Anticoagulants Flashcards
Questions 1–3 pertain to the following case.
J.M. is a 72-year-old female (weight 57 kg) who presents
to the hospital with nonvalvular atrial fibrillation
(NVAF). After her heart rate is controlled with metoprolol,
she is asymptomatic. She also has hypertension,
dyslipidemia, and depression. Her medications include
metoprolol tartrate 100 mg orally twice daily, enalapril
10 mg orally twice daily, and citalopram 20 mg orally
daily. Her heart rate is 78 beats/minute and blood pressure
is 134/86 mm Hg. Her SCr is 0.8 mg/dL and CrCl is
60 mL/minute; she has normal hepatic function.
1. Which best depicts J.M.’s CHA2D2-VASc score and
HAS-BLED score?
A. CHA2D2-VASc score 1; HAS-BLED score 1.
B. CHA2D2-VASc score 3; HAS-BLED score 1.
C. CHA2D2-VASc score 5; HAS-BLED score 4.
D. CHA2D2-VASc score 3; HAS-BLED score 2.
- Answer: B
This patient with NVAF has three risk factors for stroke,
according to the CHA2DS2-VASc score: 1 point for age
65–74 years (72 years old), 1 point for hypertension, and
1 point for female sex. Answer A is incorrect because
she would have a score of 1 using the CHADS2 score,
which would be from hypertension, but that scoring
system does not give a point for age unless the patient
is 75 or older and gives no points for being female. Her
HAS-BLED score is 1 for age older than 65. Although
Answer D has the correct CHA2DS2-VASc score, the
HAS-BLED score is incorrect. Even though the patient
has hypertension for HAS-BLED, the systolic blood
pressure needs to be greater than 160 mm Hg for it to
receive 1 point. Therefore, her score is only 1, not 2
as in Answer D. Answer C is also incorrect because it
overcalculates both the CHA2DS2-VASc score and the
HAS-BLED score. Because the patient’s CHA2DS2-
VASc score is 3 and HAS-BLED score is 1, Answer B
is correct. This patient is a candidate for anticoagulant
therapy because of stroke risk and has an acceptable
bleeding risk from warfarin therapy.
- Which is the most appropriate stroke prevention
strategy for J.M.?
A. Aspirin 325 mg orally once daily.
B. Rivaroxaban 20 mg orally once daily.
C. Apixaban 2.5 mg orally twice daily
D. Edoxaban 30 mg orally once daily.
- Answer: B
Given the patient’s CHA2DS2-VASc score of 3 and lack
of contraindications to anticoagulant therapy, she is at
high risk of ischemic stroke and needs anticoagulant
therapy, making Answer A incorrect. Apixaban would
be acceptable, but the reduced dose of 2.5 mg twice daily
is only for patients with two high-risk bleeding features
(age 80 or older, weight 60 kg or less, or SCr 1.5 mg/dL
or greater). She has one risk factor with weight less than
60 kg (57 kg), but age (72 years) and SCr (0.8 mg/mL)
do not meet the criteria. Therefore, she should receive
apixaban 5 mg twice daily, making Answer C the incorrect
apixaban dose. Answer D is incorrect because the
correct edoxaban dose for this patient would be 60 mg
daily. Rivaroxaban is only dose reduced when the CrCl
is less than 50 mL/minute. Because this patient’s renal
function is above that level, Answer B is correct for
using the correct dose of anticoagulant.
- J.M. was initiated on dabigatran and, 3 months
later, is involved in a motor vehicle accident resulting
in an intracranial hemorrhage. Which is the
most appropriate reversal strategy for J.M.?
