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A Review of the suggested anti-cancer benefits of warfarin, low-molecular weight heparin, and aspirin
*Lori B. Hornsby, PharmD, BCPS
Denise Sutter, PharmD
Kyle Sexton, PharmD
Matt Eckley, PharmD, BCOP, BCPS
Spencer Durham, PharmD, BCPS (AQ-ID)
Evidence evaluating a survival benefit with anticoagulants in cancer is controversial, but suggests there may be antitumor benefits extending beyond their ability to decrease thromboembolic events.1-13 Although the mechanisms are not completely understood, it has been suggested that anticoagulants may limit tumor growth and metastasis through inhibition of both angiogenesis and cancer cell adhesion as well as increasing the immune response and decreasing cell motility.14 Antitumor benefits from both cyclo-oxigenase (COX) and non-COX-mediated mechanisms have been postulated for aspirin. COX-mediated mechanisms have been linked to antiplatelet effects through inhibition of COX-1 while inhibition of COX-2 is thought to inhibit apoptosis, cell migration, and angiogenesis.15-16
Trials evaluating the cancer benefits of warfarin, unfractionated heparin (UFH) and low molecular weight heparin (LMWH) have focused largely on cancer progression and survival,1-13, 17-19 while aspirin has been studied primarily for cancer prevention.20-26 Although inconclusive, there is some suggestion that warfarin may be beneficial in small cell lung cancer (SCLC), particularly extensive stage.1,2,4,5 A potential cancer benefit with warfarin is also supported by trials demonstrating a lower incidence of newly diagnosed cancer in patients treated with warfarin for longer, as opposed to shorter durations after an initial venous thromboembolism (VTE).6 Data supporting cancer benefits with heparin are also inconclusive but appears to be the strongest for LMWH (vs UFH)8,9, particularly dalteparin10,11 and in patients with SCLC7,11,13 who have a better prognosis at the time of therapy7,10,12. Epidemiologic trials suggesting a cancer benefit in patients receiving aspirin were followed by randomized, controlled trials reporting a decreased risk of recurrent adenomas in patients with a history of colorectal adenomas or colorectal cancer.20 Although initial trials failed to show a protective effect for cancer prevention with aspirin given every other day21-23, meta-analyses from cardiovascular prevention trials utilizing daily doses of aspirin have demonstrated a decrease in the incidence of colorectal cancer (potentially limited to proximal disease), colorectal cancer mortality, and overall cancer mortality.24-26 This benefit appears most significant for adenocarcinoma,25-26 in patients receiving therapy for longer durations (≥5 years)24-25 and only evident after an extended period of follow-up.24-25
The potential cancer benefit with warfarin has been evaluated in a number of clinical trials with conflicting results. One of the first, published in 1984 by Zacharski et al., randomly assigned patients (n=431) to standard chemotherapy with or without warfarin. Patients were followed for a minimum of 12 months with an average duration of therapy of 26.4 weeks. Although the target prothrombin time (PT) was not given, the average PT in the warfarin group was 17.6 seconds and 11.6 seconds in the non-warfarin groups. There was no benefit found for warfarin therapy in patients with colon, head and neck, or prostate cancer; however, the median survival time more than doubled in patients with SCLC treated with warfarin (n=25) compared to those receiving placebo (n=25) (49.5 vs 23 weeks; p = 0.018).1
