A 51-year-old woman with a history of valvular heart surgery in 2001 presented with symptoms of dizziness, weakness, loss of appetite, nausea, confusion and irritability. She had been taking warfarin 10 mg daily along with other medications. Examination found bradycardia, atrial fibrillation, and signs of internal bleeding. Laboratory tests showed severe warfarin toxicity with an INR over 10. She was diagnosed with warfarin toxicity and internal bleeding. Management included fluid resuscitation, blood transfusions, and ventilation support. However, she deteriorated and died the next day.

1. WARFARIN Monitoring
(A Case with Prosthetic heart valve)
MN Arham

2. Case History
• 51 year old lady referred by the Bisho Hospital on 17th
Jan 2008 with a letter stated she is have a pace maker,
later on examination no pace maker was found.
• Patients presented with dizziness, generalized body
weakness, loss of appetite, nausea, confusion and
irritability started from last night.
• She has been operated for some valvular problem in
2001 at Cape Town
• Unmarried, non smoker and non alcoholic
• She is on Digoxin 0.125mg daily, Coversyl 4 mg daily
and Warfrin 10 mg daily from local hospital
• Known Hypertensive, No previous medical record
found

3. Examination
• Pulse 52/min, Blood Pressure 67/30, R/R 24/min, Sa O2
95% at room air, afebrile, pale and no raised JVP
• Resp: Tachypanic, vertical scar mark on the chest,
trachea central and vesicular breathing.
• GIT: Soft non tender and no vicero megaly
• CVS: Bradycardia, Apex beat 5th ICS medial to MCL,
Atrial Fibrillation and Clicks audible
• CNS: She is confused irritable and not responding to
commands properly. She is moving all her limbs, Pupil
is constricted but responsive to light & no focal sign
seen.

4. ECG
Rate is 100, Irregular Rhythm, Right axis deviation & Right bundle branch
block

5. Differential
• Hypotension (Shock)
• Warfarin Toxicity
• Internal bleed
• Digoxin toxicity
• Atrail Fib

6. Labs
Test 17/01/2009 17/01/2009 (post 18/01/2009
transfusion FFP & PCV)
Sodium 131 137
Potassium 5.4 6.0
urea 15.5 38.6
Creatinine 263 689
CRP 35.6
WBC 12.50 27.92 27.4
Hb 5.4 12.3 10.7
MCV 92 89 89
Platelets 66 122 144
INR > 10 2.20 2.64
PTT > 180 31.2 37.9
c Calcium 2.58 D-dimers 1.28 Ref : < 0.25 Digoxin: 1.9
Alb 13 mg/l nmol/L (1.0- 2.8)
Mg 0.49 Blood Culture (Negative)

7. Blood Gases
17th 16:30 17th 23:31 18th 01:35 18th 06:30
Site V A A -
PH 7.33 7.26 7.3 7.5
Pco2 kPa 1.4 3.05 2.6 2.2
Po2 kPa 6.2 7.8 7.3 3.5
Hco3 mmol/L 25 12.4 14.5 17.8
BE mmol/L -10 -15.8 -12.5 -8

8. Diagnosis
• WARFARIN Toxicity
• Internal Bleeding

9. Management
• Passed IV line rush 200 ml N/S X2
• Shifted to ICU
• Continue to push the fluids N/S to resolve the hypotension
• Patients become tachypanic, desturating, exhausted and
still low BP planed to intubate during intubation went into
arrest, CPR done, Later having Vent Fbrillation leading to
cardioversion.
• Patients return to Atrial fib and continue the ventilator
support.
• Blood (3 units) and FFP (2 units) transfused
• Almost 4.2 litres of fluids pushed in 12 hours and urine
output was 300 + 37 ml (during her stay in ICU)
• Next day patient RIP near 9:30 AM

11. WARFARIN

12. Normal haemostatic mechanisms: clotting factors of the
intrinsic and extrinsic pathways.
The reactions (in the boxes) take place on the platelet surface. The dotted lines represent
positive feedback effects from small amounts of thrombin. This greatly enhances the
activity of the coagulation network and results in large amounts of thrombin generation and
thus fibrin formation in the clot. Ref: Davidson’s Principles and practice of Medicine 20 e

