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Edoxaban noninferior to standard VTE therapy for patients with cancer
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ATLANTA — The use of edoxaban for up to 12 months appeared noninferior to subcutaneous dalteparin among patients with cancer-related venous thromboembolism, according to results from the Hokusai VTE-Cancer Study presented during the late-breaking abstract session of the ASH Annual Meeting and Exposition.
“Treatment of these cancer-associated venous thromboembolism, or VTE, is challenging because the risk [for] recurrence and the risk [for] bleeding complications with treatment are both higher in cancer patients than noncancer patients. Both complications are important because they contribute to mortality and morbidity,” Gary E. Raskob, PhD, dean and regents professor at University of Oklahoma Health Sciences Center’s College of Public Health, said during a press conference. “Importantly for oncologists, these complications may interfere with what they really want to do, which is give definitive anticancer therapy to the patient. So, avoiding these two problems is very important.”
Evidence-based guidelines recommend the use of low molecular-weight heparin (LMWH) treatment for cancer-associated VTE, but the required daily subcutaneous injections can become burdensome for patients, Raskob said.
Direct oral anticoagulants have shown to be effective and safe compared with other anticoagulation treatments among broader populations of patients with VTE. However, anticoagulants have never been directly compared with standard therapy for patients with cancer-associated VTE.
Raskob and colleagues evaluated whether edoxaban (Savaysa, Daiichi Sankyo) — an oral anticoagulant that acts as a direct factor Xa inhibitor — may better treat cancer-associated VTE than standard therapy.
Researchers randomly assigned patients with acute symptomatic or incidental VTE to receive LMWH for a minimum of 5 days followed by daily edoxaban (n = 525) — 60 mg, or 30 mg in patients with creatine clearance of 30 mL to 50 mL per minute or body weight under 60 kg —
or 200 units/kg subcutaneous dalteparin (Fragmin, Pfizer; n = 525) once daily for 1 month, followed by 150 units/kg thereafter, for 6 months up to 1 year.
A composite of the first recurrent VTE or major bleeding event during follow-up for 1 year served as the primary endpoint. Secondary endpoints included recurrent VTE and major bleeding analyzed separately, and survival free of recurrent VTE or major bleeding.
“A new aspect added into this trial for the first time is it prespecified at the gentrification of severity in bleeding events to provide more information about the nature of these bleeding events to be able to enhance risk-benefit assessments by commissions,” Raskob said.
Ninety-seven percent of patients had active cancer at baseline, and 53% had metastatic disease.
Sixty-three percent of patients (n = 657) had pulmonary embolism with or without deep vein thrombosis; the remainder had isolated DVT. Among all patients, 67% (n = 706) had symptomatic VTE and the rest were incidental.
The modified intention-to-treat analysis included 1,046 patients.
In the primary analysis, recurrent VTE or major bleeding occurred among 12.8% of patients in the edoxaban group (n = 67 of 522) compared with 13.5% in the dalteparin group (n = 71 of 524). These data met the study’s noninferiority threshold of an HR below 1.5 (HR with edoxaban = 0.97; 95% CI, 0.7-1.36). Researchers calculated a risk difference with edoxaban of –0.7% (95% CI, –4.8 to 3.4).
During the first 6 months, recurrent VTE or a major bleeding event occurred among 10.5% of patients in the edoxaban group compared with 10.7% in the dalteparin group, also meeting noninferiority (HR with edoxaban = 1.01; 95% CI, 0.69-1.46).
For the per-protocol analysis, recurrent VTE occurred among 10.4% of patients in the edoxaban group compared with 10.4% in the dalteparin group (HR with edoxaban = 0.99; 95% CI, 0.68-1.46).
In total, 6.5% of patients on the edoxaban arm experienced recurrent VTE compared with 10.3% of the dalteparin arm, for a difference in risk of –3.8% (95% CI, –7.1to –0.4). Major bleeding occurred among 6.3% of the edoxaban arm compared with 3.2% of the dalteparin arm, for a difference in risk of 3.1% (95% CI, 0.5-5.7).
