Background: RA is associated with an increased cardiovascular (CV) risk. csDMARDs are first-line treatments for RA and can mitigate this risk, but limited data exist on their CV effects. Previous trials have reported protective effects for methotrexate (MTX) and hydroxychloroquine (HCQ), but no similar data exist on sulfasalazine (SSZ) or leflunomide (LEF).

Objectives: To assess the comparative effect of csDMARDs on the risk of myocardial infarction (MI) and stroke in RA patients

Methods: Data from 6 claims/electronic health records databases across Germany, US, and UK, all mapped to the Observational Medical Outcomes Partnership (OMOP) common data model. A cohort study was conducted including patients ≥18 years old, with first RA diagnosis in 2005-2019, initiating csDMARD monotherapy with MTX, HCQ, SSZ, or LEF. Those with a prior diagnosis of other inflammatory arthritis or <1 year prior follow-up were excluded. Patients were followed until first outcome, death, loss of or 5 years follow-up. Propensity score stratification was used, and hazard ratios (HR) estimated for HCQ, SSZ and LEF compared to MTX in each dataset using Cox regression. HR were calibrated (cHR) for residual confounding using negative control outcomes. Estimates were pooled where I² for heterogeneity <0.4. Intention to treat and an on treatment analyses are reported.

Results: 145,248 patients were included (MTX: 73,996, HCQ: 49,752, SSZ: 12,256, LEF: 9,244). Pooled rates of MI and stroke for MTX were 7.64 and 10.26 per 1,000 person years respectively. Detailed estimate cHRs are shown in Figure 1 for the intention to treat analysis. MI risk with SSZ and LEF was comparable to MTX. Risk of stroke was similar between LEF and MTX, but reduced for HCQ and SSZ compared to MTX, with pooled cHR (95% CI) 0.86 (0.78 to 0.95) and 0.71 (0.52 to 0.98) for HCQ and SSZ respectively. Similar results were found for “on treatment” analyses.

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Figure 1.

Calibrated hazard ratios (cHRs) for MI and stroke

Conclusion: Overall, all four csDMARDs had similar effects on MI risk. HCQ and SSZ use were associated with a decreased risk of stroke compared to MTX. The observed differences may be attributable to differential effects on the atherosclerotic process, differential disease control, or both.

Database estimates not reported where adequate covariate balance not attained. Meta-analysis results not reported where I2>0.4. MEDICARE did not pass diagnostics for SSZ and LEF analyses. cHR: calibrated Hazard Ratio; CI: Confidence Interval; MTX: Methotrexate; HCQ: Hydroxychloroquine; SSZ: sulphasalazine; LEF: Leflunomide; THIN: The Health Improvement Network (UK); Optum: Optum de-identified Clinformatics Datamart (US); MDCR: Medicare (US); GERMANY: IQVIA Disease Analyzer EMR (Germany); CCAE: IBM MarketScan Commercial Claims and Encounters (US); AMBEMR: IQVIA Ambulatory EMR (US)

Database estimates not reported where adequate covariate balance not attained. Meta-analysis results not reported where I2>0.4. MEDICARE did not pass diagnostics for SSZ and LEF analyses. cHR: calibrated Hazard Ratio; CI: Confidence Interval; MTX: Methotrexate; HCQ: Hydroxychloroquine; SSZ: sulphasalazine; LEF: Leflunomide; THIN: The Health Improvement Network (UK); Optum: Optum de-identified Clinformatics Datamart (US); MDCR: Medicare (US); GERMANY: IQVIA Disease Analyzer EMR (Germany); CCAE: IBM MarketScan Commercial Claims and Encounters (US); AMBEMR: IQVIA Ambulatory EMR (US)

Disclosure of Interests: : Albert Prats-Uribe: None declared, Ben Illingens: None declared, David Vizcaya Employee of: Bayer, James Weaver Shareholder of: J&J Shares, Grant/research support from: Full-time employment salary from Janssen, Consultant of: Janssen employee, Employee of: Janssen, Paid instructor for: Janssen employee, have instructed at conferences, Speakers bureau: Janssen employee, have spoken at conferences, Edward Burn: None declared, Ruta Sawant Shareholder of: AbbVie, Employee of: AbbVie, Karine Marinier Employee of: Servier, Patrick Ryan: None declared, Daniel Prieto-Alhambra Grant/research support from: Professor Prieto-Alhambra has received research Grants from AMGEN, UCB Biopharma and Les Laboratoires Servier, Consultant of: DPA’s department has received fees for consultancy services from UCB Biopharma, Speakers bureau: DPA’s department has received fees for speaker and advisory board membership services from Amgen