Apixaban Significantly Reduces VTE in Cancer Patients

Alexander M. Castellino, PhD 

December 11, 2018

Patients with cancer are at an increased risk for venous thromboembolism (VTE),  and there is an ongoing debate about the use of primary thromboprophylaxis to avert potential thrombotic events. Until recently, this would be achieved with low-molecular weight heparin (LMWH) given subcutaneously, but new oral agents are now being explored in this setting.

Recently, data from the CASSINI study with the use of rivaroxaban (Xarelto, Janssen). were presented at the American Society of Hematology (ASH) 2018 annual meeting and reported by Medscape Medical News. This trial failed to meet its primary endpoint but showed a significant benefit in a subgroup of patients who adhered to therapy; an expert not involved in the study said it showed a "marginal benefit."

On the heels of that report comes another study — the AVERT with apixaban (Eliquis, Bristol-Myers Squibb) — which published on December 4 in the New England Journal of Medicine. This study found that apixaban reduced the risk of VTE by close to 60% — a significant finding. However, major bleeding was approximately twice as high in patients on apixaban compared with placebo.

"These data are practice changing," commented Alok Khorana, MD, Sondra and Stephen Hardis Chair in Oncology, director of the GI Malignancies Program, Cleveland Clinic. He was not involved in the AVERT trial and was lead investigator of the CASSINI trial.

AVERT and CASSINI Were Not Dissimilar Studies

Khorana told Medscape Medical News that both AVERT and CASSINI are similar studies in patients with solid tumors with an aim to reduce the number of VTE events. Both studies have concordant and consistent results, he said.

"The similar study design focusing on the same patient population [high risk for VTE] provides external validity," Khorana said, implying that clinical practice will likely yield similar results.

When asked why CASSINI did not meet its primary endpoint, Khorana said that the primary endpoint in AVERT (reduction in VTE) was in modified intent-to-treat (ITT) patients while CASSINI was in the pure ITT population.

CASSINI's endpoint was based on all randomized patients while AVERT's endpoint was undertaken in patients who had received at least one dose of apixaban or placebo on or before day 180, Khorana explained.

"It's not an apples-to-apples comparison," Khorana said.

Medscape Medical News approached Robert D. McBane II, MD, a cardiologist at the Gonda Vascular Center, Mayo Clinic, Rochester, Minnesota, for comments. McBane treats secondary thromboprophylaxis in cancer patients. He was not associated with the AVERT trial and was on the steering committee for the CASSINI trial.

While the two trials were similar in patient population, McBane noted that there were differences. In order to enroll in CASSINI, patients were required to have a normal ultrasound to be considered eligible. "It is likely that some patients enrolled in the AVERT study may have already experienced asymptomatic thrombotic events," he said. "It may explain why VTE events in CASSINI may have occurred at a lower rate [6% with rivaroxaban vs 8.8% with placebo] due to the exclusion of patients with asymptomatic clots," McBane said.

Why Comparison With LMWH May Not Be Appropriate

When asked to comment on why AVERT and CASSINI did not have an active comparator group such as LMWH instead of placebo, Khorana explained that currently there is no recommendation for daily LMWH use. "The ASCO [American Society for Clinical Oncology] guidelines indicate that thromboprophylaxis should be considered on a case-by-case basis and recommends against routine thromboprophylaxis," Khorana said.

"Why subject cancer patients to daily subcutaneous injections when ASCO recommends against the practice?" Khorana asked. "Moreover, both study protocols were approved by data monitoring committees across multiple centers," he said.

McBane agreed. He explained that before the oral agents were available, there were two large trials — the SAVE-ONCO and PROTECHT studies — that had both shown the utility of preventing VTE events with LMWHs.

"But the absolute reduction with these agents is modest and current guidelines such as ASCO, ESMO [European Society for Medical Oncology], and NCCN [National Comprehensive Cancer Network], do not support the use of LMWH for preventing VTE in unspecified cancer patients," he said.

McBane pointed out that the Khorana score identifies patients at risk for VTE events in the ambulatory setting only. "The use of LMWH for primary prophylaxis in an ambulatory cancer setting is very low," McBane said, indicating that the comparison with placebo was appropriate in both of the new trials of the oral agents.

Use of LMWH has several pitfalls, McBane further explained. It is painful, expensive, has no antidote, and patients with cancer may experience acquired kidney disease. He also noted that in patients who develop thrombocytopenia, it would be difficult to tease out if this was related to the cancer therapy or if it had been induced by the LWMH.

"The numbers [reduction in VTE vs major bleeding] are attractive enough to warrant an in-depth discussion about factor Xa inhibitors being used as standard treatment for primary thromboprophylaxis in cancer patients," McBane said.

"It is a balancing act: in the AVERT study, a 6% absolute reduction in a thrombotic event against a 1.7% increase in major bleeding risk," he added. 

Details of the AVERT Study

AVERT was a double-blind phase 3 study conducted in 13 Canadian centers. The senior author is Philip S. Wells, MD, of the Ottawa Hospital Research Institute in Ontario, Canada.

