Cancer patients have an increased risk of developing blood clots in the veins compared to non-cancer patients. Cancer patients who develop blood clots can lead to reduced life expectancy, delayed cancer treatment, and decreased quality of life. Prevention is the most effective way to decrease the complications associated with blood clots in the veins. Although previous clinical trials have shown some benefit on the use of medication to prevent blood clots in the veins in ambulatory cancer patients, these studies have been inconclusive in demonstrating that existing blood thinners significantly reduce the rate of blood clots in cancer patients. One possible explanation relates to the fact that these studies have included a large proportion of cancer patients who are a low risk of developing blood clots in the veins. We are proposing to identify cancer patients who are at a high risk of developing blood clots by using a validated tool at the time of their cancer diagnosis. The identified high risk cancer patients will be asked to participate in a trial to test the safety and efficacy of a new oral medication that has been used to prevent blood clots in patients undergoing surgery. We are enrolling 574 patients in 7 Canadian centers (Ottawa, Halifax, Montreal, Vancouver, Sault Ste. Marie, Toronto and Hamilton). 287 patients will receive the study drug and 287 will receive an inactive substance. Analysis will be performed to assess the safety and the superiority of the study drug.
Patients with active cancer have a heightened risk of venous thromboembolism (VTE). This risk is further increased by the initiation of chemotherapy. Although previous studies have suggested that the use of parenteral thromboprophylaxis in all ambulatory cancer patients receiving chemotherapy significantly decreases the rate of VTE, current clinical practice guidelines do not recommend routine use of thromboprophylaxis in this patient population. A major criticism of these studies has been the inclusion of patients at lower risk for VTE, which may have diluted the potential beneficial effect of the parenteral thromboprophylaxis. It is therefore imperative to appropriately risk stratify ambulatory cancer patients using a validated scoring system (e.g. Khorana risk score) in order to identify those most likely to benefit from thromboprophylaxis. Direct oral anticoagulants, such as apixaban, may offer a convenient and safe option for thromboprophylaxis. As such, AVERT will randomize 574 ambulatory cancer patients receiving chemotherapy who are at high-risk for VTE (as defined by a Khorana score of ≥2) to Apixaban 2.5 mg BID versus placebo. The primary study outcome will be the first episode of objectively documented symptomatic or incidental VTE (deep vein thrombosis and/or pulmonary embolism) within the first 6 months (180 days ± 3) following initiation of the blinded study drug for both intervention and placebo groups. The secondary safety outcomes include major bleeding, clinically relevant non-major bleeding, and overall survival rates. This study will hopefully offer evidence regarding the benefit of apixaban in ambulatory patients at high risk for VTE receiving chemotherapy.
<b>BACKGROUND: </b>Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis.<b>METHODS: </b>We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main safety outcome was a major bleeding episode.<b>RESULTS: </b>Of the 574 patients who underwent randomization, 563 were included in the modified intention-to-treat analysis. Venous thromboembolism occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P<0.001). In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P = 0.046). During the treatment period, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24).<b>CONCLUSIONS: </b>Apixaban therapy resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. The rate of major bleeding episodes was higher with apixaban than with placebo. (Funded by the Canadian Institutes of Health Research and Bristol-Myers Squibb-Pfizer Alliance; AVERT ClinicalTrials.gov number, NCT02048865.).
Background The risk of venous thromboembolism (VTE) is increased in patients with active cancer, contributing substantially to morbidity and mortality. Further, the VTE risk is even higher for patients with metastatic cancer than those with local disease. In the AVERT trial, apixaban thromboprophylaxis resulted in a significantly lower rate of venous thromboembolism and an increased rate of major bleeding than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. In this prespecified subgroup analysis of AVERT, we evaluated the efficacy and safety of apixaban thromboprophylaxis in patients with and without metastatic disease. Methods Eligible participants were randomized to receive either apixaban (2.5mg twice daily) or placebo (identical tablets twice daily) up to five days before the first administration of chemotherapy. The first dose of apixaban or placebo was given within 24 hours of the first chemotherapy administration, with the treatment period lasting 180 days. Patients were followed for up to 210 days or death, regardless of the duration of the treatment period. The primary efficacy outcome was objectively documented major VTE (proximal deep-vein thrombosis or pulmonary embolism) occurring within 180 days (±3 days ) following randomization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis criteria. For this subgroup analysis, the efficacy and safety of apixaban thromboprophylaxis was evaluated in patients with and without documented metastatic disease. The primary efficacy analysis was performed in the modified intention-to-treat population, which included all the patients who had undergone randomization and received at least one dose of apixaban or placebo on or before day 180 (±3 days). The primary safety analysis was performed in the on-treatment population, in which events were only counted if they occurred during the period the subject was taking the study drug (or up to two days post discontinuation). Results A total of 574 patients underwent randomization, with 563 patients included in the original primary efficacy and safety analysis. A total of 366 patients could be stratified according to the presence or absence of metastatic disease, with 138 having metastatic disease and 228 having non-metastatic disease. The baseline characteristics were balanced between the treatment and placebo arms in both the metastatic and non-metastatic groups (Table 1). In patients with metastatic disease, VTE occurred in 6 of out of 73 in the treatment group and 10 out of 65 in the placebo group [HR 0.55 95% CI 0.32-0.97, p=0.0381]. In patients with metastatic disease, major bleeding occurred in 3 out of 73 in the treatment group and 2 out of 65 in the placebo group [HR 1.47 95% CI 0.29-6.76, p= 0.69]. In patients with non-metastatic disease, VTE occurred in 4 out of 107 in the treatment group, and 14 out of 121 in the placebo group [HR 0.35 95% CI 0.20-0.61, p= 0.0002]. In patients with non-metastatic disease, major bleeding occurred in 1 out of 107 in the treatment group and 1 out of 121 in the placebo group [HR 1.20 95%CI 0.11-13.38, p=0.881]. Conclusions: In patients with and without metastatic disease, apixaban thromboprophylaxis was associated with a significantly lower rate of VTE compared to placebo, with no significant difference in the rate of major bleeding. This subgroup analysis thus suggests that apixaban thromboprophylaxis is both safe and effective in cancer patients regardless of the presence of absence of metastatic disease. [Formula presented] Disclosures: Wells: Daiichi Sankyo: Honoraria; BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria. Carrier: Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Servier: Honoraria. OffLabel Disclosure: Apixaban can be used as postoperative prophylaxis of DVT/PE and for treatment of DVT/PE. We looked at using apixaban 2.5mg BID for the primary thromboprophylaxis of ambulatory cancer patients initiating chemotherapy, at intermediate-high risk of venous thromboembolism.
BACKGROUND: Thromboprophylaxis for ambulatory patients with cancer is effective, although uncertainties remain on who should be targeted. Using D-dimer values from individuals enrolled to the AVERT trial, we sought to identify and validate a more efficient venous thromboembolism (VTE) risk threshold for thromboprophylaxis.
MATERIALS AND METHODS: The AVERT trial compared thromboprophylaxis with apixaban with placebo among patients with cancer with a Khorana Risk Score ≥2. The D-dimer measured at randomization was used to calculate an individualized 6-month VTE risk using the validated CATScore. A modified intention-to-treat analysis was used to assess efficacy (VTE) and safety (major and overall bleeding) in the (a) complete cohort and (b) ≥8% and < 8% 6-month VTE risk thresholds.
RESULTS: Five hundred seventy-four patients were randomized in the AVERT trial; 466 (81%) with baseline D-dimer were included in the study. Two hundred thirty-seven subjects received apixaban; 229 received placebo. In the complete cohort, there were 13 (5.5%) VTE events in the apixaban arm compared with 26 (11.4%) events in the placebo arm (adjusted hazard ratio [aHR] 0.49 [0.25-0.95], p < .05). Number needed to treat (NNT) to prevent one VTE = 17. Eighty-two (35%) and 72 (31%) patients in the apixaban and placebo arms, respectively, had a 6-month VTE risk ≥8%. In this subgroup, 7 (8.4%) VTE events occurred with apixaban and 19 (26.3%) events with placebo (aHR 0.33 [0.14-0.81], p < .05), NNT = 6. Individuals with a VTE risk <8% derived no benefit from apixaban thromboprophylaxis (aHR 0.89 [0.30-2.65), p = .84). Increased rates of overall bleeding were observed with apixaban in both the complete (aHR 2.11 [1.09-4.09], p < .05) and ≥ 8% predicted risk cohorts (aHR 2.87 [0.91-9.13], p = .07).
CONCLUSION: A 6-month VTE risk threshold of ≥8% increases the efficiency of risk-targeted thromboprophylaxis in ambulatory patients with cancer.
IMPLICATIONS FOR PRACTICE: Ambulatory patients with cancer receiving chemotherapy have an increased risk of venous thromboembolism (VTE). A Khorana Risk Score (KRS) ≥2 is currently the suggested threshold for thromboprophylaxis. Using baseline D-dimer values from individuals enrolled to the AVERT trial, this retrospective validation study identifies a 6-month VTE risk of ≥8% as a more efficient threshold for thromboprophylaxis. At this threshold, the number needed to treat to prevent one VTE is 6, compared with 17 when using a KRS ≥2. Conversely, individuals with a predicted risk of <8% derive no clinical benefit from thromboprophylaxis. Future prospective studies should validate this threshold for outpatient thromboprophylaxis.