13. Where the Warfarin (Coumarins) Act?
Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

14. Mechanism of Action of Warfarin
Coumarins (Warfarin) inhibit
hepatic synthesis of the vitamin K-
dependent coagulation factors II
(prothrombin), VII, IX, and X and the
anticoagulant proteins C & S.
Vitamin K is a cofactor in
the synthesis of these clotting factors.
The vitamin K-dependent step
involves carboxylation of glutamic
acid residues and requires
regeneration of vitamin K to its
reduced form.
Coumarins and related compounds
inhibit vitamin K 1 -2,3 epoxide
reductase, preventing vitamin K from
being reduced to its active form. The
degree of effect on the vitamin K-
dependent proteins depends on the
dose and duration of treatment with
warfarin.
Ref: Davidson’s Principles and practice of Medicine 20 e, emedicine and Medscape

15. MOA (continued...)
Warfarin cant act so soon.........
Each factor differs in its degradation half-life;
• factor II requires 60 hours
• factor VII requires 4-6 hours
• factor IX requires 24 hours
• factor X requires 48-72 hours.
• The half-lives of proteins C and S are approximately 8 and 30
hours, respectively.
• warfarin leads to hypercoagulable state occur shortly after
treatment with warfarin is started.
• Rapid loss of protein C temporarily shifts the balance in favor
of clotting until sufficient time has passed for warfarin to
decrease the activity of coagulant factors.

16. Pharmacokinetics
• The oral bioavailability of warfarin is nearly 100%.
Warfarin is highly bound (approximately 97%) to
plasma protein, mainly albumin. The high degree of
protein binding is one of several mechanisms whereby
other drugs interact with warfarin.
• Warfarin is distributed to the liver, lungs, spleen, and
kidneys. It does not appear to be distributed to breast
milk in significant amounts. It crosses the placenta and
is a known teratogen.
• Warfarin is metabolized by hepatic cytochrome P-450
(CYP) isoenzymes and in kidney which are excreted in
the bile, urine and stool*.
• Warfarin metabolism may be altered in the presence of
hepatic dysfunction or advanced age but is not affected
by renal impairment
* Majerus PW, Broze GJ, Miletich JP, Tollefsen DM. Anticoagulant thrombolytic, and antiplatelet drugs. In Hardman JG, Limbird LE,
eds. Goodman and Gilman's The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996:1347-51.

17. Pharmacokinetics
• The half-life of warfarin ranges from 20 to 60 hours.
• The mean plasma half-life is approximately 40 hours, and the
duration of effect is two to five days*. Thus, the maximum
effect of a dose occurs up to 48 hours after administration,
and the effect lingers for the next five days.
• Drug interactions are numerous and include agents from a
variety of pharmaceutical classes, such as antibacterials,
antimycobacterials, antifungals, antiarrhythmics,
anticonvulsants, antihyperlipidemics, antineoplastics,
nonsteroidal anti-inflammatory agents, H2-receptor
antagonists, immunosuppressive agents, and many others.
• Bleeding is the only expected symptom of significance in the
history. Internal bleeding may present a vast array of
symptoms or be occult.
* Majerus PW, Broze GJ, Miletich JP, Tollefsen DM. Anticoagulant thrombolytic, and antiplatelet drugs. In: Hardman JG,
Limbird LE, eds. Goodman and Gilman's The pharmacological basis of therapeutics. 9th ed. NewYork: McGraw-Hill, 996:1347-
51.

18. Drug Interactions (a long list)
• Lack of familiarity with these interactions may lead to
clinically relevant and avoidable increases or decreases of
prothrombin time (PT).
• Drugs that can prolong the prothrombin time
• Inhibition of warfarin metabolism
Allopurinol, Amiodarone Azole antifungals Capecitabine,
Chloramphenicol, Chlorpropamide, Cimetidine,
Ciprofloxacin, Cotrimoxazole, Disulfiram, Ethanol (acute
ingestion) Flutamide, Isoniazid (INH), Metronidazole,
Norfloxacin, Ofloxacin, Omeprazole, Phenytoin,
Propafenone, Propoxyphene, Quinidine, Statins
(particularly lovastatin and pravastatin), Sulfinpyrazone,
Sulfonamides, Tamoxifen, Tolbutamide, Zafirlukast,
Zileuton

