Simvastatin Reduces Frequency of Vaso-Occlusive Pain in Sickle Cell Disease: A Pilot Efficacy Trial

Background

Sicke cell disease is characterized by progressive vascular injury as a result of vaso-occlusion, ischemia-reperfusion and a sustained state of chronic Inflammation. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCD, no directed anti-inflammatory therapies for the treatment or prevention of vaso-occlusive events currently exist. Statins (3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors) have been shown to improve vascular function, independent of their lipid-lowering properties, by suppressing the inflammatory response to endothelial injury and restoring nitric oxide (NO) bioavailability. We previously documented a reduction in plasma biomarkers of inflammation and endothelial adhesion in SCD patients treated with short-term simvastatin. The objective of this study was to evaluate the potential clinical efficacy of simvastatin in reducing the frequency of vaso-occlusive pain in SCD.

Methods

This was a single-center, open-label, uncontrolled pilot trial. Subjects (Hb SS or S/beta⁰ thalassemia, >10 years of age) received once daily oral simvastatin (40mg) for 3 months. The primary outcome measure was frequency and intensity of vaso-occlusive pain, as recorded by daily electronic pain diaries, before and after simvastatin treatment. Clinical laboratory studies and plasma biomarkers (NO metabolites, hs-CRP, sVCAM-1, sICAM-1, sE-selectin, sVEGF) were evaluated at baseline, at 0.5, 1, 2 and 3 months during treatment and one month after discontinuation of simvastatin.

Results

A total of 24 subjects were enrolled (15F/9M; mean age= 19 yrs, range 10-34 yrs). Of these, 5 subjects dropped out (2 lost to follow up, 3 non-adherent to protocol) and 19 subjects completed the study. Simvastatin was well tolerated without toxicity. There were two SAE, unrelated to study drug and one AE, possibly related to simvastatin. Total cholesterol levels decreased by 10% (p=0.005) from baseline during the treatment period. There were no changes from baseline in other clinical safety laboratory parameters, including markers of hemolysis (hemoglobin (Hb), reticulocyte count, lactate dehydrogenase (LDH), total bilirubin). Average adherence with daily pain diaries was 73% (range, 47%- 97%). Pain rate (proportion of pain days) decreased by 32% (p=0.02) from baseline, while pain intensity did not change in response to treatment. The effect of simvastatin on soluble markers of inflammation was demonstrated by a 59% reduction in hs-CRP (p=0.003), 18% reduction in sE-selectin (p=0.01), 5% in sICAM-1 (p=0.03). Treatment with simvastatin had no effect on plasma levels of nitric oxide (NOx), sP-selectin, sVEGF.

Conclusions

These results, showing a reduction in the frequency of vaso-occlusive pain and a corresponding decrease in serum biomarkers of inflammation, provide preliminary clinical data to support a larger trial of simvastatin in SCD.