BACKGROUND: Apixaban has been shown to significantly decrease the rate of VTE among intermediate-to-high risk patients starting chemotherapy compared to placebo. This investigation sought to determine the impact of apixaban among different subgroups of patients with cancer.
METHODS: This is a pre-planned post-hoc analysis of the AVERT randomized controlled trial which compared apixaban to placebo for the primary prevention of VTE in ambulatory patients initiating chemotherapy. Subgroup analyses were performed based on different baseline characteristics. The primary efficacy outcome was objectively documented major VTE. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using the Cox proportional hazards model to compare the treatment effect accounting for clustering at study center level.
RESULTS: During the study period, major VTE events occurred in 4.2% and 10.2% of the apixaban and placebo groups, respectively (HR 0.41; 95%CI, 0.26-0.65). Characteristics associated with decreased risk of major VTE among patients on apixaban included: male sex (HR 0.25, 95%CI 0.12-0.48); weight > 90Kg (HR 0.18, 95%CI, 0.06-0.52); no prior history of VTE (HR 0.41, 95%CI 0.26-0.64); solid cancers (HR 0.30; 95%CI, 0.19-0.47); metastatic disease (HR 0.45; 95%CI, 0.26-0.78); and concurrent use of antiplatelet therapy (HR 0.18, 95%CI 0.10-0.33).
CONCLUSIONS: In the AVERT trial, while apixaban thromboprophylaxis reduced the risk of major VTE in most patients, patients with weight > 90 kg, solid cancers, or concurrent antiplatelet therapy experienced the greatest benefits.
Background
The risk of venous thromboembolism (VTE) is increased in patients with active cancer and the risk is highest in those with metastatic disease. The risks and benefits of thromboprophylaxis among cancer patients with metastatic disease initiating chemotherapy treatment are unknown. To address this important knowledge gap, we evaluated the efficacy and safety of apixaban thromboprophylaxis in patients with and without metastatic disease.
Methods
Post-hoc analysis of the AVERT trial, which was a randomized, placebo-controlled, double-blind trial comparing apixaban therapy to placebo for VTE prophylaxis among cancer patients who were intermediate-to-high risk for VTE and who were initiating chemotherapy. The hazards ratios (HRs) for VTE and major bleeding episodes in patients with and without metastatic disease were calculated using a Cox regression model controlling for age, gender, and center.
Results
A total of 574 patients underwent randomization and 365 patients could be stratified according to the presence (n = 138) or absence (n = 227) of metastatic disease. In patients with metastatic disease, those receiving apixaban had a significantly lower risk of VTE (HR 0.55; 95% CI 0.32 to 0.97) without a significant increase in major bleeding complications (HR 1.36 95% CI 0.27 to 6.93) compared to those on placebo. In patients without metastatic disease, the use of apixaban was also associated with a significantly lower risk of VTE (HR 0.34 95% CI 0.19 to 0.60) without a significant increase in major bleeding complications (HR 1.14 95% CI 0.08 to 15.91).
Conclusions
In patients with and without metastatic disease, apixaban thromboprophylaxis was associated with a significantly lower rate of VTE compared to placebo.
Venous thromboembolic disease (VTE) is a common complication among patients with cancer. Data reporting risk of VTE among patients receiving chemotherapy for recurrent cancer compared to those with newly diagnosed tumors is scarce. Furthermore, it is unclear if thromboprophylaxis is beneficial and safe in these specific patient populations. Post-hoc analysis of the AVERT trial which was a randomized, placebo-controlled, double-blind trial comparing apixaban therapy to placebo for VTE prophylaxis among cancer patients who were intermediate-to-high risk for VTE and who were initiating chemotherapy. The HRs for recurrent VTE and major bleeding episodes in patients with newly diagnosed and recurrent cancers were calculated using a Cox regression model controlling for age, gender, and center. Of the 563 included patients 469 and 93 patients had newly diagnosed and recurrent cancers, respectively. Patients with recurrent cancer have a higher risk of VTE (Hazard ratio (HR): 1.53 (95% CI 1.0 to 2.33; p = 0.047) and major bleeding episodes (HR 2.89 (95% CI 1.52 to 5.49; p = 0.001) compared to those with newly diagnosed cancer. In patients with newly diagnosed cancers, the use of apixaban was associated with a significantly lower risk of VTE (HR 0.45; 95% CI 0.27-0.76; p = 0.002) and a higher rate of major bleeding (HR 2.10; 95% CI 1.09-4.08; p = 0.028). In patients with recurrent cancer, apixaban was associated with a significant lower rate of VTE (HR 0.26; 95% CI 0.13-0.53; p < 0.001) without an associated significantly increased risk of major bleeding (HR 1.82; 95% CI 0.36-9.15; p = 0.466). Patients with recurrent cancer seem to be at higher risk of recurrent VTE and major bleeding complications compared to those with newly diagnosed tumors. Apixaban appears to be safe and effective in these patient populations.
