Background In patients with acute venous thromboembolism (VTE), the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation. The CARAVAGGIO trial demonstrated... Show moreBackground In patients with acute venous thromboembolism (VTE), the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation. The CARAVAGGIO trial demonstrated noninferiority of apixaban to dalteparin for treatment of cancer-associated VTE without an increased risk of major bleeding. We compared the early time course of VTE recurrence and major bleeding events of apixaban compared with dalteparin at 7, 30, and 90 days of treatment in patients with cancer-associated VTE.Methods The study design of the CARAVAGGIO trial has been described. Eligible patients were randomly assigned to receive monotherapy with either apixaban or dalteparin for 6 months. The primary efficacy outcome was the incidence of objectively confirmed recurrent VTE. The primary safety outcome was major bleeding.Results In 1,155 patients, recurrent VTE after 7, 30, and 90 days occurred in 6 (1%), 15 (2.6%), and 27 (4.7%) patients in the apixaban arm versus 5 (0.9%), 20 (3.5%), and 36 (6.2%) patients respectively in the dalteparin arm. By day 7, 30, and 90, major bleeding events had occurred in 3 (0.5%), 9 (1.6%), and 16 (2.8%) patients in the apixaban group versus 5 (0.9%), 11 (1.9%), and 17 (2.9%) patients in the dalteparin group.Conclusion The frequencies of recurrent VTE and major bleeding events at 7, 30, and 90 days of apixaban compared with dalteparin were similar in patients with cancer-associated VTE. This supports the use of apixaban for the initiation and early phase of anticoagulant therapy in cancer-associated VTE. Show less
Vedovati, M.C.; Giustozzi, M.; Munoz, A.; Bertoletti, L.; Cohen, A.T.; Klok, F.A.; ... ; Agnelli, G. 2023
Risks of recurrence and treatment-emergent bleeding are high in patients with cancer-associated venous thromboembolism (VTE) but factors associated with these risks remain substantially undefined... Show moreRisks of recurrence and treatment-emergent bleeding are high in patients with cancer-associated venous thromboembolism (VTE) but factors associated with these risks remain substantially undefined.The aim of this analysis in patients with cancer-associated VTE included in the Caravaggio study was to identify risk factors for recurrent VTE and major bleeding. Variables potentially predictive for recurrent VTE or major bleeding were evaluated in a Cox proportional hazard multivariable analysis with backward variable selection.Recurrent VTE occurred in 78 patients (6.8%) and major bleeding in 45 (3.9%). Independent risk factors for recurrent VTE were deep vein thrombosis (DVT) as index event (Hazard ratio (HR) 1.84, 95% CI 1.17–2.88), ECOG status of 1 or more (HR 1.95, 95% CI 1.11–3.43), pancreatic or hepatobiliary cancer site (HR 2.20, 95% CI 1.19–4.06), concomitant anti-cancer treatment (HR 1.98, 95% CI 1.03–3.81) and creatinine clearance (HR 1.10, 95% CI 1.00–1.20 for every 10 ml/min absolute increase). Independent risk factors for major bleeding were ECOG status of 2 (HR 2.31, 95% CI 1.24–4.29), genitourinary cancer site (HR 2.72, 95% CI 1.28–5.77), upper gastrointestinal cancer site (HR 3.17, 95% CI 1.22–8.23), and non-resected luminal gastrointestinal cancer (HR 2.77, 95% CI 1.38–5.56).This analysis of the Caravaggio study in patients with cancer-associated VTE who were on standardized anticoagulant treatment identified five independent predictors for recurrent VTE and four independent predictors of treatment-emergent major bleeding. Considering these risks could help clinicians to optimize the anticoagulant treatment in patients with cancer-associated VTE. Show less
Verso, M.; Agnelli, G.; Munoz, A.; Connors, J.M.; Sanchez, O.; Huisman, M.; ... ; Becattini, C. 2022
