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Use of Heparins in Patients with Cancer: Individual Participant Data Meta- Analysis of Randomised Trials Study Protocol

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Use of Heparins in Patients with Cancer: Individual Participant Data Meta- Analysis of Randomised Trials Study Protocol Open Access Protocol BMJ Open: first published as 10.1136/bmjopen-2015-010569 on 29 April 2016. Downloaded from Use of heparins in patients with cancer: individual participant data meta- analysis of randomised trials study protocol Holger J Schünemann,1,2 Matthew Ventresca,1,3 Mark Crowther,4 Matthias Briel,1,5 Qi Zhou,1 David Garcia,6 Gary Lyman,7,8 Simon Noble,9 Fergus Macbeth,10 Gareth Griffiths,10,11 Marcello DiNisio,12,13 Alfonso Iorio,1,14 Joseph Beyene,1,15 Lawrance Mbuagbaw,16 Ignacio Neumann,1,17 Nick Van Es,13 Melissa Brouwers,18 Jan Brozek,1 Gordon Guyatt,1 Mark Levine,1 Stephan Moll,19 Nancy Santesso,1 Michael Streiff,20 Tejan Baldeh,1 Ivan Florez,1,21 Ozlem Gurunlu Alma,22 Ziad Solh,23 Walter Ageno,24 Maura Marcucci,25 George Bozas,26 Gilbert Zulian,27 Anthony Maraveyas,28 Bernard Lebeau,29 Harry Buller,13 Jessica Evans,10 Robert McBane,30 Suzanne Bleker,13 Uwe Pelzer,31 Elie A Akl,1,32 and the IPDMA heparin use in cancer patients research group To cite: Schünemann HJ, ABSTRACT Strengths and limitations of this study Ventresca M, Crowther M, Introduction: Parenteral anticoagulants may improve et al. Use of heparins in outcomes in patients with cancer by reducing risk of ▪ In addition to our extensive search and robust ana- patients with cancer: venous thromboembolic disease and through a direct individual participant data lysis, the strength of our study relates to the possi- meta-analysis of randomised antitumour effect. Study-level systematic reviews bility of identifying patient-level effect modifiers and trials study protocol. BMJ indicate a reduction in venous thromboembolism and exploring the survival benefit suggested by our Open 2016;6:e010569. provide moderate confidence that a small survival study level meta-analysis. doi:10.1136/bmjopen-2015- benefit exists. It remains unclear if any patient ▪ This will be the first IPDMA to address the health 010569 subgroups experience potential benefits. effects of heparin on patients with cancer and to http://bmjopen.bmj.com/ Methods and analysis: First, we will perform a provide important background for decision makers in this field. Our results will likely receive attention ▸ Prepublication history and comprehensive systematic search of MEDLINE, in the next editions of several guidelines given the additional material is EMBASE and The Cochrane Library, hand search participation of several investigators in guideline available. To view please visit scientific conference abstracts and check clinical development groups (eg, the American College of the journal (http://dx.doi.org/ trials registries for randomised control trials of Chest Physicians, Cancer Care Ontario, American 10.1136/bmjopen-2015- participants with solid cancers who are administered 010569). Society of Hematology, American Society of Clinical parenteral anticoagulants. We anticipate identifying at Oncology and National Comprehensive Cancer least 15 trials, exceeding 9000 participants. Second, Network). on September 26, 2021 by guest. Protected copyright. we will perform an individual participant data meta- ▪ A number of knowledge users will be directly Received 9 December 2015 analysis to explore the magnitude of survival benefit Accepted 10 December 2015 involved in the project on various occasions. They and address whether subgroups of patients are more will take ownership through the involvement with likely to benefit from parenteral anticoagulants. All all stages of the project and coauthoring of analyses will follow the intention-to-treat principle. the publications resulting from this knowledge For our primary outcome, mortality, we will use synthesis. multivariable hierarchical models with patient-level ▪ The American Hematological Society guideline variables as fixed effects and a categorical trial panel has already been involved in the generation of variable as a random effect. We will adjust analysis the questions to be answered by this synthesis. We for important prognostic characteristics. To believe that this offers an outstanding opportunity investigate whether intervention effects vary by for dissemination. ▪ The guideline developers will use the results of this predefined subgroups of patients, we will test synthesis to inform their guideline recommenda- interaction terms in the statistical model. tions and practice. Several of the knowledge users Furthermore, we will develop a risk-prediction model For numbered affiliations see will disseminate the results through presentations at end of article. for venous thromboembolism, with a focus on clinical rounds as well as national and international control patients of randomised