Renal Impairment, Recurrent Venous Thromboembolism and Bleeding in Cancer Patients with Acute Venous Thromboembolism-Analysis of the CATCH Study.

OBJECTIVE: This article assesses the impact of renal impairment (RI) on the efficacy and safety of anticoagulation in patients with cancer-associated thrombosis from the Comparison of Acute Treatments in Cancer Hemostasis (CATCH) study (NCT01130025). MATERIALS AND METHODS: Renal function was assessed using the Modification of Diet in Renal Disease equation in patients with cancer-associated thrombosis who received either tinzaparin (175 IU/kg) once daily or warfarin for 6 months, in an open-label, randomized, multi-centre trial with blinded adjudication of outcomes. Associations between baseline RI (glomerular filtration rate [GFR] <60 mL/min/1.73m2) and recurrent symptomatic or incidental venous thromboembolism (VTE), clinically relevant bleeding (CRB), major bleeding and death were assessed using Fisher's exact test. RESULTS: Baseline-centralized GFR data were available for 864 patients (96% of study population). RI was found in 131 patients (15%; n = 69 tinzaparin). Recurrent VTE occurred in 14% of patients with and 8% of patients without RI (relative risk [RR] 1.74; 95% confidence interval [CI] 1.06, 2.85), CRB in 19% and 14%, respectively (RR 1.33; 95% CI 0.90, 1.98), major bleeding in 6.1% and 2.0%, respectively (RR 2.98; 95% CI 1.29, 6.90) and mortality rate was 40% and 34%, respectively (RR 1.20; 95% CI 0.94, 1.53). Patients with RI on tinzaparin showed no difference in recurrent VTE, CRB, major bleeding or mortality rates versus those on warfarin. CONCLUSION: RI in patients with cancer-associated thrombosis on anticoagulation was associated with a statistically significant increase in recurrent VTE and major bleeding, but no significant increase in CRB or mortality. No differences were observed between long-term tinzaparin therapy and warfarin.

Tissue Factor As a Predictor of Recurrent Venous Thromboembolism in Malignancy: Biomarker Analyses of the CATCH Trial.

Purpose Circulating tissue factor (TF) has been studied as a biomarker for predicting initial, but not recurrent, venous thromboembolism (VTE) in cancer, a setting in which predictors are incompletely understood. We evaluated the association of TF, clinical risk factors, and other biomarkers measured at the time of initial VTE with recurrent VTE in a prespecified analysis of the CATCH (Comparison of Acute Treatments in Cancer Hemostasis) trial. Methods CATCH was a randomized, multicenter trial that investigated tinzaparin 175 IU/kg once daily or dose-adjusted warfarin for 6 months in patients with cancer and acute, symptomatic VTE. TF ELISA, soluble P-selectin, d-dimer, FVIII, and C-reactive protein were assayed. Fisher's exact test was used to screen for association with VTE; competing risk regression analysis of time to recurrent VTE was conducted, accounting for multiple variables. Results The study population comprised 900 patients (recurrent VTE, n = 76; 8.4%). Of these patients, 805 had samples available for TF assay. Mean and median TF levels were 72.5 pg/mL and 50.3 pg/mL, respectively (range, 15.6 pg/mL to 4,798 pg/mL). Patients in the highest quartile of TF experienced the greatest VTE recurrence (> 64.6 pg/mL; 38 [19%] of 203 patients v 34 [6%] of 602 patients; relative risk, 3.3; 95% CI, 2.1 to 5.1; P < .001). In competing risk regression analysis of time to recurrent VTE, TF remained strongly associated with recurrent VTE (subdistribution hazard ratio [SHR], 3.3; 95% CI, 1.7 to 6.4). Other significant variables included venous compression from mass (SHR, 3.1; 95% CI, 1.4 to 6.5) and hepatobiliary cancer (SHR, 5.5; 95% CI, 2.3 to 13.6). Conclusion This is the first report, to our knowledge, to describe TF as a potential biomarker of recurrent VTE in patients with cancer who are on anticoagulation treatment. A risk-adapted strategy could help identify high-risk patients who may benefit from more intensive anticoagulation approaches.

Tinzaparin vs Warfarin for Treatment of Acute Venous Thromboembolism in Patients With Active Cancer: A Randomized Clinical Trial.

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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130025.

CATCH: a randomised clinical trial comparing long-term tinzaparin versus warfarin for treatment of acute venous thromboembolism in cancer patients.

