- CONDITION CENTERS
Postthrombotic syndrome (PTS) is a serious but preventable complication of deep vein thrombosis (DVT). It is a significant cause of chronic disability following orthopedic surgery of the lower extremities and carries considerable socioeconomic consequences for patients and health care providers.
The incidence of PTS following DVT is difficult to determine. Published reports vary from 2% to 50%,1-3 with some studies suggesting an incidence as high as 100%,4 but selection criteria, study designs, and length of follow-up differ dramatically between studies. Additionally, most published studies have been retrospective.
The incidence of PTS, however, does appear to increase with time in patients diagnosed with a venous thromboembolic (VTE) event such as DVT. In the populationbased retrospective study of the Olmsted County cohort,5 the cumulative incidence of PTS in patients diagnosed with a VTE event was 7.3%, 14.3%, 19.7%, and 26.8% after 1, 5, 10, and 20 years, respectivelysuggesting that risk persists and even increases for up to 20 years.
The most important factor contributing to the development of PTS appears to be venous valvular incompetence leading to venous reflux. The outflow obstruction caused by incomplete recanalization also is a factor, because it may result in pressure and volume changes within the vessels. Subsequent incompetence or thickening of the venous valves leads to reflux into the more proximal veins, further diminution of forward blood flow, and venous hypertension and edema. Chronic changes of the microvasculature and lymphatic system often follow, exacerbating the edema.6,7 Hyperpigmentation and inflammation of the skin in the involved leg are characteristic of PTS. Lower-extremity edema, which may become intractable, as well as chronic pain and skin ulceration, may develop.6
The risk of progression to PTS does not appear to correlate with the extent of the initial venous thrombosis or the degree of vessel occlusion.1,8 Patients with minor proximal DVT and those with isolated calf vein thrombosis seem to be as likely to develop late sequelae as patients with extensive thrombosis. The recurrence of ipsilateral DVT, however, greatly increases the risk of PTSsuggesting that preventing thrombosis with long-term anticoagulation may prevent severe PTS.1
Cost of Management
The cost of managing PTS is substantial. A 15-year retrospective investigation in Sweden studied the cost of treating superficial venous thrombosis, DVT, cellulitis, venous ulcers, varicose veins, stasis dermatitis, deep venous insufficiency, and pulmonary embolism (PE) in 257 patients with a history of DVT and 241 age-and gender-matched controls.9 The average cost of treatment of complications of thrombosis was $4659 for the patients with a history of DVT and $375 for the controls.9 Furthermore, the average per-event cost of treating primary DVT in the controls was $6083.9 Clearly, preventing DVT and its sequelae such as PTS could substantially reduce the economic burden on the health care system.
Methods of Prophylaxis
Because antithrombotic treatment of newly diagnosed DVT may not reliably prevent progression to PTS, thromboprophylaxis of postoperative DVT is the first step toward preventing the long-term sequelae of PE, recurrent thromboembolism, and PTS.10
Mechanical methods of thromboprophylaxis can be useful, particularly in high-risk patients with contraindications to pharmacologic prophylaxis. Graduated compression (antiembolism) stockings and intermittent pneumatic compression (IPC) devices currently are considered effective. The stockings are inexpensive and safe. These antiembolism stockings are for prophylaxis in the bed-ridden patient.
Once ambulation occurs, heavier support hose are required for those with swelling. These heavier stockings were used in a Dutch study.4 Patients were randomized to wear 30-to 40-mm Hg-graded elastic compression stockings or to receive no stockings for 2 years after proximal DVT. Mild-to-moderate PTS occurred in 20% of the patients who received the stockings and in 47% of the controls. Venous ulceration was seen in one patient who received the stockings and in 3 controls.4 The only major contraindication to compression stockings is peripheral arterial disease, with nonpalpable pulses and an ankle brachial index of <0.5 or signs of arterial insufficiency on physical examination.
