Statins Study in Children of Acute Kawasaki Disease With Coronary Artery Abnormalities

Kawasaki disease (KD) is acute self-limited vasculitis and occurs almost exclusively in childhood. It predominantly affects medium-sized arteries, most commonly coronary arteries. Although the use of intravenous immunoglobulin (IVIG) has obviously decreased the incidence of coronary arteries abnormalities (CAA), still a part of KD children occurs CAA, even medium, large or giant CA aneurysms. Coronary aneurysms can develop thrombus and arterial stenosis, which may cause severe cardiac events. Now KD has been the main cause of acquired heart disease in children in most areas of China mainland.

Studies have found that during the acute phase of KD, necrotizing arteritis occurs in coronary arteries. Oxidative stress, immune activation, and cellular infiltration of the vessel wall associated with secretion of proinflammatory cytokines, elastases, and matrix metalloproteinases (MMPs) are related to formation of coronary aneurysms. In addition, long-term KD vasculopathy appears ongoing vascular chronic inflammation and oxidative stress. Endothelial dysfunction, increased stiffness, and intima-media thickening have been noted in affected coronary arteries.

Statins, a hydroxymethylglutaryl coenzyme-A reductase inhibitors, has been widely used in adults for years not only for its reducing plasma cholesterol but also for its beneficial pleiotropic effects, including inflammation modulation, oxidative stress, endothelial function and angiogenesis, antithrombotic and antiplatelet effects. In recent years, statins have been considered to be used in KD children with coronary aneurysms. Several studies have shown reductions in high-sensitivity CRP, improved endothelial function and safety in such KD children treated with statins. The 2017 American Heart Association (AHA) scientific statement on KD has suggested that empirical treatment with low-dose statin may be considered for KD patients with past or current aneurysms, regardless of age or sex. The investigators have also conducted a follow-up study of atorvastatin used in long-term treatment of KD children with severe CAA. The results showed that long-term atorvastatin treatment was safe in Chinese KD children with CAA, but its dose was significantly lower than those been reported by previous studies abroad.

Based on the effects of statins on inhibition of MMP secretion and myofibroblast transformation which may anticipate the formation of CAA in acute KD, statins have been tried to be used in acute KD children with CAA. However, the relevant clinical data is very rare.Is atorvastatin safe in Chinese children of acute KD? Can atorvastatin actually contribute to control the acute inflammation of KD and improve CAA? The goal of this study is to learn about the safety and effects of atorvastatin in treatment of Chinese KD children complicated with CAA in acute phase.

• atorvastatin of dose level 1 (Drug): The study is to be designed as dose-escalation protocol and enroll a minimum of 3 subjects per dose level (level 1, 0.15 mg/kg/day; level 2, 0.25 mg/kg/day; level 3, 0.4 mg/kg/day). Participants will take atorvastatin for 6 weeks. The dose-limiting toxicities (DLTs) are used to determine the maximum tolerated dose (MTD).
• atorvastatin of dose level 2 (Drug): The study is to be designed as dose-escalation protocol and enroll a minimum of 3 subjects per dose level (level 1, 0.15 mg/kg/day; level 2, 0.25 mg/kg/day; level 3, 0.4 mg/kg/day). Participants will take atorvastatin for 6 weeks. The dose-limiting toxicities (DLTs) are used to determine the maximum tolerated dose (MTD).
• atorvastatin of dose level 3 (Drug): The study is to be designed as dose-escalation protocol and enroll a minimum of 3 subjects per dose level (level 1, 0.15 mg/kg/day; level 2, 0.25 mg/kg/day; level 3, 0.4 mg/kg/day). Participants will take atorvastatin for 6 weeks. The dose-limiting toxicities (DLTs) are used to determine the maximum tolerated dose (MTD).

Primary outcomes

• Incidence of statin-associated side effects in Chinese acute KD children with CAA [Before, 2 weeks and 6 weeks after taking atorvastatin]: Safety evaluation of atorvastatin in acute KD children, referring to the incidence of statin-associated side effects (SASE). SASE include statin-associated clinical adverse events, elevated transaminase, creatine kinase, blood glucose and hypocholesterolemia.

Secondary outcomes

• Change of levels of high-sensitivity C reactive protein (sCRP) [Before, 1 week, 2 weeks and 6 weeks after taking atorvastatin]: Changes of levels of high-sensitivity C reactive protein (sCRP) which reflex the acute KD inflammation
• Change of levels of serum amyloid A(SAA) [Before, 1 week, 2 weeks and 6 weeks after taking atorvastatin]: Change of levels of serum amyloid A(SAA) which reflex the acute KD inflammation
• Change of levels of interleukin-6 (IL-6) [Before, 1 week, 2 weeks and 6 weeks after taking atorvastatin]: Change of levels of interleukin-6 (IL-6) which reflex the acute KD inflammation
• Change of levels of NT-proBNP [Before, 2 weeks and 6 weeks after taking atorvastatin]: Change of levels of NT-proBNP which reflex the acute KD inflammation
• Change of levels of albumin [Before, 1 week, 2 weeks and 6 weeks after taking atorvastatin]: Change of levels of albumin which reflex the acute KD inflammation
• Changes of sizes of involved coronary arteries measured by echocardiography [Before, 2 weeks and 6 weeks after taking atorvastatin]: Changes of diameters of involved coronary artery aneurysms
• Changes of diameter-Z score of involved coronary arteries measured by echocardiography [Before, 2 weeks and 6 weeks after taking atorvastatin]: Changes of Z score of involved coronary artery aneurysms diameters
• Changes of degrees of other echocardiographic findings [Before, 2 weeks and 6 weeks after taking atorvastatin]: Changes of degrees of other echocardiographic findings which reflex the acute KD inflammation, including mitral regurgitation and pericardial effusion

Sex: All, ages: 2 Years to 18 Years

Inclusion Criteria:

* KD complicated with CAA, less than 20 days after the onset of KD, or more than 20 days after onset but the KD inflammation has not been controled.
* IVIG and/or other anti-inflammatory treatments have been used/are being used.
* The guardians agree to atorvastatin treatment and sign the informed consent form.

Exclusion Criteria:

* Patients with history of family hypercholesterolemia/taking statins/severe chronic diseases.
* Patients with abnormal laboratory data including CK≥500U/L, total cholesterol<3.1mmol/L, ALT or AST≥ 2 times the upper limit of normal.
* The guardians do not agree to atorvastatin treatment.

• Chen Chu, MD, Study director, Children's Hospital of Fudan University