In patients with active cancer and acute venous thromboembolism (VTE), use of the low-molecular-weight heparin (LMWH) tinzaparin led to a lower rate of clinically relevant, non-major bleeding episodes compared with warfarin, but it did not reduce other efficacy endpoints of recurrent VTE, reductions in overall mortality, or major bleeding, according to a report from the CATCH (Comparison of Acute Treatments in Cancer Hemostasis) trial recently published in JAMA.
Although clinical practice guidelines recommend treatment with a LMWH over the vitamin K antagonist warfarin in patients with cancer-associated VTE, this recommendation is based on a single, large trial more than a decade old, the study authors, led by Agnes Y. Y. Lee, MD, MSc, from the University of British Columbia in Vancouver, Canada, explained.
“These limitations may partly explain why vitamin K antagonists remain frequently used worldwide,” Dr. Lee and co-authors noted. “To provide more contemporary and global evidence for long-term LMWH therapy, we conducted the CATCH trial to compare the efficacy and safety of tinzaparin with conventional warfarin therapy for the treatment of VTE in patients with active cancer.”
The randomized, open-label CATCH study included 900 patients from 164 centers in Asia, Africa, Europe, and North, Central, and South America enrolled between August 2010 and November 2013. All patients had active cancer and objectively documented proximal deep-vein thrombosis (DVT) or pulmonary embolism (PE), a life expectancy greater than six months, and no contraindication to anticoagulation.
Patients were randomized to receive:
- Tinzaparin 175 IU/kg once daily for six months (n=449)
- Conventional therapy with tinzaparin 175 IU/kg once daily for 5 to 10 days followed by warfarin at a dose adjusted to maintain the target international normalized ratio (INR; 2.0-3.0) for 6 months (n=451)
Patients were followed for 180 days and for 30 days after the last study medication dose.
The primary efficacy endpoint was a composite of recurrent DVT, fatal or non-fatal PE, and incidental VTE. The primary safety endpoints included major bleeding, clinically relevant nonmajor bleeding, and overall mortality.
Of the patients treated in the tinzaparin group, 31 had recurrent VTE, compared with 45 patients in the warfarin group, for cumulative risks of 7.2 percent versus 10.5 percent, respectively (hazard ratio [HR] = 0.65; 95% CI 0.41-1.03; p=0.07).
Rates of the safety endpoints did not vary significantly between the tinzaparin and warfarin treatment groups:
- Major bleeding: 12 patients versus 11 patients, respectively (HR=0.89; 95% CI 0.40-1.99; p=0.77)
- Overall mortality: 150 versus 138 patients, respectively (HR=1.08; 95% CI 0.85-1.36; p=0.54)
However, the researchers did observe a clinically relevant difference in non-major bleeding between the two groups, with higher rates in the warfarin group (49 vs. 69 patients; HR=0.58; 95% CI 0.40-0.84; p=0.004).
Tinzaparin, even when given at full therapeutic dose for up to six months, was safe in a broad oncology population. There were no confirmed cases of heparin-induced thrombocytopenia, and the difference in mortality risk was also non-significant, as seen in TABLE. For patients who died during the study, cancer progression was the most frequent cause (69%), followed by other known causes (16.4%), fatal PE (12.5%), and bleeding (2.1%).
Adverse events leading to study drug discontinuation were also similar between both groups – 5.3 percent of tinzaparin-treated patients and 5.1 percent of warfarin-treated patients.
Thrombotic event rates were lower than anticipated in the warfarin group, Dr. Lee and colleagues noted: “Although we had expected a recurrence rate of 12.6 percent with warfarin [based on published data], the observed rate was only 10.5 percent.” This lower risk may reflect generally fewer risk factors for thrombosis and recurrent thrombosis in the CATCH population. “Further studies are needed to assess whether the efficacy outcomes would be different in patients at higher risk of recurrent VTE,” they noted.
The lower-than-expected incidence of recurrent VTE led Dr. Lee and co-authors to identify small sample size as one of the limitations of the CATCH trial. Other limitations included the study’s open-label design (as a source of potential bias), the 5 percent of patients who withdrew consent or were lost to follow-up, and that the CATCH study was not designed to address potential differences in relative efficacy and safety of tinzaparin versus warfarin in subgroups among patients with different types of cancer.
Overall, tinzaparin did not outperform warfarin in terms of efficacy or safety (except for reduction in the risk of clinically relevant non-major bleeding), the authors concluded. They added, however, that “the significant reduction in symptomatic DVT and results of other secondary analyses should be considered hypothesis-generating and exploratory because we did not adjust for multiple comparisons.”
|TABLE. Primary and Secondary Efficacy and Safety Outcomes|
|Tinzaparin (n=449)||Warfarin (n=451)||HR (95% CI)||p Value|
|Recurrent VTE||31 (6.9%)||45 (10.0%)||0.65 (0.41-1.03)||0.07|
|Symptomatic DVT||12 (2.7%)||24 (5.3%)||0.48 (0.24-0.96)||0.04|
|Symptomatic non-fatal PE||3 (0.7%)||2 (0.4%)||NA|
|Fatal PE||17 (3.8%)||17 (3.8%)||0.96 (0.49-1.88)||0.89|
|Incidental proximal DVT||0||1 (0.2%)||NA|
|Incidental PE||0||1 (0.2%)||NA|
|Major bleeding||12 (2.7%)||11 (2.4%)||0.89 (0.40-1.99)||0.77|
|Clinically relevant non-major bleeding||49 (10.9%)||69 (15.3%)||0.58 (0.40-0.84)||0.004|
|All bleeding||114 (25.4%)||110 (24.4%)||NA|
|All-cause death||150 (33.4%)||138 (30.6%)||1.08 (0.85-1.36)||0.54|