19. Drug Interactions (a long list)
• Inhibition of vitamin K activity
– Oral antibiotics, especially parenteral cephalosporins (Oral
cefaclor, cefixime, cefpodoxime, cefuroxime, cephalexin,
and cephradine have not been shown to interact with
warfarin.)
– High dose of penicillins (possibly due to decreased GI flora
synthesis of vitamin K)
• Additive anticoagulant effect
– Aspirin
– Heparin

20. Dosing
• The initial dose of Warfarin should approximate the chronic
maintenance dose that is anticipated. In most patients, the average
maintenance dose is 4 to 6 mg per day.
• Dose has an inverse relation with age. In patients 50 years old, the
average daily dose is 6.3 mg; in patients 70 years old, the average
daily dose is 3.6 mg*.
• As needed, doses can be easily changed by looking at the
cumulative weekly dosage and adding or subtracting 10 to 20
percent evenly over the week*** (Figure 1). This approach is
possible because of warfarin's long half-life. It is a safe and effective
way to provide sufficient anticoagulation.
• Heparin and warfarin therapies should overlap for approximately
four to five days.
•Gurwitz JH, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J. Aging and the anticoagulant response to warfarin therapy.
Ann Intern Med 1992;116:901-4.
** Ansell JE. Oral anticoagulant therapy--50 years later. Arch Intern Med 1993;153:586-96.
American Academy of Family Physicians

21. Dosing Algorithm (Figure 1)
Only one tablet strength (5 mg) is used. Fractions or multiples of the tablet can be used for different doses,
or alternative doses can be given based on the day of the week. Dose adjustments should be made based
on the total weekly dosage, with increases or decreases of 10 to 20 percent spread out over the week*.
* Carter BL. Therapy of acute thromboembolism with heparin and warfarin. Clin Pharm 1991;10: 503-18

22. Dosing Algorithm INR of 2 to 3 (Figure 2)
Algorithm for establishing a percentage change in the weekly warfarin
dosage to achieve an INR of 2 to 3. (INR=International Normalized Ratio)

23. Dosing Algorithm INR of 2.5 to 3.5 (Figure 3)

24. Anticoagulation (Prosthetic heart valves)
The goal of anticoagulant therapy is to administer the lowest possible dose of
anticoagulant to prevent clot formation or expansion. The required degree of
anticoagulation continues to evolve as studies provide more information about the
efficacy and safety of lower doses*.
INR Duration
‡--Depending on the type of mechanical valve (i.e., caged ball or caged disk) and the valve
position (mitral), some patients may benefit from INRs in the upper end of the range.
* Stein PD, Alpert JS, Copeland J, Dalen JE, Goldman S, Turpie AG. Antithrombotic therapy in patients with
mechanical and biologic prosthetic heart valves. Chest 1995;108(4 Suppl):371S-9S [Published erratum in
Chest 1996;109:592].

25. Laboratory Studies (in Toxicity)
• Blood levels of warfarin are neither readily available nor
helpful. The anticoagulant effect is best quantified by
baseline and daily repeated measurement of the PT and
the international normalized ratio (INR), which may not
be elevated until 1-2 days postingestion.
– A normal PT 48-72 hours after ingestion rules out
significant ingestion.
• Other lab tests that may be indicated include a blood
count for baseline hemoglobin and/or hematocrit or to
assess for anemia if the ingestion is more remote.
• A blood type and crossmatch or antibody screening is
indicated if substantial blood loss is suggested.
• In addition, other laboratory tests (eg, acetaminophen
level) or toxicology screening may be indicated to rule
out co-ingestions.

26. Toxic Dose
 Toxicity is related to
 the intensity of anticoagulation
 length of therapy
 the patient's underlying clinical state
 use of other drugs that may affect hemostasis or interfere with warfarin
metabolism.
 Fatal or nonfatal hemorrhage may occur from any tissue or organ
• The toxic dose is highly variable.
– Generally, a single ingestion of warfarin (10-20 mg) does not cause serious
intoxication.
– In contrast, chronic or repeated ingestion of even small amounts (2-5 mg/d)
eventually can lead to significant anticoagulation, especially in the presence of
interacting drugs.
– Patients with hepatic dysfunction, malnutrition, or a bleeding diathesis are at
greatest risk.

