Silvy Laporte1, Céline Chapelle2, Jane-Chloé Trone3, Laurent Bertoletti4, Philippe Girard5, Guy Meyer6, Maissa Safieddine7, Michel Cucherat8, Edouard Ollier9, Patrick Mismetti10. 1. Unité de Recherche Clinique, Innovation, Pharmacologie, CHU Saint-Etienne, Hôpital Nord, F-42055 Saint-Etienne, France; SAINBIOSE U1059, Université Jean Monnet, University Lyon, INSERM, F-CRIN INNOVTE Network, F-42023 Saint-Etienne, France. Electronic address: silvy.laporte@chu-st-etienne.fr. 2. Unité de Recherche Clinique, Innovation, Pharmacologie, CHU Saint-Etienne, Hôpital Nord, F-42055 Saint-Etienne, France. 3. Department of Radiation Oncology, Lucien Neuwirth Cancer Institute, Saint-Etienne, France. 4. SAINBIOSE U1059, Université Jean Monnet, University Lyon, INSERM, F-CRIN INNOVTE Network, F-42023 Saint-Etienne, France; Service de Médecine Vasculaire et Thérapeutique, CHU Saint-Etienne, Hôpital Nord, F-40255, Saint-Etienne, France. 5. Département Thoracique, L'Institut Mutualiste Montsouris, Paris, France. 6. Hopital Européen Georges Pompidou, APHP, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMRs 970, CIE1418, F-CRIN INNOVTE Network, France. 7. SAINBIOSE U1059, Université Jean Monnet, University Lyon, INSERM, F-CRIN INNOVTE Network, F-42023 Saint-Etienne, France. 8. Service de Pharmacologie, HCL, UMR CNRS 5558 Evaluation et Modélisation des Effets Thérapeutiques, Université Claude Bernard Lyon 1, Lyon, France. 9. Unité de Recherche Clinique, Innovation, Pharmacologie, CHU Saint-Etienne, Hôpital Nord, F-42055 Saint-Etienne, France; SAINBIOSE U1059, Université Jean Monnet, University Lyon, INSERM, F-CRIN INNOVTE Network, F-42023 Saint-Etienne, France. 10. Unité de Recherche Clinique, Innovation, Pharmacologie, CHU Saint-Etienne, Hôpital Nord, F-42055 Saint-Etienne, France; SAINBIOSE U1059, Université Jean Monnet, University Lyon, INSERM, F-CRIN INNOVTE Network, F-42023 Saint-Etienne, France; Service de Médecine Vasculaire et Thérapeutique, CHU Saint-Etienne, Hôpital Nord, F-40255, Saint-Etienne, France.
Abstract
OBJECTIVES: An unexpected promising effect of low molecular weight heparins (LMWHs) on survival in patients with cancer was observed in early trials in post hoc subgroup analyses but not found in more recent trials. To highlight a possible regression over time toward the lack of the antitumoral effect of LMWHs, we performed a cumulative meta-analysis of survival data from randomized controlled trials (RCTs). STUDY DESIGN AND SETTING: Medical databases were searched to identify RCTs comparing, in patients with cancer, LMWHs with placebo or no treatment in patients free of venous thromboembolism (VTE), or to vitamin K antagonists in patients who experienced an acute VTE in overall survival. The cumulative hazard ratio (HR) was estimated after each study inclusion in chronological order. RESULTS: Twenty-three studies (12,970 patients) were included. The cumulative meta-analysis of the earlier trials showed a significant improvement in overall survival with LMWHs. This apparent benefit then gradually regressed over time toward an absence of the effect of LMWHs on survival (HR: 0.98 [95% confidence interval, 0.93; 1.03]). CONCLUSION: Despite supportive experimental data and early clinical findings, the promising antitumoral effect of LMWHs in patients with cancer gradually vanished over time toward a lack of impact on overall survival. This result suggests 'p-hacking' and selective reporting of the positive results from post hoc subgroup analyses in the early studies.
OBJECTIVES: An unexpected promising effect of low molecular weight heparins (LMWHs) on survival in patients with cancer was observed in early trials in post hoc subgroup analyses but not found in more recent trials. To highlight a possible regression over time toward the lack of the antitumoral effect of LMWHs, we performed a cumulative meta-analysis of survival data from randomized controlled trials (RCTs). STUDY DESIGN AND SETTING: Medical databases were searched to identify RCTs comparing, in patients with cancer, LMWHs with placebo or no treatment in patients free of venous thromboembolism (VTE), or to vitamin K antagonists in patients who experienced an acute VTE in overall survival. The cumulative hazard ratio (HR) was estimated after each study inclusion in chronological order. RESULTS: Twenty-three studies (12,970 patients) were included. The cumulative meta-analysis of the earlier trials showed a significant improvement in overall survival with LMWHs. This apparent benefit then gradually regressed over time toward an absence of the effect of LMWHs on survival (HR: 0.98 [95% confidence interval, 0.93; 1.03]). CONCLUSION: Despite supportive experimental data and early clinical findings, the promising antitumoral effect of LMWHs in patients with cancer gradually vanished over time toward a lack of impact on overall survival. This result suggests 'p-hacking' and selective reporting of the positive results from post hoc subgroup analyses in the early studies.