Prevention Of Coronary Artery Lesions Research Articles

The Impact of Changes in Clinical Guideline on Practice Patterns and Healthcare Utilizations for Kawasaki Disease in Japan.

Objective: Previous studies showed the efficacy of glucocorticoids on prevention of coronary artery lesions (CAL) among Kawasaki disease (KD) patients, and clinical guideline for KD in Japan was changed regarding glucocorticoid use in 2012. However, little is known regarding how the guideline change had impacts on healthcare utilizations and clinical outcomes.Methods: We conducted a retrospective observational study using national inpatient database in Japan among KD patients aged under 18 years during 2010–2015. Recent trends in practice patterns were analyzed, and we divided the hospitals into four groups based on glucocorticoid use: (1) consistently using hospital, (2) started using hospital, (3) stopped using hospital, and (4) never using hospital. Then, we compared healthcare utilizations and risks of coronary artery lesions before and after the guideline change.Results: We identified 24,517 inpatients with KD. From 2010 to 2014, use of glucocorticoid increased from 8.9 to 17.4% of KD inpatients. All types of hospitals showed reduction in coronary artery lesions, but the reduction was the most prominent in hospitals that started using glucocorticoid therapy after clinical guideline change in 2012 (adjusted OR, 0.22; 95%CI, 0.07–0.68). Also, Glucocorticoid consistently using hospitals, started using hospitals, and never using hospitals showed reductions in hospitalization costs, whereas hospitals that stopped using glucocorticoids after clinical guideline change had elevated healthcare costs as opposed to natural trends observed in other groups. Guideline complying hospitals had the greatest reductions in healthcare costs.Conclusions: The early stage glucocorticoid use could be a cost-saving strategy for treatment for KD patients without increasing risks of CAL.

A low-frequency IL4R locus variant in Japanese patients with intravenous immunoglobulin therapy-unresponsive Kawasaki disease

BackgroundKawasaki disease (KD) is a systemic vasculitis which may be associated with coronary artery aneurysms. A notable risk factor for the development of coronary artery aneurysms is resistance to intravenous immunoglobulin (IVIG) therapy, which comprises standard treatment for the acute phase of KD. The cause of IVIG resistance in KD is largely unknown; however, the contribution of genetic factors, especially variants in immune-related genes, has been suspected.MethodsTo explore genetic variants related to IVIG-unresponsiveness, we designated KD patients who did not respond to both first and second courses of IVIG therapy as IVIG-unresponsive patients. Using genomic DNA from 30 IVIG-unresponsive KD patients, we performed pooled genome sequencing targeting 39 immune-related cytokine receptor genes.ResultsThe single nucleotide variant (SNV), rs563535954 (located in the IL4R locus), was concentrated in IVIG-unresponsive KD patients. Individual genotyping showed that the minor allele of rs563535954 was present in 4/33 patients with IVIG-unresponsive KD, compared with 20/1063 individuals in the Japanese genome variation database (odds ratio = 7.19, 95% confidence interval 2.43–21.47). Furthermore, the minor allele of rs563535954 was absent in 42 KD patients who responded to IVIG treatment (P = 0.0337), indicating that a low-frequency variant, rs563535954, is associated with IVIG-unresponsiveness in KD patients. Although rs563535954 is located in the 3′-untranslated region of IL4R, there was no alternation in IL4R expression associated with the mior allele of rs563535954. However, IVIG-unresponsive patients that exhibited the minor allele of rs563535954 tended to be classified into the low-risk group (based on previously reported risk scores) for prediction of IVIG-resistance. Therefore, IVIG-unresponsiveness associated with the minor allele of rs563535954 might differ from IVIG-unresponsiveness associated with previous risk factors used to evaluate IVIG-unresponsiveness in KD.ConclusionThese findings suggest that the SNV rs563535954 could serve as a predictive indicator of IVIG-unresponsiveness, thereby improving the sensitivity of risk scoring systems, and may aid in prevention of coronary artery lesions in KD patients.

