TY - JOUR
T1 - Evaluating prophylactic heparin in ambulatory patients with solid tumours
T2 - a systematic review and individual participant data meta-analysis
AU - Schünemann, Holger J.
AU - Ventresca, Matthew
AU - Crowther, Mark
AU - Briel, Matthias
AU - Zhou, Qi
AU - Noble, Simon
AU - Macbeth, Fergus
AU - Griffiths, Gareth
AU - Garcia, David
AU - Lyman, Gary H.
AU - Di Nisio, Marcello
AU - Iorio, Alfonso
AU - Mbuagbaw, Lawrence
AU - Neumann, Ignacio
AU - van Es, Nick
AU - Brouwers, Melissa
AU - Guyatt, Gordon
AU - Streiff, Michael B.
AU - Marcucci, Maura
AU - Baldeh, Tejan
AU - Florez, Ivan D.
AU - Alma, Ozlem Gurunlu
AU - Solh, Ziad
AU - Bossuyt, Patrick M.
AU - Kahale, Lara A.
AU - Ageno, Walter
AU - Bozas, George
AU - Büller, Harry R.
AU - Lebeau, Bernard
AU - Lecumberri, Ramon
AU - Loprinzi, Charles
AU - McBane, Robert
AU - Sideras, Kostandinos
AU - Maraveyas, Anthony
AU - Pelzer, Uwe
AU - Perry, James
AU - Klerk, Clara
AU - Agnelli, Giancarlo
AU - Akl, Elie A.
N1 - Funding Information:
This work was supported by a grant from the Canadian Institutes of Health Research (CIHR; knowledge synthesis grant, KRS 126594 to HJS), a government organisation that supports health research, and the Michael G DeGroote Cochrane Canada and McMaster GRADE centres. CIHR had no role in designing the study, gathering, analysing, or interpreting the data. We thank the research organisations and authors responsible for sharing clinical trial data: Sanofi, Novartis Pharma, GlaxoSmithKline, Instituto Científico y Tecnológico, University of Navarra, Velindre National Health Service Trust, Charité–Universitätsmedizin Berlin, Sunnybrook Health Sciences Centre, Hull and East Yorkshire Hospitals Trust, The Mayo Clinic, Erciyes University Medical Faculty, Technische Universität München, Academic Medical Center Amsterdam, and the Hospital Saint-Antoine. We would like to thank the colleagues who supported our earlier Cochrane systematic reviews on this topic.
Funding Information:
This work was supported by a grant from the Canadian Institutes of Health Research (CIHR; knowledge synthesis grant, KRS 126594 to HJS), a government organisation that supports health research, and the Michael G DeGroote Cochrane Canada and McMaster GRADE centres. CIHR had no role in designing the study, gathering, analysing, or interpreting the data. We thank the research organisations and authors responsible for sharing clinical trial data: Sanofi, Novartis Pharma, GlaxoSmithKline, Instituto Científico y Tecnológico, University of Navarra, Velindre National Health Service Trust, Charité–Universitätsmedizin Berlin, Sunnybrook Health Sciences Centre, Hull and East Yorkshire Hospitals Trust, The Mayo Clinic, Erciyes University Medical Faculty, Technische Universität München, Academic Medical Center Amsterdam, and the Hospital Saint-Antoine. We would like to thank the colleagues who supported our earlier Cochrane systematic reviews on this topic.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/10
Y1 - 2020/10
N2 - Background: Study-level meta-analyses provide high-certainty evidence that heparin reduces the risk of symptomatic venous thromboembolism for patients with cancer; however, whether the benefits and harms associated with heparin differ by cancer type is unclear. This individual participant data meta-analysis of randomised controlled trials examines the effect of heparin on survival, venous thromboembolism, and bleeding in patients with cancer in general and by type. Methods: In this systematic review and meta-analysis we searched MEDLINE, Embase, and The Cochrane Library for randomised controlled trials comparing parenteral anticoagulants with placebo or standard care in ambulatory patients with solid tumours and no indication for anticoagulation published from the inception of each database to January 14, 2017, and updated it on May 14, 2020, without language restrictions. We calculated the effect of parenteral anticoagulant administration on all-cause mortality, venous thromboembolism occurrence, and bleeding related outcomes through multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect, adjusting for age, cancer type, and metastatic status. Interaction terms were tested to investigate effects in predefined subgroups. This study is registered with PROSPERO, CRD42013003526. Findings: We obtained individual participant data from 14 of 20 eligible randomised controlled trials (8278 [79%] of 10 431 participants; 4139 included in the low-molecular-weight heparin group and 4139 in the control group). Meta-analysis showed an adjusted relative risk (RR) of mortality