Venous Thromboembolism in Cancer Patients: CATCH Results

Roxanne Nelson

August 18, 2015

Treatment with low-molecular-weight heparin (LMWH) is as safe and effective as warfarin in cancer patients with acute symptomatic venous thromboembolism (VTE), according to new findings.

Compared with warfarin, the LMWH tinzaparin (Innohep, LEO Pharma) did not significantly reduce the composite primary outcome of recurrent VTE, and it was not associated with reductions in overall mortality or major bleeding.

However, the risk for clinically relevant nonmajor bleeding events was significantly lower with tinzaparin (49 of 449 patients) than with warfarin (69 of 451 patients); the hazard ratio (HR) was 0.58 (P = .004).

Findings from the CATCH study, initially presented last year at the annual meeting of the American Society of Hematology, as reported by Medscape Medical News, were published in the August 18 issue of JAMA.

"We haven't had a larger confirmation until now," explained senior author Alok Khorana, MD, a medical oncologist at the Cleveland Clinic.

Clinical guidelines recommend treatment with LMWH agents over vitamin K antagonists such as warfarin, but these recommendations are largely based on results from one large randomized trial, he explained. That trial was the CLOT study, which established that dalteparin (Fragmin, Pfizer) is more effective than vitamin K antagonist therapy (N Engl J Med. 2003;349:146-115).

The fact that the recommendation is based on a single trial has been an issue, he said.

In addition, patients in the CLOT study were primarily from North America. "We wanted to conduct a study that was more representative of the global population," Dr Khorana said. The lack of diversity in the CLOT study could partly explain why vitamin K antagonists are still used widely in many countries for patients with cancer-associated thrombosis, he noted.

The CATCH trial involved patients from Africa, Asia, Central America, North America, South America, Eastern Europe, Western Europe, and the Middle East. "These results are more valid for cancer patients," Dr Khorana told Medscape Medical News.

"We found that heparin was more effective for treating symptomatic VTE, which is a major clinical end point for patients," he reported. "Outcomes were improved, and this supports the use of heparin as a first-line therapy."

CLOT vs CATCH

The CLOT study established that dalteparin is a better anticoagulant than vitamin K antagonist therapy for cancer patients, and demonstrated that there was no significant difference in the risk for bleeding between the two therapies. But there were differences in the effectiveness of LMWH between the CATCH and CLOT studies.

Dr Khorana and his colleagues note that the CATCH population had fewer risk factors for thrombosis and recurrent thrombosis than the CLOT population, and there were differences in the patient populations (CLOT had a higher rate of metastasis and higher ECOG scores). Importantly, differences between the outcomes in the two studies could be explained by the "lower than anticipated thrombotic event rates in the warfarin group."

"Although we had expected a recurrence rate of 12.6% with warfarin, the observed rate was only 10.5%," the researchers note. "This potentially affected the power of the trial to detect a benefit associated with tinzaparin."

"Unfortunately, because of the relatively low incidence of recurrence in the vitamin K antagonist arm, this trial does not demonstrate the superiority of tinzaparin over warfarin," said Mario Mandalà, MD, from the Department of Oncology and Haematology at Papa Giovanni XXIII Hospital in Bergamo, Italy.

"If we compare the results of this study and those reported in the CLOT trial, which showed the superiority of dalteparin over oral anticoagulation, a potential explanation of the apparently different results may be identified by the cancer population included in these two studies," he told Medscape Medical News.

Overall, it seems that the effect of LMWH is clear in very-high-risk patients, he pointed out, whereas in lower-risk patients, the clinical benefit of LMWH over vitamin K antagonists is more diluted.

Tailoring therapy could be the key, Dr Mandalà emphasized. "This means that if we consider patients receiving chemotherapy, as clinicians we should also consider the primary site of the tumor, the extent of the disease, the performance status, as well as the type of chemotherapy."

"Tailoring treatment according to the thrombophilic status may help to personalize the strategy, and the next challenge is how to define the thrombophilic status in order to offer the best treatment to the right patient," he added.

Lower Risk for Nonmajor Bleeding Events

The CATCH study involved 900 patients from 164 centers in 32 countries.

The 449 patients in the tinzaparin group received 175 IU/kg once daily for a median of median 168 days. The 451 patients in the warfarin group received initial tinzaparin 175 IU/kg once daily for 5 to 10 days that overlapped with and was followed by dose-adjusted warfarin for a median of 127 days.

The majority of patients (89.6%) had solid tumors (54.7% had metastatic disease) and 10.4% had a hematologic malignancy. The most common primary tumor sites were gynecologic, colorectal, upper gastrointestinal, and lung.

The qualifying symptomatic thrombotic event was deep vein thrombosis (DVT) in 75.9% of patients and pulmonary embolism with or without DVT in 21.6%. Additional thrombosis was found during baseline testing in 21.6% of patients.

Recurrent VTE occurred in 31 patients in the tinzaparin group and in 45 in the warfarin group (6-month cumulative incidence, 7.2% vs 10.5%; HR, 0.65; P = .07).

Symptomatic DVT occurred in 12 patients in the tinzaparin group and in 24 in the warfarin group, whereas symptomatic nonfatal pulmonary embolism occurred in three patients in the tinzaparin group and in two patients in the warfarin group. Seventeen patients in each group experienced a fatal pulmonary embolism, and incidental VTE occurred in two patients in the warfarin group.

There were no significant differences between the tinzaparin and warfarin groups in major bleeding (12 vs 11 patients) or in overall mortality (150 vs 138 patients).

However, treatment with tinzaparin, compared with warfarin, significantly reduced the risk for clinically relevant nonmajor bleeding (49 vs 69 patients), which included bleeding that required any medical or surgical intervention but was not fatal, did not occur in a critical area or organ, or did not cause a fall in hemoglobin of greater than 2 g/dL or lead to a transfusion of two or more units of whole blood or red cells.

Serious adverse events were similar in the tinzaparin and warfarin groups (49.2% vs 43.2%), and progression of disease was the most common reason.

This study was sponsored and funded by LEO Pharma, and received research support from the Sondra and Stephen Hardis Endowed Chair in Oncology Research and the Scott Hamilton CARES Initiative. Dr Khorana reports receiving research funding and payment for consultancy from LEO Pharma, and personal fees from LEO Pharma, sanofi-aventis, Janssen, Boehringer-Ingelheim, Genentech, Daichii Sankyo, Angiodynamics, Halozyme, and Pfizer. Several of his coauthors report relationships with industry, including LEO, manufacturer of tinzaparin.

JAMA. 2015;314:677-686. Abstract

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