Jessica Morton, Irfan A. Khan, Diana Fernández-Rodríguez, Colin Baker, Javad Parvizi.

Response/ Recommendation: The occurrence of symptomatic deep venous thrombosis (DVT) and pulmonary embolism (PE) should be used as an endpoint to evaluate the efficacy of a venous thromboembolism (VTE) prophylactic agent.

Strength of Recommendation: Moderate.

Rationale: Patients undergoing orthopaedic procedures have an increased risk of DVT and PE, collectively referred to as VTE, due to hypercoagulability, endothelial damage of blood vessels, and venous stasis¹. The development of multimodal prophylactic regimens that utilize chemical and mechanical prophylaxis have significantly reduced the incidence of perioperative VTE^2-4. Despite this, it remains crucial to continually evaluate the efficacy of VTE prophylactic agents since VTE can cause significant morbidity and mortality⁵.

The Food and Drug Administration (FDA) stated in its clinical outcome assessment (COA) compendium that asymptomatic proximal DVT, symptomatic proximal or distal DVT, non-fatal PE, or VTE-related death, among others, should be used as efficacy and safety outcomes for VTE prophylaxis studies⁶. The aim of this document is to provide a clinically useful endpoint for researchers when developing clinical trials, from amongst the COA listed⁶.

Many Phase III trials have been conducted in the last 20 years evaluating VTE prophylaxis in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA)^7-20. The purpose of those trials were to establish efficacy of VTE prophylaxis and monitor for adverse events¹¹. Commonly used primary outcomes included symptomatic VTE, asymptomatic VTE (as assessed by venography typically at the 5 – 14-day mark for standard therapy or days 28 – 35 for extended prophylaxis), and all-cause mortality^7-20.

Given that the rates of VTE are relatively low with current treatment guidelines and prophylaxis, less than 1% of primary THA and TKA and less than 1.5% of revision THA and TKA experiencing VTE occurrence²¹, it is reasonable that researchers prefer an objective measurement of an uncommon event. This has led to venographic evidence of asymptomatic DVT being used as an endpoint for determining efficacy of VTE prophylaxis. The objectivity of venographic studies is helpful to researchers since many DVT are clinically silent^4,22.

To date, despite the frequent use of venography and venous duplex for diagnosis of DVT in clinical trials, routine venous duplex and venography screening following THA and TKA is not recommended by the clinical practice guidelines developed by the American Academy of Orthopaedic Surgery (AAOS) and the American College of Chest Physicians (AACP)^23-27.

There are numerous studies that prove routine screening by ultrasound for the presence of DVT is not warranted. In a study by Schmidt et al., patients undergoing THA or TKA received a 10-day regimen of low-molecular-weight heparin (LMWH) and randomized to receive prolonged LMWH or screening for DVT by ultrasound (with a positive screen being treated appropriately). Both groups developed similar rates of proximal DVT by day 35 postoperatively (below 9%), questioning the utility of screening ultrasound²⁵. Furthermore, a recent retrospective single-center study found that in patients who underwent total joint arthroplasty and had a duplex ultrasound, only 0.7% of them had a DVT and none of them exhibited clinical symptoms²⁷. Shahi et al., found that the rate of in-patient DVT being diagnosed has decreased significantly during the past decade, likely due to less screening of asymptomatic patients, while the rate of PE development has remained stable³.

Propagation of DVT leading to a PE is a feared complication²⁸. The latter is the rationale behind screening patients for asymptomatic DVT in an effort to prevent development of a PE. However, the association between a distal DVT and PE remains unproven. In addition, many distal DVT developed in the postoperative period resolve even without a treatment²⁹. It is believed that DVT and PE can arise independently of each other and in hypercoagulable states, such as the postoperative period^30,27. In addition, a recent systematic review of contemporary trials of anticoagulation, the importance of asymptomatic DVT detected by mandatory screening was questioned³¹.

In this regard, using symptomatic DVT and PE as primary endpoints for studies evaluating the efficacy of a VTE prophylactic agent would provide clinicians with clinically important information that would help determine the best course of management of these patients.

References:

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