Innohep® (tinzaparin) vs Coumadin® (warfarin) for Treatment of Acute Venous Thromboembolism in Patients with Active Cancer

Julie Murphy, Mercer University College of Pharmacy

The American Journal of Preventive Medicine reports that while the actual number of venous thromboembolisms (VTE) is unknown, there are an estimated 300,000 to 600,000 cases in the United States annually. It is suggested that there is roughly one case per 100,000 young individuals and that risk increases to nearly one per 100 patients over the age of 80 years old. They define VTE as the inappropriate clotting of blood which can lead to a serious condition such as deep vein thrombosis (DVT) or pulmonary embolism (PE).1

Title: Tinzaparin vs Warfarin for Treatment of Acute Venous Thromboembolism (VTE) in Patients with Active Cancer2
Design Phase 3, multinational, randomized, active-controlled, open-label trial; N= 900
Objective To study the efficacy and safety of tinzaparin vs warfarin for treatment of acute, symptomatic VTE in patients with active cancer
Study Groups Tinzaparin (n= 449) verses Warfarin (n= 451)
Methods All patients were randomized within 72 hours of VTE diagnosis and stratified by tumor extent, geographic region, and VTE history. Tinzaparin patients were given 175 IU/kg daily for six months. Warfarin patients initially received warfarin plus tinzaparin 175 IU/kg daily for five to ten days until their international normalized ratio (INR) was higher than two for two consecutive days. Once at target INR, the patients received warfarin monotherapy for the remainder of the six months with INR testing completed every two weeks. A platelet count less than 50×103/μL, a bleeding event, or an invasive procedures were the only grounds for temporary drug interruption and none lasted lower than three weeks. Patients were followed through one month past their last study dose.
Duration August 2010 to November 2013
Primary Outcome Measure The number of recurrent VTE, major bleeding, clinically relevant non-major bleeding, and all-cause mortality.
Baseline Characteristics No. (%) Tinzaparin

(n = 449)

Warfarin

(n = 451)

Mean Age, years (SD) 59.7 (12.7) 58.8 (12.5)
Female 262 (58.4) 273 (60.5)
Location:
Asia and Middle East 196 (43.7) 195 (43.2)
Eastern Europe 94 (20.9) 96 (21.3)
Western Europe and North America 75 (16.7) 75 (16.6)
Central and South America 84 (18.7) 85 (18.8)
Creatinine clearance, mL/min/1.73 m2:
<30 8 (1.8) 2 (0.4)
30 ≤60 59 (13.1) 60 (13.3)
≥60 355 (79.1) 378 (83.8)
Non-calculable due to missing data 27 (6.0) 11 (2.4)
Primary tumor site:
Gynecologic 101 (22.5) 102 (22.6)
Colorectal 66 (14.7) 53 (11.8)
Upper gastrointestinal 56 (12.5) 49 (10.9)
Lung 48 (10.7) 56 (12.4)
Genitourinary 53 (11.8) 41 (9.1)
Hematologic 44 (9.8) 50 (11.1)
Breast 37 (8.2) 47 (10.4)
Known metastases 247 (55.0) 245 (54.3)
Cancer therapy:
Systemic medical therapy 189 (42.1) 193 (42.8)
Radiation 51 (11.4) 41 (9.1)
Surgery 24 (5.3) 38 (8.4)
Hospitalization ≥3 days 140 (31.2) 146 (32.4)
Immobility 33 (7.3) 45 (10.0)
ECOG performance status: 0 or 1 343 (76.4) 348 (77.2)
Previous history of VTE 27 (6.0) 30 (6.7)
Qualifying thrombotic event:
Symptomatic DVT 252 (56.1) 259 (57.4)
Symptomatic DVT with incidental PE 82 (18.3) 90 (20.0)
Symptomatic PE 48 (10.7) 44 (9.8)
Symptomatic PE with incidental DVT 11 (2.4) 11 (2.4)
Symptomatic PE and symptomatic DVT 48 (10.7) 32 (7.1)
No qualifying VTE 8 (1.8) 15 (3.3)
Results No. (%) Tinzaparin

(n = 449)

Warfarin

(n = 451)

HR (95% Confidence Interval) P Value
Recurrent VTE 31 (6.9) 45 (10.0) 0.65
(0.41-1.03)
0.07
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-cause death 150 (33.4) 138 (30.6) 1.08
(0.85-1.36)
0.54
Adverse Events Common Adverse Events: Progression of disease
Serious Adverse Events: Tinzaparin group (49.2%) and Warfarin group (43.2%)
Percentage that Discontinued due to Adverse Events: Tinzaparin group (5.3%) and Warfarin group (5.1%)
Study Author Conclusions In patients with active cancer and acute symptomatic VTE, tinzaparin 175 IU/kg daily compared with warfarin for 6 months did not significantly reduce the number 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 non-major bleeding.

In this study, active cancer was defined by confirmation of malignancy along with: a diagnosis or treatment of cancer within six months prior to enrollment; recurrent, regionally advanced, or metastatic cancer; or not complete remission of hematologic cancer. The duration of treatment was longer for tinzaparin at a median of 168 days as compared to 127 days with warfarin therapy. This was an international trial with significant patient enrollment which adds strength to the trial. The expected VTE recurrence rate with warfarin was 12.6% and the observed rate was 10.5% which possibly affected the trial’s power to detect tinzaparin benefit. The population of this trial had less risk factors for VTE when compared to similar trials which could affect the clinical usefulness of this data. Risk of clinically relevant non-major bleeding was significantly reduced in the tinzaparin group compared to warfarin. This study shows that tinzaparin therapy for six months is safe in a variety of cancers. This trial was limited by the lower incidence of recurrent VTE and the open-label design. An approximate 5% of patients withdrew consent or were lost during follow-up.2

 References

  1. Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med. 2010;38(4 Suppl):S495-501.
  2. Lee AY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs Warfarin for Treatment of Acute Venous Thromboembolism in Patients With Active Cancer: A Randomized Clinical Trial. JAMA. 2015;314(7):677-86.
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