- 1 Clinical Question
- 2 Bottom Line
- 3 Major Points
- 4 Guidelines
- 5 Design
- 6 Population
- 7 Interventions
- 8 Outcomes
- 9 Criticisms
- 10 Funding
- 11 Further Reading
- 12 Reference
In active cancer patients with a new symptomatic VTE event, does anticoagulation with LMWH (tinzaparin 175 units/kg) reduce the rate of recurrent VTE or mortality compared to vitamin K antagonists (warfarin)?
In active cancer patients with a new symptomatic VTE event, full-dose tinzaparin did not significantly reduce the frequency of recurrent VTE and did not reduce overall mortality compared to warfarin over a 6 month period. There was no difference in major bleeding episodes, but there was a lower rate of clinically relevant non-major bleeding.
VTE is a common complication of cancer or cancer therapy. Most guidelines recommend long-term treatment of symptomatic VTE in cancer patients, as the rate of recurrence is as high as 20% (1). The choice of anticoagulant has been studied in multiple trials (2-4), the largest being the CLOT trial in 2003, which showed a statistically significant reduction in symptomatic VTE with dalteparin over warfarin (notably the dalteparin dose was reduced to 75% after 1 month in the trial). Consequently, consensus guidelines have recommended LMWH use over warfarin in this patient population (the novel oral anticoagulants have yet to be properly studied in this setting). However parental anticoagulation carries extra inconveniences with expenses and with administration inconvenience.
The CATCH (Comparison of Acute Treatments in Cancer Haemostasis) trial was conducted to provide further date to support the current guidelines that recommend continued LMWH anticoagulation for cancer-associated thrombosis. The study design mirrored that of the CLOT trial, with the major exception being the use of tinzaparin at full therapeutic dose throughout the trial duration, as compared to the dalteparin. However, CATCH failed to identify a difference in VTE recurrence rate in the 6 months of follow up (7.2% for tinzaparin vs 10.5% for warfarin; hazard ratio [HR], 0.65 [95% CI, 0.41-1.03]; P = .07). No differences were identified in major bleeding or mortality, however there was a significant reduction in clinically relevant non-major bleeding (49 of 449 patients for tinzaparin vs 69 of 451 patients for warfarin; HR, 0.58 [95% CI, 0.40-0.84]; P = .004). The authors hypothesize that a lower overall incidence of VTE in the control group may be responsible for the lack of difference, and this may be secondary to a healthier patient population with fewer VTE risk factors - higher performance status, less metastatic disease, less systemic anticancer treatment and a lower history of thrombosis.
ACCP Antithrombotic therapy for VTE (2012, adapted) (5):
- In patients with VTE and no cancer, recommend VKA over LMWH for long-term therapy (grade 2C)
- In patients with VTE and cancer, recommend LMWH over VKA for long-term therapy (grade 2B)
- In patients with VTE and cancer who are not treated with LMWH, recommmend VKA over the novel oral anticoagulants for long-term therapy (grade 2C)
- Multicenter, phase 3, open-label randomized controlled trial (including
- N=900, stratified by tumor extent, geographic region and VTE history
- Tinzaparin (n=449)
- Warfarin (n=451)
- Setting: 164 centers in 32 countries (median number patients per site = 4)
- Enrollment: August 2010 to November 2013
- Follow-up: 6 months; 91% completed scheduled follow-up
- Analysis: Intention-to-treat
- Primary outcome: Composite outcome of symptomatic DVT or PE, incidental proximal DVT or PE, or fatal PE. Included safety outcomes of major bleeding, clinically relevant non-major bleeding, and all-cause mortality
- Adults (age 18+) with active malignancy
- Active malignancy, defined as:
- Cancer diagnosis within 6 months: new or recurrent cancer; both local and advanced or metastatic disease
- Cancer confirmed by histology or cytology (non-melanomatous skin cancer excluded)
- Cancer treatment occurring within past 6 months