27. Risk factor for Hemorrhagic Complications of
Anticoagulation
• The most common complication of warfarin therapy is bleeding, which
occurs in 6 to 39 percent of recipients annually **
 Age greater than 65 years¹
 Age greater than 75 years with
 concomitant atrial fibrillation (intracranial hemorrhage)²
 History of gastrointestinal bleeding³
 Comorbid disease states*
 Hypertension³
 Cerebrovascular disease**
 Serious heart disease
 Renal insufficiency
¹ Landefeld CS, Rosenblatt MW, 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;87:144-52.
² Albers GW. Atrial fibrillation and stroke: three new studies, three remaining questions. Arch Intern Med1994;154:1443-8 & Risk
factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized
controlled trials. Arch Intern Med 1994;154:1449-57 [Published erratum in Arch Intern Med1994;10:2254].
³ Routledge PA, Chapman DH, Davies DM, Rawlins MD. Pharmacokinetics and pharmacodynamics of warfarin
at steady state. Br J Clin Pharmacol 1979; 8:243-7.
* Fihn SD, McDonell M, Martin D, Henikoff J, Vermes D, Kent D, et al. Risk factors for complications of
chronic anticoagulation: a multicenter study. Ann Intern Med 1993;118:511-20.
** Hirsh J, Dalen JE, Deykin D, Poller L, Bussey H. Oral anticoagulants: mechanism of action, clinical
effectiveness, and optimal therapeutic range. Chest 1995;108(4 Suppl):231S-46S.

28. Complications
• Hemorrhagic complications, are the major concern.
• Skin necrosis, usually observed between the third and eighth days of therapy
– Can be extremely severe and disfiguring and may require treatment
through debridement or amputation of the affected tissue, limb, breast,
or penis.
– It occurs more frequently in women and in patients with preexisting
protein C deficiency and, less commonly, in men and in patients with
protein S deficiency. Patients initially become hypercoagulable because
warfarin depresses levels of the anticoagulant proteins C and S more
quickly than coagulant proteins II, VII, IX, and X.
– Extensive thrombosis of the venules and capillaries occurs within the
subcutaneous fat. Women note an intense, painful burning in areas such
as the thigh, buttocks, waist, and/or breast several days after beginning
warfarin; skin necrosis and permanent scarring may follow.
– Immediate withdrawal of warfarin therapy is indicated. Heparin can be
substituted safely for warfarin.
– Restarting warfarin therapy at a low dose (eg, 2 mg) while continuing
heparin treatment for 2-3 days may be reasonable. The dosage of
warfarin can be increased gradually over several weeks.

29. Complications (continued...)
• Warfarin crosses the placenta during pregnancy and has the
potential to cause teratogenesis and bleeding in the fetus. Warfarin
and other Coumadin derivatives cause an embryopathy commonly
termed fetal warfarin syndrome (FWS)
• Other adverse reactions that occur infrequently with chronic
warfarin therapy include agranulocytosis, alopecia, anaphylactoid
reactions, anorexia, cold intolerance, diarrhea, dizziness, elevated
hepatic enzyme levels, exfoliative dermatitis, headache, hepatitis,
jaundice, leukopenia, nausea and/or vomiting, pruritus, and
urticaria.
• Rare events of tracheal or tracheobronchial calcification are
reported in association with long-term warfarin therapy. The clinical
significance is not known. Priapism is associated with anticoagulant
administration; however, a causal relationship with warfarin is not
established.

30. How to Proceed for Toxicity?
• Initiate usual supportive measures, including intravenous
access if any suggestion of remote or active bleeding is
evident. After an acute intentional ingestion, administer
activated charcoal per local protocols. Infuse crystalloid
solution if signs of significant blood loss are present.
Emergency Department Care
• Initiate usual advanced supportive measures. Evaluate for
current or remote bleeding with a thorough physical
examination, including a rectal examination as indicated to
check for occult GI bleeding. If significant bleeding has
occurred and the patient is unstable, be prepared to treat
the patient with transfusions of packed cells and fresh
frozen plasma as first-line therapy. Further evaluation
varies, depending on the situation.

