REVIEW OF ANTICOAGULANTS

1. ANTITHROMBOTIC THERAPY FOR VTE
DISEASE : CHEST GUIDELINES 2016

2. CASE
A 44-year-old man is evaluated in follow-up for an episode of unprovoked
left proximal leg deep venous thrombosis 3 months ago. Following initial
anticoagulation with low-molecular-weight heparin, he began treatment
with warfarin. INR testing done every 3 to 4 weeks has shown a stable
therapeutic INR. He has mild left leg discomfort after a long day of
standing, but it does not limit his activity level. He tolerates warfarin well.
Family history is unremarkable, and he takes no other medications.
Which of the following is the most appropriate management?
A. Continue anticoagulation indefinitely
B. Discontinue warfarin in another 3 months
C. Discontinue warfarin now
D. Discontinue warfarin and perform thrombophilia testing

3. OBJECTIVES
 Review of anticoagulants
 Recognize subgroups of VTE
 Review guidelines for duration of therapy
 Understand differences in therapy based on type of
VTE

4. Subgroups of VTE
 Cancer-associated vs No cancer
 Provoked vs Unprovoked
 Proximal vs Distal DVT
 Upper extremity vs Lower extremity DVT

5.  PROVOKED
 Reversible cause-surgery , pregnancy ,
immobilization
 Irreversible causes – magnancy , indefinite
hypercoagulable states

 Unprovoked
 Unidentifiable causes

6. Classification of Anticoagulants

7. Parental Anticoagulants Dosing
UFH
80 U/kg IV bolus followed by 18 U/kg/hr
5000U IV bolus followed by 1000 U/hr
Enoxaparin
1 mg/kg SQ Q12H
1.5 mg/kg SQ QD
CrCl < 30: 1 mg/kg SQ Q24H
Fondaparinux
< 50kg: 5mg SQ QD
50-100kg: 7.5mg SQ QD
> 100kg: 10mg SQ QD
 Unfractioned Heparin
 80 U/kg IV bolus followed by 18 U/kg/hr
 5000U IV bolus followed by 1000 U/hr

 Enoxaparin
 1 mg/kg SC 12H
 CrCl < 30: 1 mg/kg SC 24H

 Fondaparinux
 < 50kg: 5mg SC OD
 50-100kg: 7.5mg SC OD
 > 100kg: 10mg SC OD

8. Tinzaparin
175 U/kg SC OD
CrCl < 30: use with caution
Nadroparin
171 U/kg SC OD
CrCl 30-50: reduce dose by 25-33%
CrCl < 30: use with caution

9. Oral Anticoagulants Therapy
Vitamin K Antagonist - warfarin
Started on day 1 or 2 of parenteral anticoagulation
Maintain overlap for at least 5 days.
INR goal = 2-3
Many diet, drug, and disease interactions
OR
NOAC
Rivaroxaban, Apixaban, Edoxaban, Dabigatran
Preferred VTE treatment

10. Rivaroxoban
Dosing
DVT/PE treatment: 15mg BD x 21 days followed by 20mg OD
Take with food
Extremes in weight do not influence
Does not require parenteral anticoagulation prior to initiation
Reduction in risk of recurrence: 20mg OD
Renal and hepatic impairment
 Cr Cl < 30: avoid use
 Moderate-severe hepatic impairment: avoid use

11.  Discontinuation for surgery or other procedures
 Stop rivaroxaban at least 24 hours before procedure
 Restart rivaroxaban after surgery/procedure as soon as adequate
hemostasis is established
 Switching to rivaroxaban
 From warfarin to rivaroxaban: Discontinue warfarin and start rivaroxaban as
soon as INR is below 3.0
 From anticoagulant other than warfarin to rivaroxaban: Start rivaroxaban 0 to
2 hours prior to next scheduled evening administration of the drug and omit
administration of the other anticoagulant
 From unfractionated heparin continuous infusion to rivaroxaban: Stop
infusion and start rivaroxaban at the same time

12. APIXABAN
Dosing
DVT treatment: 10mg BD x 7 days followed by 5mg BD
Does not require parenteral anticoagulation prior to initiation
Reduction in risk of recurrence: 2.5mg BD
Renal impairment
 CrCl < 30: use with caution
 Nonvalvular atrial fibrillation
 Decrease dose to 2.5 mg PO BD in patients with any 2 of the
following characteristics:
 Age ≥80 years
 Weight ≤60 kg
 Serum creatinine ≥1.5 mg/dL

13.  Hepatic impairment
 Mild : No dosage adjustment required
 Moderate/Severe: Not recommended
 Surgery/procedures
 Discontinue at least 48 hr before elective surgery or invasive
procedures with a moderate or high risk of unacceptable or clinically
significant bleeding

