Subcutaneous heparin treatment increases survival in small cell lung cancer. "Petites Cellules" Group. The effect of low molecular weight heparin on survival in patients with advanced malignancy. Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial. Intravenous heparin for the prevention of stroke progression in acute partial stable stroke. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Effect of low molecular weight heparin (Certoparin) versus unfractionated heparin on cancer survival following breast and pelvic cancer surgery: A prospective randomized double-blind trial. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group. Benefit and risk of heparin for maintaining peripheral venous catheters in neonates: a placebo-controlled trial.
A positive influence of anticoagulant treatment in small cell lung cancer (SCLC) has been suggested by experimental and clinical data.
                In a multicenter clinical trial, 277 patients with SCLC were randomized either to receive or not to receive subcutaneous heparin injections for 5 weeks at effective doses, which were monitored by blood coagulation tests. All patients received one of the two chemotherapy regimens studied in this trial, for eight courses in the case of patients with complete or partial response, and subsequently were randomized to receive delayed thoracic radiotherapy after these eight courses.
                In comparison to the 139 patients who did not receive heparin, the 138 patients who received anticoagulant treatment obtained better complete response rates (37% vs. 23%, P = 0.004), better median survival (317 days vs. 261 days, P = 0.01), and better survival rates at 1, 2, and 3 years (40% vs. 30%, 11% vs. 9% and 9% vs. 6%, respectively). At subgroups analysis, the results on survival were obtained for limited forms (P = 0.03) but not for extensive diseases (P = 0.31). No important bleeding or thrombocytopenia was related to heparin treatment.
                These results confirm the value of anticoagulant treatment in SCLC, already suspected for warfarin and now proven for heparin, but the modes of administration and the biologic explanations for this activity still warrant further investigation. Studies in cancer patients with venous thromboembolism suggested that low molecular weight heparin may prolong survival. In a double-blind study, we evaluated the effect of low molecular weight heparin on survival in patients with advanced malignancy without venous thromboembolism.
                Patients with metastasized or locally advanced solid tumors were randomly assigned to receive a 6-week course of subcutaneous nadroparin or placebo. The primary efficacy analysis was based on time from random assignment to death. The primary safety outcome was major bleeding.
                In total, 148 patients were allocated to nadroparin and 154 patients were allocated to placebo. Mean follow-up was 1 year. In the intention-to-treat analysis the overall hazard ratio of mortality was 0.75 (95% CI, 0.59 to 0.96) with a median survival of 8.0 months in the nadroparin recipients versus 6.6 months in the placebo group. After adjustment for potential confounders, the treatment effect remained statistically significant. Major bleeding occurred in five (3%) of nadroparin-treated patients and in one (1%) of the placebo recipients (P = .12). In the a priori specified subgroup of patients with a life expectancy of 6 months or more at enrollment, the hazard ratio was 0.64 (95% CI, 0.45 to 0.90) with a median survival of 15.4 and 9.4 months, respectively. For patients with a shorter life expectancy, the hazard ratio was 0.88 (95% CI, 0.62 to 1.25).
                A brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation. To prospectively assess whether low-molecular-weight heparin (LMWH) provides a survival benefit in patients with advanced cancer.
                Between December 1998 and June 2001, we performed a randomized controlled study of patients with advanced cancer. Initially, the study was double blinded and placebo controlled, with the patients receiving daily injections of 5000 U of LMWH or saline. However, because of low accrual midway through the study, the placebo injection arm was eliminated, and the study became open labeled, with patients receiving either LMWH injections plus standard clinical care or standard clinical care alone. The primary study end point was overall survival.