Participants were cancer patients with an increased risk for VTE, randomly assigned to receive apixaban 2.5 mg twice (n = 288) daily or placebo (n = 275) for a treatment period of 180 days.

Increased risk for VTE was based on a Khorana score of 2 or above, which is associated with an increased risk for VTE and mortality. The Khorana score is the total of the value assigned to each of five variables — type of cancer; prechemotherapy leukocyte count >11,000/mm3; hemoglobin <10 g/dL or the use of hematopoietic growth factors; prechemotherapy platelet count ≥350,000/mm3; and body-mass index ≥35.

For physicians who want to be in the know, McBane pointed out that it is easy to risk stratify patients for VTE on www.MDCalc.com and typing Khorana in its search field.

Reduction in VTE, Increase in Bleeding 

Participants in this trial had a mean age of 61 years. The common primary malignancies were gynecologic cancer (25.8%), lymphoma (25.3%), and pancreatic cancer (13.6%). Approximately two thirds of patients (65.4%) had a Khorana score of 2 and one quarter (25.4%) had a Khorana score of 3. Antiplatelet or nonsteroidal anti-inflammatory therapy was used by 22.8% of patients. Approximately 3% of patients had received previous VTE therapy.    

Median time on treatment was 157 days for apixaban and 155 days for placebo. The median duration of follow-up was 183 days. Adherence to therapy was high across the two groups: 83.6% for apixaban vs 84.1% for placebo.

The primary endpoint for the first episode of VTE was reported in 4.2% patients in the apixaban group and 10.2% of patients in the placebo group (absolute difference: 6%). With a hazard ratio (HR) of 0.41 (P < .001), patients receiving apixaban were at a 59% reduced risk of VTE.  During the treatment period, the absolute difference in event rate was over 6% (1% with apixaban and 7.3% with placebo; HR, 0.14). In a competing-risk analysis, which took into account deaths from causes other than VTE or bleeding, the benefits of apixaban were maintained (HR, 0.42).

VTE events were mainly driven by pulmonary embolism, which occurred at a rate three times higher in the placebo group (5.8% vs 1.7% for apixaban).

Deep vein thrombosis (DVT) occurred at an approximately two times higher frequency compared with the placebo group (4.4% vs 2.4% for apixaban).

Major bleeding — the main safety outcome — was reported in 15 patients, 3.5% and 1.8% of patients in the apixaban and placebo groups, respectively (HR, 2.00; P = .046). Three of the 15 events were a clinical emergency, but bleeding into critical organs was not noted. During the treatment period, major bleeding occurred in 2.1% and 1.1% of patients in the apixaban and placebo groups, respectively (HR, 1.89).

Severe major bleeding episodes (category 3 or 4) accounted for 20% of all major bleeding episodes, and were similar between the apixaban and placebo groups.

The between-group difference in the rate of major bleeding complications was mainly due to higher rates of gastrointestinal bleeding, hematuria, and gynecologic bleeding with apixaban compared with placebo, Wells and colleagues note. These events occurred mainly in patients who had entered the trial with gastrointestinal or gynecologic cancer. "This finding is consistent with the results of previous studies of direct oral anticoagulants involving patients with active cancer," they write.

Death from any cause was higher in patients on apixaban (12.2% vs 9.8% for placebo). However, 87% of the mortality was cancer-related or from cancer progression. 

VTE Issue Important in Clinical Practice

The AVERT investigators note that when a VTE occurring in a cancer patient receiving chemotherapy has an impact on cancer care, it increases healthcare costs and negatively impacts quality of life. The challenge to date with anticoagulation therapy is that it has involved daily injections of LMWH, which are associated with a high risk of thrombosis recurrence and serious bleeding complications. Risk of bleeding in cancer patients is further increased in the context of comorbidities such as thrombocytopenia and renal impairment, Wells and colleagues note.

"Therefore, prevention of venous thromboembolic complications is important and clinically relevant," they write.

McBane agreed. He estimated that about 20% of all VTE events occur in cancer patients.  There are about 2 million new cancer cases each year and 14 million cancer survivors, and VTE events develop in about 1 in 5 patients, he noted.

"After death from cancer and its progression, VTE is the second most common cause of death in cancer patients," he said.

AVERT was supported by the Canadian Institutes of Health Research (CIHR) and Bristol-Myers Squibb–Pfizer Alliance.

Dr Wells reports grants from Pfizer/BMS and CIHR during the conduct of the study; grants and personal fees from Bayer Healthcare; and personal fees from Medscape, Itreas, Pfizer, Janssen, Daiichi Sankyo, and Sanofi outside the submitted work. Coauthors also have disclosures, as listed on the NEJM website. Dr  Khorana has relationships with Parexel, Sanofi, Pfizer, Janssen, TriSalus, Halozyme, Seattle Genetics, AngioDynamics, LEO Pharma, Medscape/WebMD, Pharmacyclics, and Bayer. Dr McBane reports research funding from BMS/Pfizer Alliance.

N Engl J Med. Published December 4, 2018. Full Text

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