{"paper_id":"9b10a6d1-b91e-479f-a52a-cdeee2062cec","body_text":"INTRODUCTION \nReview question / Objective What is the \neffect of combined oral contraceptive pills \n(COCP) on the risk of cardiovascular \ndisease in premenopausal females with \nendometriosis? \nCondition being studied Endometriosis is one of \nthe most common enfeebling gynecologic \ndiseases affecting women of reproductive age. An \nestimate of 10% of females worldwide are \ndiagnosed with endometriosis. Endometriosis is \nlinked to cardiovascular diseases as it promotes \nchronic systemic inflammation and proatherogenic \nlipid profile. COCP effect on cardiovascular \ndisease has been studied extensively in both pre-\nand post-menopausal females. Endometriosis as \nthe disease, and COCP as its preferred treatment, \nare both associated with an increased risk of CVD. \nThis raises the question about the effect of COCP \non the risk of cardiovascular disease in \npremenopausal females with endometriosis. \nMETHODS \nParticipant or population Premenopausal females \ndiagnosed with endometriosis surgically or \nradiologically. \nIntervention Combined oral contraceptive pills, \ntaken as the only hormonal medication understudy, \nwith different types and doses of estrogen and \nprogestogen, of any generation, monophasic or \nmultiphasic, cyclic or continuous. Medical \ntreatment duration should be at least 3 months. \nComparator No COCP: Placebo or no treatment; \nProgestin only pills (POPs): any type of progestin \nused, daily PO intake. \nINPLASY 1\nInternational Platform of Registered Systematic Review and Meta-analysis Protocols\nINPLASYThe Effect of Combined Oral Contraceptive Pills on the \nRisk of Cardiovascular Diseases in Premenopausal \nFemales with Endometriosis- Systematic Review & \nMeta-Analysis\nMohamad, M1; El-Hajj Fuleihan, G2; Akl, EA3; Abu Musa, A4.\nADMINISTRATIVE INFORMATION  \nSupport -  None. \nReview Stage at time of this submission - Risk of bias assessment. \nConflicts of interest - None declared. \nINPLASY registration number: INPLASY202410028 \nAmendments - This protocol was registered with the International \nPlatform of Registered Systematic Review and Meta-Analysis Protocols \n(INPLASY) on 08 January 2024 and was last updated on 08 January \n2024.\nCorresponding author: \nMay Mohamad\nmayy.mohammad@yahoo.com\nAuthor Affiliation:                   \nAmerican University of Beirut.\nMohamad et al. INPLASY protocol 202410028. doi:10.37766/inplasy2024.1.0028\nMohamad et al. INPLASY protocol 202410028. doi:10.37766/inplasy2024.1.0028 Downloaded from https://inplasy.com/inplasy-2024-1-0028/\nINPLASY202410028\ndoi: 10.37766/inplasy2024.1.0028 \nReceived: 08 January 2024\nPublished: 08 January 2024\n\nStudy designs to be included Randomized and \nnon-randomized controlled clinical trials; Non-\nrandomized studies of intervention/s (NRSI). \nEligibility criteria Exclusion Criteria: Case reports \nand cross-sectional studies; Studies using COCP \nas complementary therapy or those comparing \nCOCP with medications other than progestin only \npills. \nInformation sources Our search includes four \nelectronic databases (Medline, Cochrane, Popline, \nEmbase) using MeSH and Keywords. The search \nstrategy was developed with the assistance of a \nmedical librarian and content experts based on \ntwo concepts: Endometriosis and COCP . We \ndeveloped the search strategy initially for Medline \nand adapted for the rest. The search was not \nlimited to language or year of publication. Google \nScholar, Clinical trial.gov, ICTRP , and references of \nincluded studies were searched as part of grey \nliterature.\nMain outcome(s) A. Clinical Outcomes \n(Cardiovascular disease):\nCardiovascular diseases include coronary heart \ndisease (CHD), cerebrovascular disease, peripheral \narterial disease (PAD).\n– Acute coronary syndrome: angina, fatal \nmyocardial infarction (MI), and nonfatal MI;\n– Stroke: Transient Ischemic Attack, fatal stroke, \nand non-fatal stroke;\n– Peripheral arterial diseases: Claudication, Acute \nLimb Ischemia, Critical Limb Ischemia, Ischemic \nAmputation, Revascularization\n– Cardiovascular mortality\n– All-cause mortality.