                Of 141 patients randomized to this clinical trial, 3 dropped out, leaving 138 patients. The median survival time was 10.5 months (95% confidence interval, 7.6-12.2 months) for the combined standard care and placebo groups. The median survival time for the combined LMWH arms was 7.3 months (95% confidence interval, 4.8-12.2 months). These median survival times were not significantly different (log-rank P = .46). The median survival times for the blinded and unblinded LMWH groups were 6.2 months and 9.0 months, respectively. The median survival times were 10.3 months for the blinded placebo arm and 10.5 months for the standard care arm. The rate of severe or life-threatening venous thromboembolism was 6% in the LMWH arms and 7% in the control arms. The rate of severe or life-threatening bleeding was 3% in the LMWH arms and 7% in the control arms. In a double-blind, placebo-controlled trial, 225 patients with acute partial stable thrombotic stroke were randomly assigned to receive continuous intravenous heparin therapy or placebo for 7 days for the prevention of stroke progression or death. No statistically significant difference between the two groups was found in degree of neurologic change; incidence of stroke progression after 7 days; or functional activity level of survivors at 7 days, 3 months and at 1 year after treatment. Compared with controls, a statistically significant greater number of patients in the group receiving heparin died in the year after the stroke. These deaths occurred 3 to 12 months after the initial stroke and probably were not related to treatment. Results of this study do not support the use of intravenous heparin to treat patients who have had acute partial stroke. The use of warfarin sodium for treating venous thromboembolism in patients with cancer is associated with a significant risk of recurrence and bleeding. The use of low-molecular-weight heparin sodium for secondary prevention of venous thromboembolism in cancer patients may reduce the complication rate.
                To determine whether a fixed dose of subcutaneous low-molecular-weight heparin is superior to oral warfarin for the secondary prophylaxis of venous thromboembolism in patients with cancer and venous thromboembolism.
                In a randomized, open-label multicenter trial performed between April 1995 and March 1999, we compared subcutaneous enoxaparin sodium (1.5 mg/kg once a day) with warfarin given for 3 months in 146 patients with venous thromboembolism and cancer.
                A combined outcome event defined as major bleeding or recurrent venous thromboembolism within 3 months.
                Of the 71 evaluable patients assigned to receive warfarin, 15 (21.1%; 95% confidence interval [CI], 12.3%-32.4%) experienced one major outcome event compared with 7 (10.5%) of the 67 evaluable patients assigned to receive enoxaparin (95% CI, 4.3%-20.3%; P =.09). There were 6 deaths owing to hemorrhage in the warfarin group compared with none in the enoxaparin group. In the warfarin group, 17 patients (22.7%) died (95% CI, 13.8%-33.8%) compared with 8 (11.3%) in the enoxaparin group (95% CI, 5.0%-21.0%; P =.07). No difference was observed regarding the progression of the underlying cancer or cancer-related death.
                These results confirm that warfarin is associated with a high bleeding rate in patients with venous thromboembolism and cancer. Prolonged treatment with low-molecular-weight heparin may be as effective as oral anticoagulants and may be safer in these cancer patients. Recent studies suggest that low molecular weight heparin (LMW heparin) therapy in malignancy may improve cancer survival following surgical resection. We studied prospectively whether cancer mortality during follow-up in women with previously untreated breast, and pelvic cancer is reduced in those who randomly received LMW heparin (Certoparin) compared to patients given unfractionated heparin (UF heparin) for thrombosis prophylaxis during primary surgery. In a prospective, randomized, double-blind clinical trial, 160 patients received Certoparin and 164 UF heparin until post-operatively day 7. Survival estimations are based on the outcome data from a subset of 140 LMW heparin - and 147 UF heparin recipients. Long-term survival in the Certoparin group compared to the UF heparin group was significantly improved after 650 days (P=0. 0066) but not thereafter when analysis was performed on all cancer cell types combined. In the probability estimates survival benefit within this time was restricted to patients with pelvic cancer but was not observed in breast cancer. However, in breast cancer patients who received LMW heparin the impact of classical tumor prognostic markers was statistically significant after 1,050 days but not after 650 days. Thus, breast cancer patients with unfavorable prognosis seem to benefit in terms of survival advantage from LMW heparin within the 650 days after surgery. These results suggest that improvement in cancer survival can be achieved after even a short course of treatment with LMWH (compared to UFH) given for DVT prophylaxis in the post-operative period. An effect of UFH on disease outcome is not excluded. Further definitive trials of LMWH vs. placebo for cancer outcome (rather then DVT) using doses and schedules that may be more optimal are indicated. A substantial clinical need exists for an alternative to vitamin K antagonists for treating deep-vein thrombosis in cancer patients who are at high risk of both recurrent venous thromboembolism and bleeding. Low-molecular-weight heparin, body-weight adjusted, avoids anticoagulant monitoring and has been shown to be more effective than vitamin-K-antagonist therapy.
                Subjects were patients with cancer and acute symptomatic proximal-vein thrombosis. We performed a multi-centre randomized, open-label clinical trial using objective outcome measures comparing long-term therapeutic tinzaparin subcutaneously once daily with usual-care long-term vitamin-K-antagonist therapy for 3 months. Outcomes were assessed at 3 and 12 months.