A new model for predicting intravenous immunoglobin-resistant Kawasaki disease in Chongqing: a retrospective study on 5277 patients

Accurate evaluation of individual risk of intravenous immunoglobin (IVIG)-resistance is critical for adopting regimens for the first treatment and prevention of coronary artery lesions (CALs) in patients with Kawasaki disease (KD). Methods: The KD patients hospitalized in Chongqing Children’s Hospital, in west China, from October 2007 to December 2017 were retrospectively reviewed. Data were collected and compared between IVIG-resistant group and IVIG-responsive group. The independent risk factors were determined using multivariate regression analysis. A new prediction model was built and compared with the previous models. Results: A total of 5277 subjects were studied and eight independent risk factors were identified including higher red blood cell distribution width (RDW), lower platelet count (PLT), lower percentage of lymphocyte (P-LYM), higher total bile acid (TBA), lower albumin, lower serum sodium level, higher degree of CALs (D-CALs) and younger age. The new predictive model showed an AUC of 0.74, sensitivity of 76% and specificity of 59%. For individual’s risk probability of IVIG-resistance, an equation was given. Conclusions: IVIG-resistance could be predicted by RDW, PLT, P-LYM, TBA, albumin, serum sodium level, D-CALs and age. The new model appeared to be superior to those previous models for KD population in Chongqing city.

Association Between Dose of Glucocorticoids and Coronary Artery Lesions in Kawasaki Disease.

Several studies revealed the efficacy of glucocorticoids on prevention of coronary artery lesions (CALs) in Kawasaki disease (KD) patients. However, impacts of different doses of glucocorticoids on clinical outcomes of KD remain unknown. Using the Japanese Diagnosis Procedure Combination inpatient database, we evaluated KD patients who were treated with normal-dose (prednisolone 0.5-4.0 mg/kg/day) or high-dose (methylprednisolone 10-40 mg/kg/day) glucocorticoids. We investigated risks of CALs and readmission, total hospitalization cost, and length of hospital stay in the acute phase of KD using propensity score matching, stabilized propensity-score inverse probability of treatment weighting, and instrumental variable methods. We identified a total of 3,220 patients with KD who were treated with normal-dose (n = 2,453) or high-dose (n = 767) glucocorticoids in addition to intravenous immunoglobulin. One-to-one propensity-matched analyses with 744 pairs demonstrated no significant differences between the normal-dose and the high-dose groups in risk of CALs (risk ratio [RR] 0.83, 95% confidence interval [95% CI] 0.49, 1.40) and risk of readmissions (RR 0.85, 95% CI 0.65, 1.11). Stabilized propensity-score inverse probability weighting and instrumental variable analyses showed similar results to the propensity score matching analyses. Risks of CALs and readmissions and total hospitalization costs were similar between the normal-dose and the high-dose glucocorticoids groups for patients with KD, whereas total length of hospital stay was shorter in the high-dose group than that in the normal-dose group.

Study design and rationale to assess Doxycycline Efficacy in preventing coronary Artery Lesions in children with Kawasaki disease (DEAL trial) – A phase II clinical trial

BackgroundKawasaki disease (KD) is the most common acquired heart disease in children of the developed world, and triggers progressive coronary artery lesions (CAL) in 30% of cases if left untreated. Despite standard anti-inflammatory treatment for KD, CAL (dilation or aneurysm) still occurs in 5–10% of children, increasing their risk for fatal coronary artery complications. CAL is mediated by enhanced matrix metalloproteinase activity and elastin breakdown induced by the inflammatory process in the coronary artery wall. Doxycycline is an effective inhibitor of matrix metalloproteinases, and has been shown to reduce elastin breakdown and CAL in a mouse model of KD, but has not been evaluated in patients. ObjectiveWe aim to evaluate the efficacy of doxycycline in the prevention of CAL in children during the acute phase of KD. DesignThis is a phase II prospective, randomized, double-blinded, clinical trial in two steps. In Step 1, any child older than 1month with the diagnosis of KD will be included. Children with KD will be included in Step 2 if they develop coronary artery dilation (z-score≥2.5) within 20days from the onset of fever. Study subjects in Step 2 will be randomized to receive a 3-week course of doxycycline or placebo. EvaluationThe efficacy of a 3-week doxycycline course during the acute phase of KD will be evaluated by measuring the decline in coronary artery z-scores from baseline with doxycycline treatment compared to placebo. Clinical trial registrationThis study was registered on clinicaltrials.gov (NCT01917721).