Background: Patients with cancer-associated venous thromboembolism (VTE) have a high risk of VTE recurrence and anticoagulant treatment-related bleeding, but the correlation of these risks with the... Show moreBackground: Patients with cancer-associated venous thromboembolism (VTE) have a high risk of VTE recurrence and anticoagulant treatment-related bleeding, but the correlation of these risks with the cancer stage is unclear.Methods: We evaluated the risks of VTE recurrence and treatment-related major bleeding according to the cancer stage in patients with VTE and solid cancer randomised to apixaban or dalteparin in the Caravaggio study. Cancer stage was categorised by expert cancer physicians according to pre-specified criteria, and study outcomes were adjudicated by an independent committee unaware of cancer stage and treatment allocation.Results: Of the 1034 patients included in this analysis, 217 (21.0%) had localised cancer, 279 (27.0%) locally advanced cancer and 503 (48.7%) metastatic cancer. Cancer stage was undetermined in 35 patients (3.4%). VTE recurrence and major bleeding rates were 2.8% and 3.2% in patients with localised cancer, respectively. In comparison to patients with localised cancer, the VTE recurrence rate was higher in patients with locally advanced cancer (7.5%, hazard ra-tio [HR] = 2.8, 95% confidence interval [CI] = 1.1-6.9) and metastatic cancer (8.7%, HR = 3.3, CI = 1.4-7.7, CI). Patients with metastatic cancer had numerically increased major bleedings compared to those with localised cancer (5.2%, HR = 1.65, CI = 0.7-3.8). The ef-ficacy and safety of apixaban and dalteparin across patients with different cancer stages were consistent with the findings observed in the overall patients with cancer randomised in the study.Conclusions: Patients with locally advanced and metastatic cancer have a higher rate of VTE recurrence than patients with localised cancer with no statistically significant difference in treatment-related major bleeding. (c) 2022 Published by Elsevier Ltd. Show less
Mahe, I.; Agnelli, G.; Ay, C.; Bamias, A.; Becattini, C.; Carrier, M.; ... ; Laporte, S. 2021
Cancer-associated thrombosis (CT) is associated with a high risk of recurrent venous thromboembolic (VTE) events that require extended anticoagulation in patients with active cancer, putting them... Show moreCancer-associated thrombosis (CT) is associated with a high risk of recurrent venous thromboembolic (VTE) events that require extended anticoagulation in patients with active cancer, putting them at risk of bleeding. The aim of the API-CAT study (NCT03692065) is to assess whether a reduced-dose regimen of apixaban (2.5mg twice daily [bid]) is noninferior to a full-dose regimen of apixaban (5mg bid) for the prevention of recurrent VTE in patients with active cancer who have completed >= 6 months of anticoagulant therapy for a documented index event of proximal deep-vein thrombosis and/or pulmonary embolism. API-CAT is an international, randomized, parallel-group, double-blind, noninferiority trial with blinded adjudication of outcome events. Consecutive patients are randomized to receive apixaban 2.5 or 5mg bid for 12 months. The primary efficacy outcome is a composite of recurrent symptomatic or incidental VTE during the treatment period. The principal safety endpoint is clinically relevant bleeding, defined as a composite of major bleeding or nonmajor clinically relevant bleeding. Assuming a 12-month incidence of the primary outcome of 4% with apixaban and an upper limit of the two-sided 95% confidence interval of the hazard ratio <2.0, 1,722 patients will be randomized, assuming an up to 10% loss in total patient-years (beta=80%; alpha one-sided=0.025). This trial has the potential to demonstrate that a regimen of extended treatment for patients with CT beyond an initial 6 months, with a reduced apixaban dose, has an acceptable risk of recurrent VTE recurrence and decreases the risk of bleeding. Show less
Giustozzi, M.; Connors, J.M.; Blanco, A.B.R.; Szmit, S.; Falvo, N.; Cohen, A.T.; ... ; Agnelli, G. 2021
Background Clinical guidelines advise similar anticoagulant treatment for symptomatic and incidental cancer-associated venous thromboembolism (VTE). We investigated clinical features and outcomes... Show moreBackground Clinical guidelines advise similar anticoagulant treatment for symptomatic and incidental cancer-associated venous thromboembolism (VTE). We investigated clinical features and outcomes of cancer patients with incidental or symptomatic VTE randomized in the Caravaggio study. Objectives We performed a predefined sub-analysis of the Caravaggio study in order to investigate the clinical features and outcomes of incidental and symptomatic VTE in patients with cancer. The relative efficacy and safety of apixaban and dalteparin in patients with incidental and symptomatic VTE was also assessed. Methods The Caravaggio study compared apixaban to dalteparin for the 6-month treatment of cancer-associated VTE. The primary efficacy