Two later studies by the Cancer and Leukemia Group B evaluated the potential benefit of warfarin in extensive (n=294) and then limited (n=347) SCLC.2-3 The extensive SCLC study by Chahinian et al. found a benefit with warfarin (dosed to achieve a PT of 1.5-2 times control) in complete and partial response rates for the warfarin group (17% and 50%) over the two non-warfarin groups randomized to differing chemotherapy regimens (8% and 43%; 10% and 38%)(p=0.012) over a median follow-up of 36 months. Survival was extended in the warfarin group (median = 9.3 months) as compared to the non-warfarin groups (median = 7.9 months for both), although this was not statistically significant (p = 0.098).22 In the limited SCLC study by Maurer et al., warfarin (dosed to achieve a PT of 1.4-1.6 times control) did not improve objective response rates over a median follow-up of 69 months. Although the median survival duration was extended for warfarin (21.4 months, 95% CI 17.0-23.1) as compared to the non-warfarin group (18.6 months, 95% CI 16.0-20.9), this did not reach statistical significance (p = 0.124).3
Two systemic analyses, one by Smorenburg et al.4 in 2001 and a Cochrane Review5 in 2007, evaluated the effect of warfarin on cancer survival. Both reviews included the trials previously discussed, a trial by Levine et al. evaluating low dose warfarin for prevention of thromboembolism in stage IV breast cancer patients during chemotherapy, and a trial by Daily evaluating the use of therapeutic dose warfarin in Dukes B or C colorectal cancer for 2 years. The review by Smorenburg did not find a benefit with warfarin in overall cancer mortality at 1 year (OR 0.89; 95% CI 0.70-1.13) and noted that neither duration nor intensity of warfarin therapy appeared to affect the overall results.4 In the Cochrane Review, there was no overall cancer mortality benefit reported for warfarin at 6 months, 1, 2, or 5 years. A mortality benefit for SCLC was found at 6 months (RR 0.69, 95% CI 0.50-0.96), mainly due to benefits seen in patients with extensive SCLC (RR 0.65, 95% CI 0.45-0.93).5 This benefit in SCLC was no longer significant at 1 year (RR 0.88, 95% CI 0.77-1.01) and consistent with findings from the Smorenburg review (OR 0.72, 95% CI 0.44-1.16).4,5 The authors of the Smorenburg review noted a benefit in SCLC with warfarin at 2 years, but the Cochran Review did not (RR 0.76, 95% CI 0.50-1.16).4,5 The Cochrane Review also noted a significant increase in both major and minor bleeding (RR 4.24, 95% CI 1.85-9.68 and RR 3.34, 95% CI 1.66-6.74 ) with warfarin therapy.5
A prospective, randomized study (n=854) by Schulman et al. evaluated the potential benefit of warfarin for cancer prevention in patients after a first episode of VTE with a follow-up period of 6-9 years (mean 8 years). The incidence of newly diagnosed cancer was found to be higher in patients treated with warfarin (target INR of 2.0-2.85) for six weeks (15.8%) as compared to those treated for six months (10.3%) (p = 0.02) (OR 1.6, 95% CI 1.1-2.4). Newly diagnosed urogenital cancers appeared to be responsible for the benefit (6.7% in the 6-week group vs 2.8% in the 6-month group). The overall difference was not statistically significant until more than 2 years after the initial event and remained significant with adjustments for sex, age, cause of initial event (idiopathic vs nonidopathic), and recurrence of event. However, older patients with initial idiopathic events were more likely to be diagnosed with cancer. Deaths secondary to cancer did not differ between the groups. It should be noted that patients were screened for cancer only at the discretion of the investigators and not all diagnoses of cancer may have been captured.6
Heparins (UFH and LMWH)
In 1994, Lebeau et al. published the first randomized trial (n=277) demonstrating a survival benefit with subcutaneous (SC) heparin in SCLC. Patients not previously treated with chemotherapy were randomized to SC heparin (n=138) or no heparin (n=139). Heparin was administered starting 1 day prior to chemotherapy at an initial dose of 500 units/kg/day (given BID or TID) and adjusted to an aPTT of 2-3 times control for 5 weeks. There was a complete response rate of 33% in those receiving heparin compared to 21% for those not receiving heparin (p=0.03). Median survival in the heparin arm was also improved (317 days vs 261, p=0.01). Survival rates at 1, 2, and 3-years were higher in the heparin group compared to the non-heparin group (40% vs 30%, 11% vs 9%, and 9% vs 6%) (p=0.012). A sub-group analysis determined a benefit in limited SCLC (n=121) as opposed to extensive (n=156) and only in those receiving an alternating chemotherapy regimen as opposed to a sequential regimen. Bleeding rates were similar in both the heparin and non-heparin groups.7