Use of Corticosteroid in Children with Unresponsiveness to Intravenous Immunoglobulin in Kawasaki Disease

Background Kawasaki Disease (KD) is a vasculitis with multi-organ involvementof unknown etiology; it is the most common cause of pediatric-heart diseases in developed countries. Treatment with Intravenous Immunoglobulin (IVIG) prevents coronary artery lesions; although there are some IVIG-resistant cases, combination therapy with corticosteroids and IVIG is one of the recommendations for treatment of these cases. The aim of this study was to compare these three options for treatment of Kawasaki Disease and to evaluate their ability to deal with coronary artery complication of Kawasaki Disease. Materials and Methods A prospective cross- sectional study of hospitalized cases of Kawasaki Disease, conducted in pediatric department of Imam Reza hospital, Mashhad-Iran, during 2013 to 2015 (18 months). Based on demographic and clinical data of these patients, children with high risk of unresponsiveness to IVIG therapy (based on Harada score), were determined and treated with IVIG and corticosteroids- combination initially. Follow-up patients for heart complications were 6 weeks. Results Twenty five patients (89.2%) out of total 28 hospitalized patients in this period of time who fulfilled diagnostic criteria were considered as complete Kawasaki Disease. Coronary Artery Lesions (CALs) were shown in 4 patients during the follow-up period, with high risk in patients with incomplete presentation (33.3% versus 12%, p <0.05). None of the children were treated with IVIG and corticosteroids combination therapy at the onset showed coronary artery lesions. Conclusion The current study showed that IVIG plus intravenous methylprednisolone (IVMP) combination therapy is a safe and effective treatment regimen in prevention of CALs.

A meta-analysis of re-treatment for intravenous immunoglobulin-resistant Kawasaki disease.

To determine the optimal drug therapy for intravenous immunoglobulin-resistant Kawasaki disease. Studies regarding drug therapy for intravenous immunoglobulin-resistant Kawasaki disease were selected from medical electronic databases including PubMed, Medline, Elsevier, and Springer Link. The effectiveness in terms of temperature recovery and coronary artery damage was compared between a second intravenous immunoglobulin treatment and glucocorticosteroid treatment for children with intravenous immunoglobulin-resistant Kawasaki disease using meta-analysis with Review Manager 5.3 software. Indices to evaluate the effects were body temperature, biomarker levels, and coronary artery lesions detected by echocardiography. Results are reported as relative risks or odds ratio with a 95% confidence interval and p<0.05. Meta-analysis included 52 patients in the second intravenous immunoglobulin treatment group and 75 patients in the glucocorticosteroid treatment control group from four studies that met our inclusion criteria. Temperatures of patients who received glucocorticosteroid treatment were effectively controlled compared with those who received a second intravenous immunoglobulin treatment (relative risk=0.73, 95% confidence interval: 0.58-0.92, p=0.007). There were no differences, however, in the incidence of coronary artery lesions between the two groups (odds ratio=1.55, 95% confidence interval: 0.57-4.20, p=0.39). Glucocorticosteroids are more effective in controlling body temperature compared with intravenous immunoglobulin re-treatment in intravenous immunoglobulin-resistant Kawasaki disease children; however, glucocorticosteroids and intravenous immunoglobulin re-treatment showed no difference in the prevention of coronary artery lesions.

Meta-analysis of the results of intravenous gamma globulin treatment of coronary artery lesions in Kawasaki disease

