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Abbreviations
AF = atrial fibrillation; ASA = acetylsalicylic acid; CAD = coronary artery disease

CHF = chronic heart failure; CV = cardiovascular

DVT = deep venous thrombosis; E F = ejection fraction; H TN = hypertension
INR = International normalized ratio; L A = left atrial ; LV = left ventricular

LMWH = low-molecular-weight heparin; MI = myocardial infarction;

PE = pulmonary embolism; TIA = transient ischemic attack
FFP = fresh frozen plasma; VKA = vitamin K antagonist
MVP = mitral valve prolapse , MVR= replacement, AVR= aortic valve replacement
UFH= unfractionated Heparin

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INR
2-3

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1. Inhibits vitamin Kdependent clotting factors

II, VII, IX, and X
2. Inhibits anticoagulant proteins C and S**
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1.Venous Thromboembolism (VTE): DVT or PE

1. DVT/PE with
reversible or timelimited risk factor.
2. 2.5 (23)
3. 1A
4. 3 months

Time-limited RF:
1. Surgery
2. immobilization
3. Estrogen
4. pregnancy
For all acute DVTs, bridging therapy is
preferred (1B).
If LMWH used, once daily suggested over
twice daily (2C)

First unprovoked PE or
proximal DVT
1A

At least 3 months; then

evaluate for risk-benefit ratio of extended
therapy.
Proximal DVT or PE:
1. If low-moderate bleeding risk
:Extended VKA (2B)
2. If high risk: 3 months of VKA(1B)
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*Rivaroxaban is
also now indicated
for VTE treatment
Low risk: 0 RF,
moderate risk: 1 RF,
high risk 2 RFs
(bleeding risk from
each risk factor
depends on the
severity of the RF,
the time interval,
and whether RF was
corrected)

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.

Elderly(Age > 65)

previous Bleeding
cancer, metastatic cancer
Abnormal)renal failure, liver failure thrombocytopenia)
previous Stroke
Diabetes
Anemia
Drug)antiplatelet therapy)
Labile INR)poor anticoagulant control)
recent surgery
frequent falls
Drug)alcohol abuse)

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2.CAD/Acute MI
Anterior MI and
LV thrombus, or
high risk of LV thrombus
(EF < 40%, anteroapical
WMA)

3monthes of
(thrombus (VKA
Then DC and
switch to dual
antiplatelet
therapy for up to
12 months,
followed by
single
antiplatelet
therapy(stent)

without stenting
VKA plus ASA (75100 mg/day) for first 3
months (1B)
BMS
Triple therapy (warfarin, ASA,
clopidogrel) for 1 month; then warfarin
plus single antiplatelet agent for 2
months
DES
Triple therapy (warfarin, ASA, clpidogrel)
for 36 months

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3.Conversion of Atrial Fibrillation

1. Elective direct current cardioversion of
AF 48 hours or unknown duration
2. 2.5 (23)
3. 7 weeks
4. 1C

Other (equal) options: dabigatran or

LMWH (treatment dose).
At least 3 weeks before and at least 4
weeks after sinus rhythm maintained.

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4.Valvular Heart Disease

Rheumatic Mitral Valve Disease with
history of systemic embolim,
LA thrombus,
Or AF

Rheumatic MVD in sinus rhythm if

LA diameter is > 55 mm )Dilated LA)

Warfarin
2.5 (23)
Long term
1A

Warfarin
2.5 (23)
Long term
2C

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5.Mechanical and Bioprosthetic Heart Valves

Bioprosthetic heart
valve

Mitral

Warfarin (2-3) 3 months

then switch to ASA 50100 mg/ day if
normal sinus rhythm

Aortic

normal sinus rhythm: ASA 50100 mg/day

(no warfarin)
Mechanical
prosthetic heart
valve: aortic

Warfarin
2.5 (23)
Long term 1B

Mechanical
prosthetic heart
valve: Mitral

Warfarin

Add ASA (50100 mg/day) if low risk of

bleeding (1B)