In a post-hoc analysis8 and a later meta-analysis9, LWMH was found to have a benefit over UFH regarding cancer related mortality. In the post-hoc analysis by Prandoni et al. comparing the efficacy and safety of LMWH to UFH in the initial treatment of proximal deep vein thrombosis (DVT), cancer related death at 6 months was lower in patients randomized to LMWH (7% or 1 of 15) as compared to UFH (44% or 8 of 18) (p=0.021).8 Although this was a post-hoc analysis with a small number of cancer patients and did not address potential confounders such as cancer type or stage, a potential advantage of LMWH over UFH was suggested and demonstrated again in a meta-analysis by Hettiarachchi et al.9 The meta-analysis included nine trials (n=3581) comparing standard therapeutic doses of LMWH to UFH for the initial treatment of VTE followed by a minimum 3 month duration of warfarin therapy. Of the 629 patients (17.6%) with a diagnosis of cancer, the mortality rate at 3 months was 15% in the LMWH group (n=46) and 22% in the UFH group (n=71) (OR 0.61, 95% CI 0.40-0.93). The difference was not attributable to differences in mortality secondary to pulmonary embolism (PE) or bleeding events. The authors did caution the interpretation of the results due to the difficulty in explaining a mortality benefit with the short duration of both therapy and follow-up in addition to concerns with extrapolating these results to cancer patients without VTE.9
The Fragmin Advanced Malignancy Outcome Study (FAMOUS) was one of the first trials (n=385) conducted with the intent to evaluate the effect of a prophylactic dose of LMWH (dalteparin 5,000 units daily) on cancer survival. Patients with advanced malignancies and a minimum life expectancy of 3 months were randomized to dalteparin or subcutaneous placebo injections for 1 year. In the intention to treat analysis, the difference in 1 year survival between groups (46% vs 41%) was not statistically significant. In a post hoc analysis of patients with a better prognosis living at least 17 months (n=55 for dalteparin, n=47 for placebo), there was a survival benefit in the dalteparin group at 2 and 3 years compared to placebo (78% vs 55% and 60% vs 36%; p=0.03). The median survival time in this subset was 43.5 months (95% CI 33-52.3 months) for dalteparin as compared to 24.3 months (95% CI 22.4-41.5) for placebo. Bleeding rates were 4.7% for dalteparin and 2.7% for placebo with all but one in the dalteparin group considered minor.10
While Altinbas et al.11 found a survival benefit with dalteparin in early SCLC, Sideras et al.17 did not find a benefit in advanced solid tumors nor did Perry et al.18 in patients with newly diagnosed malignant glioma. Altinbas randomized previously untreated patients (n=84) with early SCLC to chemotherapy in addition to either dalteparin 5,000 units daily or placebo injections for 18 weeks. The median survival was greater with dalteparin (13.0 ± 1.62 months, 95% CI 9.83-16.17) as compared to placebo (8.0 ± 0.95 months, 95% CI 6.14-9.86)(p=0.01). Survival at 1- and 2-years was higher in the dalteparin group compared to placebo (51.3% vs 29.5% and 17.2% vs 0%, respectively), with an overall decrease in the risk of death in favor of dalteparin (HR 0.56, 95% CI 0.30-0.86). Results remained significant regardless of tumor stage.11 The Sideras trial (n=141) found no mortality benefit with dalteparin 5,000 units daily in patients with advanced breast cancer who failed first-line treatment, advanced prostate cancer who failed hormonal therapy, or advanced lung or colorectal cancer.17 In the randomized, placebo controlled Prophylaxis Using Dalteparin In Glioblastoma Multiforme (PRODIGE) trial by Perry et al. (n=186), dalteparin 5,000 units administered daily for a minimum of 6 months, in World Health Organization (WHO) grade 3 or 4 newly diagnosed malignant glioma patients, did not reduce the mortality rate compared to placebo (18% vs 12.6%; HR 1.4, 95% CI 0.60-3.2). Although bleeding occurred more frequently in the dalteparin group, this did not reach statistical significance. There were 6 episodes of major bleeding (5 in the dalteparin group and 1 in the placebo group), all being intracranial.18 It should be noted that the small sample size in each of these trials as well as the advanced stage in the Sideras trial (all cancers were determined to be incurable) could have affected the results.17-18
