2 summarizes the major challenges of
warfarin therapy and represents the unmet needs of current therapy.

Recent new developments in warfarin pharmacology have uncovered major
reasons for individual responses to therapy. These include mutations in
the gene that codes for the major enzyme that metabolizes warfarin
(called CYP2C9) and mutations in the gene that codes for the enzyme that
is the target of warfarin's effect (called the vitamin K oxide reductase
complex 1 or VKORC1) (Figure 2). We now know that there are several
mutations that lead to the production of a less functional CYP2C9
enzyme, resulting in impaired warfarin metabolism. Consequently, the
concentration of warfarin increases in the blood leading to a higher
degree of anticoagulation (i.e., higher INR).^6-10^ Similarly, within
the last two years, the VKORC1 gene has been identified and mutations
have been found that result in the production of an enzyme that may be
more or less sensitive to warfarin inhibition. Thus, lower or higher
doses of warfarin, are required to interfere with enzyme function and
vitamin K factor synthesis.^11-16^ These mutations are now felt to
account for between 20 -- 50% of dose variability. They are present to
different degrees in various ethnic populations and account for, in
part, different dose requirements in these groups (Table 3).

The quality of dose management is possibly the greatest factor
responsible for a good clinical outcome (i.e., maintaining a therapeutic
INR with no thromboembolism or bleeding) in a patient on warfarin
therapy.^17^ Dose management is labor intensive requiring frequent INR
determinations, frequent patient contacts, and timely and knowledgeable
dosing decisions. Patients managed by their individual physician
(referred to as usual care), without a coordinated system of care for
this management, have more serious adverse events than do patients who
are managed within systematic programs, known as anticoagulation clinics
(ACC), where the primary responsibility is to manage warfarin
therapy.^18^ As summarized in Table 4, anticoagulation clinics maintain
their patients in therapeutic range more often and have fewer adverse
events than do patients managed in usual care settings.

Approximately 20 years ago, technology was developed that was able to
measure a PT from a fingerstick sample of blood with a small portable
instrument, much like glucose testing instruments for diabetics.^19^
This technology provided rapid turnaround of results and paved the way
for patient self-testing at home, and in many cases, patient
self-management of their warfarin dose, similar to a diabetic managing
his/her own insulin dose based on a self-measured blood sugar level.^20^
Patient self-testing (PST) or patient self-management (PSM) is not
suitable for all patients, but in properly selected and trained
individuals, such management leads to improved outcomes over usual care
and outcomes at least comparable, if not better, than those achieved by
an anticoagulation clinic. Table 5 summarizes results from a number of
trials assessing this type of care.

Unfortunately, the widespread implementation of PST or PSM is
complicated and highly dependent on the reimbursement of instruments and
test strips. Although available for over ten years, such therapy was
only approved in the United States about 6 years ago, and its use was
limited to patients who require warfarin for a prosthetic mechanical
heart valve. The process for reimbursement was also complex,
disincentivizing physicians to implement such management. Estimates
today indicate that approximately 10,000 patients are performing PST or
PSM in the US out of the 2 -- 3 million patients on warfarin therapy (\~
0.4%). This mode of therapy is spreading across Europe, although with
similar challenges. In Germany, approximately 100,000 patients with
various indications for therapy are practicing PST/PSM (\~12% of
warfarin population).

Finally, there are additional methodologies to aid in the management of
warfarin therapy. These include a number of proprietary software
programs designed to manage patient medical information, INR and dosing
data, scheduling and tracking of appointments and "no-shows", and
quality reports.^21^ The more sophisticated programs are also capable of
recommending a warfarin dose based on proprietary algorithms embedded in
the software. Such dosing programs have been shown to achieve levels of
therapeutic effectiveness equivalent to, and in some cases better, than
physician dosing.^22-24^ Some of these programs are web based enabling
multiple users and wide access. Lastly, some programs have the ability
to automatically notify patients with reminders for their next
appointment or self-testing date. The software tends to be relatively
expensive and designed for the larger anticoagulation clinics with 500
or more patients in management.

References

1\. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The
pharmacology

and management of the vitamin K antagonists. Chest
2004;126(Suppl):202S-31S.

2\. Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE.

