Therapeutic

1. Venous Thromboembolism (VTE)

2.  Venous thromboembolism (VTE) is one of the most common
cardiovascular disorders in the United States.
 VTE is manifested as deep vein thrombosis (DVT) and pulmonary
embolism (PE) resulting from thrombus formation in the venous
circulation.
 It is often provoked by prolonged immobility and vascular
injury and most frequently seen in patients hospitalized for a
serious medical illness, trauma, or major surgery.
 VTE can also occur with little or no provocation in patients who
have an underlying hypercoagulable disorder.

3.  The risk of VTE is related to several factors
including age, history of VTE, major surgery
(particularly orthopedic procedures of the lower
extremities), trauma, malignancy, pregnancy,
estrogen use, and hypercoagulable states.
 Estrogen-containing contraceptives, estrogen
replacement therapy, and many of the selective
estrogen receptor modulators (SERMs) increase the
risk of venous thrombosis.

4.  The symptoms of DVT or PE are nonspecific, and it is
extremely difficult to distinguish VTE from other
disorders on clinical signs alone.
 Therefore, objective tests are required to confirm or exclude
the diagnosis.
 Patients with DVT frequently present with unilateral leg
pain, swelling that can persist after a night’s sleep, and
cyanosis of the skin in the affected leg

5.  Signs, symptoms and risk factors can be used to categorize the
patient as at low, intermediate, or high probability of having acute
DVT.
 This model, known as the Wells Criteria, is summarized in Table.
 If the clinical probability of DVT is low, the D-dimer test can be
used to confirm the patient does not have DVT.
 The D-dimer test is a quantitative measure of fibrin breakdown in
the serum, and it is a marker of acute thrombotic activity.
 D-dimer assays are sensitive but not specific markers for VTE,
so a negative D-dimer test can be used to rule out the diagnosis
of DVT.

6.  If the D-dimer test is positive in a low
probability patient, or if the patient has a
moderate or high probability of DVT.

7.  Duplex ultrasonography is the most commonly used test to
diagnose DVT.
 It is a noninvasive test that can measure the rate and direction
of blood flow and visualize clot formation in veins of the
legs.
 Venography (also known as phlebography) is the gold standard
for the diagnosis of DVT.
 However, it is an invasive test that involves injection of
radiopaque contrast dye into a foot vein.
o It is expensive and can cause anaphylaxis and
nephrotoxicity.

8. Laboratory Tests
 The initial laboratory evaluation should include complete
blood count (CBC) with differential, coagulation studies (such
as prothrombin time [PT]/international normalized ratio [INR],
activated partial thromboplastin time [aPTT]), serum
chemistries with renal and liver function.
 Serum concentrations of D-dimer, a by-product of thrombin
generation, will be elevated in an acute event.
 A negative D-dimer in a patient with low clinical
probability of DVT can be used to rule out DVT.

9. Clinical Probability
 Apply the Wells criteria to determine the
probability that the patient’s signs, symptoms,
and risk factors are the result of DVT (Table)

12. PREVENTION
• Given that VTE is often clinically silent and potentially fatal,
prevention strategies have the greatest potential to improve patient
outcomes.
 The goal of an effective VTE prophylaxis program is to identify
all patients at risk, determine each patient’s level of risk, and select
and implement regimens that provide sufficient protection for the
level of risk.
• At the time of hospital admission, change in level of care, and prior to
discharge, all patients should be evaluated for risk of VTE, and
appropriate prophylaxis strategies should be routinely used.
• Prophylaxis should be continued throughout the period of risk.

15.  Several pharmacologic and non-pharmacologic
methods are effective for preventing VTE, and these
can be used alone or in combination.
 Non-pharmacologic methods improve venous blood
flow by mechanical means
 drug therapy prevents thrombus formation by
inhibiting the coagulation cascade.

16. Non-pharmacologic Therapy
 Ambulation as soon as possible following surgery lowers the incidence of
VTE in low-risk patients.
 Walking increases venous blood flow and promotes the flow of natural
antithrombotic factors into the lower extremities. All hospitalized patients
should be encouraged to ambulate as early as possible, and as frequently as
possible.
 Graduated compression stockings (GCS) are specialized hosiery that
provide graduated pressure on the lower legs and feet to help prevent
thrombosis.
 Compared with anticoagulant drugs, GCS are relatively inexpensive
and safe; however, they are less effective and not recommended in
moderate to higher risk patients

17.  They offer an alternate choice in low- to moderate-risk
patients when pharmacologic interventions are
contraindicated.
 When combined with pharmacologic interventions,
GCS have an additive effect.
 However, some patients are unable to wear
compression stockings because of the size or shape
of their legs, and some patients may find them hot,
confining, and uncomfortable.