BACKGROUND: Recent trials have demonstrated that thromboprophylaxis using direct oral anticoagulants is effective but associated with a higher rate of major bleeding in intermediate-to-high risk (Khorana score ≥ 2) patients with cancer initiating systemic chemotherapy. Patients with gastrointestinal cancer may be at higher risk of major bleeding complications. We sought to assess the efficacy and safety of using thromboprophylaxis with apixaban in this patient population.
METHODS: This is a post-hoc analysis of the AVERT trial, which was a randomized, placebo-controlled, double-blind clinical trial. The primary efficacy outcome was objectively documented venous thromboembolism within 180 days of randomization. The primary safety outcome was a major bleeding episode. Time-to-event analyses were performed in patients with gastrointestinal cancers (upper gastrointestinal, pancreatic/hepatobiliary and colorectal cancers).
RESULTS: A total of 130 patients from the original AVERT trial were included, with 65 patients allocated to each of the apixaban and placebo groups. VTE occurred in 3 (4.6%) patients in the apixaban group and 13 (20%) patients in the placebo group (HR: 0.27; 95% CI: 0.13-0.54; p = 0.0002). Major bleeding occurred in 2 (3.1%) patients in the apixaban group and 1 (1.5%) patient in the placebo group (HR 2.39, 95% CI 0.29-19.78, p = 0.42). None of the major bleeding events occurred in patients with upper gastrointestinal or colorectal cancers.
CONCLUSION: Primary thromboprophylaxis with apixaban therapy seems to be safe and effective in patients with gastrointestinal cancers. Major bleeding complications are uncommon in our cohort. (Funded by the CIHR and Bristol-Myers Squibb-Pfizer Alliance; NCT02048865).
Conférence»International Society on Thrombosis and Haemostasis Congress; United States. Published in: Research and practice in thrombosis and haemostasis.
Background: Apixaban was effective in preventing venous thromboembolism (VTE) in ambulatory cancer patients with Khorana score ≥2 initiating chemotherapy, but with an increased risk of bleeding. Patients with cancer have a higher risk of renal dysfunction, which may be associated with increased risks of thrombotic or bleeding complications. We sought to assess the efficacy and safety of apixaban thromboprophylaxis according to renal function in the AVERT trial. Methods: AVERT trial was a randomized, double‐blinded, placebo‐controlled trial evaluating apixaban as primary thromboprophylaxis for ambulatory cancer patients. The primary efficacy outcome was objectively confirmed VTE within 180 days of randomization. The primary safety outcome was major bleeding events. Results: Among 574 patients randomized, 66 (11.5%) patients had CrCl <60 mL/min and 508 (88.5%) had CrCl ≥60 mL/min. Patients with CrCl <60 mL/min were older, more likely to be female, had lower weight/body mass index, and poorer ECOG performance status. In patients with CrCl <60 mL/min, there were one VTE and one major bleeding event, with no differences in outcomes between apixaban and placebo. In patients with CrCl ≥60 mL/min, apixaban was associated with a significantly lower rate of VTE and overall mortality compared to placebo without an increased risk of bleeding events. The risk of VTE was significantly higher in patients with CrCl ≥60 mL/min. Conclusions: In the AVERT trial, patients with CrCl <60 mL/min did not have higher risk of thrombotic or bleeding complications compared to those with CrCl ≥60 mL/min. (Funded by the CIHR and Bristol‐Myers Squibb‐Pfizer Alliance; NCT02048865).
Cancer patients have an increased risk of developing blood clots in the veins compared to non-cancer patients. Cancer patients who develop blood clots can lead to reduced life expectancy, delayed cancer treatment, and decreased quality of life. Prevention is the most effective way to decrease the complications associated with blood clots in the veins. Although previous clinical trials have shown some benefit on the use of medication to prevent blood clots in the veins in ambulatory cancer patients, these studies have been inconclusive in demonstrating that existing blood thinners significantly reduce the rate of blood clots in cancer patients. One possible explanation relates to the fact that these studies have included a large proportion of cancer patients who are a low risk of developing blood clots in the veins. We are proposing to identify cancer patients who are at a high risk of developing blood clots by using a validated tool at the time of their cancer diagnosis. The identified high risk cancer patients will be asked to participate in a trial to test the safety and efficacy of a new oral medication that has been used to prevent blood clots in patients undergoing surgery. We are enrolling 574 patients in 7 Canadian centers (Ottawa, Halifax, Montreal, Vancouver, Sault Ste. Marie, Toronto and Hamilton). 287 patients will receive the study drug and 287 will receive an inactive substance. Analysis will be performed to assess the safety and the superiority of the study drug.
