Rheumatoid Arthritis: Statins May Cut All-Cause Mortality

Janis C. Kelly

August 17, 2015

Patients with rheumatoid arthritis (RA) who began taking statins had significantly lower all-cause mortality than those who did not take statins in a general population-based cohort study published online August 5 in the Annals of the Rheumatic Diseases.

"I think this study underscores the need for all clinicians who treat patients with RA to be aware of the increased risk of cardiovascular disease in this group of patients, and it highlights the potentially important role that statins could play in the health of patients with RA," lead author Sara R. Schoenfeld, MD, from the Division of Rheumatology, Massachusetts General Hospital, Boston, told Medscape Medical News.

"I don't think that we can say that all patients with RA should be treated with statins," she added, "but this study does show that the mortality benefits associated with statin use could be substantial. Rheumatologists and primary care doctors should be carefully evaluating whether they should start a statin on every patient with RA, and the threshold for treatment initiation could be lower."

The apparent protective effect of statins for all-cause mortality was similar to that in patients without RA, and was slightly greater than that seen in recent meta-analyses in the general population, which may reflect the higher cardiovascular disease risk associated with RA, the researchers say.

Study Analyzed Statin Initiators vs Matched Noninitiators in UK Data

The study population, which was drawn from The Health Improvement Network (THIN) computerized medical records database, which covers about 10.2 million patients in the United Kingdom, included patients aged 20 years or older who had been diagnosed with RA and who had taken at least one disease-modifying antirheumatic drug between January 2000 and December 2012. Subjects with current or prior statin use were excluded.

The study cohort of "statin initiators" was defined as patients who began taking a statin. "Noninitiators" were patients who would have been eligible for statin therapy but did not start a statin. Both groups had baseline cholesterol of 231.0 mg/dL in the propensity-matched cohorts, which included 2943 statin initiators and 2943 noninitiators.

The primary study outcome was the association between statin initiation and all-cause mortality, which was estimated using Cox proportional hazard models. Propensity score matching was used to reduce the possibility of confounding by indication, and cohorts were matched within the same calendar to account for possible changes in statin prescribing and mortality risk over time.

In randomly selected 1:1 matches, statin initiators were more likely to have cardiovascular disease, coronary heart disease risk factors, other comorbidities, and use of cardiovascular-related and other drugs than noninitiators.

After propensity score matching, which produced balanced baseline characteristics for the 2943 patients in each group, there were 432 deaths among the statin initiators and 513 deaths among the noninitiators (hazard ratio, 0.79; 95% confidence interval, 0.68 - 0.91). The hazard ratio for mortality among statin initiators was 0.65 at 1 year compared with noninitiators, 0.70 at 2 years, and 0.76 at 3 years.

"[W]e found that statin initiation was associated with a 21% lower risk of all-cause mortality among patients with RA. This association was apparent from the first year through the subsequent years of follow-up. These associations were independent of age, sex, [body mass index], socioeconomic status, relevant comorbidities, [cardiovascular] medication use, total cholesterol levels and healthcare utilization," write the authors. The statin effect was not affected by key covariates such as age, sex, socioeconomic status, RA duration, baseline cholesterol levels, or history of circulatory disease.

The authors speculate that, because of their elevated cardiovascular disease risk, patients with RA might particularly benefit from statins' dual anti-inflammatory and lipid-lowering effects.

Thomas M. MacDonald, MD, from the Medicines Monitoring Unit and Hypertension Research Centre, Ninewells Hospital & Medical School, Dundee, United Kingdom, who was not involved in the study but has long studied the relationships among cholesterol, statins, and cardiovascular outcomes, told Medscape Medical News, "The conclusion sounds about right. There is about 21% reduction in cardiovascular events per mmol of [low-density lipoprotein] reduction. Observational studies should underestimate statin benefit, as more risky people get treated over less risky, but despite this, statins still win out."

The current study provides important data supporting the protective effect of statins, Paul M. Ridker, MD, MPH, Eugene Braunwald Professor of Medicine, Harvard Medical School, and director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital, Boston, Massachusetts, told Medscape Medical News.

Dr Ridker, who was lead investigator for the JUPITER trial of rosuvastatin as primary prevention for cardiovascular events, said, "The randomized JUPITER trial previously demonstrated that individuals with inflammation [elevated C-reactive protein levels] have significantly fewer heart attacks and strokes if treated with statin therapy. Since all patients with rheumatoid arthritis have this inflammation, it would be very difficult, if not impossible, to do a new randomized trial in this patient group. It is thus very reassuring to see in this observational study data consistent with prior trials."

Should More Aggressive RA Also Be Treated With Statins?

"Our study raises a couple of interesting questions: 1) whether statins may have cause-specific mortality benefits in patients with RA (ie, reduction in cardiovascular mortality, in particular); and 2) whether patients with RA who have certain characteristics of more aggressive disease, such as seropositivity, erosions or extra-articular manifestations, may have a greater mortality benefit associated with statin therapy," Dr Schoenfeld said.

The data also raise the important clinical question of whether RA should be treated as a "coronary artery disease equivalent" similar to diabetes, she added.

"There are some data supporting that the risks are similar, but it is not clear if all patients with RA should be treated with statins for primary prevention. To address this, and also to further appreciate any potential harms of statin use in patients with RA, a randomized controlled trial of statins for primary prevention in RA would be useful. The TRACE-RA study was designed to do this, but had to be stopped early because of the low event rate. However, that study found a 34% reduction in major cardiovascular events, which, although not significant, was similar to the results from our study. The event rates in that trial may have been lower than expected due to improved care of RA patients with biologic [disease-modifying antirheumatic drugs] and other medications," Dr Schoenfeld said.

The authors, Dr Ridker, and Dr MacDonald have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online August 5, 2015. Abstract

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