Is tinzaparin better than warfarin in patients with VTE and cancer or not?

The CATCH trail results were published this week in JAMA. Read the abstract is below. Do you think this drug is useful for venous thromboembolism (VTE) treatment?

Importance  Low-molecular-weight heparin is recommended over warfarin for the treatment of acute venous thromboembolism (VTE) in patients with active cancer largely based on results of a single, large trial.

Objective  To study the efficacy and safety of tinzaparin vs warfarin for treatment of acute, symptomatic VTE in patients with active cancer.

Design, Settings, and Participants  A randomized, open-label study with blinded central adjudication of study outcomes enrolled patients in 164 centers in Asia, Africa, Europe, and North, Central, and South America between August 2010 and November 2013. Adult patients with active cancer (defined as histologic diagnosis of cancer and receiving anticancer therapy or diagnosed with, or received such therapy, within the previous 6 months) and objectively documented proximal deep vein thrombosis (DVT) or pulmonary embolism, with a life expectancy greater than 6 months and without contraindications for anticoagulation, were followed up for 180 days and for 30 days after the last study medication dose for collection of safety data.

Interventions  Tinzaparin (175 IU/kg) once daily for 6 months vs conventional therapy with tinzaparin (175 IU/kg) once daily for 5 to 10 days followed by warfarin at a dose adjusted to maintain the international normalized ratio within the therapeutic range (2.0-3.0) for 6 months.

Main Outcomes and Measures  Primary efficacy outcome was a composite of centrally adjudicated recurrent DVT, fatal or nonfatal pulmonary embolism, and incidental VTE. Safety outcomes included major bleeding, clinically relevant nonmajor bleeding, and overall mortality.

Results  Nine hundred patients were randomized and included in intention-to-treat efficacy and safety analyses. Recurrent VTE occurred in 31 of 449 patients treated with tinzaparin and 45 of 451 patients treated with warfarin (6-month cumulative incidence, 7.2% for tinzaparin vs 10.5% for warfarin; hazard ratio [HR], 0.65 [95% CI, 0.41-1.03]; P = .07). There were no differences in major bleeding (12 patients for tinzaparin vs 11 patients for warfarin; HR, 0.89 [95% CI, 0.40-1.99]; P = .77) or overall mortality (150 patients for tinzaparin vs 138 patients for warfarin; HR, 1.08 [95% CI, 0.85-1.36]; P = .54). A significant reduction in clinically relevant nonmajor bleeding was observed with tinzaparin (49 of 449 patients for tinzaparin vs 69 of 451 patients for warfarin; HR, 0.58 [95% CI, 0.40-0.84]; P = .004).

Conclusions and Relevance  Among patients with active cancer and acute symptomatic VTE, the use of full-dose tinzaparin (175 IU/kg) daily compared with warfarin for 6 months did not significantly reduce the composite measure of recurrent VTE and was not associated with reductions in overall mortality or major bleeding, but was associated with a lower rate of clinically relevant nonmajor bleeding. Further studies are needed to assess whether the efficacy outcomes would be different in patients at higher risk of recurrent VTE.

When I approach a study with marginally negative results I consider several things to help me decide if I would still prescribe the drug:

  1. Was the study powered properly? Alternatively, were the assumptions made in sample size calculations reasonable. Sample size calculations require several data points. The main ones are: desired power, type 1 error rate, expected difference in event rates between the arms of the trial. The usual offender is the authors overestimating the benefit they expect to see. The authors expected a 50% relative reduction in event rates between the 2 arms of the study. That seems high but is consistent with a meta-analysis of similar studies and the CLOT trial.  They only saw a 31% reduction. This would have meant the study needed more patients and thus is underpowered. (post hoc power 41.4%).
  2. How much of the confidence interval is on the side of being beneficial? Most of the CI in this case is below 1.0 (0.41-1.03). Thus, I pay more attention to this than the p-value (0.07). There is potentially 59% reduction in the hazard of VTE and only a 3% potential increase in VTE. This is a clinically important reduction in VTE.
  3. What are the pros and cons of the therapy? Preventing VTE is important. The risk of bleeding was less in with tinzaparin. Had the bleeding been higher then I might have had different thoughts about prescribing this drug.
  4. Are the results of this trial consistent with previous studies? If so, then I fall back on it being underpowered and likely would prescribe the drug. A metaanalysis of 7 studies found a similar reduction in VTE (HR 0.47).

Thus, I think the study was underpowered for the event rates they encountered. Had there been more patients enrolled they likely would have found a statistically significant difference between groups. I would not anticipate the results shifting from benefit to harm with more patients. It is likely the patients in this trial were “healthier” than patients in the previous trials.  I feel comfortable saying tinzaparin is likely beneficial and I would feel comfortable prescribing it.

This demonstrates the importance of evaluating the confidence interval and not just the p-value. More information can be gleaned from the confidence interval than a p-value.

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