18. Pharmacologic Therapy
 Appropriately selected drug therapies can dramatically reduce
the incidence of VTE in medical and surgical patients.
 The choice of medication and dose to use for VTE prevention
must be based on:
 The patient’s level of risk for thrombosis
 Bleeding risk
 The cost
 Availability of an adequate drug therapy monitoring system.

19.  The most extensively studied drugs for the prevention of VTE
are unfractionated heparin (UFH), the low molecular weight
heparins (LMWHs; dalteparin and enoxaparin), fondaparinux, and
warfarin.
 Generally the LMWHs provide improved protection
against VTE when compared with low-dose UFH in most
medical and surgical patients and when compared to low-dose
UFH and warfarin in major orthopedic surgery patients.
 Fondaparinux is more effective than LMWH in patients
undergoing high-risk orthopedic surgery, but it has a
heightened risk of bleeding.

20.  For hospitalized general surgical and medical
patients, the available evidence supports the
use of
 UFH (5000 Units every 12 or 8 hours),
 enoxaparin 40 mg subcutaneously (SC) daily,
 dalteparin 2500 to 5000 Units SC daily,
 or fondaparinux 2.5 mg SC daily.

21.  For the prevention of VTE following major orthopedic
surgery, current evidence supports the use of UFH,
LMWH, fondaparinux, adjusted dose warfarin, aspirin,
and the newer direct oral anticoagulants (DOACs):
apixaban, dabigatran and rivaroxaban.
 Additionally, the role of aspirin for VTE prevention
is controversial as it produces a very modest
reduction in VTE following orthopedic surgeries of
the lower extremities

22.  The effectiveness of UFH, aspirin, and warfarin is lower than
LMWH, thus current American College of Chest Physicians
(ACCP) guidelines recommend the use of LMWH or
fondaparinux preferentially over other pharmacologic options in
major orthopedic surgery patients.
 The appropriate prophylactic dose for each LMWH product in
orthopedic surgery is indication specific;
 enoxaparin 30 mg SC twice daily, enoxaparin 40 mg SC
daily, and dalteparin 5000 Units SC daily are the most
commonly used regimens.
 The dose of fondaparinux is 2.5 mg SC daily.

23.  The dose of warfarin, another commonly used option for
prevention of VTE following orthopedic surgery, must be
adjusted to maintain an INR between 2 and 3.
 Oral administration and low drug acquisition cost give warfarin
some advantages over the LMWHs and fondaparinux.
 However, warfarin does not achieve its full antithrombotic
effect for several days and requires frequent monitoring and
periodic dosage adjustments, making therapy cumbersome.
 Warfarin should only be used when a systematic patient
monitoring system is available.

24.  The oral factor Xa inhibitors rivaroxaban and apixaban are newer
options for VTE prevention following hip and knee replacement
surgery and offer a convenient alternative to traditional
anticoagulants.
 Both agents have shown superior efficacy compared to LMWH with
a similar rate of bleeding complications.
 Rivaroxaban is given at a fixed dose of 10 mg once daily, and
apixaban is given at a fixed dose of 2.5 mg twice daily. Both are
given without the need for routine laboratory monitoring and dosing
adjustments (as with warfarin) and without the inconvenience of
administration by injection (as with LMWH and fondaparinux).

25.  The optimal duration for VTE prophylaxis is not well
established but should be given throughout the period of
risk.
 For patients who have undergone total knee replacement,
total hip replacement, or hip fracture repair, prophylaxis is
recommended for a minimum of 10 to 14 days
 however, extending it up to 35 days is recommended due
to continued VTE risk up to one month postsurgery.

26. General Treatment Principles
 Anticoagulant drugs are considered the mainstay of therapy for
patients with VTE, and the therapeutic strategies for DVT and PE are
similar.
 Management decisions are guided by balancing the risks and benefits
of various treatment options.
 The treatment of VTE can be divided into three phases: acute (first
5–10 days), long term (first 3 months), and extended (beyond 3
months).
 The acute treatment phase of VTE is typically accomplished by
administering a fast-acting parenteral or a DOAC

27.  Accomplished using oral anticoagulant agents such as warfarin,
or one of the DOACs (apixaban, dabigatran, and rivaroxaban).
 In certain populations, such as patients with cancer and women who
are pregnant, the LMWHs are the preferred agents during long-term
and extended treatment phases due to better safety or efficacy.
 The etiology of VTE will guide the duration of therapy. VTE can be
provoked (by transient risk factors), unprovoked (or idiopathic) and
cancer associated.
 Patients with unprovoked or cancer associated VTE have a
significantly higher risk of recurrence compared to patients
with provoked VTE.

