Mechanical prophylactic modalities such as graduated compression stockings and intermittent pneumatic compression devices increase venous blood flow and may augment endogenous fibrinolysis, thereby leading to reductions in VTE [14]. Mechanical prophylaxis is frequently prescribed in patients at risk for VTE and who have contraindications to pharmacological prophylaxis. Mechanical VTE prophylaxis has been evaluated most recently in three trials of acute stroke patients.

In an outcome-blinded, randomized controlled trial, 2518 immobilized patients admitted to hospital within 1 week of an acute stroke were assigned to routine care plus thigh-length graduated compression stockings or to routine care alone [15]. The primary outcome of symptomatic or asymptomatic DVT in the popliteal or femoral veins occurred in 10 % patients randomized to thigh-length graduated compression stockings and 10.5 % assigned to the control group. Skin breakdown, ulceration, blisters, and skin necrosis were significantly more common in patients randomized to graduated compression stockings than in the control group (5 % vs. 1 %; odds ratio [OR] 4.18, 95 % confidence interval [CI] 2.40–7.27).

In a subsequent randomized controlled trial, 3114 immobile patients hospitalized with acute stroke were assigned to receive thigh-length graduated compression stockings or below-knee graduated compression stockings [16]. The primary outcome of symptomatic or asymptomatic DVT in the popliteal or femoral veins occurred in 6.3 % of patients who received thigh-length graduated compression stockings and 8.8 % of those who received below-knee graduated compression stockings (absolute difference, 2.5 %; 95 % CI, 0.7–4.4 %; p = 0.008). Skin breakdown occurred in 3.9 % of patients who received thigh-length graduated compression stockings and in 2.9 % of those who received below-knee graduated compression stockings.

A multicenter, randomized trial assessed pneumatic compression devices for VTE prevention in 2876 immobilized patients with acute stroke [17]. The primary outcome, DVT in the proximal veins detected on a screening venous ultrasound or any symptomatic objectively-confirmed DVT in the proximal veins within 30 days of randomization, occurred in 8.5 % of patients prescribed pneumatic compression devices and 12.1 % of those allocated to no pneumatic compression devices (absolute risk reduction, 3.6 %; 95 % CI 1.4–5.8). Excluding 323 patients who died before any primary outcome and 41 without any screening venous ultrasound, the adjusted OR was 0.65 (95 % CI 0.51–0.84; p = 0.001) in favor of pneumatic compression devices.

Because the safety and efficacy of graduated compression stockings for mechanical VTE prophylaxis remain unclear, some evidence-based guidelines recommend against their use and emphasize the importance of pharmacological prophylaxis [18]. Unfortunately, as was the case with the patient in the Clinical Vignette, adherence to mechanical prophylactic measures is often poor.

Pharmacologic agents for the prevention of VTE include subcutaneously administered unfractionated heparin, LMWH, warfarin, and fondaparinux. Low dose aspirin is also effective for prevention of VTE in patients who have undergone total hip or total knee arthroplasty [19]. Evidence-based practice guidelines provide specific recommendations for pharmacological VTE prophylaxis in a variety of patient populations [2–4, 18, 20]. Novel oral anticoagulants, including dabigatran [21], rivaroxaban [22–24], apixaban [25–27], and edoxaban [28] have been evaluated for VTE prophylaxis in large randomized controlled trials. A second-generation antisense oligonucleotide that specifically reduces factor XI levels has been evaluated for prevention of VTE in patients undergoing total knee arthroplasty [29].

The American College of Physicians (ACP) recommends assessment of risk for VTE and bleeding in all medical patients prior to initiation of VTE prophylaxis [18]. The ACP recommends pharmacological VTE prophylaxis with heparin or a related drug for VTE in medical patients, unless the bleeding risk outweighs the anticipated benefits. Furthermore, the ACP recommends against the use of mechanical prophylaxis with graduated compression stockings for VTE prevention in medical patients.

Although pharmacological thromboprophylaxis is effective for prevention of VTE [34, 35], it does not improve survival among hospitalized Medical Service patients. A double-blind, placebo-controlled, randomized trial assessed the effect of subcutaneous enoxaparin (40 mg daily) versus placebo for 10–14 days in 8307 patients who were wearing graduated compression stockings on the rate of death from any cause among hospitalized, acutely ill medical patients [36]. Study inclusion required an age of at least 40 years and hospitalization for acute decompensated heart failure, severe systemic infection with at least one VTE risk factor, or active cancer. The rate of death from any cause at day 30 was 4.9 % in the enoxaparin group versus 4.8 % in the placebo group (risk ratio, 1.0; 95 % CI, 0.8–1.2; p = 0.83). The rate of major bleeding was 0.4 % in the enoxaparin group and 0.3 % in the placebo group (risk ratio, 1.4; 95 % CI, 0.7–3.1; p = 0.35). Based on these data, use of enoxaparin plus graduated compression stockings compared with graduated compression stockings alone did not reduce the rate of death from any cause among hospitalized, acutely ill medical patients.