Nadroparin has been evaluated in two trials with mixed results.12,19 In the Malignancy and Low Molecular Weight Heparin Therapy (MALT) trial, Klerk et al. found a survival benefit with nadroparin in patients with solid malignant tumors. Individuals (n=302) with a minimum life expectancy of 1 month were randomized to nadroparin (twice daily as a treatment dose for 2 weeks followed by a daily prophylactic dose for an additional 4 weeks) or placebo and followed for an average of 1 year. Nadroparin was associated with an increased survival rate compared to placebo at both 1 and 2 years (39% vs 27% and 21% vs 11%). Median survival was 8.0 months with nadroparin and 6.6 months with placebo with an overall decrease in mortality for nadroparin (HR 0.75, 95% CI 0.59-0.96). Results were similar after adjusting for life expectancy, WHO performance status, concomitant treatment and type and histology of cancer. A sub-group analysis revealed a greater benefit for patients with a life expectancy >6 months at the initiation of therapy (HR 0.64, 95% CI 0.45-0.90) as opposed to <6 months (HR 0.88, 95% CI 0.62-1.25) with median survival increased to 15.4 months in the nadroparin group as compared to 9.4 months in the placebo group for those with a life expectancy >6 months. The benefits were significant for adenocarcinoma (HR 0.68, 95% CI 0.51-0.91) but not colorectal (HR 0.83, 95% CI 0.46-1.51) or breast cancer (HR 0.78, 95% CI 0.41-1.48). Baseline characteristics were similar between groups with the exception of cancer type. Breast cancer was more frequent in the nadroparin group while colorectal and cervical cancers were more frequent in the placebo group. A greater portion of placebo patients received chemotherapy during the trial while a greater portion of nadroparin patients received radiotherapy. There were no differences in major bleeding (3% vs 1%, p=0.12); however, clinically relevant bleeding was higher in the nadroparin group (7% vs 1%, p=0.005).12
The Prophylaxis of Thromboembolism during Chemotherapy (PROTECHT) trial (n=1150) did not find a mortality benefit with prophylactic dose nadroparin (3800 IU daily) in ambulatory patients with locally advanced or metastatic solid cancers. Patients were randomized to nadroparin or placebo for 4 months or for the duration of chemotherapy if less than 4 months. The median duration of follow-up was 111 and 113 days. Although there was a statistically significant difference found for the occurrence of thromboembolic events, there was no difference found for survival at 1-year (56.7% vs 59.3%). Bleeding rates were similar between groups. There were a large number of patients who did not complete the study for both groups (35%, nadroparin and 29%, placebo). In addition, the authors noted the potential effect of the short duration of therapy on the ability to identify a cancer related benefit in this trial.19
A 2011 Cochrane Review (n=2531) did not find an overall cancer mortality benefit with heparin products at 1 year (RR 0.93, 95% CI 0.85-1.02), but did find a difference in patients with SCLC (n=361) (RR 0.86, 95% CI 0.75-0.98). The review included 7 of the trials discussed above, in addition to a small trial by Weber et al. evaluating prophylactic dose nadroparin in 20 patients with advanced stage cancer and a trial by Pelzer et al. in 312 patients with pancreatic cancer randomized to receive a prophylactic dose of enoxaparin or no treatment, in addition to palliative chemotherapy. Eight of the nine trials compared SC LMWH (enoxaparin n=1, dalteparin n=4, nadroparin n=3) to placebo or standard therapy. Only one trial utilized SC heparin. A mortality benefit for heparin was found in a post-hoc analysis including 5 of the trials (n=1175) at 24 months (RR 0.92, 95% CI 0.88-0.97) and in an analysis of 7 of the trials (n=1381) reporting data for a time-to-event analysis (RR 0.79, 95% CI 0.67-0.93). This difference was not affected by subgroup (advanced vs nonadvanced or SCLC vs non SCLC). There were no significant differences in major (RR 1.3, 95% CI 0.59-2.88) or minor (RR 1.05, 95% CI 0.75-1.46) bleeding. It was noted that the discrepancy between the overall mortality benefit at 12 and 24 months may have been due to the inclusion of various types and stages of cancer.13
