Department of Pharmaceutical Care (Dr. Schleich) and Department of Family Medicine, Carver College of Medicine (Drs. Schleich and Ray), University of Iowa, Iowa City kevin-schleich@uiowa.edu
The authors reported no potential conflict of interest relevant to this article.
Superficial thrombophlebitis or superficial vein thrombosis (SVT) is estimated to occur 6 times more frequently than VTE.50 Management of patients with isolated, uncomplicated thrombophlebitis who are at low risk for extension of the SVT involves symptomatic treatment with nonsteroidal anti-inflammatory drugs, topical agents, or compression therapy. However, depending on risk for progression, anticoagulation may be recommended.51
Patients at intermediate risk for extension or propagation of SVT are candidates for anticoagulation. The CHEST guidelines recommend fondaparinux 2.5 mg subcutaneous injections daily for 45 days instead of LMWH or warfarin.13 However, if patients decline 6 weeks of daily injections, the guidelines acknowledge that rivaroxaban 10 mg daily may be an alternative.13
Certain situations should prompt one to consider using a treatment dose of a DOAC for 3 months. These include cases in which the SVT is located within 3 cm of the deep venous system,expands despite an appropriate prophylactic regimen, or recurs after discontinuation of prophylactic anticoagulation.13,50
Acute coronary syndrome
The American College of Cardiology/American Heart Association (ACC/AHA) recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.52 Data are mixed regarding longer-term anticoagulation in addition to dual antiplatelet therapy in outpatient settings to prevent thrombosis recurrence in the absence of AF.
For patients at intermediate risk for extension of superficial vein thrombosis who decline daily subcutaneous injections of fondaparinux, rivaroxaban 10 mg/d may be an alternative.
The APPRAISE-2 trial enrolled high-risk patients with ACS within 7 days of the event.53 Apixaban 5 mg twice daily was compared with placebo in patients taking aspirin or aspirin plus clopidogrel. The trial was terminated early because major bleeding events increased with apixaban without reduction in recurrent ischemic events. The ATLAS ACS-TIMI 46 trial evaluated different rivaroxaban doses (5-20 mg daily) in ACS patients.54 The study revealed possible thrombosis benefit but also increased risk for bleeding, particularly at higher doses. As a result, another study—ATLAS ACS 2-TIMI 51—was conducted and compared the use of low-dose rivaroxaban (2.5 mg twice daily or 5 mg twice daily) vs placebo for patients with recent ACS.55 All patients were receiving low-dose aspirin, and approximately 93% of patients in each group also were receiving clopidogrel or ticlopidine. As in the APPRAISE-2 trial, rivaroxaban increased the rate of major bleeding and intracranial hemorrhage; however, it did not increase the incidence of fatal bleeding. Unlike APPRAISE-2, rivaroxaban significantly reduced the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, or stroke (absolute risk reduction = 1.8%; number needed to treat = 56 for combined rivaroxaban doses).55
A secondary subgroup analysis combined data from the ATLAS ACMS-TIMI 46 and ATLAS ACS 2-TIMI 51 trials to evaluate outcomes in patients receiving aspirin monotherapy when combined with rivaroxaban 2.5 mg twice daily or 5 mg twice daily or with placebo.56The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. When the 2 trials were evaluated separately, neither rivaroxaban dose was associated with reduction of the primary efficacy outcomes compared with aspirin alone. However, when the data were pooled, both the combined rivaroxaban doses (particularly the 5-mg dose) were associated with reduced cardiovascular outcomes. From a safety perspective, the 2.5-mg twice-daily dose of rivaroxaban was the only dose not associated with increased major bleeding risk. Thus, the 2.5-mg twice-daily dose of rivaroxaban may not provide sufficient cardiovascular benefit in patients with ACS, while the larger dose may increase the risk for nonfatal major bleeding events.56
The European Medicines Agency57 approved rivaroxaban 2.5 mg twice daily for ACS, and the 2020 ESC guidelines58 consider it an appropriate therapeutic option in addition to aspirin for patients at high ischemic risk and low bleeding risk. ACS is not an FDA-approved indication for DOACs, and the ACC/AHA Guideline for the Management of ACS, last updated in 2014, does not include DOACs for ACS unless patients have AF.52 Ongoing trials are further investigating rivaroxaban for ACS, so the use of DOACs in the post-acute phase of ACS may become clearer in the future.59