31. How to Proceed for Toxicity?
• For acute ingestions, with no bleeding
– Obtain a baseline PT/INR and repeat within 24-48 hs
– Administer activated charcoal if it was not already given in the field.
– Gastric lavage is unnecessary if rapid administration of activated charcoal is
feasible. Do not induce emesis.
– Treat any co-ingestions, evaluate the patient for suicidal intention.
– Avoid drugs that may enhance bleeding or decrease metabolism of the
anticoagulant.
– Do not administer vitamin K prophylactically because
1. it is not needed in most patients
2. its presence masks the onset of anticoagulant effects in patients who do
require prolonged treatment and follow-up care.
– If the PT time is elevated, treatment with vitamin K is appropriate. Because
vitamin K does not immediately restore therapeutic levels of clotting
factors, treat patients who are experiencing acute hemorrhage with fresh
frozen plasma (FFP).
– Recombinant activated factor VII, while costly, may have an advantage over
FFP in that it does not carry a risk of transmission of viral disease, allergic
reaction, or volume overload*.
* Miller MA, Levy PD, Hile D. Rapid identification of surreptitious brodifacoum poisoning by analysis of vitamin K-
dependent factor activity. Am J Emerg Med. May 2006;24(3):383

32. How to Proceed for Toxicity?
• Chronic intoxication resulting from therapeutic use of warfarin can be evaluated with a
careful physical examination and a measurement of the PT and INR.
– If INR is higher < 6 and the patient is not bleeding, withhold warfarin for 2-3 days and
restart when the INR approaches the therapeutic range.
– If INR is >6 but less than 10 and the patient is not bleeding, or the INR is < 6 but the
patient requires more rapid reversal (eg, for elective surgery), administer 5-10 mg
of vitamin K-1 orally with the expectation that the INR will begin to fall within 8 hours
with a maximal effect in about 24 hours.
– If the INR is > 10 and the patient is not bleeding, a higher daily dose of oral vitamin K-1
may be administered.
– If very rapid reversal of anticoagulant effect is essential because of serious bleeding,
administer fresh frozen plasma. Successful reversal of severe coagulopathy and life-
threatening hemorrhage has been reported using recombinant activated factor
VII. While costly, this therapy may have an advantage over FFP in that it does not carry a
risk of transmission of viral disease, allergic reaction, or volume overload*.
Note: If the patient has a critical need for ongoing anticoagulation (eg, mechanical heart
valve), heparin should be given as a temporary measure while fully reversing the effects
of warfarin.
* Miller MA, Levy PD, Hile D. Rapid identification of surreptitious brodifacoum poisoning by analysis of vitamin K-
dependent factor activity. Am J Emerg Med. May 2006;24(3):383

33. How to Proceed for Toxicity?
• Packed red cells and fresh frozen plasma may be required for
immediate management of life-threatening hemorrhagic
complications.
• Alternative treatments to FFP include prothrombin complex
concentrates or recombinant factor VIIa. Data are limited on the
use of recombinant factor VIIa for the reversal of warfarin-induced
coagulopathy.
• Vitamin K is the only effective antidote for long-term management,
but reversal of anticoagulation takes several hours.
• Administering vitamin K IV has no advantage, and reports have
documented acute cardiovascular collapse after administration by
this route, presumably caused by an anaphylactoid reaction. IM or
SC administration may cause hematoma. In the authors' opinion,
oral administration, when possible, is preferred.

34. Algorithm for Warfarin Rx patient

35. Algorithm for Warfarin Rx patient
(continued..)
NOTE: Clinical judgment should be used when assessing the severity of
bleeding. In addition, patients who are given doses of vitamin K that
leave them refractory to warfarin should receive heparin until
warfarin therapy is again therapeutic.
• *--Rapid reversal of major warfarin overdose should be treated by
following the steps for managing serious bleeding.
• †--In patients with life-threatening bleeding or serious warfarin
overdose, PCC should be given with IV vitamin K, 10 mg. If PCC
(PCC=prothrombin complex concentrate) contains factor VII,
vitamin K administration is not usually necessary.
• ‡--Patients with an INR of less than 6 may not require vitamin K
administration for reversal; if vitamin K is administered, a dose of
0.5 to 1 mg is sufficient.