Observational studies were the first to suggest an association with aspirin use and lower rates of cancer. The first randomized, controlled trials examined the effect of aspirin on colorectal adenomas. Although there appeared to be a benefit for the prevention of adenomas, this benefit was not seen for cancer. It was postulated the length of follow up may have been inadequate to detect a delayed cancer benefit.20 Aspirin dosed every other day in both the Physician’s Health Study (PHI) and the Women’s Health Study (WHS) failed to show a benefit, further questioning the anti-cancer effects of aspirin.21-22 More recently however, several meta-analyses by Rothewell and colleagues, have reported benefits of aspirin on cancer incidence, metastasis, and mortality.24-26 Data from trials originally designed to determine the cardiovascular benefits of aspirin were utilized for these analyses. Information was abstracted from in-trial data during active treatment, in addition to long term data (up to 20 years of follow-up) from the evaluation of death certificates and cancer registries.24-26 In the three analyses overall cancer occurrence was decreased by 12% while the incidence of colorectal cancer was decreased by 24%. Overall cancer mortality was reduced by approximately 20% and colorectal cancer mortality by 34%. The greatest benefit appears to be with adenocarcinomas (as opposed to nonadenocarcinomas), in patients with colorectal cancer (proximal rather than distal) without metastasis at the time of diagnosis and with longer durations of therapy.24-26
In a meta-analysis (n=2967) of four randomized controlled trials in patients with a history of colorectal adenomas or cancer, aspirin was found to reduce the relative risk of recurrent adenomas by 17%.20 Aspirin doses of 81-325mg (n=450 low dose; n=1228 higher dose) or placebo were given for a minimum of 1 year with an average follow up of 33 months. Of the 2698 with follow-up colonoscopies, 33% (n=507) receiving aspirin developed adenomas compared to 37% (n=424) receiving placebo (RR 0.83, 95% CI 0.72-0.96). The greatest reduction was seen during the first year of follow-up. Advanced lesions (defined as tubulovillous or villous adenomas, adenomas ≥ 1cm or with high-grade dysplasia, or invasive cancer) were detected in 9% of the aspirin group and 12% of the placebo group (RR 0.72, 95% CI 0.57-0.90). The effect of aspirin on advanced lesions was greater for those with a family history of colorectal cancer (RR 0.53, 95% CI 0.33-0.83) and had no effect on those without (RR 0.92, 95% CI 0.67-1.28). High-dose aspirin was not associated with a statistically significant reduction for overall adenoma recurrence (RR 0.85, 95% CI 0.70-1.03) but was significant for a reduction in advanced lesions (RR 0.71, 95% CI 0.56-0.92). For low-dose aspirin, the opposite was found (RR 0.83, 95% CI 0.71-0.96 for overall adenoma recurrence and RR 0.83, 95% CI 0.44-1.58 for advanced lesions). There were no significant differences between the aspirin and placebo groups in regards to the occurrence of colorectal cancer (0.54% vs 0.62%, p=0.81), new cancer diagnosis (2.62% vs 1.86%, p=0.18), death (0.95% vs 0.85%, p=0.85), or major bleeding (2.50% vs 2.79%, p=0.64).20