A. Protamine.
B. Fresh frozen plasma (FFP).
C. Andexanet alfa
D. Idarucizumab.
- Answer: D
Answer A is incorrect; although protamine is an antidote
for UFH and a partial antidote for LMWH, it
would not be expected to reverse a direct thrombin
inhibitor. Answer B is incorrect; FFP does not provide enough clotting factors to reverse a direct thrombin
inhibitor. Idarucizumab is a fully humanized antibody
to dabigatran and will bind dabigatran more strongly
than thrombin. Idarucizumab is an effective reversal
agent for dabigatran (Answer D is correct). Answer C
is incorrect; andexanet alfa is a recombinant factor Xa
that binds factor Xa inhibitors but does not affect the
direct thrombin inhibitor, dabigatran.
Questions 4 and 5 pertain to the following case.
B.T. is 68-year-old male (height 183 cm, weight 96 kg)
who recently underwent surgical aortic valve replacement
with a bioprosthetic valve and is recovering
well. He also has hypertension, dyslipidemia, systolic
heart failure, and a history of sustained ventricular
tachycardia. His medications include carvedilol 25 mg
orally twice daily, lisinopril 10 orally mg daily, furosemide
40 mg orally daily, amiodarone 400 mg orally
daily, and atorvastatin 80 mg orally daily. His CrCl is 40
mL/minute, hepatic function is normal, and other laboratory
data are within normal limits.
4. Which is the most appropriate antithrombotic regimen
for B.T.?
A. Aspirin 81 mg orally daily.
B. Warfarin 7.5 mg orally daily to an INR of 2.5–3.5.
C. Apixaban 5 mg orally twice daily.
D. Dabigatran 150 mg twice daily.
- Answer: A
Patients with a bioprosthetic surgical aortic or mitral
valve who are at low risk of bleeding can receive warfarin
for at least 3 months, up to 6 months, but the INR
target is 2.0–3.0. The higher INR goal of 2.5–3.5 is for a
patient receiving a mechanical mitral valve. In addition,
the initial warfarin dose is too high for a patient who is
taking amiodarone. A more appropriate starting dose
would be 2 mg or 2.5 mg daily. Therefore, Answer B is
incorrect for several reasons. Neither DOAC would be
used unless the patient had concomitant AF. Although
data are limited, it is generally thought that patients
with AF with bioprosthetic valves can receive therapy
with a DOAC. This patient does not have AF and
does not require anticoagulation for the valve, making
Answers C and D incorrect. Answer A, low-dose aspirin,
is all that is indicated because of the lower thrombogenic
potential of a bioprosthetic valve compared
with a mechanical valve.
- Which best depicts how long B.T. should receive
therapy?
A. At least 1 month.
B. At least 3 months.
C. At least 1 year
D. Indefinitely.
- Answer: D
According to the 2020 ACC/AHA guidelines, indefinite
low-dose aspirin therapy is indicated for patients receiving
a bioprosthetic aortic or mitral valve, making Answer
D correct. The duration in Answer A is too short and
might be confused with the duration of dual antiplatelet
therapy in patients with a bare metal stent. Answer
B would be the minimal therapy duration if the patient
were receiving warfarin therapy for this bioprosthetic
surgical aortic valve. Answer C is also incorrect and
might be confused with the duration of dual antiplatelet
therapy for patients receiving a drug-eluting stent.
- Which best depicts M.R.’s number of venous
thromboembolism (VTE) risk factors?
A. 3.
B. 4.
C. 5.
D. 6.
- Answer: C
This patient has five risk factors for developing VTE: age
older than 40 (51 years), obesity (BMI 36 kg/m2), recent
surgery, immobility, and person who smokes, making
Answer C correct and Answers A, B, and D incorrect.
- Which is the most appropriate treatment strategy
for M.R.?
A. Enoxaparin 100 mg subcutaneously every
12 hours and dabigatran 150 mg orally
twice daily; after 5 days, enoxaparin can be
discontinued.
B. Rivaroxaban 15 mg orally twice daily for 7
days, followed by 20 mg orally once daily.
C. Enoxaparin 100 mg subcutaneously every 12
hours for 5 days; then initiate edoxaban 60 mg
orally once daily.