3 (2.53.5)
Long term 2C
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1.a 30 y/o woman receiving warfarin for aproximal DVT. She was taking
oral contraceptives at the time her DVT was diagnosed;
they have since been discontinued. Which of the following is correct
with regards to recommended duration of warfarin?
A. 3 months
B. 6 months
C. 1 year
D. Indefinite
2.a 63 y/o woman with Mechanical Mitral valve replacement(MVR)
3. Mechanical AVR, HTN, dyslipidemia. Meds:
warfarin 8 mg/d, aspirin 81 mg/d, lisinopril, atorvastatin. What is
M.H.s goal INR?
A. 1.5 2.5
B. 1.8 2.6
C. 2 3
D. 2.5 3.5
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Specific patients may need a lower starting dose

(5 mg/day or, in some cases, 23 mg/day).
i. Elderly
ii. Very low body weight
iii. Concurrent interacting drug (enzyme inhibitor)
iv. Malnourished or nothing by mouth for more than 3 days
v. Liver disease
vi. Congestive heart failure
vii. High risk of bleeding
viii. Prolonged fever
ix. Hyperthyroid state
x. Low albumin

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a.fully inhibit factor II

b.prevent possible activation with rapid depletion of protein C
and S until INR is therapeutic for at least 24 hours.
a. Begin warfarin on day1(preferred)or day2 of UFH or LMWH.
b. CHEST guidelines suggest initiating warfarin at 10 mg/day
for the first 2 days, followed by INR-based dosing (2C).
Otherwise, 5 mg/day is generally sufficient.

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a.INR seen today is the result of the doses given

during the past 45 days. Takes 57 days to reach
full effect, given the half-life of factor II
b. Half-lives of vitamin Kdependent clotting factors
VII = 6 hours
IX = 24 hours
X = 36 hours

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I. If INR is high, hold 1-2 doses, resume at lower

dose
II. No need to adjust dose if INR is within 0.1 of
goal (monitor closely)
III. 2012 CHEST guidelines single out-of-range INR is
0.5 above or below goal,continue current dose
and recheck INR within 1-2 weeks (2C)
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1. bridging with LMWH/UFH for a single

subtherapeutic INR in a patient normally
stable (2C).
2. routine use of vitamin K supplementation (2C).
3. routine use of pharmacogenetic testing to
guide the dosing of warfarin (1B).

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1. Bleeding
Epistaxis, hematuria,GI hemorrhage, bleeding gums
,easy bruising often with therapeutic INR.

2. Skin necrosis (rare)

3. Purple toe syndrome (rare),
4. Teratogenicity (category X)
SC.heparin or LMWH is safe.
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i. HTN (1 point)
ii. Abnormal renal/liver function (1 or 2 points; 1 point each)
iii. Stroke (1 point)
iv. Bleeding history or predisposition (1 point)
v. Labile INR (1 point)
vi. Elderly (age older than 65 years)
vii. Drugs (concomitant antiplatelet/NSAID use) and/or EtOH abuse (1 or
2 points; 1 point each)

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1. Reduced warfarin absorption (e.g., cholestyramine,

sucralfate)

2. Enzyme induction (decreases INR and warfarin

effects)
a. CYP3A4 (e.g., rifampin, carbamazepine, phenobarbital, St.
Johns wort)
b. Other (e.g., griseofulvin, nafcillin, dicloxacillin, phenytoin
[inhibition; then induction])

c. Delay in onset
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3. Enzyme inhibition (increases INR and warfarin effects)

a. S-warfarin* (CYP2C9) (e.g., metronidazole,
trimethoprim/sulfamethoxazole, fluconazole, isoniazid,
fluoxetine, sertraline, amiodarone, clopidogrel, lovastatin)
b. R-warfarin (CYP3A3/4/5) (e.g., omeprazole, clarithromycin,
erythromycin, azole antifungals, nefazodone, fluoxetine,
amiodarone, cyclosporine, sertraline, grapefruit juice,
ciprofloxacin, norfloxacin, protease inhibitors, diltiazem,
verapamil, isoniazid, metronidazole)
4. Antiplatelet effects NSAIDs and aspirin also increase the risk of
ulcers, providing a site from which to bleed.
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5. Reduced clearance of warfarin (e.g., propafenone)