and safety outcomes were recurrent VTE and major bleeding. Results Two hundred thirty patients (20%) had incidental and 925 (80%) symptomatic VTE. Pulmonary embolism with or without deep vein thrombosis as index event, colorectal cancer, Eastern Cooperative Oncology Group (ECOG) score of 0, and locally advanced or metastatic cancer were more frequent in patients with incidental VTE. Deep vein thrombosis as index event, hematological cancer, and ECOG score of 2 were more frequent in patients with symptomatic VTE. Ten patients (4.3%) with incidental and 68 (7.4%) with symptomatic VTE had recurrent VTE (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.29-1.10). Major bleeding occurred in 12 (5.2%) patients with incidental VTE and in 33 (3.6%) patients with symptomatic VTE (HR 1.43, 95% CI 0.74-2.77). When comparing apixaban to dalteparin in patients with symptomatic and incidental VTE, the HR for recurrence was 0.73 (95% CI 0.45-1.19) and 0.41 (95% CI 0.11-1.56), respectively, and the HR for major bleeding 0.93 (95% CI 0.47-1.83) and 0.96 (95% CI 0.31-2.96), respectively. Conclusions Compared to cancer patients with symptomatic VTE, those with incidental VTE have different clinical features at presentation, with a numerically lower incidence of recurrent VTE and a numerically higher incidence of major bleeding. Show less
Giustozzi, M.; Valerio, L.; Agnelli, G.; Becattini, C.; Fronk, E.M.; Klok, F.A.; ... ; Barco, S. 2021
Introduction: Sex and the presence of specific provoking risk factors, along with age, influence the presentation and prognosis of venous thromboembolism (VTE). We investigated the presentation,... Show moreIntroduction: Sex and the presence of specific provoking risk factors, along with age, influence the presentation and prognosis of venous thromboembolism (VTE). We investigated the presentation, course and quality of life in women and men with acute VTE classified according to their VTE provoking factors.Methods: PREFER in VTE is an international, non-interventional registry of patients with a first episode of acute symptomatic VTE. Baseline provoking factors were classified as follows: major transient, minor transient, active cancer, and none identifiable. The primary outcome was recurrent VTE. Quality of life and treatment satisfaction were secondary outcomes.Results: Of 3,455 patients with acute VTE, 1,623 (47%) were women. The mean age at the time of VTE was 61 (SD 18) in women, 60 (SD 15) in men. The distribution of provoking risk factors was similar between sexes, despite a tendency for higher frequency of minor and major transient risk factors in women, and cancer or unprovoked VTE in men. At 12-month follow-up, VTE recurrence was reported in 74 (6.5%) women and 80 (6.4%) men (absolute risk difference-0.1%, 95% CI-1.9%; +2.1%). In patients with unprovoked VTE, the VTE recurrence rate was 38/612 (6.2%) in women and 53/798 (6.6%) in men (absolute risk difference-0.4, 95% CI-3.0; +2.1%). Multivariable Cox regressions confirmed the absence of sex differences. Quality of life and treatment satisfaction scores one year after VTE were lower in women than in men irrespective of the provoking risk factors (p<0.001 for both scores).Conclusions: Despite differences in the provoking risk factors for VTE, women and men had a similar rate VTE recurrence at one year. After acute VTE, women had lower quality of life and treatment satisfaction scores. Show less
Verso, M.; Munoz, A.; Bauersachs, R.; Huisman, M.V.; Mandala, M.; Vescovo, G.; ... ; Agnelli, G. 2021
Background: Whether concomitant administration of anticancer agents influences the efficacy and safety of oral anticoagulants in patients treated for cancer-associated venous thromboembolism (VTE)... Show moreBackground: Whether concomitant administration of anticancer agents influences the efficacy and safety of oral anticoagulants in patients treated for cancer-associated venous thromboembolism (VTE) is undefined. The pharmacological interaction between anticancer agents and direct oral anticoagulants is perceived as a concern.Methods: We evaluated the effects of concomitant administration of anticancer agents on recurrent VTE, major bleeding and death in patients with cancer-associated VTE randomised to receive apixaban or dalteparin in the Caravaggio study.Results: Anticancer agents were concomitantly given to 336 patients (58.3%) treated with apixaban and to 332 patients (57.3%) treated with dalteparin. In patients treated with apixaban, recurrent VTE occurred in 20 (6.0%) and 12 (5.0%) among patients treated or not treated with anticancer agents, respectively (hazard ratio [HR] = 1.14; 0.55-2.38); major bleeding occurred in 12 (3.6%) and 10 (4.2%) patients , respectively (HR = 0.79; 0.34-1.82), and death occurred in 74 (22.0%) and 61 (25.4%) patients , respectively (HR = 0.71; 0.51-1. 