D. Unfractionated heparin (UFH) 4000-unit
bolus, followed by 1000 units/hour and warfarin
7.5 mg orally daily to an INR of 2.0–3.0,
discontinuing UFH when a therapeutic INR is
reached.
- Answer: C
Answer B is incorrect because the duration of higher-
intensity rivaroxaban should be 21 days, not 7 days.
Apixaban’s duration of higher-intensity therapy is 7
days. Answer D is incorrect because the UFH dosing is
insufficient. This is the dosing in patients with an acute
coronary syndrome. Patients receiving dabigatran or
edoxaban must first receive at least 5 days of injectable
therapy. The dosing of enoxaparin and the DOAC is
correct in both Answers A and C, but the DOAC should
not be overlapped with the injectable anticoagulant,
making Answer A incorrect and Answer C correct.
- A male (weight 125 kg) is admitted for the treatment
of a DVT with a PE. He is administered a
10,000-unit bolus of UFH and initiated on an infusion
of 2000 units/hour. Twelve hours into the infusion,
he begins to vomit blood. Which is the most
appropriate protamine dose for this patient?
A. 100 mg.
B. 50 mg.
C. 22.5 mg.
D. 11.25 mg.
- Answer: B
Protamine 50 mg is the correct dose for this patient. To
calculate the dose, add the amount of UFH administered
in the past 2½ hours, which gives a total of 5000
units of UFH. A dose of 1 mg of protamine for every
100 units of UFH equals a protamine dose of 50 mg
(Answer B is correct). Because the bolus dose was
administered more than 3 hours ago, it is not part of the
calculation. Although 100 units would be the calculated
dose according to the bolus, the bolus was administered
too long ago to be considered (Answer A is incorrect).
The doses of 11.25 and 22.5 mg are incorrect because
they consider only the amount of UFH received in the
past 30 and 60 minutes, respectively, not the past 2–2½
hours (Answers C and D are incorrect).
- A White female(height 163 cm, weight 65 kg) presents
with recent hip fracture surgery. She has normal
renal and hepatic function. Which is the most
appropriate regimen for preventing VTE in this
patient?
A. Dabigatran 110 mg orally once 2 hours after
surgery, followed by 220 mg orally once daily.
B. Enoxaparin 30 mg subcutaneously once daily.
C. Fondaparinux 2.5 mg subcutaneously once daily.
D. Edoxaban 60 mg orally once daily.
- Answer: C
Although dabigatran can be used for VTE prevention in
patients with hip replacement surgery, it is not indicated
in patients with hip fracture surgery, making Answer
A incorrect. The correct enoxaparin dose for hip fracture
surgery is 30 mg subcutaneously twice daily or
enoxaparin 40 mg subcutaneously every 12 hours,
making Answer B incorrect. Edoxaban is not indicated
for orthopedic surgery in the United States. All studies
with edoxaban were done only in Japan, making
Answer D incorrect. Answer C is correct because this
is the correct dosing of fondaparinux for orthopedic
surgical procedures.
Patient Case
Questions 1–4 pertain to the following case.
B.D. is a 73-year-old male (height 175 cm, weight 80 kg) with newly diagnosed NVAF. He also has a history of
hypertension, dyslipidemia, stable ischemic heart disease, and systolic heart failure. His medications include
aspirin 81 mg orally daily, enalapril 10 mg orally daily, atorvastatin 80 mg orally daily, metoprolol succinate 200
mg orally daily, furosemide 40 mg orally daily, spironolactone 25 mg orally daily, and amlodipine 10 mg orally
daily. His heart rate is 72 beats/minute and blood pressure is 122/72 mm Hg. His laboratory values include K 4.9
mEq/L, stable SCr 1.9 mg/dL, and blood glucose 101 mg/dL.