Neither the Physician’s Health Study (PHS)21 nor the Women’s Health Study (WHS)22 detected a benefit of aspirin for cancer prevention in patients randomized to aspirin or placebo. Aspirin was given every other day as opposed to daily in both studies at a dose of 325mg for the PHS and 100mg for the WHS. The PHS (n=22,071) included physicians 40-84 years of age while the WHS (n=39,876) included women ≥45 years of age. The aspirin arm of the PHS trial was terminated after an average follow-up of 5 years due to the cardiovascular benefits observed while the WHS included a 10 year follow-up. In the PHS there were no differences found for the development of colorectal cancer at any time, including a later analysis at 12 years23 for those originally assigned to aspirin or those who switched to aspirin at the end of the 5 year trial. The WHS failed to find an advantage of aspirin for prevention of total cancer, colorectal cancer, breast cancer, lung cancer, and overall cancer mortality with the exception of mortality secondary to lung cancer (RR 0.70, 95% CI 0.50-0.99). Whether the every other day dosing of aspirin in these trials along with low compliance in the WHS (average of 73% defined as taking at least two-third of the study drug) contributed to the results is uncertain.21,22
The first meta-analysis by Rothewell et al. included 5 randomized, controlled trials (n=14,033) with aspirin doses ranging from 30-300mg per day (low-dose) to 500-1200mg per day (high-dose). Mortality data were available for all trials through death certificates and cancer registry data and incidence of colorectal cancer was available for 3 trials. After a median treatment of 6 years (range of 1-8.6 years) and median follow-up of 18.3 years (range of 17-27 years), aspirin use decreased the 20 year risk of colon cancer (HR 0.76, 95%CI 0.60-0.96) and mortality due to colorectal cancer (HR 0.66, 95% CI 0.51-0.85). The benefit for occurrence appeared to be site specific for the proximal colon (HR 0.45, 95% CI 0.28-0.74) but not the distal colon (HR 1.10, 95% CI 0.73-1.64), nor for rectal cancers (HR 0.90, 95%CI 0.63-1.30). The authors noted similar benefits specifically with low- dose (75mg daily) therapy; however, these differences did not reach statistical significance for all outcomes. A longer treatment duration (≥5 years) was found to be associated with a mortality benefit (p=0.04).24
The second meta-analysis included patient level data from 8 randomized trials (n=25,570) with a mean or median treatment duration of at least 4 years and 20-year follow-up data available for 3 of the 8 trials utilizing death certificates and cancer registry data. Aspirin doses ranged from 75mg-1200 mg per day. The risk of overall cancer related mortality during treatment was reduced with the use of aspirin (OR 0.79, 95% CI 0.68-0.92) and remained significant with doses of 75-100 mg per day (OR 0.81, 95% CI 0.68-0.97). In the 7 trials with data regarding time of death, aspirin reduced deaths due to cancer (HR 0.82, 95% CI 0.70-0.95) with a more pronounced effect seen after 5 years of scheduled trial treatment (HR 0.66, 95% CI 0.50-0.87). Site specific data were available for 6 trials. Aspirin did not have an effect on the risk of death for any individual cancer type during 0-5 years of follow-up. There was a benefit seen however for death due to combined gastrointestinal cancers (HR 0.46, 95% CI 0.27-0.77) and all solid cancers (HR 0.64, 95% CI 0.49-0.85) with follow-up of ≥5 years. For the analysis of long-term cancer related deaths from 3 trials (n=12,659), aspirin was found to decrease the 20-year risk of cancer related mortality for combined gastrointestinal cancers (HR 0.65, 95% CI 0.54-0.78) and combined solid tumors (HR 0.80, 95% CI 0.72-0.88). There was no benefit seen for death due to solid cancers with scheduled treatment of <5 years (HR 1.06, 95% CI 0.82-1.39), but was significant with treatment for 5-7.4 years (HR 0.79, 95% CI 0.70-0.90) and greatest for treatment ≥7.5 years (HR 0.69, 95% CI 0.54-0.88). Death from gastrointestinal cancers was reduced with treatment ≥7.5 years (HR 0.41, 95% CI 0.26-0.66). Due to the apparent benefit related to duration of therapy, the 10,502 patients with scheduled treatment duration of at least 5 years were analyzed. In this subset, aspirin use was associated with a reduced 20-year risk of death from gastrointestinal (HR 0.65, 95% CI 0.53-0.78) and non-gastrointestinal solid