14. EDOXABAN
 DVT or PE Treatment
 Indicated for treatment in patients who have been initially treated with
a parenteral anticoagulant for 5-10 days
 >60 kg: 60 mg PO OD
 ≤60 kg: 30 mg PO OD
Renal impairment (DVT/PE)
 >50 mL/min: No dosage adjustment required
 15-50 mL/min: 30 mg PO OD
 Renal impairment (NVAF)
 CrCl >95 mL/min: Do not use; increased ischemic stroke compared with
warfarin
 CrCl >50 to 95 mL/min: No dosage adjustment required
 CrCl 15-50 mL/min: 30 mg PO OD

15.  Hepatic impairment
 Mild (Child-Pugh A): No dose adjustment required
 Moderate-to-severe (Child-Pugh B/C): Not recommended;
 Transition to edoxaban
 From warfarin or other vitamin K antagonists (VKAs): Discontinue
warfarin and start edoxaban when INR ≤2.5
 From oral anticoagulants other than warfarin or other VKAs:
Discontinue current oral anticoagulant and initiate edoxaban at the
time of the next scheduled dose of the previous oral anticoagulant
 From low molecular weight heparin (LMWH): Discontinue LMWH and
initiate edoxaban at the time of the next scheduled administration of
LMWH
 From unfractionated heparin: Discontinue heparin infusion and initiate
edoxaban 4 hr later

16. DABIGATRAN
 DVT or PE Treatment
 Indicated for patients who have been treated with a parenteral anticoagulant for 5-10
days
 CrCl >30 mL/min: 150 mg PO BD
 CrCl ≤30 mL/min or on dialysis: not indicated
 Stroke Prophylaxis With Atrial Fibrillation
 Prevention of stroke and systemic embolism associated with nonvalvular atrial
fibrillation
 CrCl >30 mL/min: 150 mg PO BID
 CrCl 15-30 mL/min: 75 mg PO BID
 CrCl <15 mL/min or dialysis: not recommended

17.  Discontinuation for surgery and other interventions
 Discontinue dabigatran 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days
(CrCl <50 mL/min) before invasive or surgical procedures because of
the increased risk of bleeding
 Consider longer times for patients undergoing major surgery, spinal
puncture, or placement of a spinal or epidural catheter or port, in
whom complete hemostasis may be required

18. NOAC Parenteral
needed
Weight adj Unique Reversal
Rivaroxaban No No Take with food No
Apixaban No ~ No Pregnancy B No
Edoxaban Yes Yes CrCl > 95:
avoid
No
Dabigatran Yes No GI upset Praxbind,
dialyzable

19. NOAC Evidence
4 new RCTs and extensive clinical experience
Risk reduction similar between NOACs and VKA
Risk reduction greater with LMWH than VKA in patients with cancer
Risk reduction seems to be similar between all NOACs (No direct comparison)
Risk of bleeding less with NOACs than VKA
GI bleeding may be higher, though
Risk may be less with apixaban
Risk of fatal bleeding similar between VKA and NOACs
Conclusion, less bleeding and greater convenience with NOACs

20. Choice of Anticoagulant

 DVT/PE and no Cancer:

 NOAC>VKA>LMWH

DVT/PE and Cancer:
 LMWH>VKA>NOAC

22. Duration of anticoagulants
Four durations of treatment:
(1) 4 or 6 weeks; short term
(2) 3 months; long term
(3) longer than 3 months but still a time-limited course of therapy
(usually 6 or 12 months); or
(4) extended (also termed “indefinite”; no scheduled stopping date)
therapy

23. RISK FACTOR RATE OF RECURRENCE
SURGERY 3 % AT 5 YEARS
NON SURGICAL 15 % AT 5 YEARS
UNPROVOKED 30 % AT 5 YEARS
CANCER 15 % ANNUAL RISK

24. Risk Factors for Bleeding on
Anticoagulant Therapy
Age >65
Previous bleeding
Cancer
Metastatic cancer
Renal failure
Liver failure
Thrombocytopenia
Previous stroke
Diabetes
Anemia
Antiplatelet therapy
Poor anticoagulant control
NSAID use
Low risk 0 risk factors
Moderate risk 1 risk factor
High risk ≥2 risk factors

25.  In patients with a proximal & distal DVT of the leg or PE
provoked by surgery or non surgical transient risk factor,

 Treatment with anticoagulation for 3 months is preferred over

(i) treatment of a shorter period ,
(ii) treatment of a longer, time-limited period (eg 6, 12, or 24 months) , or
(iii) extended therapy (no scheduled stop date) .
.