BACKGROUND: Low-molecular-weight heparin (LMWH) is recommended and commonly used for extended treatment of cancer-associated thrombosis (CAT), but its superiority over warfarin has been demonstrated in only one randomised study. We report here the rationale, design and a priori analysis plans of Comparison of Acute Treatments in Cancer Haemostasis (CATCH; NCT01130025), a multinational, Phase III, open-label, randomised controlled trial comparing tinzaparin with warfarin for extended treatment of CAT. METHODS/DESIGN: The primary objective is to assess the efficacy of tinzaparin in preventing recurrent venous thromboembolism (VTE) in patients with active cancer and acute, symptomatic proximal deep vein thrombosis and/or pulmonary embolism. The secondary objectives are to determine: safety of tinzaparin given over 6 months; clinical and laboratory markers for recurrent VTE and/or major bleeding; 6-month overall mortality; incidence and severity of post-thrombotic syndrome; patient-reported quality of life; and healthcare resource utilisation. Nine hundred patients are randomised to receive tinzaparin 175 IU/kg once daily for 6 months or initial tinzaparin 175 IU/kg once daily for 5-10 days and dose-adjusted warfarin (target INR 2.0-3.0) for 6 months. The primary composite outcome is time to recurrent VTE, including incidental VTE and fatal pulmonary embolism. All patients are followed up to 6 months or death, whichever comes sooner. Blinded adjudication will be performed for all reported VTE, bleeding events and causes of death. Efficacy will be analysed using centrally adjudicated results of all patients according to intention-to-treat analysis. An independent Data Safety Monitoring Board is reviewing data at regular intervals and an interim analysis is planned after 450 patients have completed the study. DISCUSSION: The results will add significantly to the knowledge of the efficacy, safety and cost effectiveness of tinzaparin in the prevention of recurrent VTE in patients with cancer and thrombosis. Prospective data will emerge on the clinical significance of incidental VTE and risk stratification in patients with CAT. Results on post-thrombotic syndrome, quality of life and healthcare resource utilisation will inform decision makers on how to secure better patient care. If tinzaparin is shown to be more effective than warfarin, CATCH will provide valuable confirmatory data to support the use of the LMWH tinzaparin for extended treatment of CAT.

Safety profile of tinzaparin versus subcutaneous unfractionated heparin in elderly patients with impaired renal function treated for acute deep vein thrombosis: the Innohep® in Renal Insufficiency Study (IRIS).

INTRODUCTION: Trials comparing the use of full dose unfractionated heparin (UFH) or low molecular weight heparins (LMWHs) in very elderly patients with impaired renal function are lacking. IRIS aimed to assess whether LMWH is at least as safe as UFH in this population. MATERIALS AND METHODS: The study included renally impaired patients ≥70 years with acute symptomatic lower limb deep vein thrombosis (DVT). Patients were randomized to initial treatment with either tinzaparin 175 IU/kg once daily (n=269) or activated partial thromboplastin time-adjusted UFH twice daily (n=270). After acute management both groups received vitamin K antagonist to day 90. RESULTS: The trial was stopped prematurely due to a difference in mortality favoring the UFH group (11.5 vs. 6.3%; p=0.035). Rates of clinically relevant bleedings by day 90 were similar in the tinzaparin (11.9%) and UFH (11.9%) groups, as were rates of confirmed recurrent venous thromboembolism (VTE) (2.6 vs. 1.1%; p=0.34). As the mortality difference could not be explained by bleedings or recurrent VTE, a post-hoc analysis was performed. This identified six baseline characteristics significantly correlated with mortality, of which five were over-represented in the tinzaparin group. CONCLUSION: The IRIS study was a challenging study involving patients (mean age 83 years) usually excluded from clinical studies, but its early termination has left questions unanswered. The mortality difference observed with tinzaparin vs. UFH in elderly, renally-impaired patients with DVT cannot be explained on the basis of bleedings or recurrent VTE, and may reflect an imbalance of mortality risk factors at baseline.

Epidermal growth factor receptor expression analysis in chemotherapy-naive patients with advanced non-small-cell lung cancer treated with gefitinib or placebo in combination with platinum-based chemotherapy.

PURPOSE: Two large, randomized, placebo-controlled trials (IRESSA NSCLC Trial Assessing Combination Therapy; INTACT 1 and 2) in non-small-cell lung cancer (NSCLC) failed to show survival benefit for gefitinib (IRESSA) in combination with first-line platinum-based chemotherapy. Epidermal growth factor receptor (EGFR) staining was assessed retrospectively in relation to survival response to gefitinib in combination with chemotherapy. METHODS: Tumor biopsies obtained prior to start of therapy were assessed by immunohistochemistry for EGFR using the Dako EGFR pharmDx assay (Dako, Denmark). Analyses were stratified by trial and performed independently for patients randomized to placebo and gefitinib as well as for both treatment groups combined. A restricted backwards elimination Cox regression analysis was conducted to identify independent EGFR factors that were statistically significant (P < 0.10), and these were also tested for treatment interaction to assess if they served as predictive factors. RESULTS: Analyses found two statistically significant EGFR-based prognostic factors representing growth pattern and percent membrane staining in patients treated with gefitinib (P = 0.0023), placebo (P = 0.0128), and both combined (P < 0.0001). The prognostic effect was independent of other known prognostic factors. There was no predictive effect of either the growth pattern or membrane staining variable. CONCLUSIONS: While some previous studies indicate that higher EGFR expression correlates with poor survival, our analyses provide statistically significant evidence that the combination of EGFR expression and growth pattern is a strong prognostic indicator for improved survival within this setting. The effects of membrane staining and growth pattern are still significant when adjusting for mutation.