6. Increased degradation of clotting factors
(e.g.,levothyroxine)

7. CHEST guidelines recommend avoiding

concomitant NSAIDs (including COX-2 inhibitors)
and antibiotics (2C). Antibiotics with evidence of
increased risk of bleeding:
Trimethoprim/sulfamethoxazole, quinolones,
metronidazole, cephalosporins, doxycycline,
amoxicillin.
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INR

Situation

4.5-10

No
evidence
of
bleeding

Action
Recommend against routine vitamin K
Omit one or two doses of warfarin, and monitor INR more
often. Restart warfarin at a lower dose when the INR is in the
therapeutic range

More
than 10

Omit the next several warfarin doses and give oral vitamin K1
(510 mg). Monitor INR closely and repeat vitamin K1, if
necessary. Resume warfarin at a lower dose when INR is in the
desired range

VKA-associated
major bleeding

Hold warfarin, give vitamin K1 510 mg by slow IV injection plus

prothrombin complex concentrate (recommended over FFP).
If needed, repeat vitamin K1 injection every 12 hours

FFP = fresh frozen plasma; INR = international normalized ratio; IV = intravenous; VKA
= vitamin K antagonist.
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foods with Medium-High Vitamin K Content: Green vegetables,

Liver, Green tea.
:
May result in increased INR and a lower warfarin dose requirement
1. Malnourished/nothing by mouth
2. Recent major surgery
3. Chronic heart failure (especially acutely decompensated)
4. Liver disease
5. Hyperthyroid state (increased clearance of clotting factors) (opposite
occurs in hypothyroid state)
6. Prolonged fever (increased clearance of clotting factors)
7. Diarrhea
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a. Mild: Nosebleeds, bleeding gums, easy bruising

b. More severe: Hematuria, hematemesis, hemoptysis,
melena, bright red blood per rectum.

= (PTpatient/PTmean), PT = prothrombin time.

a. In general, check INR within 12 weeks after dose
adjustment.
c. Latest CHEST guidelines state that if INR is consistently
stable, suggest INR testing frequency of up to 12 weeks
(2B)
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A 79-year-old man is taking warfarin 5 mg/day for atrial fibrillation. His other conditions
are depression and gastroesophageal reflux disease. His medications include fluoxetine 20
mg (started 1 month ago) and omeprazole 40 mg/day (started 6 months ago). He has
warfarin 5-, 2-, and 1-mg tablets at home. His INR was last checked 6 weeks ago and was in
range at that time. He denies any signs or symptoms of bleeding.
You check his INR, and it is 8.
A. Hold warfarin for 1 day and then reinitiate it at a lower dose (no need to recheck INR).
B. Hold warfarin for 2 days and then reinitiate it at a lower dose (no need to recheck INR).
C. Hold warfarin for 2 days, recheck INR, and reinitiate warfarin at a lower dose when INR
approaches 3.
D. Hold warfarin, give oral vitamin K 2.5 mg for 1 day, and reinitiate warfarin at a lower
dose when INR approaches 3.

A. 5 mg 2 days/week and 2.5 mg 5 days/week.

B. 2.5 mg/day.
C. 4 mg/day.
D. 4.5 mg 2 days/week and 5 mg 5 days/week.
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a. Pregnant woman receiving

anticoagulation for VTE should be
switched to LMWH (not UFH).
Avoid dabigatran, rivaroxaban, and apixaban.
b.Pregnant woman with acute VTE,
Anticoagulant should be continued for at
least 6 weeks postpartum (for a minimum
total therapy duration of 3 months).
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c. If a woman with a mechanical heart valve

becomes pregnant:
i. Use adjusted-dose twice-daily LMWH or UFH throughout
pregnancy OR
ii. Use adjusted-dose twice-daily LMWH or UFH until 13th
week of pregnancy; then switch to warfarin; then switch back
to LMWH or UFH close to delivery

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can be safely used while a woman is breastfeeding;

use these rather than dabigatran, rivaroxaban, or apixaban.