Intermittent pneumatic leg compression is effective for preventing DVT in patients undergoing general surgery. In major orthopedic surgery, IPC alone has not been found as effective for preventing proximal DVT in patients undergoing hip surgery as anticoagulants.11 According to 2004 guidelines for VTE prevention issued by the American College of Chest Physicians (ACCP), the use of IPC is an alternative option to pharmacologic prophylaxis in patients undergoing knee replacement surgery and may provide additional efficacy when used as an adjuvant to pharmacologic prophylaxis in hip replacement patients. No recommendation is made for the use of IPC in hip fracture patients.12
Although the benefits of mechanical prophylaxis have been documented, mechanical prophylaxis alone is not adequate in many cases. Thus, the ACCP has issued guidelines recommending the use of mechanical devices in combination with pharmacologic therapy for the prevention of VTE events in high-risk patients.12
Among the currently used agents are oral vitamin K antagonists (warfarin) and the heparins (unfractionated heparin and the low-molecular-weight heparins [LMWHs]). These agents have shown efficacy in the prevention of VTE events in patients undergoing major orthopedic surgery, but they often fail to provide protection in an appreciable number of patients. The use of the LMWHs is associated with failure rates of 16% in elective hip replacement, 31% in total knee replacement, and 27% in hip fracture surgery.13 Similarly, warfarin therapy is associated with failure rates of 22%, 47%, and 24% in hip replacement, knee replacement, and hip fracture surgery, respectively.13
Recently, Missmenti et al published a meta-analysis that indicates that oral anticoagulants are not as effective for orthopedic prophylaxis as LMWH, and the bleeding complications are similar. Rebuttals to that analysis also have appeared, but the venographic incidence of thrombosis has been shown to be higher with the oral anticoagulants than with LMWH, as seen above. Many clinicians are concerned only with symptomatic eventswhich some other experts and I think is a mistake.13
If one agrees with the principle that it is important to prevent every clot, symptomatic or not, to reduce the incidence of PTS, more effective antithrombotic drugs with favorable safety profiles are required. To address such issues, newer antithrombotic agentssuch as the direct thrombin inhibitors (DTIs) and the selective factor Xa inhibitorshave been designed. These agents specifically inhibit pivotal coagulation proteins, such as thrombin (activated factor II) and activated factor X.14,15
Recombinant hirudin is a member of the DTI class of antithrombotic agents. Recombinant hirudin binds to and inactivates thrombin, is well tolerated, and has not been associated with immune-mediated thrombocytopenia.16 The therapeutic advantage of recombinant hirudin and other DTIs over heparin may lie in their mechanism of action, which is independent of antithrombin III (ATIII) and which, therefore, allows inactivation of clot-bound as well as free thrombin.17,18 The recombinant hirudin desirudin has been evaluated in clinical trials for the prevention of VTE events in patients undergoing major orthopedic surgery and has demonstrated clinical benefit.19,20
The DTI ximelagatran, the oral prodrug of melagatran, is currently under investigation for use in the prevention of VTE events in patients undergoing major orthopedic surgery.14,21,22 This agent binds to thrombin noncovalently and also acts as a competitive inhibitor. A phase 2 dose-finding study compared ximelagatran with enoxaparin as prophylaxis for VTE after total knee replacement. The highest dose of ximelagatran (24 mg) produced a 30% overall reduction in relative risk for VTE events, compared with enoxaparin. The absolute difference between the 2 groups was not significant, however.21 Recently published phase 3 results of ximelagatran thromboprophylaxis in hip and knee replacement populations have failed to demonstrate a significant benefit for a regimen of postoperative melagatran followed by oral ximelagatran, compared with the LMWH enoxaparin.23
Unfortunately, an FDA review panel has advised against FDA approval for ximelagatran because of possible liver toxicity as well as concerns about myocardial infarction with short-term use in the orthopedic trials. The final status of this drug and its eventual role in the marketplace are not known at this time.
Fondaparinux, a synthetic pentasaccharide, is the first of a novel class of antithrombotic agents called the selective factor Xa inhibitors. It acts exclusively by inhibiting activated factor X through a conformational change in the ATIII molecule.24 Recent results of clinical trials with fondaparinux have shown it to be an effective antithrombotic agent for preventing VTE after high-risk orthopedic surgery, with a highly significant (P<.001) overall 55.3% common odds reduction in VTE risk, compared with the LMWH enoxaparin, and without any increased risk of death or clinically relevant bleeding.25-29 Fondaparinux recently received FDA approval for use following total hip and knee replacements and extended prophylaxis in patients following hip fracture repair. It is a likely candidate to reduce the incidence and clinical impact of PTS. This drug has a number of desirable features, including a nonbiologic source and protein specificity, which limit undesirable drug-drug interactions. In addition, because it acts by inducing a conformational change in the ATIII molecule, once the ATIII molecule is saturated, excess fondaparinux produces no additional anticoagulation effect. Because it is devoid of any inhibitory activity against formed thrombin molecules, fondaparinux may be less likely to cause bleeding. Finally, there are no effects on platelets or platelet factor 4, and heparin-induced thrombocytopenia has not been observed with this drug.
The incidence of all DVT following major orthopedic surgeries remains high. Effective agents are required to reduce the overall incidence of DVT, which will help diminish the incidence of PTS. The use of these agents will benefit the patient, as well as lowering the considerable costs associated with this chronic disorder. Newer antithrombotic agents have become available that have been designed to lower the overall incidence of DVT in high-risk orthopedic patients. Based on accepted surrogate end points that link venographically detected DVT and occurrences of PTS, it is anticipated that the efficacy of newer thrombotic agents in preventing venographically detectable DVT also would help decrease the occurrence of PTS. This hypothesis needs to be confirmed in future studies.
Dr. Caprini is professor of surgery at Northwestern University, Feinberg School of Medicine; professor of biomedical engineering at Northwestern University; and director of surgical research at Evanston Northwestern Healthcare. He has received an unrestricted educational grant from Organon Sanofi-Synthélabo LLC.
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