tumors (HR 0.79, 95% CI 0.69-0.91), with the greatest effects seen with esophageal and colorectal cancers. The beneficial effects of aspirin were not observed until approximately 5 years for esophageal cancer and 10 years for stomach and colorectal cancers. The mortality benefit with pancreatic cancer was not observed until 20 years and only for those with a scheduled treatment duration of greater than 7.5 years. The non-gastrointestinal solid cancer benefits were mainly derived from benefits in lung cancer. Based on histological type, aspirin reduced the death associated with adenocarcinomas but had no effect on non-adenocarcinomas. The effect of aspirin on breast and gynecologic cancers was not evaluated due to the low number of women in these studies. Overall, the absolute risk reduction at 20-years for gastrointestinal cancer was 2.18% (1.14%-3.22%) and non-gastrointestinal solid cancers was 1.88% (0.57-3.19%).25
The third meta-analysis found a beneficial effect for aspirin on the risk of metastasis. This analysis included data from 5 randomized controlled trials (n=17,285) utilizing aspirin doses of ≥75 mg per day compared to placebo. There were 987 diagnoses of new solid cancers during a mean trial follow-up of 6.5 years. Treatment with aspirin decreased the incidence of new cancers (OR 0.88, 95% CI 0.78-0.99) with an even greater effect on the risk of death due to cancer (OR 0.77, 95% CI 0.65-0.91). There was uncertainty regarding metastasis in 21% (n=212) of cancer cases although this did not differ between groups. For the remaining 775 solid cancers cases, aspirin use was found to decrease the incidence of in-trial distant metastasis (HR 0.64, 95% CI 0.48-0.84). This benefit remained significant when metastasis was assumed in those with an unknown status (OR 0.75, 95% CI 0.63-0.89). The risk of metastasis was reduced with aspirin use for adenocarcinomas (HR 0.60, 95% CI 0.46-0.78) but not nonadenocarcinomas and remained significant for adenocarcinomas without metastasis at diagnosis (with later development of metastasis on follow-up) (HR 0.46, 95% CI 0.29-0.73) as well as adenocarcinomas with metastasis at the time of diagnosis (HR 0.69, 95% CI 0.50-0.95). For those with colorectal cancer without metastasis at the time of diagnosis, the risk of future metastasis was further reduced (HR 0.26, 95% CI 0.11-0.57) as well as in those who remained on treatment with aspirin up until the time of diagnosis or after diagnosis (HR 0.31, 95% CI 0.15-0.62 for all adenocarcinomas and HR 0.13, 95% CI 0.03-0.56 for colorectal cancer). As in the previous analysis, a mortality benefit was detected in adenocarcinomas (HR 0.65, 95% CI 0.53-0.82) but not nonadenocarinomas (HR 1.06, 95% CI 0.84-1.32).26
Any potential cancer benefits with warfarin or LMWH should be weighed against their increased risk of bleeding. Although some results appear promising, routine use of anticoagulant therapy in cancer patients without a recent thromboembolic event is not currently recommended.27 Additional trials are needed to provide more definitive evidence; however, the clinical utility of warfarin in this setting is questionable due to its unpredictable dose response, numerous interactions, and 4-6 fold increased risk of bleeding in cancer patients as compared to non-cancer patients.28 Future research with LMWH seems more promising. The focus of such research should be to identify patient characteristics (cancer type, stage, and prognosis) most likely to benefit in addition to the most appropriate dose and duration of therapy. The chemoprotective effects of aspirin are encouraging and may add to aspirin’s cardiovascular benefits and overall risk-benefit profile; however, the U.S. Preventive Services Task Force in their most recent recommendations considers the absolute benefit insufficient to recommend aspirin in average risk patients due to the risk of gastrointestinal bleeding, hemorrhagic stroke, and renal effects.29 Future research with aspirin will also need to focus on determining the most effective dose, optimal duration of therapy, and subset of patients most likely to benefit.
