VTE in Solid Tumours: Efficacy and Safety Profile

Efficacy and Safety Profile

Lee AY et al. N Engl J Med 2003;349:146–153 (CLOT)1.

Study Design: 

A multicentre, randomised, open-label clinical trial in patients with active cancer and newly diagnosed, symptomatic proximal deep vein thrombosis (DVT), pulmonary embolism (PE) or both (N=676). Patients were assigned to receive either subcutaneous Fragmin® (200 IU/kg), once daily for five to seven days (maximum daily dose 18,000 IU) followed by oral anticoagulation with a VKA for six months (target INR, 2.5), or subcutaneous Fragmin® alone for 6 months (200 IU/kg once daily for one month [maximum daily dose 18,000 IU], followed by a daily dose of approximately 150 IU/kg for five months).

Primary endpoint: First episode of symptomatic, recurrent DVT, PE or both, during a 6 month period.

Secondary endpoint: Clinically overt bleeding and death.

Of the 676 consenting patients, 90% of patients had solid tumours. The most frequent sites of solid tumours were:

  • Breast (15.9%)
  • Brain (3.9%)
  • Pancreas (4.2%)
  • Gynaecologic system (10.0%)
  • Genitourinary tract (12.7%)
  • Lung (13.3%)
  • Colorectal area (15.9%) 


Symptomatic, recurrent DVT, PE, or both occurred in 8.0% (n=27) of patients in the Fragmin® group and 15.7% (n=53) of patients in the VKA group over the six month study period (P=0.002). Treatment with Fragmin® resulted in a 52.0% relative risk reduction of recurrent VTE versus VKA at 6 months (HR: 0.48; 95% CI: 0.30–0.77; P=0.002; absolute risk reduction = 8%). There was no significant difference between the number of patients in the Fragmin® group and the VKA group who had major bleeding (6% vs. 4%; P=0.27), or any bleeding (14% vs. 19%; P=0.09).


In adult patients with active cancer and newly diagnosed, symptomatic proximal DVT, PE or both, Fragmin® was more effective than a VKA in reducing the risk of recurrent VTE without increasing the risk of bleeding


Prandoni P et al. Blood 2002;100:3484–3488.2

Study Design:

Prospective, follow-up study in thrombosis patients (N=842) to determine whether those with cancer (n=181) have a higher risk for recurrent VTE or bleeding during anticoagulant treatment than those without cancer (n=661). Patients were treated with an initial course of high-dose adjusted i.v. standard heparin or body weight-adjusted LMWH. Sodium warfarin was started during the first week of treatment and continued for a period of at least 3 months.

Primary endpoint: Cumulative incidence of VTE or bleeding over 12 months of anticoagulation treatment.


The 12 month cumulative incidence of recurrent VTE in cancer patients was 20.7% (95% CI, 15.6%–25.8%) versus 6.8% (95% CI, 3.9%–9.7%) in patients without cancer (HR: 3.2; 95% CI, 1.9–5.4). The 12-month cumulative incidence of major bleeding was 12.4% (95% CI, 6.5%–18.2%) in patients with cancer and 4.9% (95% CI, 2.5%–7.4%) in patients without cancer (HR: 2.2; 95% CI, 1.2–4.1).

Recurrence and bleeding were both related to cancer severity and occurred predominantly during the first month of anticoagulant therapy but could not be explained by sub- or over-anticoagulation.


Patients with cancer were three times more likely to experience recurrent VTE, and twice as likely to experience major bleeding during anticoagulation treatment than patients without cancer. There appears to be an association between the extent of cancer at baseline and the subsequent risks of complications.


Woodruff S et al. J Thromb Thrombolysis 2016;42:494–5043.

Study Design:

Post hoc analysis of the CLOT study, a multicentre, randomised, open-label clinical trial in patients with active cancer and newly diagnosed, symptomatic proximal DVT, PE or both (n=676). Patients randomly assigned to Fragmin® received once-daily subcutaneous injections of Fragmin® 200 IU/kg (maximum daily dose 18,000 IU) for 1 month, followed by injections of 150 IU/kg for the remaining 5 months. Those in the VKA group received once-daily VKA for 6 months, with initial overlapping subcutaneous Fragmin® 200 IU/kg once daily for at least 5 days until INR was 2.0–3.0 for 2 consecutive days.

Primary endpoint:

Rates of recurrent VTE.

Secondary endpoint:

Incidence of bleeding events.


Overall, fewer Fragmin®-treated patients (2/74 [2.7 %]) experienced  at least 1 days adjudicated symptomatic rVTE compared with VKA-treated patients (15/88 [17.0 %]; HR=0.15 [95 % confidence interval 0.03–0.65]; p=0.01).

Bleeding event rates for both treatments were similar (p=0.47).


Compared with VKA, Fragmin® significantly reduced the risk of rVTE in patients with cancer and renal impairment (p=0.01) while exhibiting a comparable safety profile.


1. Lee AY et al. N Engl J Med 2003;349:149–153.
2. Prandoni P et al. Blood 2002;100:3484–3488.
3. Woodruff S et al. J Thromb Thrombolysis 2016;42:494–504.

*Including, but not limited to: congestive cardiac failure (NYHA class III or IV), acute respiratory failure or acute infection, who also have a predisposing risk factor for VTE such as age over 75 years, obesity, cancer or previous history of VTE.~
†In patients with chronic renal insufficiency or acute renal failure.

PP-FRA-GBR-0145.  June 2019