Very-low-dose warfarin reduced thromboembolism in patients with metastatic breast cancer who were receiving chemotherapy
ACP J Club. 1994 Sept-Oct;121:34. doi:10.7326/ACPJC-1994-121-2-034
Levine M, Hirsh J, Gent M, et al. Double-blind randomised trial of very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet. 1994 Apr 9;343:886-9.
To assess the safety and efficacy of very-low-dose warfarin in preventing venous thrombosis in patients with metastatic breast carcinoma receiving chemotherapy.
3-year randomized, double-blind, placebo-controlled trial.
8 cancer treatment centers in Ontario, Canada; 2 in Connecticut, USA; and 1 in Italy.
315 women (mean age 56.5 y) had metastatic breast carcinoma and began first- or second-line chemotherapy ≤ 4 weeks before study entry. Exclusion criteria were Eastern Cooperative Oncology Group performance status of ≥ 3, underlying bleeding disorder or peptic ulcer disease, direct bilirubin levels > twice normal, prothrombin time international normalized ratio (INR) of ≥ 1.3, platelet count < 50 × 109/L, history of alcohol abuse, overt brain metastases, presence of psychiatric or affective disorder, need for long-term oral anticoagulant therapy, expected survival < 3 months, concurrent hormonal treatment, and inability to attend follow-up visits for geographical reasons. 4 patients were excluded from analysis because they did not start chemotherapy. 84% of patients completed the study treatment.
Patients were stratified by center and presence or absence of a central venous catheter and were randomly assigned to receive either very-low-dose warfarin, 1-mg daily for 6 weeks (n = 152), or placebo (n = 159). After 6 weeks, the dose was adjusted to maintain the prothrombin time at an INR of between 1.3 and 1.9. Treatment with warfarin or placebo continued for 1 week after termination of chemotherapy.
Main outcome measures
Rates of venous thromboembolism (VTE) including deep venous thrombosis (DVT) or pulmonary embolism (PE), hemorrhage, and survival.
1 patient (0.6%) in the warfarin group had a thromboembolic event compared with 7 patients (4.4%) in the placebo group (P = 0.031); the groups did not differ for rate of all or major hemorrhage or mortality (P = 0.6) (Table).
Very-low-dose warfarin was safe and effective in reducing the rate of thromboembolic events in women with metastatic breast carcinoma receiving chemotherapy.
Source of funding: National Cancer Institute of Canada.
For article reprint: Dr. Mark Levine, OCTRF Hamilton Regional Cancer Centre, 699 Concession Street, Hamilton, Ontario L8V 5C2, Canada. FAX 905-575-6323.
Table. Very-low-dose warfarin vs placebo to prevent venous thrombosis for women with metastatic breast cancer who were receiving chemotherapy
|Outcomes at up to 3-year follow-up||Very-low-dose warfarin||Placebo||RRR (95% CI)||NNT (CI)|
|Thrombolic event||0.7%||4.4%||85% ( 9 to 98)||27 (12 to 336)|
|Major hemorrhage||0.7%||1.3%||48% (-93 to 296)||Not significant|
|Mortality||57%||62%||8% (-10 to 24)||Not significant|
|All hemorrhage||5.3%||3.1%||67% (-41 to 378)||Not significant|
*Abbreviations defined in Glossary; RRR, RRI, NNT, NNH, and CI calculated from data in article.
Patients with cancer are at increased risk for VTE. The causes include immobility, procoagulants produced by tumor cells, and chemotherapy. Approximately 5% of patients with stage II breast cancer who are receiving chemotherapy develop thrombosis, prompting recommendations for prophylactic Greenfield filters or chronic oral anticoagulation, or both. These recommendations have met with little acceptance because of the invasive nature of the former and the monitoring and potential for hemorrhage associated with the latter. These considerations are especially pertinent for a condition in which the number-needed-to-treat to prevent death from VTE may be several hundred persons.
In their very well-constructed trial, Levine and colleagues showed that very low doses of warfarin reduced the incidence of VTE in patients with advanced breast cancer from 4.4% to 0.7% (6 DVTs and 1 PE vs 1 PE) during a mean of about 200 days of chemotherapy; major hemorrhagic events in each group were about 1%. Survival was not affected.
Two questions arise: 1) Should all patients with cancer receive anticoagulants in preparation for chemotherapy? and 2) Is Levine and colleagues' regimen better than a fixed low dose of 1 mg of warfarin daily? First, without confirmatory data from chemotherapy trials in patients with other or less advanced cancers, it seems premature to recommend this as a universal approach for patients with cancer despite the rarity of adverse effects. Second, in the study, patients took only 1 mg of warfarin for the first 6 weeks and subsequently were gradually increased to a mean dose of 2.6 mg of warfarin daily (INR 1.3 to 1.9). Only 1 event occurred in the treated group (at 202 days) compared with 3 events in the placebo group during the first 35 days. This suggests that even a 1-mg dose of warfarin might be effective. A trial evaluating a small fixed dose of 1 mg daily compared with the study regimen would be valuable. If effective, cumbersome monitoring could be avoided, making the treatment highly attractive to clinicians.
John S. Kizer, MD
University of North CarolinaChapel Hill, North Carolina, USA