1. Which best depicts B.D.’s CHA2DS2-VASc score?
A. 2.
B. 3.
C. 4.
D. 5.
- Answer: B
This patient’s CHA2DS2-VASc score is 3: 1 point for
age 65–74 years (73 years), 1 point for hypertension,
and 1 point for heart failure (Answer B is correct). A
score of 2 (Answer A) would be correct when using
the CHADS2 score instead of the CHA2DS2-VASc
score because his age would not give any points in the
CHADS2 score. The patient’s history of stable ischemic
heart disease may be assumed to be 1 point for vascular
disease, but this is only 1 point in patients with a prior
MI, peripheral artery disease, or aortic disease, making
Answer C incorrect. Given his score of 3, Answer D
would also be incorrect.
Patient Case (Cont’d)
2. Which is most accurate regarding DOAC therapy for reducing the risk of stroke in patients with NVAF such
as B.D.?
A. All the DOACs significantly reduced ischemic stroke in the phase III trials compared with warfarin.
B. All the DOACs significantly reduced hemorrhagic stroke in the phase III trials compared with warfarin.
C. Apixaban is more effective than rivaroxaban because apixaban was superior to warfarin in the
ARISTOTLE trial and rivaroxaban was only noninferior to warfarin in the ROCKET-AF trial.
D. Dabigatran was studied in patients with highest risk across the phase III trials and should not be used in
patients with a CHADS2 score less than 3.
- Answer: B
The DOAC phase III trials must be critically evaluated
to dispel any misconceptions clinicians may have concerning
the conclusions of these data. Only dabigatran
significantly reduced ischemic stroke in the RE-LY trial,
but this may be questioned by the lack of blinding in the
trial (Answer A is incorrect). The benefit of the DOACs
in each of their respective trials was a significant reduction
in hemorrhagic stroke. This drove the overall benefit
and safety for all the agents (hemorrhagic stroke is
counted as an efficacy and safety end point in all the
trials) (Answer B is correct). Although clinicians may
reach the conclusions in Answer C, evidence is insufficient
to make this claim; cross-trial comparisons are
inappropriate because of the different risks of patients
studied and the different sample sizes of the trials.
The 0.3% absolute difference in the ARISTOTLE and
ROCKET-AF trials makes it difficult to conclude that
one agent is more efficacious than the other without a
head-to-head randomized controlled trial. Answer D is
also incorrect because bleeding was similar to warfarin
in the RE-LY trial with dabigatran and lower with
edoxaban in the ENGAGE trial. Despite these data, the
bleeding rates in the trials cannot be compared because
of the different times in which bleeding events were
accrued in the trials.
- Which is the most appropriate regimen for reducing B.D.’s risk of stroke?
A. Dabigatran 75 mg orally twice daily.
B. Rivaroxaban 20 mg orally once daily.
C. Apixaban 5 mg orally twice daily.
D. Edoxaban 60 mg orally once daily.
- Answer: C
Given the patient’s CHA2DS2-VASc score of 3, he is at
high risk of ischemic stroke and should receive anticoagulation.
The patient’s CrCl is about 40 mL/minute
using the Cockcroft-Gault equation with total body
weight. Although any of the agents listed would be are correct. The dabigatran dose should not be reduced
from 150 mg twice daily to 75 mg twice daily until
the CrCl is less than 30 mL/minute, making Answer
A incorrect. Both rivaroxaban and edoxaban should be
dose reduced when the CrCl is less than 50 mL/minute
in patients with NVAF. Rivaroxaban should be reduced
from 20 mg daily to 15 mg daily, and edoxaban should
be reduced from 60 mg daily to 30 mg daily, making
Answers B and D incorrect. Apixaban is listed at the
typical dose and is not reduced to 2.5 mg daily unless
the patient meets two of three criteria (age 80 or older,
weight 60 kg or less, or SCr 1.5 mg/dL or greater). This
patient has the elevated SCr, but his age and weight do
not meet these criteria. Therefore, full-dose apixaban is
correct (Answer C) for this patient.
- Six months later, B.D. elects to undergo PCI for the management of his coronary artery disease. He has had
no medication changes, and his vital signs and laboratory information remain consistent. Which is the best
available evidence-based approach to B.D.’s antithrombotic therapy?