at 1 year of 0·99 (95% CI 0·93–1·06) and a hazard ratio of 1·01 (95% CI 0·96–1·07). The number of patients with venous thromboembolic events was 158 (4·0%) of 3958 with available data in the low-molecular-weight heparin group compared with 279 (7·1%) of 3957 in the control group. Major bleeding events occurred in 71 (1·7%) of 4139 patients in the control population and 88 (2·1%) in the low-molecular-weight heparin group, and minor bleeding events in 478 (12·1%) of 3945 patients with available data in the control group and 652 (16·6%) of 3937 patients in the low-molecular-weight heparin group. The adjusted RR was 0·58 (95% CI 0·47–0·71) for venous thromboembolism, 1·27 (0·92–1·74) for major bleeding, and 1·34 (1·19–1·51) for minor bleeding. Prespecified subgroup analysis of venous thromboembolism occurrence by cancer type identified the most certain benefit from heparin treatment in patients with lung cancer (RR 0·59 [95% CI 0·42–0·81]), which dominated the overall reduction in venous thromboembolism. Certainty of the evidence for the outcomes ranged from moderate to high. Interpretation: Low-molecular-weight heparin reduces risk of venous thromboembolism without increasing risk of major bleeding compared with placebo or standard care in patients with solid tumours, but it does not improve survival. Funding: Canadian Institutes of Health Research.
AB - Background: Study-level meta-analyses provide high-certainty evidence that heparin reduces the risk of symptomatic venous thromboembolism for patients with cancer; however, whether the benefits and harms associated with heparin differ by cancer type is unclear. This individual participant data meta-analysis of randomised controlled trials examines the effect of heparin on survival, venous thromboembolism, and bleeding in patients with cancer in general and by type. Methods: In this systematic review and meta-analysis we searched MEDLINE, Embase, and The Cochrane Library for randomised controlled trials comparing parenteral anticoagulants with placebo or standard care in ambulatory patients with solid tumours and no indication for anticoagulation published from the inception of each database to January 14, 2017, and updated it on May 14, 2020, without language restrictions. We calculated the effect of parenteral anticoagulant administration on all-cause mortality, venous thromboembolism occurrence, and bleeding related outcomes through multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect, adjusting for age, cancer type, and metastatic status. Interaction terms were tested to investigate effects in predefined subgroups. This study is registered with PROSPERO, CRD42013003526. Findings: We obtained individual participant data from 14 of 20 eligible randomised controlled trials (8278 [79%] of 10 431 participants; 4139 included in the low-molecular-weight heparin group and 4139 in the control group). Meta-analysis showed an adjusted relative risk (RR) of mortality at 1 year of 0·99 (95% CI 0·93–1·06) and a hazard ratio of 1·01 (95% CI 0·96–1·07). The number of patients with venous thromboembolic events was 158 (4·0%) of 3958 with available data in the low-molecular-weight heparin group compared with 279 (7·1%) of 3957 in the control group. Major bleeding events occurred in 71 (1·7%) of 4139 patients in the control population and 88 (2·1%) in the low-molecular-weight heparin group, and minor bleeding events in 478 (12·1%) of 3945 patients with available data in the control group and 652 (16·6%) of 3937 patients in the low-molecular-weight heparin group. The adjusted RR was 0·58 (95% CI 0·47–0·71) for venous thromboembolism, 1·27 (0·92–1·74) for major bleeding, and 1·34 (1·19–1·51) for minor bleeding. Prespecified subgroup analysis of venous thromboembolism occurrence by cancer type identified the most certain benefit from heparin treatment in patients with lung cancer (RR 0·59 [95% CI 0·42–0·81]), which dominated the overall reduction in venous thromboembolism. Certainty of the evidence for the outcomes ranged from moderate to high. Interpretation: Low-molecular-weight heparin reduces risk of venous thromboembolism without increasing risk of major bleeding compared with placebo or standard care in patients with solid tumours, but it does not improve survival. Funding: Canadian Institutes of Health Research.
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U2 - 10.1016/S2352-3026(20)30293-3
DO - 10.1016/S2352-3026(20)30293-3
M3 - Article
C2 - 32976752
AN - SCOPUS:85091212570
SN - 2352-3026
VL - 7
SP - e746-e755
JO - The Lancet Haematology
JF - The Lancet Haematology
IS - 10
ER -