Patients with rheumatoid arthritis (RA) who were treated with a statin appeared to experience cardiovascular (CV) benefits similar to what has been observed in other populations, with risk reduction of roughly one-third, a large but prematurely terminated U.K. clinical trial suggested.
Among RA patients randomized to 40 mg of atorvastatin daily, 1.6% had confirmed CV events during 2.5 years of follow-up as did 2.4% of those given placebo, for a nonsignificant adjusted hazard ratio of 0.60 (95% CI 0.32-1.15, P=0.127), according to George D. Kitas, MD, PhD, of Russells Hall Hospital in Dudley, England, and colleagues.
However, “the best estimate of the ‘true’ reduction in CV events in the atorvastatin versus placebo arm is 34%,” they reported, based on further analyses that found an additional nonsignificant hazard ratio of HR 0.66 (95% CI 0.39-1.11, P=0.115).
This observed lack of statistical significance was attributed by the investigators to an “unexpectedly low event rate and resulting limited statistical power to detect an effect during the planned 5 years of follow-up, [which] led to premature termination of the trial,” they wrote in Arthritis & Rheumatology.
Almost half of RA deaths are linked with CV causes, with high-grade systemic inflammation likely playing an important role. Risk algorithms used for the general population have been inaccurate in RA, resulting in uncertainty as to which patients are suitable candidates for statin therapy. This has led some authorities to suggest that all RA patients receive statins, and therefore raises the question, “Is statin therapy beneficial in the primary prevention of CV disease among RA patients who do not have an indication using population-based CV risk scores?” wrote Katherine P. Liao, MD, and Daniel H. Solomon, MD, of Harvard University in Boston, in an accompanying editorial.
To address this question, Kitas and colleagues undertook a double-blind study at 102 centers that was intended to enroll 5,400 patients, and followed them for 5 years, but the low rate of major vascular events led to a loss of power and early termination after the inclusion from 2007 to 2011 of only 3,002 patients. The predicted annual rate of major events was expected to be 1.6% to 1.8%, which the investigators noted, “seemed, if anything, conservative.” Yet at the time of study termination, the annual rate of events in the combined groups was only 0.70%.
Participants’ mean age was 61, three-quarters were women, and almost all were white. Disease duration averaged 11 years.
At baseline, 40.3% of patients had Disease Activity Scores in 28 joints of 3.2 or lower, indicating remission or low disease activity. More than 85% were on conventional disease-modifying antirheumatic drugs, particularly methotrexate, 17% were taking corticosteroids, and 16% were receiving biologics.
On the individual components of the composite CV endpoint, rates for the atorvastatin and placebo groups were:
- Nonfatal myocardial infarction, coronary revascularization, or coronary death: 0.9% vs 1.5%
- Ischemic stroke or transient ischemic attack: 0.4% vs 0.8%
- Non-coronary arterial revascularization: 0.2% vs 0.1%
- Other CV death: 0% for both
- Peripheral atherosclerotic event: 0.1% vs 0%
- Suspected coronary heart disease death: 0.1% for both
Overall, a similar rate of death was seen in the two arms (1.7% vs 1.8%).
The estimated reduction in CV event risk for each 1 mmol/L reduction in low-density lipoprotein cholesterol was 42% (95% CI -14 to 70).
A total of 19.8% of patients in the atorvastatin group and 19.5% in the placebo group reported adverse events.
“From a clinical perspective, the safety outcomes are as important as CV event reduction. RA patients typically have multiple comorbidities and polypharmacy, often with potentially hepatotoxic drugs” such as methotrexate, the investigators observed.
For potentially statin- and liver-related adverse events, the investigators reported 249 cases of new or significant muscle pain, 132 in the atorvastatin group and 117 in the placebo group, which did not differ significantly. Among patients with muscle pain, nine in the statin group and four in the placebo group had concurrent elevations of alanine transaminase or aspartate transaminase greater than twice the upper limit of normal. These liver function abnormalities were transient and were not considered related to therapy, although two patients in the statin arm and one in the placebo arm were withdrawn from the study.
In addition, no patients had elevated creatine kinase above 10 times the upper limit of normal.
In the atorvastatin group, compliance decreased from 89% at the first 3-month study visit to 39% at 60 months, while the corresponding numbers in the placebo group were 89% and 25%, respectively. The low rate of adherence to atorvastatin also may have contributed to the lack of statistical significance seen in the study, noted Liao and Solomon, who were not involved in the trial.
At the end of follow-up, no differences were seen in measures of RA disease activity, severity, or quality of life, although C-reactive protein levels were lower in the statin group (2.59 vs 3.60 mg/L, P<0.0001).
The study has important implications for clinical practice, according to the investigators, such as that currently treated RA patients could derive similar benefits from statins as other patient groups. However, the low rate of CV events seen demonstrated that many patients with RA — even those older than 50 and with long disease duration — appear to have low risks for CV events, which “does not support prescribing statins to all RA patients,” they argued.
“Instead, the decision to prescribe should be based on assessment of the individual RA patient’s risk using, at present, the relevant national or international recommendations and risk assessment tools while disease-specific algorithms are developed and validated,” they concluded.
The study was funded by Arthritis Research UK and the British Heart Foundation.
The authors reported financial support from Roche, AbbVie, Pfizer, Novartis, UCB, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Amgen, Sanofi, Boehringer Ingelheim, Janssen, Novo Nordisk, AstraZeneca, Bayer, and Rexgenero.