6.A 30-year-old pregnant woman had a DVT during her pregnancy at

36 weeks,
7.26 weeks.
She received low-molecular-weight heparin (LMWH) until delivery
(at 40 weeks). She has now delivered a healthy baby boy, whom she is
breastfeeding. Which best represents how long she should now receive
warfarin, after delivery?
A. Warfarin is C.I in women who are breastfeeding; continue LMWH.
B. Warfarin should be used for 6 weeks.
C. Warfarin should be used for 3 months.
D. Warfarin should be used for the rest of her life.

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1.
2.
3.
4.
5.
6.

Stop warfarin approximately 5 days before surgery

In 2 days, start therapeutic dose LMWH
Give last dose of LMWH 24 hours before surgery
IV UFH 46 hours before surgery
consider half dose if using once-daily LMWH
Check INR day before surgery if feasible; give 1-2 mg vitamin K if INR
1.5
7. Post-op, commence
LMWH (24 hr after minor surgery;
48-72 hr if major surgery/high bleeding risk) and
warfarin (12-24 hr after surgery)
8. Continue LMWH until warfarin therapeutic
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8.A 77 y/o man with AF, HTN, diabetes, and h/o TIA 3 years ago.
Having major abdominal surgery in 1 week and will need to hold his
warfarin.
Which of the following is the most appropriate LMWH bridge therapy?
A. No bridge LMWH is needed; just hold warfarin
B. Enoxaparin 30 mg BID
C. Enoxaparin 1mg/kg BID
D. Either enoxaparin 30 mg BID or 1 mg/kg BID are options

9.A 65-year-old man is taking warfarin for a DVT 2 months ago. He

will be undergoing major abdominal surgery in 1 week and will need
to hold his warfarin.
Which is the most appropriate LMWH bridge therapy for him?
A. No bridge LMWH is needed; just hold warfarin.
B. Administer enoxaparin 30 mg twice daily.
C. Administer enoxaparin 1 mg/kg twice daily.
D. Enoxaparin either 30 mg twice daily or 1 mg/kg twice daily is an
appropriate option.
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Any mechanical mitral valve,

older aortic valve (caged
ball, tilting disk)
recent stroke/TIA (past 6
mo.)

Bileaflet aortic valve

and one or more RFs

Bileaflet aortic
valve without AF or
other RFs. for
stroke

CHADS2 score of 5 6
recent stroke/TIA (past 3
mo.) Rvh disease.

CHADS2 score 3 or 4

CHADS2 score 02
and no previous
stroke/TIA

Recent VTE (past 3 mo.)

severe thrombophilia
eg.(dec in prot. C,S)

VTE in the past 312

months, non severe
thrombophilic cond.

VTE more than 12

months ago with
no risk factors

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(single- or multi-tooth extractions or root canal)

suggest continuing VKA and using oral pro-hemostatic agent
(aminocaproic or tranexamic acid mouthwash) or
discontinuing VKA 23 days before procedure (2C).

suggest continuing VKA and using local measures (2C)

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a. Consider using UFH instead of LMWH in severe

CKD.
b. Very limited data with LMWH in patients with
CrCl less than 20 mL/minute or on hemodialysis
c. Enoxaparin is the LMWH best studied in CKD;
preferred agent
d. Prophylaxis of VTE:in severe CKD, recommended
enoxaparin dose is 30 mg once daily.
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1.If LMWH is used in patients with severe CKD

(CrCl less than 30 mL/minute),
Recommended to use 50% of the usual dose of enoxaparin
(e.g., 1 mg/kg once daily for therapeutic dose or bridging)
2.Strongly consider UFH in patients with a CrCl less than 20
mL/minute or on hemodialysis.
3.Consider anti-Xalevel monitoring in severe CKD