00). In patients treated with dalteparin, recurrent VTE occurred in 24 (7.2%) and 22 (8.9%) among patients treated or not treated with anticancer agents, respectively (HR = 0.71; 0.40-1.28); major bleeding occurred in 16 (4.8%) and 7 (2.8%) patients, respectively (HR = 1.78; 0.66-4.79 ), and death occurred in 87 (26.2% ) and 66 (26.7 %) patients, respectively (HR = 0.85; 0.62-1.18). The comparative efficacy and safety of apixaban and dalteparin was not different in patients treated or not treated with anticancer agents. No effect on recurrent VTE, major bleeding or death was observed with inhibitors or inducers of P-glycoprotein and/or CYP3A4.Conclusion: In our study, concomitant administration of anticancer agents had no effect on the risk of VTE recurrence or major bleeding in patients treated with apixaban or dalteparin for cancer-associated VTE.(c) 2021 Elsevier Ltd. All rights reserved. Show less
Huisman, M.V.; Levi, M.; Royen, E.A. van; Breederveld, C.; Buller, H.R.; Peters, M.; ... ; Agnelli, G. 2021
Background Direct oral anticoagulants are recommended for the treatment of cancer-associated thrombosis (CAT) as an alternative to low-molecular-weight heparin (LMWH), but an increased bleeding... Show moreBackground Direct oral anticoagulants are recommended for the treatment of cancer-associated thrombosis (CAT) as an alternative to low-molecular-weight heparin (LMWH), but an increased bleeding risk in patients with gastrointestinal cancer was reported. The Caravaggio study compared apixaban and dalteparin for the treatment of patients with CAT. Here we describe sites of bleeding, associated cancer sites, clinical presentation, and course of major bleeding in patients included in the Caravaggio study.Methods The Caravaggio study was a multinational, randomized, open-label, noninferiority study. Bleeding events and the severity of major bleedings were adjudicated by a committee unaware of treatment allocation using predefined criteria; for the purpose of this analysis, data were analyzed in the safety population.Results Major bleeding occurred in 22 of 576 patients on apixaban (3.8%) and in 23 of 579 patients on dalteparin (4.0%). The sites of major bleeding and their distribution according to the type of cancer were similar between the two treatment groups. Major bleeding occurred in nine patients with gastrointestinal cancer in each treatment group. The clinical presentation of major bleeding was severe or fatal in 6 patients on apixaban and in 5 patients on dalteparin, while the clinical course was severe in 5 patients on apixaban and in 7 patients on dalteparin.Conclusion Apixaban is a safe alternative to LMWH for the treatment in patients with CAT. No excess in gastrointestinal bleeding was observed in patients who received apixaban, including those with gastrointestinal cancer. Show less
Giustozzi, M.; Agnelli, G.; Toro-Cervera, J. del; Klok, F.A.; Rosovsky, R.P.; Martin, A.C.; ... ; Huisman, M.V. 2020
Background International guidelines have endorsed the use of edoxaban or rivaroxaban as an alternative to low-molecular-weight heparin (LMWH) for the treatment of acute venous thromboembolism (VTE)... Show moreBackground International guidelines have endorsed the use of edoxaban or rivaroxaban as an alternative to low-molecular-weight heparin (LMWH) for the treatment of acute venous thromboembolism (VTE) in cancer patients. Recently, a large randomized controlled trial of apixaban versus dalteparin in patients with cancer was completed. We performed an updated meta-analysis to assess the efficacy and safety of direct oral anticoagulants (DOACs) versus LMWH in patients with cancer-associated VTE. Methods MEDLINE, EMBASE, and CENTRAL (Cochrane Controlled Trials Registry) were systematically searched up to March 30, 2020 for randomized controlled trials comparing DOACs versus LMWH for the treatment of VTE in patients with cancer. The two coprimary outcomes were recurrent VTE and major bleeding at 6 months. Data were pooled