Background:
Although high-dose intravenous immunoglobulin plus aspirin reduces the risk of coronary artery damage, 5-10% of children with Kawasaki disease (KD) will go on to develop coronary artery aneurysms that may result in myocardial ischemia, infarction, or death. Arterial damage in KD results from immune activation and vessel wall infiltration by myofibroblasts, neutrophils, and T-cells with secretion of pro-inflammatory cytokines, elastases, and matrix metalloproteinases. Resolution of inflammation and recovery from the acute illness occurs through T-cell regulation. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, have extensive anti-inflammatory effects that target all of these pathways. These effects are independent of their cholesterol-lowering effect. Given these anti-inflammatory effects, statins would be a reasonable therapy to block coronary artery abnormality (CAA) progression in KD
Methods:
We designed a Phase I/IIa, two-center, dose-escalating, 6-week open-label study of atorvastatin. Acute KD patients within the first 20 days after fever onset are eligible if they are between the ages of 2 and 17 years old, have had fever for ≥ 3 days, and have ≥ 2 clinical criteria with LAD/RCA z-score ≥ 2.5 or a coronary artery aneurysm (≥ 1.5 x the adjacent segment). Dose escalation (0.125-0.75 mg/kg/day) follows a 3+3 design with evaluations for dose limiting toxicities at 2 and 6 weeks after enrollment. The primary outcome measure is safety with secondary outcome measures including the pharmacokinetics (PK) of atorvastatin, changes in measures of oxidative stress and inflammation, enumeration and characterization of regulatory T-cells, and echocardiographic changes in the internal diameter of the coronary arteries.
Results:
To date we have enrolled 9 subjects, 7 at Rady Children’s Hospital San Diego and 2 at Children’s Hospital Colorado. The median age at enrollment was 4 years with 5/9 (55%) males and a median illness day at enrollment of 6 days. The median baseline Z worst score was 3.5. The study is currently enrolling at the second dose level.
Conclusions:
The safety, tolerability, and PK of atorvastatin for acute KD patients will be established by this clinical trial.
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