Largest Trial of VTE Prophylaxis in Cancer Patients on Chemo

Zosia Chustecka

February 15, 2012

February 15, 2012 — The largest study to date of thromboprophylaxis in cancer patients on chemotherapy shows that the use of a heparin product significantly reduces the risk for thromboembolic events with no apparent increase in bleeding.

The positive results add to several previous studies showing a benefit from thromboprophylaxis in cancer patients, and reopen an ongoing debate about whether such use should be routine.

The latest study, known as SAVE-ONCO, was conducted in 3212 cancer patients who were beginning chemotherapy and used the hemisynthetic ultra-low-molecular-weight heparin (LMWH) semuloparin (Visamerin, Sanofi; marketed in Europe, but not available in the United States). The study, by Giancarlo Agnelli, MD, from the University of Perugia, Italy, and colleagues, is published in the February 16 issue of the New England Journal of Medicine.

Semuloparin significantly reduced the incidence of venous thromboembolism (VTE), compared with placebo (1.2% vs 3.4%; hazard ratio [HR], 0.36; P < .001), without significantly increasing the risk for clinically relevant bleeding (2.8% vs 2.0%; HR, 1.4) or major bleeding (1.2% vs 1.1%; HR, 1.05).

"This study showed the benefit of thromboprophylaxis with semuloparin in a large group of patients, across a broad representation of cancers, both locally advanced and metastatic disease, and a wide range of chemotherapy regimens," the authors report. "However, stratification for the risk of venous thromboembolism among patients with cancer may be clinically useful," they add.

This is an important point, said Alok Khorana, MD, associate professor and vice chief of hematology/oncology, University of Rochester, New York. Even though SAVE-ONCO was the largest and most ambitious study of this issue to date, "I do not believe that the results of this study, even in combination with other studies, can lead to broad recommendations for prophylaxis," he told Medscape Medical News.

Although the relative risk reduction was quite significant and there were no concerns about bleeding — so clinicians can be assured of safety — the absolute risk for VTE was low, and therefore the absolute risk reduction was not as impressive as the relative risk reduction, Dr. Khorana explained. In addition, certain subgroups of patients (e.g., those with ovarian cancer) had almost no events, he noted.

Although not listed as an author, Dr. Khorana was the national coordinating physician for SAVE-ONCO. He noted that the rate of VTE seen in North America is higher than that seen elsewhere, "reinforcing the widely held consensus that American clinicians see a lot of VTE."

He also noted that the SAVE-ONCO group has previously reported a subgroup analysis, which showed that patients at high risk derive greater benefit than those at low risk.

"I certainly don't think that prophylaxis should be recommended for all cancer patients," he said. It is likely to be useful in patients who are at high risk, such as myeloma patients on thalidomide- or lenalidomide-based regimens, and perhaps those with pancreatic cancer.

Guidelines on thromboprophylaxis in cancer patients from the American Society of Clinical Oncology are currently being updated, and should be out later this year, he said.

One issue for clinicians in the United States is that the 2 largest studies to date — this SAVE-ONCO study using semuloparin and the PROTECHT study using nadroparin, reported in 2008 — were conducted with drugs that are not available in the United States.

For American clinicians, the available options are the LMWH products enoxaparin (Lovenox) and dalteparin (Fragmin), he said. There are data supporting their use for prophylaxis in pancreatic cancer (from the CONKO and FRAGEM studies) and data supporting the use of aspirin instead of enoxaparin for prophylaxis in myeloma patients (Blood. 2012;119;933-939).

Could semuloparin, which is awaiting approval in the United States, offer a better option? It is an ultra-LMWH product that is potentially more effective with less bleeding than the LMWH products, Dr. Khorana said, but there are no head-to-head studies in the cancer setting.

One Answer, More Questions

The SAVE-ONCO study had more patients than the previous 9 thromboprophylaxis in cancer trials combined, which were included in a recent Cochrane review (Cochrane Database Syst Rev. 2011; 4:CD006652), according to an accompanying editorial by Elie Akl, MD, MPH, PhD, from the State University of New York at Buffalo, and Holger Schünemann, MD, PhD, from McMaster University in Hamilton, Ontario, Canada.

The editorialists note that the findings from SAVE-ONCO largely confirm the results of that review.

They pooled data from SAVE-ONCO, the Cochrane review, and another recent clinical trial of 503 patients (J Clin Oncol. 2011;29:2071-2076).

According to Drs. Akl and Schünemann, these pooled data strengthen confidence in the estimated risk reduction for VTE and the nonsignificant risk for major bleeding, and "firm up a survival benefit that is probably small."

From the pooled data, they calculated some numbers-needed-to-treat for benefit and for harm.

If 1000 patients with cancer treated with chemotherapy were to use a prophylactic dose of LMWH, over a period of 12 months, death would be averted in approximately 30 patients, VTE would be averted in approximately 20 patients, and 1 patient would have a major bleeding episode, they note.

In an interview with Medscape Medical News, Dr. Akl suggested that physicians use these estimates when discussing the option of thromboprophylaxis with cancer patients who are on chemotherapy.

"Clinicians need to engage the patient in the decision-making process," he said. "This is a great example of shared decision making," he continued; the clinician's role is to present the option of thromboprophylaxis and to explain the benefits and drawbacks of the intervention.

Cancer increases the risk for VTE, and chemotherapy increases it further. Developing a VTE will involve hospital admission, which some patients are anxious to avoid at all costs, Dr. Akl said. Also, once a VTE develops in a cancer patient, treatment with therapeutic doses of LMWH will probably be necessary for the remainder of the patient's life, he explained. In addition, complications, such as a pulmonary embolism, can be fatal.

Thromboprophylaxis reduces the risk for these complications. Plus, the pooled data suggest that there is a small overall survival benefit, which was not seen in any of the individual studies, he explained.

The pooled data show that the absolute risk reduction of VTE is around 2%, which is a reasonable benefit, but it needs to be weighed against the burden of injecting LMWH every day.

There is also uncertainty over some of the data, he explained. In addition, there is a small risk of bleeding, and there might be cost implications, because some medical insurance companies might not cover the cost of prophylactic LMWH in this setting.

In his clinical experience, some cancer patients already feel overwhelmed with chemotherapy and decide not to take on this extra burden of daily subcutaneous injections. "It's really up to each individual patient to look at these numbers and decide whether or not to take up this option," Dr. Akl said.

The SAVE-ONCO study was funded by Sanofi. Dr. Agnelli reports serving as a consultant for sanofi-aventis; and receiving honoraria from sanofi-aventis, Bayer, and Bristol-Myers Squibb. Several coauthors are employees of Sanofi. Dr. Khorana reports serving as a consultant for sanofi-aventis, Leo Pharma, Eisai, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, and Roche/Genentech. Dr. Akl and Dr. Schünemann have disclosed no relevant financial relationships.

N Engl J Med. 2012;366: 601-609, 661-662. Abstract, Editorial

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