                Of 200 patients, 100 received tinzaparin and 100 received usual care. At 12 months, the usual-care group had an excess of recurrent venous thromboembolism; 16 of 100 (16%) versus 7 of 100 (7%) receiving low-molecular-weight heparin (P=.044; risk ratio=.44; absolute difference -9.0; 95% confidence interval [CI], -21.7 to -0.7). Bleeding, largely minor, occurred in 27 patients (27%) receiving tinzaparin and 24 patients (24%) receiving usual care (absolute difference -3.0; 95% CI, -9.1 to 15.1). In patients without additional risk factors for bleeding at the time of randomization, major bleeding occurred in 0 of 51 patients (0%) receiving tinzaparin and 1 of 48 patients (2.1%) receiving usual care. Mortality at 1 year was high, reflecting the severity of the cancers; 47% in each group died.
                Our findings confirm the limited but benchmark data in the literature that long-term low-molecular-weight heparin is more effective than vitamin-K-antagonist therapy for preventing recurrent venous thromboembolism in patients with cancer and proximal venous thrombosis. The optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism is still a matter of debate.
                We performed a multicenter trial comparing six weeks of oral anticoagulant treatment with six months of such therapy in patients who had a first episode of venous thromboembolism. Anticoagulant therapy consisted of warfarin or dicumarol. Of the 902 patients enrolled, 5 were later excluded because they had congenital protein C deficiency; 443 were randomly assigned to receive six weeks of oral anticoagulant therapy with a targeted international normalized ratio (INR) of 2.0 to 2.85, and 454 were randomly assigned to receive six months of such therapy. The initial diagnoses were confirmed by means of venography in cases of deep-vein thromboses (n = 790) and with perfusion-ventilation scanning or angiography in cases of pulmonary embolism (n = 107); recurrences were confirmed in the same way.
                After two years of follow-up, there had been 123 recurrences of venous thromboembolism that met the diagnostic criteria, 80 in the six-week group (18.1 percent; 95 percent confidence interval, 14.5 to 21.6) and 43 in the six-month group (9.5 percent; 95 percent confidence interval, 6.8 to 12.2). The odds ratio for recurrence in the six-week group was 2.1 (95 percent confidence interval, 1.4 to 3.1). There was no difference in mortality or the rate of major hemorrhage between the six-week and six-month groups.
                Six months of prophylactic oral anticoagulation after a first episode of venous thromboembolism led to a lower recurrence rate than did treatment lasting for six weeks. The difference between the two groups occurred between 6 weeks and 6 months after the start of treatment, and the rates of recurrence remained nearly parallel for 1 1/2 years thereafter. Heparin addition to infusion fluids is used to prolong catheter patency in newborns. Heparin may also induce adverse effects such as bleeding complications and immune-mediated heparin-induced thrombocytopenia (HIT). One objective was peripheral venous catheter patency with heparinization of continuous infusions (0.5 IU/mL). Secondary objectives were incidences of bleeding, clinically manifest HIT, HIT antibodies, and catheter-related complications.
                Inclusion criteria were anticipated need for intravenous peripheral infusion (>or=5 days for HIT-related endpoints) and postnatal age <28 days at study entry. Exclusion criteria were bodyweight <1000 g, congenital malformation, need for therapeutic anticoagulation or mechanical ventilation, and severe bleeding. HIT antibodies were assessed by enzyme-linked immunosorbent assay.
                A total of 145 infants received heparin, and 151 infants received saline. Patient characteristics, number of additional drugs, duration of treatment, and location and size of catheters did not differ. Patency of catheters was 7.4 hours longer in the heparin group (33.8 hours vs 26.4 hours, P<.0001), but the total numbers of catheters did not differ (565 vs 692, P=.3). No infant developed HIT antibodies. Incidences of bleeding complications and thrombocytopenia were comparable between groups.
                Balancing the benefits against the risks of heparin addition and the rare complication of HIT, we will not use 0.5 IU/mL heparin addition to parenteral fluids.
Heparin was associated with a significant reduction of death at 24 months but not 12 months. It was also associated with a reduction in venous thromboembolism but based on the RCTs in this review it had no significant effect on major bleeding, minor bleeding or QoL. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides and integrate the patient's values and preferences.