trials. conferences. Correspondence to Ethics and dissemination: Aside from maintaining ▪ Weaknesses of our study are in the risk of not obtain- Dr Holger Schünemann; participant anonymity, there are no major ethical ing data from all studies that will be identified. [email protected] concerns. This will be the first individual participant Schünemann HJ, et al. BMJ Open 2016;6:e010569. doi:10.1136/bmjopen-2015-010569 1 Open Access BMJ Open: first published as 10.1136/bmjopen-2015-010569 on 29 April 2016. Downloaded from data meta-analysis addressing heparin use among patients with influential guideline panel made a conditional recom- cancer and will directly influence recommendations in clinical mendation against the use of heparin because they were practice guidelines. Major cancer guideline development uncertain as to whether or not the intervention reduced organisations will use eventual results to inform their guideline mortality. Since then, new trials have been published and recommendations. Several knowledge users will disseminate we have updated our study-level systematic review (see results through presentations at clinical rounds as well as national fi and international conferences. We will prepare an evidence brief table 1 for the summary of ndings table and online and facilitate dialogue to engage policymakers and stakeholders in supplementary appendix 1 for the detailed evidence fi acting on findings. pro le). Trial registration number: PROSPERO CRD42013003526. There are several key questions that remain unanswered by this study-level meta-analysis. First, the analysis of mortality remains inconclusive (the CI for the relative risk included the value of 1.0), but survival ana- lysis suggested a statistically significant mortality benefit. INTRODUCTION Unfortunately, this cannot be further investigated Cancer is a leading cause of death worldwide. In without IPD. Second, given the broad inclusion criteria Canada, approximately 145 000 new cases are diagnosed in the randomised controlled trials (RCTs), it is unclear annually.1 The risk of venous thromboembolic complica- whether the effects are restricted to subgroups of tions is elevated in patients with cancer.23The annual patients defined by the type (ie, primary tumour site) or risk of suffering a venous thromboembolic event (VTE), stage of cancer (eg, local vs metastatic).13 Third, there is estimated from control groups of randomised trials in uncertainty about the appropriate duration of treatment patients with solid cancer, is 4–5%.4 Patients who experi- and whether or not there is an interaction with the ence VTE frequently require hospital admission and/or administration of chemotherapy and hormone therapy prolonged anticoagulant therapy. VTE is also associated (ie, the coadministration of chemotherapy or hormone with impairments in function of day-to-day life and pain, therapy may potentiate the beneficial effects of paren- in addition to increased costs.5 teral anticoagulants). Fourth, there is uncertainty Heparin and other LMWHs, such as fondaparinux and whether heparin has a direct antitumour effect. IPDMA danaparoid, do not have intrinsic anticoagulant activity might be able to shed more light on this issue if survival but potentiate antithrombin III, which inhibits activated is prolonged independently of the occurrence of VTE. coagulation agents. These agents constitute indirect antic- Fifth, the baseline risk for VTEs and the risk of bleeding oagulants as their activity is mediated by plasma cofactors.6 are unknown in many of these patients and it is possible Heparin and its low-molecular weight derivatives are not that patient data from these trials can be used to absorbed orally and must be administered parenterally by develop risk-prediction models. http://bmjopen.bmj.com/ intravenous infusion or subcutaneous injections.7 To develop the best recommendations for patient care Researchers have hypothesised that heparin may improve and to make socially responsible decisions, guideline outcomes in patients with cancer through an antitumour panels and others developing recommendations must be effect in addition to its antithrombotic effect.8 This antitu- informed by the best possible summary of the evidence. mour activity of heparin, mechanistically, includes the Study-level meta-analysis does not allow for the evalu- inhibition of cell–cell interaction by blocking cell-adhesion ation of modifying factors and for survival analysis based molecules (selectins), the inhibition of extracellular- on prognostic factors of individual patients. An IPDMA matrix protease heparanase and the inhibition of angio- can help resolve these issues. on September 26, 2021 by guest. Protected copyright. genesis.9 In a 1992 clinical trial comparing nadroparin, a The results of this synthesis will directly inform the LMWH, to unfractionated heparin (UFH) in patients with recommendations of the next update of several
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