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  • Association between baseline vitamin D metabolite levels and long-term cardiovascular events in patients with rheumatoid arthritis from the CIMESTRA trial: protocol for a cohort study with patient-record evaluated outcomes

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Rheumatology
Protocol
Association between baseline vitamin D metabolite levels and long-term cardiovascular events in patients with rheumatoid arthritis from the CIMESTRA trial: protocol for a cohort study with patient-record evaluated outcomes
  1. M Herly1,2,
  2. K Stengaard-Pedersen3,
  3. K Hørslev-Petersen4,
  4. M L Hetland5,
  5. M Østergaard5,
  6. R Christensen6,
  7. B B Løgstrup7,
  8. P Vestergaard8,
  9. J Pødenphant9,
  10. P Junker1,
  11. T Ellingsen1
  1. 1Department of Rheumatology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
  2. 2Odense Patient data Explorative Network (OPEN), University of Southern Denmark, Odense, Denmark
  3. 3Department of Rheumatology, Centre of Cancer and Inflammation, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
  4. 4King Christian 10th Hospital for Rheumatic Diseases, Southern University of Denmark, Graasten, Denmark
  5. 5Department of Rheumatology, COPECARE, Copenhagen University Hospital, Glostrup, Denmark
  6. 6Musculoskeletal Statistics Unit, The Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
  7. 7Department of Cardiology, Aarhus University Hospital, Skejby, Denmark
  8. 8Departments of Clinical Medicine and Endocrinology, Aalborg University, Denmark
  9. 9Department of Rheumatology, Copenhagen University Hospital, Gentofte, Denmark
  1. Correspondence to Mette Herly; Mette.herly{at}rsyd.dk

Abstract

Introduction Cardiovascular morbidity and mortality is increased in patients with rheumatoid arthritis (RA), and among these patients, the prevalence of hypovitaminosis D is high. Moreover, low vitamin D levels have been associated with increased cardiovascular risk in healthy subjects.

Objective To evaluate the long-term risk of cardiovascular events in patients having low total 25-hydroxyvitamin D levels at baseline compared with patients with normal levels, in an efficiently treated, closed cohort of patients with an early diagnosis of RA.

Methods and analysis This study is a prospective, closed, blinded endpoint cohort study, based on secondary analyses from a previous randomised trial (CIMESTRA study; NCT00209859, approved September 1999) including 160 patients with an early diagnosis of RA from Danish University clinics. Primary outcome will be the proportion of patients with any cardiovascular event in the follow-up period, evaluated using systematic journal audits. Logistic regression models will test the hypothesis that there are more cardiovascular events in enrolled patients with a low level of vitamin D (< 50 nmol/L). Secondarily, Cox regression models, based on survival analysis, will determine the extent to which independent variables (including different levels of vitamin D at baseline) predict whether a cardiovascular event will occur, and also when this will be.

Ethics and dissemination All patients have received verbal and written information before enrolment, and have given written consent at baseline. To disseminate comprehension of factors of prognostic importance to cardiovascular outcome in RA, we will attempt to have a first draft ready no later than 1 year after the adjudication process has finished. If low vitamin D levels can predict cardiovascular events in RA, it is relevant to take into account in a prediction model, to be considered by patients, physicians and other decision-makers.

Trial registration number The parental controlled trial is registered as NCT00209859.

  • Rheumatoid Arthritis
  • Cardiovascular co-morbidity
  • Vitamin D metabolites

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/bmjopen-2016-014816

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    Footnotes

    • Contributors All authors contributed to conception and design, data acquisition or analysis and interpretation of data, and took part in drafting or revising the article. All authors give their final approval of this version to be published, and agree to be accountable for all aspects of the work. MH, TE: conceived the idea for the study; they are the primary sponsors of the study. MH: wrote the draft and the following alterations. RC: data manager (together with MH), was responsible for the statistical analysis plan, and contributed to the methodological and statistical analysis section. BBL: cardiological supervisor, contributed to construction of the outcome adjudication protocol, and will be part of the adjudication working group when data entry is started. PV: endocrinological supervisor, managed any considerations concerning vitamin D metabolites and measurements. KS-P, MHL KH-P: principal investigators in the parental study (NCT00209859), and both are together with JP, MØ, PJ and MH members of the original CIMESTRA steering group, responsible for initiating and maintaining the CIMESTRA Study, thereby providing data for this study. They all carefully read and commented on the manuscript draft. TE is main supervisor, and supervised the writing process, and contributed to construction of the outcome adjudication protocol, and is also member of the CIMESTRA steering group.

    • Funding The Danish Rheumatism Association provided financial support to scientific personnel and for vitamin D metabolite analyses. Silkeborg Region Hospital Research Fond and Research Foundation at Regional Hospital Midt provided financial support for vitamin D metabolite analyses. Faculty Stipendiate of University of Southern Denmark provided financial support to scientific personnel. Novartis Healthcare Denmark A/S provided the ciclosporin (SandimmunNeoral) and placebo-ciclosporin and sponsored an independent good clinical practice monitor. Nycomed provided methotrexate (Emthexate), folic acid (Apovit) and calcium/vitamin D (CaviD) supplementation. Schering-Plough provided betamethasone (Diprospan) and MSD provided alendronate (Fosamax). Pfizer Denmark provided an ‘unrestricted grant’ to the project. The Parker Institute, Bispebjerg and Frederiksberg Hospital (RC) is supported by a core grant from the Oak Foundation (OCAY-13–309). The sponsors were not involved in the study design, data collection, analysis or interpretation, and had no influence on the publishing of data.

    • Competing interests None declared.

    • Ethics approval NCT00209859, Danish Health Authority (3-3013-930/1/), Danish Data Protection Agency (2008-58-0035).

    • Provenance and peer review Not commissioned; externally peer reviewed.