26. In patients with a first VTE that is an unprovoked proximal DVT of
the leg or PE should have atleast 3 month anticoagulant therapy
(i) low or moderate bleeding risk ,extended anticoagulant therapy > long term
(ii) high bleeding risk , long term > extented therapy
In patients with a second unprovoked VTE and who have a
(i) low and moderate bleeding risk , extended anticoagulant therapy > long term
(ii) high bleeding risk , long term > extented therapy

27. In patients with DVT of the leg or PE and active cancer
(“cancer-associated thrombosis”) and who do not have a high
bleeding risk, recommendation are extended anticoagulant therapy
(no scheduled stop date) over 3 months of therapy .

28. Aspirin for Extended Treatment of VTE
In patients with an unprovoked proximal DVT or PE who are stopping
anticoagulant therapy and do not have a contraindication to aspirin, aspirin over
no aspirin to prevent recurrent VTE is suggested
These recommendations are based on two randomized trials.
Extended anticoagulant therapy reduce recurrent VTE by more than
80% and Aspirin by 33 % .

29. Whether and How to Prescribe Anticoagulants to Patients
With Isolated Distal DVT
 Two management options for isolated DVT
1) treat patients with anticoagulant therapy or
2) follow-up US examination (eg, after 1 and 2 weeks, or sooner if
there is concern )

30. Risk factors for extension of distal DVT that would favor
anticoagulation over surveillance:
(1) D-dimer is positive
(2) thrombosis is extensive (eg, >5 cm in length, involves multiple
veins, >7 mm in maximum diameter);
(3) thrombosis is close to the proximal veins;
(4) there is no reversible provoking factor for DVT;
(5) active cancer;.
(6) history of VTE; and
(7) inpatient status.
(8) Severe symptoms
(9) DVT that are detected using a selective approach to whole-leg
US

31.  Surveillance over anticoagulation

 1) thrombosis that is confined to the muscular veins of the calf ( soleus,
gastrocnemius) to have a lower risk of extension than thrombosis that
involves the axial ( ie, true deep; peroneal, tibial ) veins.

 2) high bleeding risk

 3) whereas distal DVT detected by routine whole-leg US

32. In patients with acute, isolated, distal DVT of the leg who are
managed with serial imaging,
(i) no anticoagulation if the thrombus does not extend
(ii) suggest anticoagulation if the thrombus extends but remains
confined to the distal veins or extends into the proximal veins

33. CDT for Acute DVT of the Leg
In patients with acute proximal DVT of the leg,
anticoagulant therapy alone over CDT is preferred.
It was based on various randomized trials and cavenent study
(Catheter-Directed Venous Thrombolysis in Acute Iliofemoral
Vein Thrombosis Study) which shows CDT is associated with
an increase in transfusion (twofold), intracranial bleeding
(threefold),PE (1.5-fold), and vena caval filter insertion
(twofold);

34. CDT is preferred over anticoagulation in
patients having
1) Iliofemoral DVT,
2) Symptoms for <14 days,
3) Good functional status,
4) Life expectancy of >1 year, and
5) low risk of bleeding

35. Role of IVC Filter for Acute DVT or PE
In patients with acute DVT or PE who are treated with
anticoagulants, recommendations are against the use of an IVC
filter.
These recommendations are based on PREPIC 1 and PREPIC 2
trial (Prevention du Risque d’Embolie Pulmonaire par Interruption
Cave) which showed placement of a permanent IVC filter
increased DVT, decreased PE, and did not influence VTE (DVT
and PE combined) or mortality

36. Compression Stocking to Prevent PTS
In patients with acute DVT of the leg , compression stockings
routinely to prevent PTS are not recommended
These were based on findings of two small, single-center,
randomized trials in which patients and study personnel were not
blinded to stocking use (non placebo stocking) .

37. Subsegmental PE
Subsegmental PE refers to PE that is confined to the subsegmental pulmonary
arteries.
There is uncertainty whether these patients should be anticoagulated for two
reasons :
First because of false positive findings
Second, because a true subsegmental PE arises from a small DVT, the risk of
progressive or recurrent VTE without anticoagulation is expected to be lower.
.

38. Diagnosis of subsegmental PE
(1) the CT pulmonary angiogram is of high quality with
good opacification of the distal pulmonary arteries;
(2) there are multiple intraluminal defects;
(3) defects involve more proximal subsegmental arteries
(ie, are larger);
(4) defects are seen on more than one image;
(5) defects are surrounded by contrast rather than
appearing to be adherent to the pulmonary artery walls;
(6) defects are seen on more than one projection;
(7) patients are symptomatic, as opposed to PE being
an incidental finding;
(8) there is a high clinical pretest probability forPE;
(9) D-dimer level is elevated, particularly if the
increase is marked and otherwise unexplained.

