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which would bind to antithrombin 94% and increase antithrombin affinity for Factor Xa by
300-fold (103–105). The specific binding and small size of fondaparinux also results in
a lack of cross-reactivity with platelet Factor IV, resulting in a substantially reduced ability
to promote HIT (51,106). Early research demonstrated its effectiveness in prevention of
DVT in hip and knee replacement with a fixed, once-daily subcutaneous injection (107).
A large study program in hip replacement, knee replacement, and hip fracture repair
introduced fondaparinux to orthopedic care. Fondaparinux was compared to both the
European and North American conventional doses of enoxaparin in a randomized, double-
blind fashion. Fondaparinux reduced the occurrence of venographically detected venous
thrombosis over 50% better than did enoxaparin (108). Patients undergoing knee
replacement experienced a higher bleeding rate in the fondaparinux group (109).
An analysis of the timing of dosage initiation demonstrated that excess bleeding risk was
attributable to drug administration less than four hours after surgery, similar to the LMWH
trial by Hull (89). The researchers found that the preferred administration time for
fondaparinux came six to eight hours after surgery (108,110). Subsequently it was found
that next-day (!24 hr) administration maintained efficacy but reduced bleeding in
patients following total hip or knee replacement (111). Pharmacoeconomic studies have
demonstrated that fondaparinux is more cost-effective when chosen instead of enoxaparin
in several models in the United States and Europe (112–116).
With regard to extended prophylaxis in orthopedic surgery, Eriksson pursued the
ability of fondaparinux to reduce VTE events in patients undergoing hip fracture repair.
Compared to seven days of prophylaxis, 30 days of fondaparinux prophylaxis reduced the
event rate from 35% to 1.4%. Additionally, the symptomatic event rate was significantly
reduced from 2.7% to 0.3%, nearly eliminating VTE (96). This trial is a significant
contribution to patient care. First, it confirmed the ability of a venogram to accurately
predict the effects on clinical VTE events; both were prevented by 90%. Second, unlike
previous studies, this study was able to identify beneficial effects on symptomatic
events alone in only 656 patients, confirming the benefit of fondaparinux prophylaxis.
Additionally, with four weeks of fondaparinux treatment, major bleeding was no different
from placebo.
With its success in DVT prevention after orthopedic surgery, fondaparinux was
studied in other indications as well. Abdominal surgery patients at risk for postoperative
DVT were assigned to fondaparinux or a pre-op/post-op dosage of dalteparin in a
double-blind fashion. Both drugs reduced the VTE rate similarly; however, unexpectedly,
fondaparinux reduced the VTE rate in the cancer cohort significantly compared to
dalteparin. Major bleeding was low for both agents (117). This is the first study comparing
fondaparinux to LMWH in a cancer cohort. These interesting results await larger, more
specific trials in cancer patients receiving surgical treatment as well as DVT prevention in
patients being medically treated for cancer.
A European placebo-controlled trial was undertaken to determine the effect of
fondaparinux inthe prevention of VTE in patientshospitalized for medical illness. Thiswas
possible due to the low rate of heparin or LMWH utilization in medical patients at the time
the trial was conducted. Fondaparinux significantly reduced the VTE rate in medical
patients compared to placebo from 10.5% to 5.6%, with no significant difference in major
bleeding. Additionally, fondaparinux reduced the rate of death due to PE from 1.5% to 0%
(57). This was the first time a single study demonstrated reduced mortality in medical
prophylaxis patients. Previous meta-analysis of many LMWH studies demonstrated
reduced mortality in medical and cancer patients receiving prophylaxis as described earlier.
Fondaparinux is undergoing evaluation by the FDA for prophylaxis after abdominal
surgery and in medical prophylaxis. Its place in therapy has been addressed for its current
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indications in orthopedics by the Consensus Conference Guidelines (6). It has been given
FDA approval in hip fracture patients for both standard and extended prophylaxis, is
a useful prophylactic agent in high-risk patients, and can prevent VTE better than LMWH.
Proper administration time after surgery, and avoidance in patients with severe renal
dysfunction (creatinine clearance !30 ml/min), will optimize its safety. This agent
demonstrates again that patient-specific risk assessment is needed in order to enjoy the
benefits and minimize the risk of thrombosis prophylaxis.
