Postthrombotic Syndrome Following Orthopedic Surgery

Pharmacy Times, Volume 0,0

Postthrombotic syndrome (PTS) is a serious but preventablecomplication of deep vein thrombosis(DVT). It is a significant cause of chronic disability followingorthopedic surgery of the lower extremities and carriesconsiderable socioeconomic consequences for patientsand health care providers.

The incidence of PTS following DVT is difficult to determine.Published reports vary from 2% to 50%,1-3 with somestudies suggesting an incidence as high as 100%,4 but selectioncriteria, study designs, and length of follow-up differdramatically between studies. Additionally, most publishedstudies have been retrospective.

The incidence of PTS, however, does appear to increasewith time in patients diagnosed with a venous thromboembolic(VTE) event such as DVT. In the populationbasedretrospective study of the Olmsted County cohort,5the cumulative incidence of PTS in patients diagnosedwith a VTE event was 7.3%, 14.3%, 19.7%, and 26.8%after 1, 5, 10, and 20 years, respectively—suggesting thatrisk persists and even increases for up to 20 years.

Risk Factors

The most important factor contributing to the developmentof PTS appears to be venous valvular incompetence leading tovenous reflux. The outflow obstruction caused by incompleterecanalization also is a factor, because it may result in pressureand volume changes within the vessels. Subsequent incompetenceor thickening of the venous valves leads to reflux intothe more proximal veins, further diminution of forward bloodflow, and venous hypertension and edema. Chronic changesof the microvasculature and lymphatic system often follow,exacerbating the edema.6,7 Hyperpigmentation and inflammationof the skin in the involved leg are characteristic of PTS.Lower-extremity edema, which may become intractable, aswell as chronic pain and skin ulceration, may develop.6

The risk of progression to PTS does not appear to correlatewith the extent of the initial venous thrombosis or thedegree of vessel occlusion.1,8 Patients with minor proximalDVT and those with isolated calf vein thrombosis seem to beas likely to develop late sequelae as patients with extensivethrombosis. The recurrence of ipsilateral DVT, however,greatly increases the risk of PTS—suggesting that preventingthrombosis with long-term anticoagulation may preventsevere PTS.1

Cost of Management

The cost of managing PTS is substantial. A 15-year retrospectiveinvestigation in Sweden studied the cost of treatingsuperficial venous thrombosis, DVT, cellulitis, venousulcers, varicose veins, stasis dermatitis, deep venous insufficiency,and pulmonary embolism (PE) in 257 patients witha history of DVT and 241 age-and gender-matched controls.9 The average cost of treatment of complications ofthrombosis was $4659 for the patients with a history ofDVT and $375 for the controls.9 Furthermore, the averageper-event cost of treating primary DVT in the controls was$6083.9 Clearly, preventing DVT and its sequelae such asPTS could substantially reduce the economic burden on thehealth care system.

Methods of Prophylaxis

Because antithrombotic treatment of newly diagnosedDVT may not reliably prevent progression to PTS, thromboprophylaxisof postoperative DVT is the first step towardpreventing the long-term sequelae of PE, recurrent thromboembolism,and PTS.10

Mechanical Prophylaxis

Mechanical methods of thromboprophylaxis can be useful,particularly in high-risk patients with contraindicationsto pharmacologic prophylaxis. Graduated compression(antiembolism) stockings and intermittent pneumatic compression(IPC) devices currently are considered effective.The stockings are inexpensive and safe. These antiembolismstockings are for prophylaxis in the bed-ridden patient.

Once ambulation occurs, heavier support hose arerequired for those with swelling. These heavier stockingswere used in a Dutch study.4 Patients were randomized towear 30-to 40-mm Hg-graded elastic compression stockingsor to receive no stockings for 2 years after proximal DVT.Mild-to-moderate PTS occurred in 20% of the patients whoreceived the stockings and in 47% of the controls. Venousulceration was seen in one patient who received the stockingsand in 3 controls.4 The only major contraindication tocompression stockings is peripheral arterial disease, withnonpalpable pulses and an ankle brachial index of <0.5 orsigns of arterial insufficiency on physical examination.

Intermittent pneumatic leg compression is effective forpreventing DVT in patients undergoing general surgery. Inmajor orthopedic surgery, IPC alone has not been found aseffective for preventing proximal DVT in patients undergoinghip surgery as anticoagulants.11 According to 2004 guidelinesfor VTE prevention issued by the American College ofChest Physicians (ACCP), the use of IPC is an alternativeoption to pharmacologic prophylaxis in patients undergoingknee replacement surgery and may provide additionalefficacy when used as an adjuvant to pharmacologic prophylaxisin hip replacement patients. No recommendationis made for the use of IPC in hip fracture patients.12

Pharmacologic Prophylaxis

Although the benefits of mechanical prophylaxis havebeen documented, mechanical prophylaxis alone is notadequate in many cases. Thus, the ACCP has issued guidelinesrecommending the use of mechanical devices in combinationwith pharmacologic therapy for the prevention ofVTE events in high-risk patients.12

