Randomized Controlled Trial

. 2022 Sep 13:378:e071375.

doi: 10.1136/bmj-2022-071375.

Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial

Rebecca C Auer¹, Michael Ott², Paul Karanicolas³, Muriel Rebecca Brackstone², Shady Ashamalla³, Joel Weaver⁴, Vicky Tagalakis⁵, Marylise Boutros⁵, Peter Stotland⁶, Antonio Caycedo Marulanda⁷, Husein Moloo¹, Shiva Jayaraman⁸, Suni Patel⁹, Grégoire Le Gal^{10

11}, Silvana Spadafora¹², Steven MacLellan¹³, Daniel Trottier¹⁴, Derek Jonker¹¹, Timothy Asmis¹¹, Ranjeeta Mallick¹⁵, Amanda Pecarskie¹¹, Tim Ramsay¹⁴, Marc Carrier¹⁶; PERIOP-01 investigators

Collaborators, Affiliations

Collaborators

PERIOP-01 investigators:
Shaheer Tadros, Isabelle Raiche, Lara Williams, Reilly Musselman, Carolyn Nessim, Shady Ashamalla, Darlene Fenech, Terry Zweip, Niel Parry, Daryl Gray, Ken Leslie, Carol-Ann Vasilevsky, Gabriela Ghitelescu, Julio Faria, Hugh MacDonald

Affiliations

¹ Department of Surgery, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
² Department of Surgery, London Health Sciences Centre, London, ON, Canada.
³ Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
⁴ Department of Surgery, Queensway Carleton Hospital, Ottawa, ON, Canada.
⁵ Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada.
⁶ Department of Surgery, North York General Hospital, North York, ON, Canada.
⁷ Department of Surgery, Health Science North, Sudbury, ON, Canada.
⁸ Department of Surgery, St Joseph's Health Centre, Toronto, ON, Canada.
⁹ Department of Surgery, Kingston Health Sciences Centre, Kingston, ON, Canada.
¹⁰ Department of Medicine, Institut du Savoir Montfort, Ottawa, ON, Canada.
¹¹ Department of Medicine University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
¹² Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, ON, Canada.
¹³ Department of Surgery, Humber River Hospital, Toronto, ON, Canada.
¹⁴ Department of Surgery, Montfort Hospital, Ottawa, ON, Canada.
¹⁵ Clinical Epidemiology Program, Method Centre, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
¹⁶ Department of Medicine University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada mcarrier@toh.ca.

PMID: 36100263
PMCID: PMC9468899
DOI: 10.1136/bmj-2022-071375

Randomized Controlled Trial

Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial

Rebecca C Auer et al. BMJ. 2022.

. 2022 Sep 13:378:e071375.

doi: 10.1136/bmj-2022-071375.

Authors

Collaborators

PERIOP-01 investigators:
Shaheer Tadros, Isabelle Raiche, Lara Williams, Reilly Musselman, Carolyn Nessim, Shady Ashamalla, Darlene Fenech, Terry Zweip, Niel Parry, Daryl Gray, Ken Leslie, Carol-Ann Vasilevsky, Gabriela Ghitelescu, Julio Faria, Hugh MacDonald

Affiliations

¹ Department of Surgery, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
² Department of Surgery, London Health Sciences Centre, London, ON, Canada.
³ Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
⁴ Department of Surgery, Queensway Carleton Hospital, Ottawa, ON, Canada.
⁵ Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada.
⁶ Department of Surgery, North York General Hospital, North York, ON, Canada.
⁷ Department of Surgery, Health Science North, Sudbury, ON, Canada.
⁸ Department of Surgery, St Joseph's Health Centre, Toronto, ON, Canada.
⁹ Department of Surgery, Kingston Health Sciences Centre, Kingston, ON, Canada.
¹⁰ Department of Medicine, Institut du Savoir Montfort, Ottawa, ON, Canada.
¹¹ Department of Medicine University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
¹² Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, ON, Canada.
¹³ Department of Surgery, Humber River Hospital, Toronto, ON, Canada.
¹⁴ Department of Surgery, Montfort Hospital, Ottawa, ON, Canada.
¹⁵ Clinical Epidemiology Program, Method Centre, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
¹⁶ Department of Medicine University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada mcarrier@toh.ca.

PMID: 36100263
PMCID: PMC9468899
DOI: 10.1136/bmj-2022-071375

Abstract

Objective: To determine the efficacy and safety of extended duration perioperative thromboprophylaxis by low molecular weight heparin when assessing disease-free survival in patients undergoing resection for colorectal cancer.

Design: Multicentre, open label, randomised controlled trial.

Settings: 12 hospitals in Quebec and Ontario, Canada, between 25 October 2011 and 31 December 2020.

Participants: 614 adults (age ≥18 years) were eligible with pathologically confirmed invasive adenocarcinoma of the colon or rectum, no evidence of metastatic disease, a haemoglobin concentration of ≥8 g/dL, and were scheduled to undergo surgical resection.

Interventions: Random assignment to extended duration thromboprophylaxis using daily subcutaneous tinzaparin at 4500 IU, beginning at decision to operate and continuing for 56 days postoperatively, compared with in-patient postoperative thromboprophylaxis only.

Main outcome measures: Primary outcome was disease-free survival at three years, defined as survival without locoregional recurrence, distant metastases, second primary (same cancer), second primary (other cancer), or death. Secondary outcomes included venous thromboembolism, postoperative major bleeding complications, and five year overall survival. Analyses were done in the intention-to-treat population.

Results: The trial stopped recruitment prematurely after the interim analysis for futility. The primary outcome occurred in 235 (77%) of 307 patients in the extended duration group and in 243 (79%) of 307 patients in the in-hospital thromboprophylaxis group (hazard ratio 1.1, 95% confidence interval 0.90 to 1.33; P=0.4). Postoperative venous thromboembolism occurred in five patients (2%) in the extended duration group and in four patients (1%) in the in-hospital thromboprophylaxis group (P=0.8). Major surgery related bleeding in the first postoperative week was reported in one person (<1%) in the extended duration and in six people (2%) in the in-hospital thromboprophylaxis group (P=0.1). No difference was noted for overall survival at five years in 272 (89%) patients in the extended duration group and 280 (91%) patients in the in-hospital thromboprophylaxis group (hazard ratio 1.12; 95% confidence interval 0.72 to 1.76; P=0.1).

Conclusions: Extended duration to perioperative anticoagulation with tinzaparin did not improve disease-free survival or overall survival in patients with colorectal cancer undergoing surgical resection compared with in-patient postoperative thromboprophylaxis alone. The incidences of venous thromboembolism and postoperative major bleeding were low and similar between groups.

Trial registration: ClinicalTrials.gov NCT01455831.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Canadian Institute of Health Research, Ottawa Hospital Academic Medical Organisation, and Leo Pharma, as well as through generous patient donations through the Ottawa Hospital Foundation for the submitted work. MC has received research funding from BMS, Pfizer, and Leo Pharma, and honorariums from Bayer, Pfizer, BMS, Servier, and Leo Pharma. VT received consulting honorariums from Pfizer-BMS and Daiichi-Sankyo and has received research funding from Sanofi. MB received consulting honorariums from Johnson and Johnson. ACM received consulting honorariums from Johnson and Johnson. MO received consulting honorariums from Johnson and Johnson Ethicon. All other authors declare no competing interests.

Figures

**Fig 2**
Kaplan-Meier plot of cumulative event rates of disease-free survival

See this image and copyright information in PMC

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Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial

Collaborators

Affiliations

Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial

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