39.  Other risk factors for VTE in pt of subsegmental PE are the
patients who are
1.hospitalized or
2. Reduced mobility
3. Active cancer (particularly if metastatic or being treated
with chemotherapy);
4. No reversible risk factor for VTE such as recent surgery.
Favors anticoagulation

40. In patients with subsegmental PE (no involvement of more
proximal pulmonary arteries) and no proximal DVT in the legs
who have a
(i)low risk for recurrent VTE clinical surveillance over
anticoagulation is suggested
(ii) high risk for recurrent VTE , anticoagulation over clinical
surveillance

41. Treatment of Acute PE Out of the Hospital
Patients who satisfy all of the following criteria are suitable for treatment
of acute PE out of the hospital:
(1) clinically stable with good cardiopulmonary reserve;
(2) no contraindications such as recent bleeding, severe renal or liver
disease, or severe thrombocytopenia (ie, <70,000/mm3);
(3) expected to be compliant with treatment; and
(4) the patient feels well enough to be treated at home.

42. Systemic Thrombolytic Therapy for PE
Pulmonary Embolism Thrombolysis trial, which randomized
1,006 patients with PE and right ventricular dysfunction
showed that thrombolytic therapy prevented cardiovascular
collapse but increased major (including intracranial) bleeding;
with no convincing net benefit from thrombolytic therapy.
However favored “rescue thrombolytic therapy” on patients
who developed cardiovascular collapse after initially being
treated with anticoagulant therapy alone

43. PE With Hypotension
 AT 10 suggsts that thrombolytic thearapy over
anticoagulation in pt with acute PE with hypotension (ie,
systolic BP <90 mm Hg for 15 min) and without high
bleeding risk.

44. PE Without Hypotension
 In most patients with acute PE not associated with
hypotension, recommendations are against systemically
administered thrombolytic therapy
 In selected patients with acute PE who deteriorate after
starting anticoagulant therapy but have yet to develop
hypotension and who have a low bleeding risk,
thrombolytic therapy is suggested.

45.  Indications of thrombolytic therapy
1.Progressive increase in heart rate,
2.Decrease in systolic BP (which remains >90 mm Hg),
3. Increase in jugular venous pressure,
4. Worsening gas exchange,
5.Signs of shock (eg, cold sweaty skin, reduced urine output, confusion),
6. Progressive right heart dysfunction on echocardiography, or an
7. Increase in cardiac biomarkers.

46. Catheter-Based Thrombus Removal for the
Initial Treatment of PE
In patients with acute PE who are treated with a
thrombolytic agent, systemic thrombolytic
therapy using a peripheral vein over CDT is
recommended
In patients with acute PE associated with hypotension
and who have (i) a high bleeding risk,
(ii) failed systemic thrombolysis, or (iii) shock that is
likely to cause death before systemic thrombolysis
can take effect (eg, within hours), CDT > NO THERAPY

47. Thrombolytic Therapy in Patients With Upper
Extremity DVT
Thrombolysis is most likely to be of benefit in patients who meet the
following criteria:
1. severe symptoms
2.thrombus involving most of the subclavian vein and the axillary vein;
3.symptoms for <14 days;
4.Good functional status;
5.life expectancy of >1 year; and
6.Low risk for bleeding.

48. In patients with UEDVT who undergo
thrombolysis, same intensity and duration of
anticoagulant therapy as in patients with UEDVT
who do not undergo thrombolysis

49. Management of Recurrent VTE on
Anticoagulant Therapy
Unusual occurrence so reevaluate:
 Diagnosis
 Compliance
 Underlying malignancy

If occurs while on therapeutic VKA or NOAC therapy, suggest
switching to LMWH therapy at least temporarily and for at least 1
month
If occurs while on long-term LMWH, suggest increasing dose
by 1/4 -1/3

50. SUMMARY
 Non-Cancer: NOAC > VKA > LMWH
 Cancer: LMWH
 Recurrent: Switch to LMWH or increase LMWH dose
 Provoked risk factor : long term > extented / short term
 Unprovoked / cancer : extented > long term
 Thrombolytic: only in massive or deteriorating PE
 Compression stockings: do not routinely use
 Subsegmental [PE: base therapy on risk
 Aspirin > no aspirin in unprovoked dvt
 Isolated distal dvt : severe symptoms or risk fctors anticoagulation >
surviellance.
 PE with hypotension and progressive worsening on anticoagulant therapy
thrombolytic therapy > anticoagulation