36. Studies support the use of Warfarin for
Prosthetic heart valves
• The most convincing evidence that oral anticoagulants are
effective in patients with prosthetic heart valves comes from a
study of patients randomized to receive warfarin in uncertain
intensity versus either of 2 aspirin-containing platelet-
inhibitor drug regimens for 6 months*
• The incidence of thromboembolic complications in the group
that continued warfarin was significantly lower than that of
the groups that received antiplatelet drugs (relative risk
reduction 60% to 79%). The incidence of bleeding was highest
in the warfarin group.
* C.K. Mok, J. Boey, R. Wang et al., Warfarin versus dipyridamole-aspirin and pentoxifylline-aspirin for the prevention
of prosthetic heart valve thromboembolism: a prospective clinical trial. Circulation 72 (1985), pp. 1059–1063

37. Studies support the use of Warfarin for
Prosthetic heart valves
• Another study³ of patients with mechanical prosthetic valves
treated with aspirin and dipyridamole found no difference in
efficacy between moderate-intensity (INR 2.0 to 3.0) and high-
intensity (INR 3.0 to 4.5) warfarin regimens, but more bleeding
occurred with the high-intensity regimen.
• One study of patients with bioprosthetic heart valves found a
moderate dose regimen (INR 2.0 to 2.25) as effective as a more
intense regimen (INR 2.5 to 4.0) but associated with less bleeding ¹.
• A second study², involving patients with mechanical prosthetic
heart valves, found no difference in effectiveness between a very
high-intensity regimen (INR 7.4 to 10.8) and a lower-intensity
regimen (INR 1.9 to 3.6), but the higher-intensity regimen produced
more bleeding.
¹ R. Hull, J. Hirsh, R. Jay et al., Different intensities of oral anticoagulant therapy in the treatment of proximal-vein
thrombosis. N Engl J Med 307 (1982), pp. 1676–1681
² A.G.G Turpie, J. Gunstensen, J. Hirsh et al., Randomized comparison of two intensities of oral anticoagulant
therapy after tissue heart valve replacement. Lancet 1 (1988), pp. 1242–1245
³ J.N. Saour, J.O. Sieck, L.A.R. Mamo et al., Trial of different intensities of anticoagulation in patients with
prosthetic heart valves. N Engl J Med 322 (1990), pp. 428–432.

38. Studies support the use of Warfarin for
Prosthetic heart valves
A more recent randomized trial
showed that addition of aspirin
(100 mg/d) to warfarin (INR 3.0 to
4.5) improved efficacy compared
with warfarin alone ¹. This
combination of low-dose aspirin
and high-intensity warfarin was
associated with a reduction in all-
cause mortality, cardiovascular
mortality, and stroke at the
expense of increased minor
bleeding.
¹ A.G. Turpie, M. Gent, A. Laupacis et al., A comparison of aspirin with placebo in patients treated with warfarin after
heart-valve replacement. N Engl J Med 329 (1993), pp. 524–529

39. OPTIMAL ORAL ANTICOAGULANT
THERAPY IN PATIENTS WITH
MECHANICAL HEART
VALVES
A retrospective study of 16
081 patients with mechanical
heart valves in the
Netherlands attending 4
regional anticoagulation
clinics (target INR 3.6 to 4.8)
found a sharp rise in the
incidence of embolic events
when the INR fell to <2.5,
whereas bleeding increased
when the INR rose to >5.0².
² S.C. Cannegieter, F.R. Rosendaal, A.R. Wintzen et al., Optimal oral anticoagulant therapy in patients with mechanical heart
valve prostheses: the Leiden artificial valve and anticoagulation study. N Engl J Med 333 (1995), pp. 11–17