- Current hematologic malignancy not in complete remission
- Acute symptomatic VTE event - proximal DVT, PE or both
- VTE defined by standard imaging techniques
- ECOG status 0-2 at time of VTE event
- Contraindication to anticoagulation
- Renal impairment - CrCl under 20mL/min/1.73m2
- Known hypersensitivity to tinzaparin or warfarin
- History of HIT
- Therapeutic anticoagulation for >72hrs prior to being randomized OR on anticoagulation at time of thrombosis
- Life expectancy < 6 months
- Women of childbearing potential or fertile men not using effective contraception
- Persons unlikely to comply with protocol or involved in another study
- Mean age: 59 years
- Asia/Middle East: 43%
- Eastern Europe: 21%
- Western Europe/N. America: 17%
- Central/S. America: 19%
- Cancer types
- Gynecologic: 22.5%
- GI: 25%
- Lung: 12%
- GU: 10%
- Hematologic: 10%
- Breast: 9%
- Other: 10%
- Presence of known metastatic disease: 55%
- Currently receiving cancer therapy: 53%
- ECOG 0-1: 77%
- Prior history of VTE: 6%
- Randomized within 72 hours of symptomatic VTE to:
- tinzaparan 175 IU/kg (LMWH group) or
- tinzaparin 175 IU/kg and warfarin, with discontinuation of tinzaparin once INR above 2.0 for 2 days
- INR monitoring at least once every 2 weeks in control group
- Efficacy outcomes (recurrent VTE) determined by dedicated imaging (if symptomatic), or imaging for another reason (if incidental finding)
- Major bleeding events defined as per previous studies (6), while non-major bleeding events were those requiring medical or surgical intervention not meeting the previous definition
- Follow-up visits occurred on days 7, 14, 30, and then every 30 days until study end at day 180
- If recurrent VTE was confirmed, end-of-treatment assessments were conducted and therapy for recurrent thrombosis was initiated according to local practice.
Comparisons are LMWH vs. warfarin.
- Recurrent VTE (composite outcome; cumulative risk)
- 7.2% vs. 10.5% (hazard ratio [HR], 0.65 [95% CI, 0.41-1.03]; P = .07)
- Major bleeding event
- 2.7% vs. 2.4% (HR, 0.89 [95% CI, 0.40-1.99]; P = .77)
- Clinically relevant non-major bleeding
- 10.9% vs. 15.3% (HR, 0.58 [95% CI, 0.40-0.84]; P = .004)
- Mortality (cumulative risk)
- 34.7% vs. 32.2% (HR, 1.08 [95% CI, 0.85-1.36]; P = .54)
Drug discontinuation seen in 5.3% of LMWH vs. 5.1% of warfarin patients. Serious adverse events occurred in 49.2% vs 43.2% - disease progression listed as most common reason (further details not provided). No reported episodes of HIT.
- Lower incidence of recurrent VTE in control group may have lowered power of the trial to detect beneficial effect associated with LMWH
- Open-labed design a potential source of bias
- Warfarin group had time in therapeutic range of 47%, similar to CLOT study but lower than studies in non-cancer populations
Sponsored and funded by LEO Pharma (manufacturers of Innohep) and research support from private research funds. LEO Pharma had a role in all aspects of the study.
1. Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B,Marchiori A, Sabbion P, Prins MH, Noventa F, Girolami A: Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002, 100:3484–3488.
2. Lee AY, Levine MN, Baker RI, et al; Randomized Comparison of Low-Molecular-Weight Heparin vs Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin vs a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-153.
3. Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J: Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost 2006, 12:389–396.
4. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002;162(15):1729-1735.
5. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest.2012;141(2 suppl):e419S-e494S.
6. Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in nonsurgical patients. J Thromb Haemost. 2005;3(4):692-694.
Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA; for the CATCH Investigators. Tinzaparin vs Warfarin for Treatment of Acute Venous Thromboembolism in Patients With Active Cancer: A Randomized Clinical Trial. JAMA. 2015 Aug 18;314(7):677-86.