Ximelagatran
For many years warfarin was the only oral anticoagulant available for long-term
thrombosis prophylaxis in patients with chronic atrial fibrillation and mechanical heart
valves, and as primary treatment after an initial period of heparin therapy in patients with
VTE. Warfarin has also been the mainstay of long-term prophylaxis in VTE. It has
been widely used as primary thrombosis prophylaxis after major orthopedic surgery,
particularly in joint replacements and following hip fracture surgery. However, warfarin
has a slow onset of action and is inconvenient because it requires frequent coagulation
monitoring and dose adjustments. In addition, the anticoagulant properties of warfarin can
be affected by certain foods, alcoholic beverages, and a wide variety of medications. The
logistics of managing warfarin may be cumbersome in certain clinical situations,
particularly in those individuals who do not have access to coagulation clinics or other
advanced health-care management systems that specialize in patient monitoring. A small
subset of patients exists in whom maintaining appropriate levels of anticoagulation is
a difficult chore due to warfarin resistance or other factors (118).
Over the past few years a new oral anticoagulant called ximelagatran has been
developed. Taken orally, this drug undergoes a rapid biotransformation in the GI tract to
melagatran. It directly inhibits thrombin, both clot-bound and circulating in plasma.
Melagatran is not metabolized, and 80% of the drug is excreted renally. It is not bound to
plasma proteins and has a low potential for food or drug interactions. This drug does not
require routine anticoagulant monitoring; however, it does require liver enzyme tests
(AST, ALT, bilirubin) monthly. Fixed dosing produces a predictable dose response and it
must be taken twice daily. Melagatran reaches a peak concentration in the blood in
two hours and has a four-to-five-hours half-life. It has a pharmacokinetic profile
comparable to LMWH. This drug has undergone an extensive clinical trial program
involving nearly 30,000 patients. The clinical areas involved in these studies include
DVT prophylaxis after orthopedic surgery and in medically ill patients, DVT treatment
both primary and extended prophylaxis, atrial fibrillation, and in patients with certain
acute coronary syndromes (119–122). This clinical program has been very successful
regarding efficacy endpoints; however, at the present time, concern over liver function
test elevations has prevented this drug from achieving FDA approval in the United States
(123). The drug has been approved for short-term use in a number of European countries
and has been used in about 50,000 patients. To date, no serious liver-related problems
have been observed.
KEY POINTS
† Venous thromboembolism (VTE) is a major cause of mortality particularly in
the elderly, in those undergoing surgery and in those with cancer.
† Longer term the post-thrombotic syndrome occurs in 25% of those with a DVT.
Venous Thrombosis Prophylaxis 189
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† All patients should undergo a formal risk assessment for VTE.
† Physical measures such as graduated compression stockings and intermittent
pneumatic compression are effective.
† Physical measures should be particularly considered in those where anti-
coagulants are contraindicated or where there is high risk.
† Pharmacological prophylaxis includes unfractionated heparin and low-molecu-
lar weight heparin.
† Newer agents including direct factor Xa inhibitors are being developed and
introduced.
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15
Venous Thrombolysis of the Extremities
Ahmad Bhatti
Division of Vascular Surgery, Loyola University Medical Center, Maywood, Illinois,
U.S.A.
Nicos Labropoulos
Vascular Laboratory, Division of Vascular Surgery, New Jersey Medical School, Newark,
New Jersey, U.S.A.
Marc Borge
Interventional Radiology, Department of Radiology, Loyola University Medical Center,
Maywood, Illinois, U.S.A.
INTRODUCTION
Thrombolysis first gained popularity in the 1960s when it was used systemically for
pulmonary emboli (PE). Dotter et al. advanced thrombolytic treatment in 1974 when
they introduced catheter directed thrombolysis. Extremity venous thrombosis can confer
significant morbidity and mortality, and thrombolysis has been increasingly employed in
an attempt to curb these. Deep venous thrombosis (DVT) can cause outflow obstruction
producing venous hypertension, which may result in signs and symptoms of chronic
venous disease (CVD) (1–4). Additionally, proximal DVT may result in more severe
forms of CVD such as limb-threatening venous gangrene (e.g., phlegmasia) due to
significant impairment of venous outflow (5,6). Various treatments, including antic-
oagulation, thrombolysis, surgery, and endovascular modalities are in use in attempts to
reduce acute and long-term morbidity from DVT.
INDICATIONS
The indications for thrombolysis in DVT remain controversial (7). Acutely, patients can
develop limb swelling, pain, and edema. Rarely, phlegmasia can develop with severe acute
venous obstruction. Thrombolytic treatment in phlegmasia has been described, and is
probably the least controversial indication (8–12). Conservative treatment of DVT with
anticoagulation may help retard progression of thrombosis and help ameliorate acute
symptoms. However, conclusive data showing a reduction of PTS with anticoagulation is
lacking (13,14). The inflammatory process caused by the deep venous thrombosis often
causes extensive permanent damage to the vein walls and valves. In the legs the lack of
valve function can leave patients with long-term sequela of venous insufficiency. In the
upper extremities DVT can result in chronic venous obstruction. Patients may develop
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