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increase dose by 30% in morbidly obese patients ([BMI] of

40 kg/m2 or greater).
i. Weight-based dosing should use actual body weight in
obese patients (BMI greater than 27 kg/ m2), up to a
max. of 190 kg.
Enoxaparin: Twice-daily dosing should be used with no
dose capping (maximum dose).
ii. BMI greater than 40 kg/m2 or weight greater than 190 kg,
consider initiating dosing according to actual body weight
and monitoring anti-Xa levels with dose adjustment, if
required.
iii. Some recommend using UFH in very obese patients.
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:
LMWH, fondaparinux,apixaban,dabigatran,rivaroxaban,
low-dose UFH, adjusted-dose VKA, or aspirin (all 1B),
or
Intermittent pneumatic compression device (IPCD) (1C),
are recommended for a minimum of 1014 days
,preferred 35 day in major orthopedic surgury.
LMWH preferred to other agents.
If patients decline injections, apixaban or dabigatran
(1B) are recommended over other agents.
Rivaroxaban or VKA is recommended next.
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10.A 68-year-old man presents with a second unprovoked DVT. His first
unprovoked DVT was 3 years ago, at which time he completed 3
months of warfarin therapy. He has hypertension, diabetes, and CKD
(CrCl 25 mL/minute). Which is the most appropriate management of
this DVT?
A. Enoxaparin 1 mg/kg twice daily initially; then warfarin indefinitely.
B. Enoxaparin 1 mg/kg once daily initially; then warfarin for 3 months.
C. Enoxaparin 1 mg/kg twice daily initially; then rivaroxaban
indefinitely.
D. Enoxaparin 1 mg/kg once daily initially; then rivaroxaban for 3
months.

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a. Oral direct thrombin inhibitor (DTI)

b. Indicated only for the prevention of stroke and
systemic embolism in patients with nonvalvular AF.
c. Dose:
150 mg orally twice daily
CrCl 1530 mL/minute: 75 mg twice daily.
e. Contraindications: Active pathologic bleeding;
hypersensitivity to dabigatran; mechanical prosthetic
heart valve (new C.I December 2012); not
recommended for bioprosthetic heart valves
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f. Drug interactions:
i. Avoid using dabigatran with P-glycoprotein (Pgp) inducers (e.g.,
rifampin), which reduce exposure to dabigatran.
ii. Concomitant Pgp inhibitors: Consider reducing dose to 75 mg twice
daily if concomitant ketoconazole or dronedarone and CrCl 3050.
Avoid dabigatran with CrCl less than 30 and Pgp inhibitors above
plus verapamil, amiodarone, clarithromycin, and quinidine.
iv. Surgery/reversal:
(a) Discontinue dabigatran 12 days (CrCl of 50 mL/minute or greater) or 35
days (CrCl less than 50 mL/minute) before procedure. Consider a longer
time for major surgery or spinal puncture/catheter.
(b) No antidote; can be removed by hemodialysis, but limited experience

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a. Oral direct factor Xa inhibitor

.
Clinical studies show superiority to enoxaparin, with
no difference in major bleeding events.
i. Dose: 10 mg orally once daily, starting at least
610 hours after surgery.
CrCl less than 30 mL/minute: AVOID

ii. Duration: 35 days for hip replacement

12 days for knee replacement
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.
Dose:20 mg orally OD with evening meal
CrCl 1550 mL/minute: 15 mg OD.
CrCl less than 15 mL/minute: AVOID
.
Dose:15 mg orally twice daily for first 21 days after
event; then 20 mg orally once daily for remaining
treatment (studied for 6 months of treatment) and
long-term reduction in risk of recurrent DVT/PE.
CrCl less than 30 mL/minute: AVOID
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Active major bleeding, hypersensitivity, severe CKD,