- Zacharski L, Henderson W, Rickles F, Forman W, et al. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate: Final report of VA cooperative study #75. Cancer 1984;53:2046-52.
- Chahinian A, Propert K, Ware J, Zimmer B, et al. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. American Society of Clinical Oncology 1989;7:993-1002.
- Maurer L, Herndon J, Hollis D, Aisner J, et al. Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study. American Society of Clinical Oncology 1997;15:3378-87.
- Smorenburg S, Vink R, Otten H, Swaneveld F, Buller H. The effects of vitamin K-antagonists on survival of patients with malignancy: a systematic analysis. Letter to the editor. Thromb Haemost 2001:86:1586-7.
- Akl E, Kamath G, Kim Y, Yosuico V, et al. Oral anticoagulation may prolong survival of a subgroup of patients with cancer: a Cochrane Systematic Review. J Exp Cancer Res 2007;26:175-84.
- Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. NEJM 2000;342:1953-8.
- Lebeau B, Chastang C, Brechot J, Capron F, et al. Subcutaneous heparin treatment increases survival in small cell lung cancer. “Petites Cellules” Group. Cancer 1994;74:38–45.
- Prandoni P, Lensing A. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992;339:441-5.
- Hettiarachchi R, Smorenburg S, Ginsberg J, Levine M, et al. Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread. Thrombosis and Haemostasis 1999;82:947-52.
- Kakkar A, Levine M, Kadziola Z, Lemoine N, et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the Fragmin Advanced Malignancy Outcome Study (FAMOUS). Journal of Clinical Oncology 2004;22:1944–8.
- Altinbas M, Coskun H, Ozkan M, Eser B, et al. A randomized clinical trial of combination chemotherapy with and without low molecular weight heparin in small cell lung cancer. Journal of Thrombosis and Haemostasis 2004;2:1266–71.
- Klerk C, Smorenburg S, Otten H, Lensing A, et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. Journal of Clinical Oncology 2005;23:2130–5.
- Akl E, Gunukula S, Barba M, Yosuico V, et al. Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database of Systematic Reviews 2011, Issue 1. Art No.: CD006652. DOI: 10.1002/14651858.CD006652.pub2.
- Bobek V, Kovarik J. Antitumor and antimetastatic effect of warfarin and heparins. Biomedicine and Pharmacotherapy 2004;58:213-19.
- Garcia-Albeniz X and Chan A. Aspirin for the prevention of colorectal cancer. Best Pract Res Clin Gastroenterol 2011;25:461-72.
- Thun M, Jacobs E, and Patrono C. The role of aspirin in cancer prevention. Nat Rev Clin Oncol 2012;9:259-67.
- Sideras K, Schaefer P, Okuno S, Sloan J, et al. Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial. Mayo Clinic Proceedings 2006;81: 758–67.
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Lori B. Hornsby, PharmD, BCPS
Associate Clinical Professor
Department of Pharmacy Practice
Auburn University Harrison School of Pharmacy (AUHSOP)
Ambulatory Clinical Pharmacist
Columbus Regional Healthcare System
Denise Sutter, PharmD
PGY1 Pharmacy Practice Resident
Saint Joseph Hospital
AUHSOP 2013 Graduate
Kyle Sexton, PharmD
PGY1 Pharmacy Practice Resident
AUHSOP 2013 Graduate
Matthew E. Eckley, PharmD, BCOP, BCPS
Clinical Pharmacy Specialist, Oncology
Spencer Durham, PharmD, BCPS (AQ-ID)
Assistant Clinical Professor
Department of Pharmacy Practice
Auburn University Harrison School of Pharmacy (AUHSOP)
Clinical Pharmacist, Medical Oncology
The Medical Center
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