A. Rivaroxaban 10 mg orally daily plus clopidogrel 75 mg orally daily.
B. Apixaban 2.5 mg orally twice daily plus clopidogrel 75 mg orally daily.
C. Adjusted-dose warfarin to an INR of 2.0–3.0 plus aspirin 81 mg orally daily plus clopidogrel 75 mg
orally daily.
D. Edoxaban 15 mg orally once daily plus aspirin 81 mg orally daily plus clopidogrel 75 mg orally daily.
- Answer: A
Trials to date have mainly evaluated the safety of the
listed regimens. Answer D would not be supported by
the currently available evidence until dosing or safety
data become available. Answer B would be incorrect
because the apixaban dose evaluated in the AUGUSTUS
trial was 5 mg twice daily. Answer A (rivaroxaban plus
clopidogrel) and Answer C (warfarin, aspirin, and
clopidogrel) were compared in the PIONEER AF-PCI
trial, with the rivaroxaban regimen significantly reducing
clinically relevant bleeding. Because of better
safety, Answer A is correct and Answer C is incorrect.
The 10-mg dose of rivaroxaban is correct because the
patient’s CrCl is 40 mL/minute. In the trial, patients
with a CrCl of 30–50 mL/minute received rivaroxaban
10 mg daily instead of 15 mg daily.
Patient Case
Questions 5 and 6 pertain to the following case.
S.D. is a 62-year-old female (height 165 cm, weight 80 kg) with a history of significant primary mitral regurgitation.
Her echocardiogram reveals significant leaflet flaring that is not amendable to mitral valve repair. She also has
a history of hypertension, dyslipidemia, and gout. Her medications include lisinopril 10 mg orally daily, hydrochlorothiazide
25 mg orally daily, simvastatin 40 mg orally daily, and allopurinol 300 mg orally daily. Her heart rate
is 68 beats/minute and blood pressure is 128/74 mm Hg. Her CrCl is 68 mL/minute. She is scheduled to undergo
valve replacement surgery and will receive a mechanical mitral valve. You are discussing the oral anticoagulant
postoperative plan with S.D.’s team.
5. Which is the optimal regimen for preventing thrombosis?
A. Adjusted-dose warfarin to an INR goal of 2.5–3.5 plus aspirin 81 mg orally daily.
B. Adjusted-dose warfarin to an INR goal of 2.0–3.0 plus aspirin 81 mg orally daily.
C. Adjusted-dose warfarin to an INR goal of 2.0–3.0.
D. Adjusted-dose warfarin to an INR goal of 2.5–3.5.
- Answer: D
In patients receiving a mechanical heart valve, only
those with an indication for antiplatelet therapy need
to have aspirin therapy added to their regimen, making
Answers A and B incorrect. Answer C is the INR goal
for a mechanical aortic valve and is therefore incorrect.
Because of the higher thrombotic risk of a mitral valve
than an aortic valve, the INR goal should be higher,
making Answer D correct.
- Which best describes thrombotic risk in patients with valve replacement surgery?
A. Bioprosthetic valves carry a higher risk of thrombosis than mechanical valves.
B. The highest risk of thrombosis with bioprosthetic valve placement is during the first year after surgery.
C. All patients with mechanical heart valves require bridging therapy during invasive procedures.
D. Valve replacement in the mitral position carries a higher risk of thrombosis than in the aortic position
- Answer: D
Answer A is incorrect because mechanical valves have
a higher risk of thrombosis than bioprosthetic valves. This is shown by the class 1 recommendation for warfarin
therapy for mechanical heart valves compared with
aspirin therapy for bioprosthetic valves. The highest
risk of thrombosis with a bioprosthetic valve is during
the first 3 months after valve placement, not out to 1
year, making Answer B incorrect. Answer C is also
incorrect; although patients with a mechanical mitral
valve and those with an aortic valve with risk factors
for TE should receive bridge therapy during invasive
procedures, patients with a bileaflet mechanical aortic
valve and no risk factors for TE need not receive bridge
therapy. Answer D is correct; because of the larger
valve size and slower flow through the mitral valve than
through the aortic valve, mitral valves carry a higher
risk of thrombosis. This is shown by the more aggressive
anticoagulant regimen, regardless of the type of
valve used (bioprosthetic or mechanical).