moderate-sever hepatic impairment, or any hepatic
disease associated with coagulopathy
i. Increased risk of thromboembolic events with
discontinuation without other anticoagulant coverage
ii. Bleeding
iii. Moderate CKD (CrCl from 30 mL/minute to less than 50
mL/minute): Closely observe for signs of bleeding.
v. Severe hepatic impairment: Avoid in moderate to severe
hepatic impairment.
vi. Prosthetic heart valves: not recommended.
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:
i. Avoid concomitant use with combined Pgp and strong CYP3A4 inhibitors
ii. Avoid concomitant use with combined Pgp and strong CYP3A4 inducers
(e.g., carbamazepine, phenytoin, rifampin, St. Johns wort).
iii. Use in patients with CrCl 1550 mL/minute receiving concomitant
combined Pgp and weak or moderate CYP3A4 inhibitors
(a) Discontinue rivaroxaban at least 24 hours before the procedure, and
reinitiate it after the procedure as soon as adequate hemostasis is
established.
(b) Short half-life (59 hours), so reversal and re-anticoagulation occur
quickly
(c) No antidote; not expected to be dialyzable
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a.Oral direct factor Xa inhibitor

b. Reduction of the risk of stroke and systemic
embolism in patients with nonvalvular AF.
c
exist
1. age 80 or older
2. body weight of 60 kg or less
3. serum creatinine of 1.5 mg/dL or greater

of CYP3A4 and Pgp

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i. Increased risk of stroke with discontinuation in AF

ii. Bleeding
iii. Prosthetic heart valves ,not recommended
(a) Discontinue at least
48 hours before elective surgery/invasive procedures with a
moderate-high risk of clinically significant bleeding.
24 hours a low risk of bleeding.
(b) Anticoagulant effect lasts about 24 hours after the last
dose.
(c) No antidote; not expected to be dialyzable
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:
(a)2.5 mg orally twice daily when coadministered with
strong dual inhibitors of CYP3A4 and Pgp (e.g.,
ketoconazole, itraconazole, ritonavir, clarithromycin).
(b) AVOID if already taking 2.5 mg twice daily as well as
a strong dual inhibitor of CYP3A4 and Pgp.

Avoid concomitant use of apixaban with strong

dual inducers of CYP3A4 and Pgp (e.g., rifampin,
carbamazepine, phenytoin, St. Johns wort).

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a. FDA approved
b. Specific inhibitor of human thrombin
c. Structure similar to hirudin, the naturally occurring
anticoagulant in the peripharyngeal glands of the medicinal
leech
d. Indicated for DVT prophylaxis in patients undergoing elective
hip replacement surgery
e. Dose: 15 mg subcutaneously every 12 hours; give initial dose
515 minutes before surgery. Duration of up to 12 days has
been well tolerated.

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Daily (aPTT) and Scr monitoring are; reduce dose

if peak aPTT level exceeds 2 times control
(after holding until aPTT returns to less than 2
times control).
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Enoxaparin 30 mg SC q12h

Enoxaparin 40 mg SC q24h
Dalteparin 5000 units SC q24h
UFH 5000 units SC q8hq12hA.
: Surgery, major trauma, lower extremity injury,
Immobility, malignancy, sepsis, heart failure, respiratory failure, venous
compression, previous VTE, increasing age, pregnancy, ESA , obesity, and
CVL.
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11.A 75-year-old woman (height 65 inches, weight 68 kg) who is intubated

requires mechanical ventilation for an acute exacerbation of chronic
obstructive pulmonary disease. She has a medical history of heart failure and
hypertension. Her laboratory values are normal except for a Cr of 1.9 mg/dL.
Which is the most appropriate recommendation to prevent a VTE in this
patient?
A. Initiate intermittent pneumatic compression.
B. Administer fondaparinux 2.5 mg subcutaneously once daily.
C. Administer enoxaparin 30 mg subcutaneously once daily.
D. Administer heparin continuous intravenous infusion to maintain an aPTT
of 5070 seconds.

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