\nB. Surrogate Outcomes (Cardiovascular profile):\nCardiovascular profile is defined as lipid profile, \ninflammatory, and coagulation parameters.\n– Lipid Profile: Castelli Index 1: (total cholesterol \n(TC)/ high-density lipoprotein (HDL)), low-density \nlipoprotein (LDL), Triglycerides (TG);\n– Serum Inflammatory Markers: Interleukin 6 (IL-6), \nHigh sensitivity C-Reactive Protein (hs-CRP);\n– Coagulation profile: Fibrinogen, homocysteine, \nProthrombin Time (PT), activated Partial \nThromboplastin Time (aPTT), and Thrombin Time \n(TT);\nThe minimal follow up duration for surrogate and \nclinical outcomes is 3 months and 1 year, \nrespectively.\nQuality assessment / Risk of bias analysis We \nwill assess the risk of bias of each outcome in \nduplicate and independently using Cochrane Risk \nof Bias Tool 2 (ROB2) for RCTs and the risk of bias \n(confounding, selection bias, reporting of selective \noutcomes, inadequate methods of ascertainment \nof exposure and outcomes) in comparative \nobservational studies using the criteria \nrecommended by GRADE. Using GRADE “Grades \nof Recommendations Assessment, Development \nand Evaluation”, we will evaluate the quality of \nevidence by outcome. \nStrategy of data synthesis We will use random-\neffects model to quantitatively synthesize study. \nWe will perform the meta-analyses of RCTs \nseparate from that of observational studies.\n• Using Review Manager software (Revman), we \nwill pool the means of each continuous outcome in \nRCTs separately from the adjusted means (when \napplicable) of cohorts and case-control studies. \nAfter the collection of number of events per each \ntreatment arm for each categorical outcome in \nRCTs, we will pool the effect estimates to yield an \noverall Relative risk (in addition to absolute risk, \nwhen applicable) and will pool the adjusted effect \nestimates (when applicable) of observational \nstudies to yield an overall Odds ratio (in addition to \nabsolute risk, when applicable). We will compare in \nparallel the effect estimates of randomized vs \ncomparative observed studies for each outcome.\n• We will test for heterogeneity between studies: \n(I^2: 0-100). In case of high heterogeneity (I^2>=50 \nor P<0.1), we will attempt to provide an \nexplanation by subgroup analysis. \nIn case quantitative synthesis is not appropriate, \nwe will report a narrative summary of the findings. \nSubgroup analysis Subgroup analysis, when \napplicable and data are available, will include the \nfollowing, smoking status, age, COCP generations. \nIn case data were not available other factors can \nbe added to subgroup analysis, e.g.: BMI, \ntreatment duration, time of assessment and \ncardiovascular risk. \nSensitivity analysis We will perform sensitivity \nanalysis for studies of high risk of bias (omitting vs \ninclusion of those studies) and for studies with \nmissing data (considering “data are not randomly \nmissing” and replacing missing data using \nimputation methods). \nCountry(ies) involved Lebanon. \nKeywords Endometriosis; cardiovascular risk; \np re m e n o p a u s a l w o m e n ; c o m b i n e d o r a l \ncontraceptives; progestin only pills; systematic \nreview; meta-analysis. \nContributions of each author \nAuthor 1 - May Mohamad.\nINPLASY 2Mohamad et al. INPLASY protocol 202410028. doi:10.37766/inplasy2024.1.0028\nMohamad et al. INPLASY protocol 202410028. doi:10.37766/inplasy2024.1.0028 Downloaded from https://inplasy.com/inplasy-2024-1-0028/\n\nEmail: mam119@mail.aub.edu\nAuthor 2 - Ghada El-Hajj Fuleihan.\nEmail: gf01@aub.edu.lb\nAuthor 3 - Elie Akl.\nEmail: ea32@aub.edu.lb\nAuthor 4 - Antoine Abu Musa.\nEmail: antoine.abu.musa@gmail.com\nINPLASY 3Mohamad et al. INPLASY protocol 202410028. doi:10.37766/inplasy2024.1.0028\nMohamad et al. INPLASY protocol 202410028. doi:10.37766/inplasy2024.1.0028 Downloaded from https://inplasy.com/inplasy-2024-1-0028/","source_license":"CC0","license_restricted":false}