The objective of this study was to evaluate the efficacy of intravenous gamma globulin (IVGG) therapy on the prevention of coronary artery lesions (CALs) in patients with Kawasaki disease (KD), with reference to the literature on meta-analyses in randomized controlled studies. Studies from 1984 to the end of 2000 obtained from the National Library of Medicine or from the bibliographies of these articles were used in the analysis. The total number of patients with KD covered in 17 articles was 4020. All the articles were examined for the number of doses per day, the duration of administration, and the total number of IVGG doses. The number of patients in each group was counted, and the incidence of CALs was evaluated at 30 or 60 days after onset. The results of these searches were further analyzed by meta-analytical methods. The administration of IVGG significantly decreased the incidence of CALs in a dose-dependent manner: at 30 days after onset the incidence of CALs was 29.4% without IVGG but 21.6% with a total dosage of IVGG < 1000 mg/kg, 10.8% with a total dosage of 1000-2000 mg/kg, and 10.2% with a total dosage of > or =2000 mg/kg. Compared with the incidence of CALs without IVGG, the odds ratio (OR) was 0.662 [95% confidence interval (CI) 0.519-0.815)] at <1000 mg/kg, 0.292 (95% CI 0.222-0.371) with 1000-2000 mg/kg, and 0.274 (95% CI 0.207-0.349) with > or =2000 mg/kg. At 60 days, the values had decreased to 17.3%, 13.8% [OR 0.767 (95% CI 0.585-1.005)], 5.8% [OR 0.296 (95% CI 0.200-0.436)], and 4.9% [OR 0.244 (95% CI 0.170-0.349)], respectively. The meta-analyses also indicated that high doses of IVGG (> or =2000 mg/kg per day) given in a single dose prevented CALs more effectively than the same dosages divided into five daily doses in the patients with KD: The incidence of CALs at 30 days after disease onset was 2.4% with a single dose versus 12.9% with divided doses. Compared with divided doses, the OR with a single dose was 0.164 (95% CI 0.064-0.393) and 2.8% versus 6.1% at 60 days [OR 0.450 (95% CI 0.206-0.956)]. We clearly confirmed that higher doses of IVGG (> or =2000 mg/kg per day) administered in a single infusion were more effective for preventing CALs, as evaluated during both the subacute and convalescent phases of KD.

Meta-analysis of the results of intravenous gamma globulin treatment of coronary artery lesions in Kawasaki disease

The objective of this study was to evaluate the efficacy of intravenous gamma globulin (IVGG) therapy on the prevention of coronary artery lesions (CALs) in patients with Kawasaki disease (KD), with reference to the literature on meta-analyses in randomized controlled studies. Studies from 1984 to the end of 2000 obtained from the National Library of Medicine or from the bibliographies of these articles were used in the analysis. The total number of patients with KD covered in 17 articles was 4020. All the articles were examined for the number of doses per day, the duration of administration, and the total number of IVGG doses. The number of patients in each group was counted, and the incidence of CALs was evaluated at 30 or 60 days after onset. The results of these searches were further analyzed by meta-analytical methods. The administration of IVGG significantly decreased the incidence of CALs in a dose-dependent manner: At 30 days after onset the incidence of CALs was 29.4% without IVGG but 21.6% with a total dosage of IVGG < 1000 mg/kg, 10.8% with a total dosage of 1000–2000 mg/kg, and 10.2% with a total dosage of ≥2000 mg/kg. Compared with the incidence of CALs without IVGG, the odds ratio (OR) was 0.662 [95% confidence interval (CI) 0.519–0.815)] at <1000 mg/kg, 0.292 (95% CI 0.222–0.371) with 1000–2000 mg/kg, and 0.274 (95% CI 0.207–0.349) with ≥2000 mg/kg. At 60 days, the values had decreased to 17.3%, 13.8% [OR 0.767 (95% CI 0.585–1.005)], 5.8% [OR 0.296 (95% CI 0.200–0.436)], and 4.9% [OR 0.244 (95% CI 0.170–0.349)], respectively. The meta-analyses also indicated that high doses of IVGG (≥2000 mg/kg per day) given in a single dose prevented CALs more effectively than the same dosages divided into five daily doses in the patients with KD: The incidence of CALs at 30 days after disease onset was 2.4% with a single dose versus 12.9% with divided doses. Compared with divided doses, the OR with a single dose was 0.164 (95% CI 0.064–0.393) and 2.8% versus 6.1% at 60 days [OR 0.450 (95% CI 0.206–0.956)]. We clearly confirmed that higher doses of IVGG (≥2000 mg/kg per day) administered in a single infusion were more effective for preventing CALs, as evaluated during both the subacute and convalescent phases of KD.