University Medical Center Rotterdam, Erasmus MC, The Netherlands. Artrose is geen risicofactor voor hart-en vaatziekten; een prospectieve populatie-studie. TA Hoeven, MJ Leening, PJ Bindels, JB van Meurs, OH Franco, M Kavousi, A Hofman, MA Ikram, JC Witteman, SM Bierma-Zeinstra University Medical Center Rotterdam, Erasmus MC, The Netherlands. - Thank you for allowing me to present “Disability and not osteoarthritis predicts cardiovascular disease; a population-based cohort study.” I am Sita Bierma-Zeinstra, from at the departments of Orthopedics and General Practice at the ErasmusMC, in Rotterdam, I will be presenting on behalf the first author Theun Hoeven, one of my PhD students, who unfortunately could not be here.  

Artrose Meest frequente gewrichtsaandoening Veroorzaakt enorm veel pijn en invaliditeit Belangrijkste risicofactoren; leeftijd, vrouwelijk geslacht en obesitas

Achtergrond Voorgaande studies suggereren associatie tussen artrose (OA) en hart-en vaatziekten (HVZ) - cross-sectionele studies - disease specific mortality studies Verschillende potentiele mechanismen - metabole / laag-gradige inflammatoire processen - OA gelinkte medicatie - invaliditeit - bias Kan gerapporteerde relatie worden gebruikt in de praktijk? - rode vlag? - Recently OA has been linked with cardiometabolic disorders, predominantly in women. - Several cross-sectional and disease specific mortality studies suggest an association between OA and cardiovascular disease (CVD). - This association might arise from different potential mechanisms that I won’t go into now because of time restrictions. - For the development of treatment strategies in clinical practice, the mechanism beyond the relation between OA and CVD is relevant. “Should you for example prescribe statins for patients with OA?”

Onderzoeksvragen Is artrose risicofactor voor toekomstige hart-en vaatziekten? Rol van invaliditeit in potentiële associatie tussen artrose en HVZ? - We formulated the following research questions; - Is OA an additional risk factor for future cardiovascular disease? Should having OA be another red flag to start CVD prevention apart from the already existing risk factors for CVD. - What is the role of disability in the association between OA and CVD? Methods applied in clinical epidemiology that I will discuss in the next slides helped us to answer these rather methodological questions.

De ERGO-studie (Rotterdam Study) Prospectieve populatie-gebaseerde cohort studie in ouderen (n >11,000) Onderzoek: prevalentie en determinanten van ziekte Uitgebreide onderzoeken: interviews, bloed-afname, lichamelijk onderzoek, echo’s X-foto’s. Follow-up: elke 4-5 jaar, digitale links naar huisarts-dossiers en apotheek - Our study was embedded in the Rotterdam study; a population-based cohort study involving persons aged 55 years and older. - The aim of the Rotterdam study is to investigate prevalence and determinants of disease. - Follow-up takes place every 4-5 years since 1991. - At baseline and during follow-up persons are extensively examined by among others blood sampling, physical examinations and ultrasounds.

Design: Deelnemers Eerste cohort van de ERGO-studie (RS-I, ≥ 55 jaar, 1990-1992) Selectie Vrij van HVZ op baseline Bezochten onderzoekscentrum op baseline (X-rays) - Data was available for 4,648 persons aged 55 years and older and free of cardiovascular disease - They were classified on the basis of X-rays and symptoms into those with and those without OA - Disability was categorized as any versus none, defined by the Stanford Health assessment questionnaire; this was done independent of the presence of OA. - We gathered information on cardiovascular risk factors as well; knowing age, gender, body mass index, hypertension, diabetes, cholesterol and smoking.

Design: Determinanten Artrose: - Röntgen OA: X- knie, heup, of hand (KL ≥ 2) - Klinisch OA: Röntgen OA + corresponderende gewrichtsklachten - Self-reported OA: “Heeft u last van gewrichtsklachten die door een arts aan artrose worden toegeschreven?” - Totaal OA burden: (opgetelde KL scores heupen, knieën, en handen) Invaliditeit: Stanford Health Assessment Questionnaire (0-3, enige klachten versus geen klachten) Covariaten: leeftijd, geslacht, body mass index, hypertensie, diabetes mellitus, totaal cholesterol/HDL cholesterol ratio, en roken - Data was available for 4,648 persons aged 55 years and older and free of cardiovascular disease - They were classified on the basis of X-rays and symptoms into those with and those without OA - Disability was categorized as any versus none, defined by the Stanford Health assessment questionnaire; this was done independent of the presence of OA. - We gathered information on cardiovascular risk factors as well; knowing age, gender, body mass index, hypertension, diabetes, cholesterol and smoking.