Antithrombotic therapy for venous thromboembolic disease: The Seventh
ACCP

Conference on Antithrombotic and Thrombolytic Therapy. Chest
2004;126:401S-

428S.

3\. Go AS, Hylek EM, Phillips JA, et al. Prevalence of diagnosed atrial
fibrillation

in adults: national implications for rhythm management and stroke
prevention;

the Anticoagulation and Risk Factors in Atrial Fibrillation study. JAMA

2001;285:2370-2375.

4\. Pengo V, Pegoraro C, Cucchini U, Iliceto S. Worldwide management of
oral

anticoagulant therapy: the ISAM study. J Thromb Thrombolysis
2006;21:73-77.

5\. Kirkwood TBL. Calibration of reference thromboplastins and
standardization

of the prothrombin time ratio. Thromb Haemost 1983;49:238--244.

6\. Aithal GP, Day CP, Kesteven PJ, et al. Association of polymorphisms
in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of
bleeding complications. Lancet 1999;353:717--719.

7\. Tabrizi AR, Zehnbauer BA, Borecki IB, McGrath SD, Buchman TG,
Freeman BD. The frequency and effects of cytochrome P450(CYP)2C9
polymorphisms in patients receiving warfarin. J Am Col Surg
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8\. Joffe HV, Xu R, Johnson FB, Longtine J, Kucher N, Goldhaber SZ.
Warfarin dosing and cytochrome P450 2C9 polymorphisms. Thromb Haemost
2004;91:1123-1128.

9\. Visser LE, van Schaik RHN, van Vliet M, Trienekens PH, De Smet PAGM,
Vulto AG, Hofman A, van Duijn CM, Stricker BH Ch. The risk of bleeding
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alleles on acenocoumarol or phenprocoumon. Thromb Haemost 2004;92:61-66.

10\. Gage BF, Eby C, Milligan PE, Banet GA, Duncan JR, McLeod HL. Use of
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warfarin. Thromb Haemost 2004;91:87-94.

11\. Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hortnagel K, Pelz
HJ, Lappegard K, Selfried E, Scharrer I, Tuddenham EGD, Muller CR, Strom
TM, Oldenburg J. Mutations in VKORC1 cause warfarin resistance and
multiple coagulation factor deficiency type 2. Nature 2004;427:537-541.

12\. Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW.
Identification of the gene for vitamin K epoxide reductase. Nature
2004;427:541-544.

13\. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL,
Blough DK, Thummel KE, Veenstra DL, Rettie AE. Effect of VKORC1
haplotypes on transcriptional regulation and warfarin dose. N Engl J Med
2005;352:2285-2293.

14\. D'Andrea G, D'Ambrosio RL, Di Perna P, Chetta M, Santacroce R,
Brancaccio V, Grandone E, Margaglione M. A polymorphism in the VKORC1
gene is associated with an interindividual variability in the
dose-anticoagulant effect of warfarin. Blood 2005;105:645-649.

15\. Geisen C, Watzka M, Sittinger K, Steffens M, Daugela L, Seifried E,
Muller CR, Wienker TF, Oldenburg J. VKORC1 haplotypes and their impact
on the inter-individual and inter-ethnical variability of oral
anticoagulation. Thromb Haemost 2005;94:773-779.

16\. Rost S, Fregin A, Hunerberg M, Bevans CG, Muller CR, Oldenburg J.
Site-directed mutagenesis of coumarin-type anticoagulant-sensitive
VKORC1. Thromb Haemost 2005;94:780-786.

17\. Ansell JE. Anticoagulation management as a risk factor for adverse
events: Grounds for improvement. J Thromb Thrombolys
1998;5(suppl)(S13-S18).

18\. Ansell JE. Anticoagulation management clinics for the out-patient
control of oral anticoagulants. Current Opinion Pulmonary Med
1998;4:215-219.

19\. Lucas FV, Duncan A, Jay R, et al. A novel whole blood capillary
technique

for measuring prothrombin time. Am J Clin Pathol 1987;88:442--446.

20\. Ansell JE, Hughes R. Evolving models of warfarin management:
Anticoagulation clinics, patient self-monitoring, and patient
self-management. Am Heart J 1996;132:1095--1100.