Patient Case
7. B.G. is a 62-year-old male (height 175 cm, weight 110 kg) hospitalized for a heart failure exacerbation. He has
symptoms when doing only limited exertion and has been out of bed only to use the bathroom for the past 3
days. His medical history also includes stable ischemic heart disease, hypertension, type 2 diabetes, and a PE
2 years ago. He smokes 2 packs/day and drinks 1 glass of wine with dinner most evenings. His medications
include bisoprolol 5 mg orally daily, lisinopril 10 mg orally daily, aspirin 81 mg orally daily, ranolazine 1000
mg orally twice daily, furosemide 40 mg orally daily, spironolactone 25 mg orally daily, and metformin 1000
mg orally twice daily. His blood pressure today is 110/70 mm Hg and heart rate is 58 beats/minute. His laboratory
values are normal except for a BNP of 1498 ng/mL. Which is the most appropriate VTE prevention
strategy for B.G.?
A. Administer fondaparinux 5 mg subcutaneously daily.
B. Administer apixaban 2.5 mg orally twice daily.
C. Administer enoxaparin 40 mg subcutaneously daily.
D. His risk does not warrant prophylactic therapy.
- Answer: C
This patient has several risk factors for VTE and
requires prophylaxis (Answer D is incorrect). Although
fondaparinux is effective and safe for VTE prophylaxis
in medically ill patients, the appropriate dose is
2.5 mg subcutaneously daily, not 5 mg daily (Answer
A is incorrect). Although apixaban has been studied
for VTE prophylaxis, it lacked efficacy and safety
when evaluated for extended prophylaxis (Answer B is
incorrect). Several studies have shown the efficacy and
safety of enoxaparin 40 mg subcutaneously once daily
for VTE prophylaxis in medically ill patients (Answer
C is correct).
Patient Case
8. A 48-year-old male (height 178 cm, weight 90 kg) presents to the ED with pain and swelling in his left leg.
On examination, his leg is warm to the touch and tender and has 3+ pitting edema below the knee. His
D-dimer is positive, and his duplex ultrasonography identifies a femoral-popliteal DVT. He understands
that he will need to receive anticoagulant therapy but wants to avoid any injections, if possible. He has good
insurance coverage. His other medical conditions are hypertension, HIV, and dyslipidemia. His medications
include benazepril 20 mg orally daily, ritonavir 100 mg orally daily, darunavir 800 mg orally daily, emtricitabine
200 mg/tenofovir disoproxil fumarate 300 mg orally daily, and atorvastatin 10 mg orally daily. His
vital signs are stable, and his CrCl is 78 mL/minute. Which is the most appropriate anticoagulant regimen to
initiate for this patient?
A. Rivaroxaban 15 mg orally twice daily for 21 days, followed by 20 mg orally daily.
B. Edoxaban 60 mg orally daily.
C. Warfarin 2.5 mg orally daily.
D. Apixaban 5 mg orally twice daily for 7 days, followed by 2.5 mg orally twice daily.
- Answer: D
This patient can be treated for his DVT event without
receiving injectable anticoagulation. Both rivaroxaban
and apixaban provide this ability. Because edoxaban
requires at least 5 days of injectable therapy before initiation
and warfarin must be bridged with injectable
anticoagulation for at least 5 days, Answers B and C
are incorrect. The rivaroxaban regimen in Answer A is
the standard regimen, but the patient is taking a protease
inhibitor. Protease inhibitors, especially ritonavir,
are potent P-gp and CYP3A4 inhibitors and are contraindicated
with the use of rivaroxaban, making Answer
A incorrect. Although the typical apixaban regimen for
VTE treatment is 10 mg twice daily for 7 days followed
by 5 mg twice daily, patients receiving potent P-gp and
CYP3A4 inhibitors can still use apixaban but at a 50%
dose reduction, making Answer D correct.
