Abstract
Background: Ambulatory cancer patients at high-risk for venous thromboembolism (VTE) can be identified using a validated risk score. We evaluated the benefit of outpatient thromboprophylaxis with dalteparin in such high-risk patients in a multicenter randomized controlled trial.
Methods: Cancer patients at high risk for VTE (Khorana score ≥3) and initiating a new systemic chemotherapy regimen were screened for VTE and, if negative, randomized to either dalteparin 5000 units daily subcutaneously or no prophylactic anticoagulation for 12 weeks. Subjects in both arms were screened with lower extremity ultrasounds every 4 weeks on study. Primary efficacy endpoint was any VTE over 12 weeks and primary safety endpoint was clinically relevant bleeding events over 13 weeks. The study was terminated due to poor accrual.
Results: Of 117 enrolled patients, 19 were not randomized due to the presence of VTE on initial screening (N=10, 8.5%) or for other reasons (N=9). The mean age was 59 years with 46% female and 54% male, similar in both arms. The most common primary sites of cancer were pancreas, gastro-esophageal junction, lung and lymphoma. Over three-fourths of patients in each arm had an ECOG performance status of 0 or 1.Of 98 patients randomized, VTE occurred in 12% (N=6/50) of patients on the dalteparin arm and 21% (N=10/48) on the control arm (hazard ratio, HR 0.69, 95% CI 0.23-1.89) (absolute risk reduction 9%, relative risk reduction 42%, number needed to treat = 12). Major bleeding was similar (N=1) in each arm but clinically relevant bleeding was higher in the dalteparin arm (N=7 versus 1 in the control arm) (HR = 7.0, 95% CI 1.2-131.6). There was no difference in overall survival.
Conclusions: Thromboprophylaxis is associated with a non-significant reduced risk of VTE with no effect on major bleeding or survival but increased risk of clinically relevant bleeding in this underpowered study population. The Khorana score successfully identifies patients with high incidence of VTE both at baseline and during study. The high incidence of baseline VTE suggests that consideration should be given to screening high-risk patients in clinical practice prior to starting systemic therapy. Future studies should continue to focus on risk-adapted approaches to reduce the burden of VTE in cancer. (Funded by NIH/NHLBI R01HL095109; clinicaltrials.gov identifier: NCT00876915).
Baseline Characteristics of Patients Enrolled in the PHACS trial
| Dalteparin | Observation | Total | |
|---|---|---|---|
| Enrolled (n) Baseline VTE, n (%) DVT PE Other reasons for not randomizing Randomized (n) Age, mean (SD), y | --- --- --- --- --- 50 60 (10) | --- --- --- --- --- 48 58 (12) | 117 10 (9%) 6* (5%) 4 (3%) 9 98 59 (11) |
| Gender, n (%) | |||
| Female | 21 (42%) | 24 (50%) | 45 (46%) |
| Male | 29 (58%) | 24 (50%) | 53 (54%) |
| Primary Tumor Site, No. (%) | |||
| Gynecologic | 4 (8%) | 4 (8%) | 8 (8%) |
| Colorectal | 1 (2%) | 3 (6%) | 4 (4%) |
| GE junction | 8 (16%) | 4 (8%) | 12 (25%) |
| Lung | 6 (12%) | 7(15%) | 13 (27%) |
| Genitourinary | 2 (4%) | 0 (0%) | 2 (2%) |
| Lymphoma | 5 (10%) | 2 (4%) | 7 (15%) |
| Breast | 1 (2%) | 1 (2%) | 2 (2%) |
| Pancreatic | 19 (38%) | 17 (35%) | 36 (37%) |
| Gastric | 4 (8%) | 6 (13%) | 10 (10%) |
| Other | 0 (0%) | 4 (8%) | 4 (4%) |
| Previous history of VTE, n (%) | 4 (8%) | 2 (4%) | 6 (6%) |
| Dalteparin | Observation | Total | |
|---|---|---|---|
| Enrolled (n) Baseline VTE, n (%) DVT PE Other reasons for not randomizing Randomized (n) Age, mean (SD), y | --- --- --- --- --- 50 60 (10) | --- --- --- --- --- 48 58 (12) | 117 10 (9%) 6* (5%) 4 (3%) 9 98 59 (11) |
| Gender, n (%) | |||
| Female | 21 (42%) | 24 (50%) | 45 (46%) |
| Male | 29 (58%) | 24 (50%) | 53 (54%) |
| Primary Tumor Site, No. (%) | |||
| Gynecologic | 4 (8%) | 4 (8%) | 8 (8%) |
| Colorectal | 1 (2%) | 3 (6%) | 4 (4%) |
| GE junction | 8 (16%) | 4 (8%) | 12 (25%) |
| Lung | 6 (12%) | 7(15%) | 13 (27%) |
| Genitourinary | 2 (4%) | 0 (0%) | 2 (2%) |
| Lymphoma | 5 (10%) | 2 (4%) | 7 (15%) |
| Breast | 1 (2%) | 1 (2%) | 2 (2%) |
| Pancreatic | 19 (38%) | 17 (35%) | 36 (37%) |
| Gastric | 4 (8%) | 6 (13%) | 10 (10%) |
| Other | 0 (0%) | 4 (8%) | 4 (4%) |
| Previous history of VTE, n (%) | 4 (8%) | 2 (4%) | 6 (6%) |
*NOTE: 1 subject had both DVT and PE at baseline screening
Abbreviations: DVT, deep vein thrombosis; PE pulmonary embolism; VTE, venous thromboembolism; ECOG: Eastern Cooperative Oncology Group
Cumulative Incidence Curves for the Primary Efficacy Outcome in the Intention-to-Treat Population, According to Study Arm.
Cumulative Incidence Curves for the Primary Efficacy Outcome in the Intention-to-Treat Population, According to Study Arm.
Khorana:Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; sanofi: Consultancy, Honoraria. Off Label Use: Randomized trial of dalteparin as prophylaxis. The drug is approved for treatment of cancer-associated thrombosis but not for prophylaxis.. Francis:Eisai: Consultancy, Research Funding; Portola: Consultancy, Honoraria; NHLBI: Consultancy; Lilly: Consultancy. Kuderer:Hospira: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy. Carrier:Leo Pharma: Consultancy, Research Funding; BMS: Research Funding; Bayer: Consultancy, Honoraria; Pfizer: Consultancy. Ortel:Instrumentation Laboratory: Consultancy; Instrumentation Laboratory: Research Funding; Eisai: Research Funding; Daiichi Sankyo: Consultancy. Wun:Janssen: Consultancy. Iyer:Ipsen Pharmaceuticals: Consultancy; Genentec: Research Funding; Bristol Myers Squibb: Honoraria. Lyman:Amgen: Research Funding.
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