November's Paper of the Month looks at the Efficacy and safety of extended duration to perioperative thromboprophylaxis
Paper title, authors, journal:
Auer RC, Ott M, Karanicolas P, Brackstone MR, Ashamalla S, Weaver J, Tagalakis V, Boutros M, Stotland P, Marulanda AC, Moloo H, Jayaraman S, Patel S, Le Gal G, Spadafora S, MacLellan S, Trottier D, Jonker D, Asmis T, Mallick R, Pecarskie A, Ramsay T, Carrier M; PERIOP-01 investigators. 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. BMJ. 2022 Sep 13;378:e071375. doi: 10.1136/bmj-2022-071375.
What is known about the subject?
Warfarin has been reported to decrease cancer recurrence in patients with melanoma while Heparins, in particular, low molecular weight heparin (LMWH), tinzaparin, have shown antimetastatic properties in preclinical models by potentially inhibiting tumour cell invasion of the extracellular matrix, hindering protection of tumour cells in the circulation from immune mediated destruction, and impairing neovascularisation of micrometastases due to an antiangiogenic effect.
An initial meta-analysis assessing the effect of low molecular weight heparin on cancer outcomes reported that the use of LMWH improved overall survival (1). However, more recent analyses including all published studies to date have been unable to support an overall survival benefit for cancer patients (2).
The perioperative period might be the ideal setting to study the antimetastatic effects of LMWH because surgery results in a hypercoagulable postoperative state and an inability to clear micrometastatic disease when the disease is present after surgical resection, leading to potential cancer recurrence and worse survival (3). The PERIOP-01 trial was a multicentre, open label, randomised controlled trial comparing extended duration to in-hospital thromboprophylaxis using LMWH.
Study methodology
Patients were followed up for up to five years or to death, regardless of the duration of study drug. The primary outcome was disease-free survival at three years in the intention-to-treat population. Secondary outcome measures were venous thromboembolism, major surgery-related bleeding events, major bleeding events, clinically relevant non-major bleeding events, postoperative complications, transfusion requirements, overall survival at five years, wound infection, and anastomotic leakage.
What the study adds?
The PERIOP-01 trial showed that extended duration perioperative thromboprophylaxis with tinzaparin did not result in an improvement in disease-free survival at three years compared with in-hospital thromboprophylaxis among patients with localised invasive colorectal cancer without evidence of metastatic disease who were eligible to undergo surgical resection. Furthermore, rates of venous thromboembolism and postoperative major bleeding complications were low in this patient population, and similar between groups. The study showed no significant reduction in symptomatic venous thromboembolism between the extended duration and in-hospital thromboprophylaxis groups (2% vs. 1%).
Discussion of the study results
Rates of venous thromboembolism were low (<2%) without significant differences between the two groups. A recent meta-analysis of randomised trials reporting a 30-day incidence of clinical venous thromboembolism of 1.4% in patients receiving extended duration and 0.3% in patients receiving thromboprophylaxis in hospital after major abdominal or pelvic surgery.
Unlike previous randomised controlled trials, screening ultrasounds of the lower extremities were not undertaken. The study stated that “use of asymptomatic deep vein thrombosis (DVT) of the lower extremities diagnosed on screening ultrasound or venography is often used as a surrogate outcome measure; however, its clinical relevance remains unclear”. This can be debated. Because there is evidence that sub-clinical DVT might affect post-operative outcome.
A limitation of the trial was the open label design, which could be associated with a risk of bias regarding the frequency of outcomes, as compared with the frequency that might have been observed in a placebo-controlled trial. The trial was stopped early after the recommendations from the data monitoring and safety board leading to under-powering of the primary outcome.
Implications for colorectal practice
Most centres use an extended duration of perioperative thromboprophylaxis with LMWH as a prophylaxis against asymptomatic thrombo-embolic events. The study was under-powered to assess these events. As the authors reported in the study limitations, no screening ultrasounds was used unlike previous randomised controlled trials.
The evidence that cancer and surgery increase the risk of thrombo-embolic events is strong but the effect of extended thrombo-embolic prophylaxis will continue to be debated. A large sample size randomised trial would be difficult to conduct. New tools to investigate this (and other gaps in our knowledge) are needed.
References
- Lazo-Langner A, Goss GD, Spaans JN, Rodger MA. The effect of low-molecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials. J Thromb Haemost2007;5:729-37. doi:10.1111/j.1538-7836.2007.02427.x.
- Montroy J, Lalu MM, Auer RC, et al. The efficacy and safety of low molecular weight heparin administration to improve survival of cancer patients: a systematic review and meta-analysis. Thromb Haemost2020;120:832-46. doi:10.1055/s-0040-1709712
- Auer RA, Scheer AS, McSparron JI, et al. Postoperative venous thromboembolism predicts survival in cancer patients. Ann Surg2012;255:963-70. doi:10.1097/SLA.0b013e31824daccb. pmid:22504195
- Knoll W, Fergusson N, Ivankovic V, et al. Extended thromboprophylaxis following major abdominal/pelvic cancer-related surgery: a systematic review and meta-analysis of the literature. Thromb Res2021;204:114-22. doi:10.1016/j.thromres.2021.06.010.
- Lewis-Lloyd CA, Humes DJ, West J, Peacock O, Crooks CJ. The Duration and Magnitude of Postdischarge Venous Thromboembolism Following Colectomy. Ann Surg. 2022 Sep 1;276(3):e177-e184.