by the Mantel-Haenszel method and compared by relative risk ratios (RRs) and 95% confidence intervals (CIs). Results Four randomized controlled studies (2,894 patients) comparing apixaban, edoxaban, or rivaroxaban with dalteparin were included in the meta-analysis. Recurrent VTE occurred in 75 of 1,446 patients (5.2%) treated with oral factor Xa inhibitors and in 119 of 1,448 patients (8.2%) treated with LMWH (RR 0.62; 95% CI 0.43-0.91;I-2, 30%). Major bleeding occurred in 62 (4.3%) and 48 (3.3%) patients receiving oral factor Xa inhibitors or LMWH, respectively (RR 1.31; 95% CI 0.83-2.08;I-2, 23%). Conclusion In patients with cancer-associated VTE, oral factor Xa inhibitors reduced the risk of recurrent VTE without a significantly higher likelihood of major bleeding at 6 months compared with LMWH. Show less
Background Recent guidelines recommend consideration of the use of oral edoxaban or rivaroxaban for the treatment of venous thromboembolism in patients with cancer. However, the benefit of these... Show moreBackground Recent guidelines recommend consideration of the use of oral edoxaban or rivaroxaban for the treatment of venous thromboembolism in patients with cancer. However, the benefit of these oral agents is limited by the increased risk of bleeding associated with their use.Methods This was a multinational, randomized, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication. We randomly assigned consecutive patients with cancer who had symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive oral apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) or subcutaneous dalteparin (at a dose of 200 IU per kilogram of body weight once daily for the first month, followed by 150 IU per kilogram once daily). The treatments were administered for 6 months. The primary outcome was objectively confirmed recurrent venous thromboembolism during the trial period. The principal safety outcome was major bleeding.Results Recurrent venous thromboembolism occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for noninferiority). Major bleeding occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40 to 1.69; P=0.60).Conclusions Oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding. (Funded by the Bristol-Myers Squibb-Pfizer Alliance; Caravaggio ClinicalTrials.gov number, NCT03045406.) Show less
Agnelli, G.; Becattini, C.; Bauersachs, R.; Brenner, B.; Campanini, M.; Cohen, A.; ... ; Caravaggio Study Investigators 2018
Background: Knowledge of independent, baseline risk factors for catheter-related thrombosis (CRT) may help select adult cancer patients who are at high risk to receive thromboprophylaxis.... Show moreBackground: Knowledge of independent, baseline risk factors for catheter-related thrombosis (CRT) may help select adult cancer patients who are at high risk to receive thromboprophylaxis. Objectives: We conducted a meta-analysis of individual patient-level data to identify these baseline risk factors. Patients/Methods: MEDLINE, EMBASE, CINAHL, CENTRAL, DARE and the Grey literature databases were searched in all languages from 1995 to 2008. Prospective studies and randomized controlled trials (RCTs) were eligible. Studies were included if original patient-level data were provided by the investigators and if CRT was objectively confirmed with valid imaging. Multivariate logistic regression analysis of 17 prespecified baseline characteristics was conducted. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. Results: A total sample of 5636 subjects from five RCTs and seven prospective studies was included in the analysis. Among these subjects, 425 CRT events were observed. In multivariate logistic regression, the use of implanted ports as compared with peripherally implanted central venous catheters (PICCs), decreased CRT risk (OR, 0.43; 95% CI, 0.23-0.80), whereas past history of deep vein thrombosis (DVT) (OR, 2.03; 95% CI, 1.05-3.92), subclavian venipuncture insertion technique (OR, 2.16; 95% CI, 1.07-4.34) and improper catheter tip location (OR, 1.92; 95% CI, 1.22-3.02), increased CRT risk. Conclusions: CRT risk is increased with use of PICCs, previous history of DVT, subclavian venipuncture insertion technique and improper positioning of the catheter tip. These factors may be useful for risk stratifying patients to select those for thromboprophylaxis. Prospective studies are needed to validate these findings. Show less