Patient Cases
9. A 49-year-old male (height 175 cm, weight 100 kg) was diagnosed with an idiopathic DVT 3 weeks ago. He
currently takes warfarin 8 mg orally daily. He missed his INR readings last week when he went on a short
vacation. Today, his INR is 10.4. He is not currently bleeding and has no risk factors for bleeding. In addition
to holding his warfarin dose, which is the best initial strategy for managing this patient’s high INR?
A. Hold warfarin only.
B. Hold warfarin and administer 4PCC 50 units/kg intravenously.
C. Hold warfarin and administer vitamin K 5 mg orally.
D. Hold warfarin and administer vitamin K 10 mg intravenously.
- Answer: C
Because this patient is not bleeding and rapid reversal
is unnecessary, 4PCC is not needed (Answer B is
incorrect). The patient’s lack of bleeding also makes
high-dose (10 mg) intravenous vitamin K unnecessary
(Answer D is incorrect). For an INR over 10 with
no bleeding, the dose of oral vitamin K should be 5
mg, making Answer C correct and Answer A (simply
holding the warfarin dose without a reversal agent)
incorrect.
- A 58-year-old male is receiving enoxaparin 40 mg subcutaneously daily for VTE prophylaxis. While trying
to shave himself at 6 p.m., he cuts his neck, and the medical team cannot stop the bleeding. His last enoxaparin
dose was administered at 8 a.m. Which would be the most appropriate protamine dose (in milligrams) for
this patient?
A. 10.
B. 20.
C. 40.
D. 50.
- Answer: B
Protamine is acceptable for the reversal of enoxaparin
therapy because it reverses about 50%–60% of
the anticoagulant effect of LMWH. One milligram of
protamine will reverse 100 anti-Xa units of LMWH.
One milligram of enoxaparin equals 100 anti-Xa units.
Thus, 1 mg of protamine will reverse 1 mg of enoxaparin.
Typically, a dose of 40 mg of protamine would
be used to reverse a dose of 40 mg of enoxaparin.
However, when the last dose of enoxaparin is more than
8 hours before the need for protamine, one-half the dose
should be administered. Therefore, a dose of 20 mg of
protamine (Answer B is correct) would be appropriate
in this patient, not a dose of 40 mg (Answer C is
incorrect). The dose of 10 mg would be too low for this
setting, making Answer A incorrect. Although 50 mg
of protamine (Answer D) is the maximum dose to be
administered at one time, it is more than twice as much
protamine as would be required in this patient setting
and is incorrect.
Warfarin in detail
Vitamin K antagonist (VKA) – Racemic mixture of S- and R-isomers
i. Inhibits vitamin K recycling by competitively inhibiting vitamin K epoxide reductase.
Ultimately, this prevents the γ-carboxylation of clotting factors II, VII, IX, and X, leaving
these factors to bind to phospholipid membranes and unable to take part in coagulation.
ii. Also inhibits carboxylation and activation of natural anticoagulants, protein C, protein S.
iii. S-warfarin is about 4-fold more potent than R-warfarin.
b. Several trials have shown a 70%–80% relative risk reduction in stroke and systemic embolism with
warfarin therapy compared with placebo.
c. Dosing for NVAF is based on requirements to achieve an INR goal of 2.0–3.0. Time to pharmacologic
effect of warfarin requires consideration of the elimination half-life of inhibited clotting
factors: factor VII = 6 hours; factor IX = 24 hours; factor X = 36 hours; factor II = 72 hours.
