Trial of Atorvastatin for the primary prevention of cardiovascular events in patients with RA (TRACE RA): A randomised trial in 2986 RA patients

Background: Patients with RA are at increased risk from cardiovascular disease (CVD) compared with the general population, due to classical (e.g. hypertension and dyslipidaemia) and novel (e.g. systemic inflammation) risk factors. It remains unclear whether primary prevention strategies for CVD are effective in conditions of high grade inflammation such as RA. The TRial of Atorvastatin for the primary prevention of Cardiovascular Events in patients with Rheumatoid Arthritis (TRACE RA) addressed the hypothesis that atorvastatin 40 mg daily is superior to placebo for the primary prevention of CVD events in RA (ISRCTN: 41829447).

Methods: Prospective, randomized, double-blind, placebo-controlled, multicentre trial in RA patients aged >50 years or RA duration >10 years; without known atherosclerotic disease, diabetes, myopathy; not already taking statin. All patients were given lifestyle advice. The primary endpoint was a composite of CVD death, non-fatal myocardial infarction, cerebrovascular accident (excluding haemorrhagic stroke), transient ischaemic attack, hospitalized angina, coronary and non-coronary revascularization. Secondary endpoints included safety outcomes and lipid changes. The trial was designed to have 80% power at P < 0.05 to detect a 32% risk reduction with atorvastatin based on 1.8% event rate, using intention to treat analysis over 5 years. Cox regression stratified by centre, Fisher’s exact test and the Mann–Whitney test were used for analysis, as appropriate.

Results: Trial duration was August 2007 to December 2012. A total of 2986 patients from 102 centres were randomized and followed up for a median of 2.53 years (interquartile range 1.94–3.50), providing 7908 patient-years of follow up. Atorvastatin and placebo groups were well-matched for age, sex, ethnicity, weight, BMI, RA duration, activity, severity and seropositivity, blood pressure, lipid and glucose levels, diabetes, family history of CVD or diabetes. Current smoking was higher in the atorvastatin group (18.4% v 14.5%, P = 0.019). Reduction in low-density lipoprotein cholesterol (LDL-c) levels was significantly higher in the atorvastatin group (1.07 mmol/l) compared with placebo (0.14 mmol/l, P < 0.001). In the atorvastatin group 24 patients had a CVD event, compared with 36 in the placebo (hazard ratio 0.66, 95% CI 0.40, 1.11, P = 0.119). The overall event rate was lower (0.76%) than anticipated (1.80%) and the investigators were instructed by the funders to terminate the trial early. Any reported adverse events were similar: 294 (19.7%) in the atorvastatin and 292 (19.5%) in the placebo group, P = 0.927.

Conclusion: Atorvastatin 40 mg daily resulted in significantly greater reduction of LDL-c compared with placebo. The 34% (60% to +11%) reduction of risk for a major CVD event compared with placebo, although not statistically significant due to the early termination of the trial, is in line with expectations based on the Cholesterol Treatment Trialists’ Collaboration meta-analysis of the effect of statins in other populations. Statin therapy was safe in patients with RA.