40. Warfarin Ischemic Stroke and Intracranial
Hemorrhage
One of the physician's most difficult tasks is to decide whether
the risk of anticoagulation outweighs the potential benefit
of warfarin therapy in an elderly patient.
• Data from the Stroke Prevention in Atrial Fibrillation (SPAF II)
trial² suggest that the safety of anticoagulation in the elderly
can be maximized through careful monitoring and
maintenance of an INR between 2 and 3.
• Another recent study³ investigated the incidence of ischemic
stroke in elderly patients with atrial fibrillation who were
receiving anticoagulant therapy. This study found that
subtherapeutic INRs (i.e., those below 2) have associated risks
of thrombotic events.
² Stroke prevention in atrial fibrillation study: final results. Circulation 1991;84:527-39
³ Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic
anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335:540-6.

41. Warfarin and
Intracranial
Haemorrhage
One study¹ found that the risk of
intracranial hemorrhage among
the elderly is highest in patients
with poor control (large
variations in INR), patients
receiving high-intensity therapy
(INR greater than 4) and
patients older than 80 years.
Fig: Adjusted Relative risk s for bleeding
complications and 95% confidence
interval according to age category
¹ Fihn SD, Callahan CM, Martin DC, McDonell MB, Henikoff JG, White RH. The risk for and severity of bleeding complications
in elderly patients treated with warfarin. Ann Intern Med 1996;124:970-9.

42. International Guidelines
Guidelines developed by the European Society of Cardiology¹ called for
anticoagulant intensity in proportion to the thromboembolic risk to specific
types of prosthetic heart valves.
• For 1st gen valves, an INR of 3.0 to 4.5 was recommended. An INR of 3.0 to
3.5 was considered sensible for 2nd genvalves in the mitral position,
whereas an INR of 2.5 to 3.0 was deemed sufficient for 2nd gen valves in the
aortic position.
The American College of Chest Physicians guidelines² of 2001 recommended
• an INR of 2.5 to 3.5 for most patients with mechanical prosthetic valves and
of 2.0 to 3.0 for those with bioprosthetic valves and low-risk patients with
bileaflet mechanical valves (such as the St Jude Medical device) in the aortic
position.
• Similar guidelines have been promulgated conjointly by the American
College of Cardiology and the American Heart Association³. In contrast, a
higher upper limit of the therapeutic range (INR 4.8 to 5.0) has been
recommended by some European investigators.
¹ Gohlke-Barwolf, J. Acar, C. Oakley et al., Guidelines for prevention of thromboembolic events in valvular heart disease: Study
Group of the Working Group on Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 16 (1995), pp. 1320–
1330.
² P.D. Stein, J.S. Alpert, J.E. Dalen et al., Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.
Chest 114 Suppl (1998), pp. 602S–610S
³ ACC/AHA guidelines for the management of patients with valvular heart disease: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular
Heart Disease). J Am Coll Cardiol 32 (1998), pp. 1486–1588.

43. Conclusion of
the studies
Warfarin compared to Aspirin
• Increased bleeding incidence with warfarin and increased
thromboembolic complication with aspirin and vice versa.
Warfarin alone
• Less bleed with moderate regimen (INR 2.0-2.25) as compared to
intense one (INR 2.5-4.0).
• Low INR leads to embolic Event and high leads to bleed.
• Increased Intracranial bleed in
1. Elderly
2. Poor control
3. High intensity therapy
Note: All studies suggest that tighter control of therapy at an INR range of 2 to
3 is superior to use of lower level of anticoagulation.

44. Final Comment
1. Identify the therapeutic goal
2. Estimate the chronic maintenance dosage based on the
presence of factors associated with hyperresponsiveness
or hyporesponsiveness, such as concomitant drug use,
liver disease and poor nutrition.
3. Initiate therapy at the patient's anticipated maintenance
dosage.
4. Loading doses are not necessary.
5. Make any necessary adjustments by looking at the
cumulative weekly dosage and adding or subtracting 10 to
20 percent evenly over the week.
6. Remain alert to potential warfarin-drug interactions and
educate your patients also.

45. References
• Lai MW, Klein-Schwartz W, Rodgers GC, Abrams JY, Haber DA, Bronstein AC. 2005 Annual Report of
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47. THANK
YOU