SAN DIEGO – Twelve weeks of rosuvastatin therapy was associated with reduced systemic inflammation, but no improvement in pulmonary function in a randomized, placebo-controlled trial in 99 patients with stable chronic obstructive pulmonary disease.
However, a prespecified analysis of patients with elevated results on high-sensitivity C-reactive protein tests (hsCRP) found that those with levels higher than the median of 1.7 mg/dL at baseline showed improved endothelial function with the statin, compared with placebo, Dr. Anke Neukamm reported at an international conference of the American Thoracic Society.
Dr. Anke Neukamm
The findings provided a small ray of positivity for the anti-inflammatory effects of statins in chronic obstructive pulmonary disease (COPD) on a day when two larger randomized, controlled studies reported that rosuvastatin did not reduce mortality in patients with sepsis-associated acute respiratory distress syndrome and simvastatin did not reduce exacerbations in patients with moderate to severe COPD.
Dr. Neukamm’s RODEO study (Effect of Rosuvastatin Treatment in Patients With Stable Chronic Obstructive Pulmonary Disease) randomized patients with stable chronic COPD to once-daily rosuvastatin 10 mg or placebo for 12 weeks. The groups did not differ significantly in the primary endpoint peripheral vasodilator function expressed as a reactive hyperemia ratio. In the subgroup analysis of patients with elevated hsCRP levels, however, the reactive hyperemia index improved from approximately 2.5 at baseline to 2.8 after 12 weeks of rosuvastatin and worsened from 2.6 to 2.5 in the placebo group, leaving a statistically significant difference between groups at the end of treatment, said Dr. Neukamm of Akershus University Hospital, Lørenskog, Norway.
This suggested "a clear improvement of endothelial function in the statin group," she said.
Some physicians in the audience disputed the results, noting that rosuvastatin’s effects would not have reached statistical significance if endothelial function had not worsened in the placebo group.
Dr. Neukamm remained cautiously optimistic. Targeting statin therapy for patients with COPD to those with increased systemic inflammation as indicated by elevated hsCRP levels might improve vascular function, she said in an interview. Patients in the study were "a very select group with a lower cardiovascular risk" than patients in other COPD studies. Without larger prospective trials, "we don’t know if this small improvement in endothelial function would translate" into better clinical outcomes, she said.
Among secondary endpoints, circulating hsCRP levels decreased from 1.4 mg/L at baseline to 1.2 mg/L in the rosuvastatin group, compared with a change from 1.8 mg/L to 2.2 mg/L in the placebo group. The difference between groups was significant. Levels of the inflammatory marker interleukin-6 remained stable at 4.1 pg/mL in the statin group and increased from 3.4 pg/mL to 4.4 pg/mL in the placebo group, also a significant difference between groups.
The trial excluded patients with a history of coronary artery disease, other diagnosed lung disease (except asthma), uncontrolled arterial hypertension, or diabetes, or patients who had used statins in the prior 4 weeks or who had a clear indication for statin use.
Thirty-three adverse events included COPD acute exacerbations, constipation, diarrhea, nausea, myalgia, and vertigo. Seven serious adverse events included hospitalizations for COPD exacerbations, atrial flutter in one patient, and pituitary apoplexy in one patient.
Patients had a mean age of 65 years, 48% were female, and 25% had a history of hypertension. They had a smoking history of a mean 37 pack-years. Baseline patient characteristics were similar between groups except for a higher percentage of current smokers in the placebo group (49%), compared with the rosuvastatin group (26%).
Stable COPD and acute exacerbations have been associated with systemic inflammation as reflected in increased levels of CRP and other inflammatory markers. Cardiovascular disease is a major comorbidity in patients with COPD, and inflammation is a hallmark of the atherosclerotic process, Dr. Neukamm said. Endothelial dysfunction, which is an early predictor of atherosclerosis, has been shown to be increased in patients with COPD.
A previous observational study of 2,708 patients with COPD suggested that long-term statin therapy was associated with a significant 78% decrease in mortality in those with hsCRP levels greater than 3 mg/L and a nonsignificant 21% decreased mortality in those with lower hsCRP levels (Pulm. Pharmacol. Ther. 2013;26:212-7).
The study was funded by the Norwegian Extra Foundation for Health and Rehabilitation and by AstraZeneca, which makes a brand name formulation of rosuvastatin. Dr. Neukamm has been a speaker for AstraZeneca.
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