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Coagulants

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Heparin

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Heparin, Low-Molecular-Weight

Tinzaparin

Dalteparin

Thromboplastin

Arginine

Patients assigned at random to receive prophylactic dalteparin injections

No prophylactic therapy for VTE prevention given (Subjects receiving standard of care)

Used as a control for the secondary outcome of evaluating tissue factor in collected blood samples

Potency is described in international anti-Xa units (IU). One unit (anti-Xa) of dalteparin sodium, average molecular weight 5,000, corresponds to the activity of one unit of the 1st International Standard for Low Molecular Weight Heparin (LMWH)with respect to inhibition of coagulation Factor Xa in plasma utilizing the chromogenic peptide substrate S-2765 (N-alpha-Benzyloxycarbonyl-D-arginyl-glycyl-arginine-pNA.2HCl).

dalteparin injection

Charles W. Francis, MD

Some cancer patients starting a new chemotherapy regimen are likely to develop blood clots, also known as venous thromboembolism (VTE). Blood clots can cause symptoms and can occasionally be life-threatening. The purpose of this study is to determine if a daily injection of a blood-thinner, dalteparin, for 12 weeks can safely and effectively reduce the frequency of blood clots. Dalteparin is currently approved for prevention of blood clots following surgery and in hospitalized patients but not specifically for cancer outpatients.

VTE is an increasingly frequent complication of cancer and anti-cancer therapies. It is associated with increased mortality and other significant adverse consequences. Risk factors for VTE in the cancer population have been identified, and multiple studies have also shown that VTE can be prevented in high-risk populations with the use of thromboprophylaxis. This study evaluated the safety and efficacy of prophylaxis in a high-risk subgroup of cancer patients identified by a validated risk model developed by us previously called the "Khorana Score." Correlative studies evaluated the value of tissue factor as a predictive biomarker of VTE. The purpose of this study was to conduct a prospective, randomized clinical trial comparing the safety and efficacy of prophylaxis with dalteparin to no treatment in reducing VTE in high-risk ambulatory cancer patients initiating chemotherapy and to establish the value of TF as a predictive marker for VTE in ambulatory cancer patients receiving chemotherapy.

PHACS was a randomized multi-center clinical trial. Eligible patients were enrolled and underwent baseline screening ultrasonography of the lower extremities to rule out pre-existing DVT and a chest CT scan to rule out PE. If negative, patients were then randomized to receive either dalteparin 5000 units subcutaneously daily or observation for a study period of 12 weeks. The first day of dalteparin prophylaxis coincided with the first day of initiation of a new systemic chemotherapy regimen. The patients were seen every 4 weeks (±1 week) at the time of regularly scheduled chemotherapy cycle visits for serial ultrasonography of lower extremities during study period (i.e. at 4, 8 and 12 weeks.) A chest CT scan was performed at 12 weeks. Compliance was measured by asking patients about missed doses at these 4-weekly visits as well as by asking patients to fill an injection diary.

A Study of Dalteparin Prophylaxis in High-Risk Ambulatory Cancer Patients

A Prospective Randomized Multicenter Study of Dalteparin Prophylaxis in High-Risk Ambulatory Cancer Patients

The percentage of patients who developed a Venous thromboembolism were recorded within 12 weeks following randomization including all adjudicated occurrences of symptomatic DVT, PE and upper extremity thrombus as well as all asymptomatic DVT and PE detected by lower extremity ultrasonography and chest CT.

The percentage of patients who experienced a clinically significant bleeding event were recorded (including major and clinically significant non-major bleeding) over 13 weeks (12 weeks of study and an additional week of observation). Major bleeding was defined as being clinically overt and satisfying one of the following: decrease in hemoglobin of 2.0 g/dL, leading to transfusion of 2 or more units of blood or packed red cells, occurring in a critical site (intraocular, spinal/epidural, intracranial, retroperitoneal, or pericardial) or leading to death. Clinically significant non-major bleeding was defined as clinically overt, not meeting criteria for major bleeding and with one of the following characteristics: multiple-source, spontaneous hematoma \> 25 cm², epistaxis \> 5 mins, macroscopic hematuria not related to instrumentation, spontaneous rectal bleeding, gingival bleeding \> 5 mins, hemoptysis, hematemesis or prolonged bleeding (\> 5 minutes) after venipuncture.

Blood samples were obtained to measure the value of Tissue Factor at baseline compared between high risk for VTE and low risk for VTE ambulatory cancer patients.

Blood samples were obtained to measure the value of D-Dimer at baseline compared between high risk for VTE and low risk for VTE ambulatory cancer patients

Blood samples were obtained to measure the value of Human F12 at baseline compared between high risk for VTE and low risk for VTE ambulatory cancer patients

Blood samples were obtained to measure the value of TFPI at baseline compared between high risk for VTE and low risk for VTE ambulatory cancer patients

Blood samples were obtained to measure the value of FVIIa at baseline compared between high risk for VTE and low risk for VTE ambulatory cancer patients

Blood samples were obtained to measure the value of TAT at baseline compared between high risk for VTE and low risk for VTE ambulatory cancer patients

National Heart, Lung, and Blood Institute (NHLBI)

Eisai Inc.

University of Rochester

Professor emeritus

Patients will be assigned at random to receive prophylactic dalteparin injections

dalteparin injection: Potency is described in international anti-Xa units (IU). One unit (anti-Xa) of dalteparin sodium, average molecular weight 5,000, corresponds to the activity of one unit of the 1st International Standard for Low Molecular Weight Heparin (LMWH)with respect to inhibition of coagulation Factor Xa in plasma utilizing the chromogenic peptide substrate S-2765 (N-alpha-Benzyloxycarbonyl-D-arginyl-glycyl-arginine-pNA.2HCl).

Dalteparin Injection

No prophylactic therapy for VTE prevention given (Subjects just receiving standard of care)

No Therapy

High Risk Randomized to Dalteparin Injection

High Risk Randomized to No Therapy

Ambulatory cancer patients deemed Low risk based on a Khorona score of 0-2

Low Risk

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Canada

United States

Region of Enrollment

Charles Francis, MD

Percentage of Patients With Venous Thromboembolisms

Percentage of Patients Who Experienced Clinically Significant Bleeding Events.

High Risk participants ambulatory cancer patients with Khorona scores 3+

High Risk

Low Risk ambulatory cancer patients with Khorona scores of 0-2

From 98 high risk patients, 89 provided blood samples used for this analysis. From the low risk group, all 101 subjects provided blood samples for analysis.

The Value of Tissue Factor (TF) at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients

The Value of D-Dimer at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients

The Value of Human F12 at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients

The Value of Tissue Factor Pathway Inhibitor (TFPI) at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients

The Value of Factor VIIa (FVIIa) at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients

The Value of Thrombin Antithrombin (TAT) at Baseline Prior to Chemotherapy in Ambulatory Cancer Patients

High Risk Dalteparin Injection

High Risk No Therapy

Subjects deemed low or medium risk for VTE by Khorona score. These subjects did not enter into the study but supplied a one-time baseline blood sample for use as a control in the studies Secondary Objective of establishing the value of TF as a predictive marker for VTE.

Spots Global Cancer Trial Database for dalteparin injection