Michael B. Streiff, MD
The standard of care for patients with cancer who suffer dangerous blood clots has been painful and expensive daily injections with unfractionated or low-molecular-weight heparin (LMWH). Now clinical trial findings published in the New England Journal of Medicine1
have helped convince a National Comprehensive Cancer Network (NCCN) panel to make a change. The guideline committee has designated a direct oral anticoagulant (DOAC) as a preferred frontline treatment for most patients with cancer-associated venous thromboembolism (VTE).2
“This is the biggest change we’ve made to the [VTE] treatment guidelines in years, and it may well be the most welcome change we’ve ever made,” said guideline committee chair Michael B. Streiff, MD, medical director of the Johns Hopkins Hospital Special Coagulation Laboratory at Johns Hopkins Medicine in Baltimore, Maryland.
“Nearly every patient I have treated over the years asked me about oral alternatives to low-molecular- weight-heparin, and a significant number of them chose to switch from low-molecular- weight-heparin to warfarin—even though they knew it wasn’t as effective—because they simply couldn’t stand the idea of performing 1 more injection into an abdomen that already looked like a very bruised pincushion,” Streiff said in an interview with OncologyLive®
Overall, the new guidelines for the therapeutic management of VTE have been extensively revised. Edoxaban (Savaysa), an oral factor Xa inhibitor that is part of a new class of DOACs, has been added as a category 1 recommendation as part of a combination regimen with LMWH. Two other DOACs, rivaroxaban (Xarelto) and apixaban (Eliquis), may be considered as a monotherapy alternative for acute anticoagulation in patients who have reasons to avoid LMWH (Table
Clinical Trial Findings
The Hokusai VTE Cancer trial, which helped pave the way for the guideline change, was designed as a noninferiority study for patients with cancer who had acute symptomatic or incidental VTE, including deep-vein thrombosis (DVT), acute symptomatic pulmonary embolism (PE), or incidentally detected PE. Patients received a lead-in therapeutic dose of LWMH for at least 5 days and were then randomized to edoxaban or dalteparin (Fragmin), an LMWH. Edoxaban was administered orally at 60 mg daily with or without food, and dalteparin was given subcutaneously at 200 IU/kg daily for 1 month followed by 150 IU/kg daily.1
Table. NCCN Recommendations for Anticoagulant Therapy for VTE2
The primary outcome was a recurrence of VTE or major bleeding. VTE recurrence was defined as symptomatic new DVT or PE, incidental new DVT or PE involving segmental or more proximal pulmonary arteries detected by imaging tests conducted for other reasons, or fatal PE or unexplained death. Major bleeding was associated with a hemoglobin decrease of ≥2 g/dL, a transfusion of ≥2 units of blood, occurrence in a critical site, or contributing to death.
After 12 months of follow-up, 67 of the 522 patients (12.8%) treated with edoxaban had experienced VTE recurrence or major bleeding compared with 71 of the 524 patients (13.5%) who received dalteparin (HR, 0.97; 95% CI, 0.70- 1.36). The findings for edoxaban met the primary endpoint for noninferiority (P
= .006) but were not statistically superior (P
There was a trend toward edoxaban superiority in preventing recurrent VTE, which occurred in 41 patients (7.9%) who received the drug versus 59 patients (11.3%) who had dalteparin, for a difference in risk of −3.4 percentage points (HR, 0.71; 95% CI, 0.48-1.06; P
= .09). Nevertheless, edoxaban was associated with a significantly higher risk of major bleeding, which occurred in 36 patients (6.9%) versus 21 patients (4.0%) with dalteparin, for a difference in risk of 2.9 percentage points (HR, 1.77; 95% CI, 1.03- 3.04; P
The trial results were a major departure from those of earlier studies that pitted oral medications against heparin in clot-prone patients with cancer. Most of these older trials tested warfarin, an oral drug that inhibits the synthesis of vitamin K–dependent clotting factors, against LMWH, and their outcomes were greatly discouraging to patients who wanted a safe way to escape injections. A pooled analysis of such trials found recurrent VTE in 12.4% of patients who used warfarin compared with 7.3% for those who had used LMWH, according to a presentation at the 2018 NCCN Annual Conference.3