Design: Uitkomst maten Incidente HVZ Myocard infarcten, coronaire revascularisaties en mortaliteit, CVA Directe links study base met medische dossier huisarts Regelmatige screening diagnoses bij huisartspraktijk - alle beschikbare informatie (ontslagbrieven, ECGs, neuroimaging, etc) - 2 arts-onderzoekers en 1 specialist Follow-up interviews en onderzoeken bij onderzoeks-centrum Consultatie lokale bevolkingsregister Digital linkage of the study base with medical files at the GP office. Moreover, the entire medical record of each participant is checked on a regular basis for diagnoses of interest. All available information, such as discharge reports, ECGs, and neuroimaging results are copied from the medical records or are obtained from the hospitals. Subsequently each potential CVD event is adjudicated according to standardised definitions by two independent research physicians and either an experienced cardiologist or neurologist.

Design: Statistische analyse Imputeren missing values (1%) co-variaten (expectation maximalisation) Hazard Ratios voor incidente HVZ (Cox proportional hazard models) geadjusteerd : leeftijd en geslacht geadjusteerd : leeftijd, geslacht en cardiovasculaire RF Sensitiviteits-analyses alleen myocard infarcten, ischaemische CVA, coronaire mortaliteit alleen voor vrouwen

Resultaten: Study populatie en follow-up RS I 7,983 personen 1,907 bezochten onderzoekscentrum niet 1,428 hadden HVZ op baseline 4,648 personen beschikbaar HVZ assessment tijdens follow-up - 67.6 jaar - 61% vrouwen - Röntgen OA (Knie:21%,Heup:10%, Hand:30%) - Klinische OA (Knie:7%, Heup:3%, Hand:7%) Mediane follow-up 14.4 jaar (interquartile range 7.6 jaar) 41 personen lost to follow-up (< 1 %) 1,230 personen met HVZ events tijdens follow-up

Resultaten: Knie OA en het risico op incidente HVZ Hazard ratio (95%CI) Totale HVZ (n=1230) P-value Rontgen OA Model 1 1.00 (0.87 to 1.15) 0.96 Model 2 0.99 (0.86 to 1.15) 0.92 Klinische OA 1.08 (0.88 to 1.33) 0.45 1.09 (0.88 to 1.34) 0.43 Self-reported OA 1.08 (0.93 to 1.24) 0.32 1.09 (0.94 to 1.26) 0.26 Model 1: adjusted for age and gender Model 2: adjusted for age, gender and CVD risk factors - Hazard ratios adjusted for cardiovascular risk factors for developing cardiovascular disease were calculated. - We chose incident CVD as outcome measure, comprising myocardial infarctions, surgical or percutaneous coronary revascularisations, coronary mortality or stroke Various sources for potential events were consulted to achieve complete follow-up, linkage of medical records to the study base, regular screening of medical record’s at the GP’s office, follow-up interviews and examination at the research centre, and consultation of the central registry of the local municipality. This resulted in a high quality documentation and follow-up. We looked at women separately because in earlier research we found association between subclincial measures of arteroscelories and hand and knee OA in women only We looked at the other sites with OA and the total OA burden but found similar results.

Resultaten: Invaliditeit en het risico op incident HVZ Hazard ratio (95% CI) Totale HVZ (n=1230) P-value Invaliditeit Model 1 1.30 (1.15 to 1.46) <0.001 Model 2 1.26 (1.12 to 1.42) Invaliditeit onderste extremiteiten 1.22 (1.08 to 1.38) 0.002 1.19 (1.05 to 1.34) 0.008 Model 1: adjusted for age and gender Model 2: adjusted for age, gender and CVD risk factors - Results for disability and risk of incident cardiovascular disease are shown in this table. - Again, model 1 is adjusted for age and gender - Model 2 is adjusted for age, gender, body mass index, hypertension, cholesterol, diabetes and current smoking. This table shows that disability does predict cardiovascular disease.

Resultaten: HVZ-vrije survival curves (leeftijd & geslacht geadjusteerd) - CVD-free survival curves for non-disabled and disabled persons are shown here to present our findings graphically, more visually. - The blue line represents non-disabled participants - The green line represents the disabled participants - The figure at the left shows results for patients with clinical knee OA - The figure at the right shows results for persons without clinical knee OA - You can see that the graphs are similar, supporting that disability is a risk factor for future cardiovascular disease, independent of the presence of OA.

Conclusies Artrose geen risico-factor voor toekomstige HVZ in dit cohort (55+) Invaliditeit voorspelt HVZ: - onafhankelijk andere cardiovasculaire risico-factoren - onafhankelijk aanwezigheid van artrose Artrose gerelateerde invaliditeit en comorbiditeit zou eerdere rapportages over relatie tussen artrose en HVZ kunnen verklaren. - From this study, we can conclude that; - Osteoarthritis is not an additional risk factor for future CVD. - Disability predicts cardiovascular disease, independent of the presence of osteoarthritis. Disability should therefore be prevented, also in the presence of OA. - The close relation between disability and OA may explain earlier findings of a relation between OA and risk of CVD.  

Financiële support Deze studie werd mogelijk gemaakt door subsidies van het Reumafonds, de NWO, en ZonMw. - This study is supported by grants from among others the Dutch Artritis Foundation, I have no disclosures.