Researchers observed 33 major bleeds in the edoxaban group and 17 in the dalteparin group. The rates of category 3 or category 4 major bleeding events — indicating severe or life-threatening bleeds — appeared similar among the groups (2.3% for both)
“Major bleeding is less severe with edoxaban, but rates of severe bleeding were similar,” Raskob said.
Survival at 1 year without recurrent VTE and major bleeding also appeared similar for patients treated with edoxaban (55%) or dalteparin (56.5%).
“Treatment with oral edoxaban is noninferior to subcutaneous injections with dalteparin for primary outcomes of recurrent VTE or major bleeding,” Raskob said. “The low rate of recurrent VTE with oral drugs was offset by similar increase in risk [for] major bleeding.” – by Melinda Stevens
Reference:
Raskob GE, et al. LBA-6. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Raskob reports consultant roles with Bayer Healthcare, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Janssen, Johnson and Johnson, Pfizer and Portola; and honoraria from Bristol-Myers Squibb, Daiichi Sankyo, Medscape and Pfizer. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Michael M. Millenson, MD, FACP
Treatment with LMWH has been the recommended standard of care for patients with cancer-associated VTE, based primarily on the strength of the CLOT trial. However, this treatment requires daily subcutaneous injections which can be burdensome — and costly — for patients. Indeed, patterns-of-care analyses have suggested that a significant proportion of patients are unable to comply with this recommended therapy.
The recent emergence of the direct oral anticoagulants has naturally led to interest in testing these drugs for patients with acute VTE and active cancer. To date, however, the published experience with use of direct oral anticoagulants among patients with cancer and VTE has been limited to retrospective subset analyses of outcomes of patients with cancer in the pivotal trials comparing direct oral anticoagulants with conventional short-term heparin followed by vitamin K antagonists, with uncertainty regarding just how “active” these patients with cancer really were.
The Hokusai VTE Cancer Study, reported by Raskob and colleagues, is one of the first prospective, randomized trials to directly compare outcomes with a direct oral anticoagulant (specifically edoxaban) vs. standard LMWH (dalteparin) among patients with cancer-associated VTE. The trial clearly demonstrates noninferiority in terms of the composite endpoint of recurrent VTE or major bleeding, with a lower risk for recurrent VTE seen with edoxaban (7.9% vs 11.3%), albeit with a numerically higher risk for bleeding. That said, there was no difference in the frequency of severe major bleeding events between the two arms based on central adjudication.
These results are consistent with those reported in the Select-D pilot trial from the United Kingdom, which compared outcomes with rivaroxaban (Xarelto, Janssen) vs. dalteparin among patients with cancer and VTE. In sum, the VTE recurrence rate at 6 months was lower with rivaroxaban vs. dalteparin (4% vs. 11%), with a similar risk for major bleeding — although there was numerically more total bleeding seen with rivaroxaban.
Taken together, these trials suggest that the use of oral anticoagulants may be a reasonable option for upfront treatment of acute VTE in patients with active cancer. Nonetheless, a number of important questions remain, and the decision of whether to use a direct oral anticoagulant vs. LMWH in patients with cancer-associated VTE will require an individualized and nuanced discussion with each patient. For example, potential use of a direct oral anticoagulant will require a careful assessment for potential drug-drug interactions with the patient’s other oral medications. Those patients at particularly high risk for bleeding (eg, patients with gastric or esophageal cancer) may fare better with a LMWH given the perception of a slightly lower risk for bleeding. Finally, we still await the results of other large, prospective randomized trials of oral anticoagulants vs. LMWHs (eg, ADAM-VTE, CONKO-011, etc) to help inform the optimal management of this challenging clinical problem.
References:
Lee AYY, et al. New Engl J Med. 2003;doi:10.1056/NEJMoa025313.
Young A, et al. Abstract 625. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
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