Functional clotting factors already produced must “run their course” and cannot be inhibited with
higher doses, regardless of the INR.
d. Initial starting dose is typically 5 mg orally daily, but doses of up to 10 mg daily may be required
depending on patient-related factors (e.g., concomitant medication use that induces the metabolism
of warfarin). A lower starting dose (2–3 mg orally daily) should be considered in patients with
the following: advanced age, low body weight (less than 45 kg), drug interactions, malnutrition,
heart failure, hyperthyroid state, low albumin or liver disease, certain ethnic groups (e.g., Asian
populations)
i. Dosing algorithms are available to help with initiating therapy. In the outpatient setting, an
INR should be measured at least weekly until the INR stabilizes
ii. Using pharmacogenomic data can achieve a faster therapeutic INR and fewer INRs of 4 or less
but has not reduced thrombotic or bleeding events. Therefore, using pharmacogenomic data is
not part of standard of care.
iii. In patients receiving a parenteral direct thrombin inhibitor or in lupus cases when the INR
is not reflective of dosing, a factor VII or X concentration has been used with some success.
A chromogenic factor X assay is likely most reliable for measuring the anticoagulant
activity of warfarin in these patients, especially those with INR values greater than 3.0.
warfarin inr monitoring
Follow-up INR monitoring
i. INR values on a specific day are the result of warfarin doses taken over the previous 3–4 days,
and dosing changes made on a specific day are not fully represented in the INR for 3–5 days.
It takes 5–7 days to see the full effect of a stable warfarin dose.
ii. If the INR is out of the therapeutic range in the outpatient setting, the total weekly dose should
be increased or decreased by 5%–20%, depending on the INR; if the INR is greater than
4.0, the clinician should consider holding one or two doses before resuming the agent at the
reduced maintenance dose.
iii. If the INR was previously stable or therapeutic and a single out-of-range INR is 0.5 or less
above or below the therapeutic range, current dosing can be continued; the INR should be
rechecked within 1–2 weeks.
iv. In general, no need to adjust dose if INR is within 0.1 of goal, but would monitor more closely
(especially if below goal).
v. If the INR decreases to 1.8 or less, the risk of ischemic stroke in AF increases by 60%, whereas
the risk of bleeding does not significantly increase until the INR is greater than 4.0.
vi. VKA therapy is well managed when the individual patient’s time in therapeutic range (TTR) is
greater than 65%–70%. If this level of TTR is not achieved, strategies should be implemented
to improve the patient’s TTR (e.g., more regular INR tests, education/counseling to better
control diet, alcohol, drug interactions, medication adherence referral to a dedicated anticoagulation
clinic).
warfarin drug interactions
f. Drug-drug interactions
i. S-warfarin mainly metabolized by CYP2C9 > CYP3A4.
ii. R-warfarin mainly metabolized by CYP1A2, CYP3A4 > CYP2C19
iii. Enzyme induction will produce a reduced INR and warfarin effect, increasing the risk of
thrombosis (e.g., phenytoin, phenobarbital, carbamazepine, rifampin, St. John’s wort).
iv. Enzyme inhibition will produce an increased INR and warfarin effect, increasing the risk of
bleeding.
(a) S-warfarin – CYP2C9 > CYP3A4 (e.g., metronidazole, trimethoprim/sulfamethoxazole,
fluconazole, isoniazid, fluoxetine, sertraline, amiodarone)
(b) R-warfarin – CYP1A2 and CYP3A4 > CYP2C19 (e.g., clarithromycin, erythromycin,
azole antifungals, fluoxetine, amiodarone, cyclosporine, sertraline, grapefruit juice, ciprofloxacin,
protease inhibitors, diltiazem, verapamil, isoniazid, metronidazole)
v. Antiplatelet agents through a pharmacodynamic effect (e.g., aspirin, P2Y12 inhibitors, NSAIDs,
fish oil, gingko, garlic)
vi. Agents that compete for renal clearance (e.g., amiodarone, propafenone, cimetidine)
vii. Agents that reduce vitamin K synthesis in the intestinal flora (e.g., antibiotics)
viii. Reduced warfarin absorption (e.g., cholestyramine, sucralfate)
