VTE Treatments Similarly Safe, Effective, but Not Identical

Pam Harrison

September 24, 2014

Most treatment strategies used to treat acute venous thromboembolism (VTE) are as safe and effective as the currently recommended combination of low-molecular-weight heparin (LMWH) plus a vitamin K antagonist, but they are not interchangeable, a large network analysis shows. The analysis confirms that there can be a "wrong choice" for some patients, according to an expert not involved in the study.

For example, the combination of unfractionated heparin (UFH) plus a vitamin K antagonist is associated with a higher risk for recurrent VTE compared with the LMWH–vitamin K combination.

In addition, the risk for major bleeding is also significantly lower with rivaroxaban and apixaban, which are both novel oral anticoagulants, relative to the same comparator strategy.

"To our knowledge, this network meta-analysis is the largest review, including nearly 45,000 patients, assessing the clinical outcomes and safety associated with different anticoagulation strategies for the treatment of acute [VTE]," lead author Lana Castellucci, MD, stated in a university news release. Dr. Castellucci is from the Ottawa Hospital Research Institute, University of Ottawa, Ontario, Canada.

"All management options, with the exception of the UFH-vitamin K antagonist combination, were associated with similar clinical outcomes compared with a management strategy using the LMWH vitamin K antagonist combination," she added.

The study was published in the September 16 issue of JAMA.

The investigators analyzed 45 trials with 44,989 patients. The primary clinical outcome was recurrent VTE; the primary safety outcome was major bleeding.

Compared with the LMWH–vitamin K antagonist combination, a treatment strategy using the UFH–vitamin K antagonist combination was associated with a 42% increased risk for recurrent VTE (hazard ratio [HR], 1.42; 95% credible interval [CrI], 1.15 - 1.79), the authors report.

Some 84% of patients taking the UFH–vitamin K antagonist combination experienced recurrent VTE during 3 months of treatment compared with 30% of patients taking LMWH-vitamin K antagonist combination.

Rivaroxaban and apixaban were both associated with a lower risk for major bleeding compared with a LMWH–vitamin K antagonist combination. Specifically, rivaroxaban was associated with a 45% lower risk for major bleeding (HR, 0.55; 95% CrI, 0.35 - 0.89) and apixaban was associated with a 69% lower risk for bleeding (HR, 0.31; 95% CrI, 0.15 - 0.62) compared with standard-of-care management for acute thromboembolism.

All other treatment regimens were associated with bleeding risks that did not differ from the LMWH–vitamin K antagonist combination.

As the authors point out, despite the analysis identifying a higher risk for recurrent VTE with the UFH–vitamin K antagonist combination, "there are clinical circumstances that necessitate the use of UFH."

These include its use in patients with severe renal insufficiency as well as in those with massive or submassive pulmonary embolism who are potential candidates for thrombolysis or thrombectomy.

"We provide estimates on symptomatic recurrent VTE and major bleeding outcomes (both patient-important outcomes), which are clinically relevant and are what clinical practice guideline recommendations are based on," the authors write.

They add, "[T]hese risks...are important to help clinicians assess the benefit-harm balance of the various treatment options and tailor their therapeutic approaches accordingly."

"Wrong Choice"

Asked to comment on the study, Deepak Bhatt, MD, MPH, executive director of interventional cardiovascular programs, Brigham and Women's Hospital Heart and Vascular Center, and professor of medicine, Harvard Medical School, Boston, Massachusetts, told Medscape Medical News that the results of the meta-analysis are not news to physicians who are familiar with the new strategies for the prevention and treatment of VTE, but the broader medical community may not appreciate the shift in thinking that has occurred during the last few years concerning the appropriate management of these patients.

"For many years, unfractionated heparin plus a vitamin K antagonist, essentially warfarin, was considered the standard of care, and everyone used it," Dr. Bhatt said.

However, he added, a number of trials now support the concept that a combination of LMWH plus warfarin or a vitamin K antagonist is better than unfractionated heparin plus a vitamin K antagonist.

Indeed, Dr. Bhatt pointed out that the data on which investigators based this particular conclusion are robust, in that they are based on 22 randomized clinical trials in which the combination of unfractionated heparin plus a vitamin K antagonist and LMWH plus a vitamin K antagonist were directly compared.

"It's pretty clear form this meta-analysis that there is a wrong choice (ie, the unfractionated heparin plus warfarin choice), inasmuch [as] current data no longer support this combination as being the best," Dr. Bhatt observed.

Dr. Bhatt also felt that the analysis supports the possibility that some of the novel oral anticoagulants, mainly apixaban and rivaroxaban, appear to be associated with less major forms of bleeding.

"This might offer some additional advantages, realizing that these agents would end up being more expensive than the combination of LMWH plus warfarin, though likely more convenient as well," he suggested.

At the same time, Dr. Bhatt reiterated that dosing with LMWH and some of the novel oral anticoagulants can be tricky in patients with marked renal insufficiency, and they may be contraindicated in patients with very low glomerular filtration rates as well, "so there is still a role for unfractionated heparin plus warfarin in these patients. It's not dead yet."

Several coauthors report receiving speaker fees or grants from one or more of the following companies: Biomerieux, Bayer, Pfizer, Sanofi, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer and Leo Pharma. Several authors report support or awards from the Heart and Stroke Foundation of Ontario the Canadian Institutes of Health Research, Canadian Network and Centre for Trials Internationally and the Canadian Institutes of Health Research Drug Safety and Effectiveness Network. The other authors and Dr. Bhatt have disclosed no relevant financial relationships.

JAMA. 2014;312:1122-1135. Abstract

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