Several randomized control trials evaluating the safety and efficacy of VTE prophylaxis in medical patients after discharge have been reported. In one of the initial studies of thromboprophylaxis in Medical Service patients after discharge, Extended Clinical prophylaxis in Acutely Ill Medical patients (EXCLAIM), extended-duration enoxaparin 40 mg daily reduced VTE incidence compared with placebo (2.5 % vs. 4 %; absolute risk difference favoring enoxaparin, −1.53 % [95 % CI, −2.54 to −0.52 %]) but increased major bleeding (0.8 % vs. 0.3 %; absolute risk difference favoring placebo, 0.51 % [95 % CI, 0.12–0.89 %]) [33]. The Multicenter, Randomized, Parallel group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients Comparing Rivaroxaban with Enoxaparin (MAGELLAN) trial evaluated 35-day therapy with rivaroxaban 10 mg daily versus standard 10-day therapy with enoxaparin [22]. While the rate of VTE was the same in both groups, major bleeding was increased in the extended duration rivaroxaban group. The Apixaban Dosing to Optimize Protection from Thrombosis (ADOPT) trial compared the novel oral anticoagulant apixaban 5 mg daily with enoxaparin for extended duration thromboprophylaxis [25]. Thirty-day thromboprophylaxis with apixaban did not significantly decrease VTE compared with enoxaparin but did increase the frequency of major bleeding. The LIFENOX trial evaluated the effect of enoxaparin and compression stockings versus compression stockings alone on 30-day mortality in acutely ill medical patients [36]. Enoxaparin was not associated with a decrease in mortality after 30 days. The Discharge Alert Trial was a randomized controlled trial to test whether a hospital staff member’s thromboprophylaxis alert to an Attending Physician prior to discharge would increase the rate of extended out-of-hospital prophylaxis and, in turn, reduce the incidence of symptomatic VTE at 90 days [37]. Physician alerts did not significantly decrease symptomatic VTE rates at 90 days. In aggregate, these five trials demonstrated no net clinical benefit with extended duration thromboprophylaxis in discharged medical patients. A currently-enrolling trial will evaluate the superiority of extended-duration anticoagulation with a factor Xa inhibitor betrixaban (for up to 35 days in hospital and post-discharge) compared with injectable enoxaparin (for 10 days) for VTE prevention in acute medically ill patients (ClinicalTrials.gov Identifier: NCT01583218). Another currently-enrolling trial will assess the efficacy and safety of a 45-day course of rivaroxaban 10 or 7.5 mg orally once daily versus placebo for prevention of symptomatic VTE and VTE-related death in high-risk medically ill patients after hospital discharge (ClinicalTrials.gov Identifier: NCT02111564).

VTE risk among orthopedic surgery patients remains significantly elevated even after discharge from the hospital. Extended out-of-hospital prophylaxis with warfarin or LMWH has been established as safe and effective in the prevention of VTE among orthopedic surgery patients [31, 32, 38]. Fondaparinux (2.5 mg subcutaneously once daily) has been shown to safely reduce the risk of VTE in patients undergoing hip replacement, major knee surgery, and hip fracture repair [39–42]. The American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines for Prevention of VTE in Orthopedic Surgery Patients also condones the use of aspirin for VTE prophylaxis in patients undergoing major orthopedic surgery [2].

Novel oral anticoagulants, including dabigatran [21], rivaroxaban [23, 24], apixiban [26, 27], and edoxaban [28] have been shown to be safe and effective for VTE prevention after orthopedic surgery. However, only rivaroxaban (10 mg orally daily) is currently approved by the U.S. Food and Drug Administration (FDA) for VTE prevention following knee or hip arthroplasty.

In an open-label, parallel-group study, investigators randomly assigned 300 patients undergoing elective unilateral total knee arthroplasty to receive either 200 or 300 mg daily of an antisense oligonucleotide that specifically reduces factor XI levels (FXI-ASO) or enoxaparin 40 mg daily [29]. The primary efficacy outcome of symptomatic VTE or DVT assessed by mandatory bilateral venography occurred in 27 % of patients who received the 200 mg dose of FXI-ASO and in 4 % of those who received the 300 mg dose, compared with 30 % of those who received enoxaparin. The 200 mg regimen was non-inferior, while the 300 mg regimen was superior compared with enoxaparin (p < 0.001). The frequency of bleeding was similar in both the FXI-ASO groups (3 and 3 %) but lower than that of the enoxaparin group (8 %).