Among the currently used agents are oral vitamin Kantagonists (warfarin) and the heparins (unfractionatedheparin and the low-molecular-weight heparins [LMWHs]).These agents have shown efficacy in the prevention of VTEevents in patients undergoing major orthopedic surgery,but they often fail to provide protection in an appreciablenumber of patients. The use of the LMWHs is associatedwith failure rates of 16% in elective hip replacement, 31%in total knee replacement, and 27% in hip fracture surgery.13Similarly, warfarin therapy is associated with failure rates of22%, 47%, and 24% in hip replacement, knee replacement,and hip fracture surgery, respectively.13

Recently, Missmenti et al published a meta-analysis thatindicates that oral anticoagulants are not as effective fororthopedic prophylaxis as LMWH, and the bleeding complicationsare similar. Rebuttals to that analysis also haveappeared, but the venographic incidence of thrombosis hasbeen shown to be higher with the oral anticoagulants thanwith LMWH, as seen above. Many clinicians are concernedonly with symptomatic events—which some other expertsand I think is a mistake.13

If one agrees with the principle that it is important to preventevery clot, symptomatic or not, to reduce the incidenceof PTS, more effective antithrombotic drugs withfavorable safety profiles are required. To address such issues,newer antithrombotic agents—such as the direct thrombininhibitors (DTIs) and the selective factor Xa inhibitors—have been designed. These agents specifically inhibit pivotalcoagulation proteins, such as thrombin (activated factorII) and activated factor X.14,15

Recombinant hirudin is a member of the DTI class ofantithrombotic agents. Recombinant hirudin binds to andinactivates thrombin, is well tolerated, and has not beenassociated with immune-mediated thrombocytopenia.16The therapeutic advantage of recombinant hirudin andother DTIs over heparin may lie in their mechanism ofaction, which is independent of antithrombin III (ATIII)and which, therefore, allows inactivation of clot-bound aswell as free thrombin.17,18 The recombinant hirudindesirudin has been evaluated in clinical trials for the preventionof VTE events in patients undergoing major orthopedicsurgery and has demonstrated clinical benefit.19,20

The DTI ximelagatran, the oral prodrug of melagatran, iscurrently under investigation for use in the prevention ofVTE events in patients undergoing major orthopedic surgery.14,21,22 This agent binds to thrombin noncovalently andalso acts as a competitive inhibitor. A phase 2 dose-findingstudy compared ximelagatran with enoxaparin as prophylaxisfor VTE after total knee replacement. The highest dose ofximelagatran (24 mg) produced a 30% overall reduction inrelative risk for VTE events, compared with enoxaparin. Theabsolute difference between the 2 groups was not significant,however.21 Recently published phase 3 results of ximelagatranthromboprophylaxis in hip and knee replacement populationshave failed to demonstrate a significant benefit for aregimen of postoperative melagatran followed by oral ximelagatran,compared with the LMWH enoxaparin.23

Unfortunately, an FDA review panel has advised againstFDA approval for ximelagatran because of possible liver toxicityas well as concerns about myocardial infarction withshort-term use in the orthopedic trials. The final status ofthis drug and its eventual role in the marketplace are notknown at this time.

Fondaparinux, a synthetic pentasaccharide, is the first ofa novel class of antithrombotic agents called the selectivefactor Xa inhibitors. It acts exclusively by inhibiting activatedfactor X through a conformational change in theATIII molecule.24 Recent results of clinical trials with fondaparinuxhave shown it to be an effective antithromboticagent for preventing VTE after high-risk orthopedic surgery,with a highly significant (P<.001) overall 55.3% commonodds reduction in VTE risk, compared with the LMWHenoxaparin, and without any increased risk of death or clinicallyrelevant bleeding.25-29Fondaparinux recently received FDA approval for use followingtotal hip and knee replacements and extended prophylaxisin patients following hip fracture repair. It is a likelycandidate to reduce the incidence and clinical impact of PTS.This drug has a number of desirable features, including anonbiologic source and protein specificity, which limit undesirabledrug-drug interactions. In addition, because it acts byinducing a conformational change in the ATIII molecule,once the ATIII molecule is saturated, excess fondaparinuxproduces no additional anticoagulation effect. Because it isdevoid of any inhibitory activity against formed thrombinmolecules, 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 beenobserved with this drug.

The incidence of all DVT following major orthopedic surgeriesremains high. Effective agents are required to reducethe overall incidence of DVT, which will help diminish theincidence of PTS. The use of these agents will benefit thepatient, as well as lowering the considerable costs associatedwith this chronic disorder. Newer antithrombotic agentshave become available that have been designed to lower theoverall incidence of DVT in high-risk orthopedic patients.Based on accepted surrogate end points that link venographicallydetected DVT and occurrences of PTS, it is anticipatedthat the efficacy of newer thrombotic agents in preventingvenographically detectable DVT also would helpdecrease the occurrence of PTS. This hypothesis needs to beconfirmed in future studies.

Dr. Caprini is professor of surgery at Northwestern University,Feinberg School of Medicine; professor of biomedical engineering atNorthwestern University; and director of surgical research at EvanstonNorthwestern Healthcare. He has received an unrestricted educationalgrant from Organon Sanofi-Synth&#233;labo LLC.

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