21\. Oertel LB, Mungall D. Software applications in anticoagulation
management, in **Managing Oral Anticoagulation Therapy: Clinical and
Operational Guidelines**, eds. JE Ansell, LB Oertel, AK Wittkowsky.
2^nd^ Ed, Facts & Comparisons, St. Louis, Mo, page 9:1.

22\. Poller L, Wright D, Rowlands M. Prospective comparative study of
computer programs used for management of warfarin. J Clin Pathol 1993;
46:299--303.

23\. Ageno W, Turpie AGG. A randomized comparison of a management

computer-based dosing program with a manual system to monitor oral
anticoagulant therapy \[abstract\]. J Thromb Thrombolysis 1998;
5(suppl):S69.

24\. Poller L, Shiach CR, MacCallum P, et al. The European Concerted
Action on Anticoagulation (ECAA): multicenter randomized study of
computerized anticoagulant dosage. Lancet 1998; 352:1505--1509.

Table 1. Indications for warfarin therapy^1^.

1\. Prophylaxis and/or treatment of venous thrombosis and its extension,
and pulmonary embolism.

2\. Prophylaxis and/or treatment of the thromboembolic complications
associated with atrial fibrillation and/or cardiac valve replacement.

3\. To reduced the risk of death, recurrent myocardial infarction, and
thromboembolic events such as stroke or systemic embolization after
myocardial infarction.

^1^Physicans Desk Reference, 2006 Thomson PDR, Montvale, NJ, page 933.

Table 2. Drawbacks of warfarin therapy.

1\. Onset and offset of action is delayed.

2\. Requires frequent blood test monitoring because:

\- the dose response is unpredictable,

\- it has a narrow therapeutic range above which or below which bleeding
or thromboembolism can occur, and

\- multiple factors (illness, drugs, diet, etc.) may influence dose
response.

3\. The monitoring assay has serious limitations.

4\. The reversibility of anticoagulant affect is slow.

5\. Requires labor-intensive follow up, expert dose management, and
frequent

patient communication.

Table 3. Frequency of genetic polymorphisms in different ethnic groups.

CYP2C9 Polymorphisms^1^

[CYP2C9\*1]{.underline} [CYP2C9\*2]{.underline} [CYP2C9\*3]{.underline}

Caucasians 79% - 89% 8% - 19% 6% - 10%

Native Canadians 91% 3% 6%

African Americans 98% 1.5% - 3.6% 0.05% - 1.5%

Asians 95% - 98% 0% 1.7% - 5%

VKORC1 Haplotypes^2^

[H1H2]{.underline} [H8H9]{.underline}

Euro Americans 37% 58%

African Americans 14% 49%

Asian American 89% 10%

^1^CYP2C9\*1 is the wild type (i.e., common genotype) and the \*2 and
\*3 represent polymorphisms that have reduced functional capacity to
metabolize the S enantiomer of warfarin. From^\ ^Takahashi H, Echizen H.
Pharmacogenetics of warfarin elimination and its clinical implications.
Clin Pharmacokinetics 2001;40:587-603.

^2\ ^H1, H2 and H8, H9 represent different haplotypes (combinations of
polymorphisms) that produce an enzyme that is either more or less
sensitive to warfarin inhibition. From reference 13.

Legends

Figure 1. Within the coagulation cascade, there are 4 coagulation
factors that require vitamin K for their normal synthesis: factors II,
VII, IX, and X. When vitamin K is absent (or interfered with by warfarin
therapy), these normal functioning factors are degraded based on their
normal metabolic half-lives (half-life in hours indicated next to the
respective factor). New factors are synthesized, but without vitamin K,
are non-functional (see figure 2).

Figure 2. Vitamin K participates in a carboxylation reaction to add a
"-COOH" group to glutamic acid moieties in the precursor proteins.
Vitamin K is oxidized in the process. Vitamin K can be reduced and
recycled by a vitamin K oxide reductase enzyme, the target for warfarin
inhibition. Warfarin is a racemic mixture of stereo isomers, the S and R
enantiomer. The S enantiomer is the more potent component and is
metabolized by the p450 hepatic enzyme, CYP2C9.