29.  In the absence of contraindications, the treatment of VTE should
initially include a rapid-acting injectable anticoagulant (eg, UFH,
LMWH, fondaparinux) or a rapidly acting DOAC (eg, apixaban,
rivaroxaban).
 If warfarin is used for oral anticoagulation, it should be initiated
on the same day as the parenteral anticoagulant, and the
parenteral agent should be overlapped for a minimum of 5 days
and until the INR is greater than or equal to 2 for at least 24
hours.

30.  Due to significant variability in interpatient response and changes in
patient response over time, UFH requires close monitoring and
periodic dose adjustment.
 The response to UFH can be monitored using a variety of
laboratory tests including the aPTT, the whole blood clotting
time, activated clotting time (ACT) and the plasma heparin
concentration.
o Although it has several limitations, the aPTT is the
most widely used test in clinical practice to monitor
UFH.

31.  Side effects associated with UFH include
o bleeding,
o thrombocytopenia,
o hypersensitivity reactions, and, with prolonged use,
o alopecia,
o hyperkalemia,
o and osteoporosis.
 Bleeding is the most common adverse effect associated with
antithrombotic drugs including UFH therapy UFH is FDA
pregnancy category C and may be used to treat VTE during
pregnancy.

32.  UFH should be stopped immediately and the source of bleeding
treated.
 If necessary, use protamine sulfate to reverse the effects of UFH.
 The usual dose is 1 mg protamine sulfate per 100 units of UFH, up to
a maximum of 50 mg, given as a slow IV infusion over 10 minutes.
 The effects of UFH are neutralized in 5 minutes, and the effects of
protamine persist for 2 hours.
 If bleeding is not controlled or the anticoagulant effect rebounds,
repeated doses of protamine may be administered

33.  Heparin-induced thrombocytopenia (HIT) is a very serious adverse
effect associated with UFH use.
 Platelet counts should be monitored every 2 to 3 days during the
course of UFH therapy.
 HIT should be suspected if the platelet count drops by more than 50%
from baseline or to below 150 × 103/mm3 (150 × 109/L).
 HIT should also be suspected if thrombosis occurs despite UFH use.
 Immediate discontinuation of all heparin-containing products including
the use of LMWHs is in order.
 Alternative anticoagulation with direct thrombin inhibitors (DTIs)
should be initiated.

34.  Routine monitoring of LMWHs activity and dose adjustments are not
required in most patients.
 LMWHs have longer plasma half-lives, allowing once- or twice-
daily administration, improved SC bioavailability, and dose-
independent renal clearance.
 They are also associated with a lower incidence of HIT and osteopenia.
 Two LMWHs are currently available in the United States: dalteparin
and enoxaparin.
 The dose of LMWHs for the treatment of VTE is determined based on
the patient’s weight and is administered SC once or twice daily.

35.  Direct thrombin inhibitors (DTIs) are considered the drugs of choice for
the treatment of VTE in patients with a diagnosis or history of HIT.
 Several injectable DTIs are approved for use in the US including
lepirudin, bivalirudin, argatroban, and desirudin
 In patients with acute VTE, a rapid-acting anticoagulant (UFH, LMWH,
or fondaparinux) should be overlapped with warfarin for a minimum of
5 days and until the INR is greater than 2 and stable.
 This is important because the full antithrombotic effect will not be
reached until 5 to 7 days or even longer after initiating warfarin
therapy.

36.  Adjustments in the maintenance warfarin dose should be
determined based on the total weekly dose and by reducing or
increasing the weekly dose by increments of 5% to 25%.
 When adjusting the maintenance dose, wait at least 7 days to
ensure a steady state has been attained on the new dose before
checking the INR again.
 Checking the INR too soon can lead to inappropriate dose
adjustments and unstable anticoagulation status

37.  The World Health Organization (WHO) recommended the INR to
monitor warfarin therapy.
 For treatment and prevention of VTE, the INR target is 2.5
with an acceptable range of 2 to 3.
 Before initiating warfarin therapy, a baseline PT/INR and CBC should
be obtained.
 After initiating warfarin therapy the INR should be monitored at least
every 2 to 3 days during the first week of therapy.
 Once a stable response to therapy is achieved, INR monitoring is
performed less frequently, weekly for the first 1 to 2 weeks, then every 2
weeks, and every 4 to 6 weeks thereafter if the warfarin dose and the
patient’s health status are stable.