Clinical Review

Decision Making in Venous Thromboembolism

Journal of Clinical Outcomes Management. 2015 May;22(5)

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There are solid data for the use of anticoagulation in SVT. In the STEFLUX (Superficial ThromboEmbolism and Fluxum) study, participants received the LMWH parnaparin at one of 3 doses: 8500 IU once daily for 10 days followed by placebo for 20 days, 8500 IU once daily for 10 days and then 6400 IU once daily for 20 days, or 4250 IU once daily for 30 days. Those who received the intermediate dosing had lower rates of DVT, PE, and relapse/SVT recurrence in the first 33 days [124].In the CALISTO trial, fondaparinux 2.5mg per day for 45 days effectively reduced the risk of symptomatic DVT, PE, or SVT recurrence or extension and was not associated with any increased major bleeding compared to placebo [125].A Cochrane review included 30 studies involving over 6500 participants with SVT of the lower extremities. The treatments used in these studies included fondaparinux, LMWH, UFH, non-steriodal anti-inflammatory agents, topical treatment, and surgery. According to the findings, use of fondaparinux at prophylactic dosing for 6 weeks is considered a valid therapeutic option for SVT [126].It is our practice to consider the use of anticoagulants (generally LMWH or fondaparinux) as part of the treatment regimen for SVT.

Target-Specific Oral Anticoagulants And Treatment of VTE

Because of warfarin’s narrow therapeutic window, need for frequent monitoring, significant drug and food interactions, and unfavorable kinetics, the target-specific oral anticoagulants (TSOACs) have been developed with the aim of offering alternatives to warfarin therapy ( Figure 3 ). These drugs have been developed to inhibit either thrombin or factor Xa to disrupt the coagulation cascade. Since these drugs bind directly to coagulation factor, they are associated with rapid onset of action, a wide therapeutic window, fewer drug interactions than warfarin, and predictable dose-response allowing for fixed dosing without lab monitoring.

The direct thrombin inhibitor dabigatran directly binds to thrombin in a concentration-dependent manner [127].Peak plasma concentration is achieved within 0.5 to 2.0 hours after ingestion, and its half-life is 12 to 17 hours. Use of dabigatran in both primary and secondary prevention of VTE has been extensively studied, especially in orthopedic surgery where there have been 4 main trials (RE-MOBILIZE, RE-MODEL, RE-NOVATE, and RE-NOVATE I and II). While RE-MOBILIZE showed that dabigatran 220 mg or 150 mg once daily was inferior to enoxaparin 30 mg twice daily in preventing VTE after total knee arthroplasty, RE-MODEL and RE-NOVATE I and II demonstrated that dabigatran 150 mg or 220 mg once daily was noninferior to enoxaparin 40 mg once daily for prevention of VTE in patients undergoing total knee replacement and hip replacement [128–131].The side effect profile was also promising, with no significant differences in the frequency of major bleeding between dabigatran and enoxaparin. Pooled data and meta-analyses from these trials have demonstrated that for prevention of VTE associated with hip or knee surgery, dabigatran 220 mg or 150 mg once daily is as effective as 40 mg of enoxaparin given daily or 30 mg given twice a day, with a similar bleeding profile [132,133].

More recently, dabigatran been used in the acute treatment and secondary prevention of VTE. In the RE-COVER trial, dabigatran 150 mg twice daily was compared to warfarin (INR 2–3) in the treatment of acute VTE for 6 months, after an initial treatment period of up to 9 days with LMWH or UFH. Dabigatran was noninferior to warfarin with respect to 6-month incidence of recurrent symptomatic objectively confirmed VTE and related deaths, and was not associated with increased bleeding [134].In the RE-MEDY and RE-SONATE trials of extended anticoagulation, dabigatran was as effective as warfarin for prevention of recurrent VTE when continued after 3 months of initial anticoagulation and associated with less bleeding, and was more effective than placebo in preventing recurrent VTE but associated with a higher risk of bleeding [135].Unexpectedly, the risk of acute coronary syndrome was slightly higher in the dabigatran group than the warfarin group, as seen in other studies.