Data collection
All KD patients admitted to the NUNH Hospital, at which all authors formerly worked, were assigned initial treatment according to the Harada score, which is frequently used to predict increased risk of CAL before IVIG treatment in Japan. The Harada score comprises the following criteria: (1) white blood cell count > 12,000/mm
3, (2) platelet count < 350,000/mm
3, (3) C-reactive protein (CRP) concentration > 4.5 mg/dL, (4) hematocrit < 35%, (5) serum albumin concentration < 3.5 mg/dL, (6) age < 12 months, and (7) male sex. For KD patients with at least four of these seven attributes, aspirin and IVIG therapy is typically administered, and for patients with less than three attributes, only aspirin is administered [
16].
There are currently no guidelines in any country that recommend withholding IVIG treatment in acute KD, thus we conventionally adopted the Harada score protocol whereby ASA alone is given to selected patients with KD in Japan. ASA alone is generally not recommended in acute KD, although the 19th and 21st Nationwide Surveys reported that ASA alone was administered to 14.0% and 10.0%, respectively, of patients with KD in Japan (Tables
1 and
2). It is also noteworthy that the group assigned to dalteparin and ASA alone in this study received non-standard therapy that is not currently recommended in any country, including Japan.
Table 1
Number and percentage of cases according to components of therapy in patients with KD at the NUNH Hospital in patients in the 19th Nationwide survey (2005–6) and the first cohort (low-dose IVIG)
Total | 20,475 | 100.0 | 126 | 100.0 | |
Dosage of IVIG | Cases | % | Cases | % | |
2 g/kg | 11,612 | 56.7 | 3 | 2.1 | 0.001 |
1 g/kg/day × 2 d | 4,800 | 23.4 | 3 | 2.1 | 0.001 |
400 mg/kg/day × 5 d | 231 | 1.1 | 95 | 75.4 | 0.001 |
Various dosages of IVIG | 879 | 4.3 | 0 | 0 | 0.01 |
Aspirin alone (no IVIG) | 2,866 | 14.0 | 25 | 19.8 | 0.07 |
Dalteparin | 0 | 0 | 126 | 100.0 | |
Age (months) | -* | 22 (0–167) | |
Male sex | 11,892 (58.1%) | 68 (54.0%) | 0.37 |
Table 2
Number and percentage of cases according to components of therapy in patients with KD at the NUNH Hospital between the 21st Nationwide survey (2009–10) and the second cohort (high-dose IVIG)
Total | 23,730 | 100.0 | 112 | 100.0 | |
Dosage of IVIG | Cases | % | Cases | % | |
2 g/kg | 17,547 | 74.0 | 85 | 75.9 | 0.75 |
1 g/kg/day × 2 d | 2,803 | 11.8 | 5 | 4.5 | 0.01 |
400 mg/kg/day × 5 d | 20 | 0.08 | 4 | 3.6 | 0.001 |
Various dosages of IVIG | 868 | 3.65 | 0 | 0 | 0.04 |
Aspirin alone (no IVIG) | 2,492 | 10.5 | 18 | 16.1 | 0.06 |
Dalteparin | 0 | 0 | 112 | 100.0 | |
Age (months) | -* | 19 (0–66) | |
Male sex | 13,515 (57.0%) | 59 (52.7%) | 0.39 |
The IVIG dose was chosen by the treating clinician, with variations across both cohorts from 400 mg/kg/day for 5 days, to 2 g/kg over 12 h for 1 day, or 1 g/kg over 12 h for 2 days.
The study design was retrospective and comprised two parts. Subjects in the first cohort (n = 126 patients with KD) were admitted to the NUNH Hospital between January 2004 and June 2008. The control data were sourced from the 19th Nationwide Survey of KD performed from January 2005 through December 2006 [
17]. The patients were treated with either dalteparin at 75 IU/kg/day as a continuous intravenous infusion until clinical improvement along with low-dose IVIG (400 mg/kg/day for 5 consecutive days) and aspirin at 30 mg/kg/day or a combination of dalteparin and aspirin at the same doses. IVIG and dalteparin infusions were given simultaneously, with the patients requiring a second intravenous access line for IVIG. The dose of aspirin was decreased to 5 mg/kg/day if the patient was afebrile, clinically improving, and/or had CRP < 1.0 mg/dL. Dalteparin was administered until the patient was afebrile, clinically improving, and/or had CRP < 1.0 mg/dL (Table
1).
Subjects in the second cohort (n = 112 patients with KD) were admitted to NUNH Hospital between June 2010 and February 2012. Control data were sourced from the 21st Nationwide Survey of KD performed from January 2009 through December 2010. The patients were treated with either dalteparin at 75 IU/kg/day as a continuous intravenous infusion and high-dose IVIG (2 or 1 g/kg over 12 h for 1 or 2 days, respectively) and aspirin 30 mg/kg/day or a combination of dalteparin and aspirin at the same doses. IVIG and dalteparin infusions were given simultaneously, with the patients requiring a second intravenous access line for IVIG. The aspirin dose was decreased to 5 mg/kg/day in patients who were afebrile, clinically improving, and/or had a CRP < 1.0 mg/dL. Dalteparin was administered until the patient was afebrile, clinically improving, and/or had CRP < 1.0 mg/dL (Table
2).
A survey of CAL was performed using echocardiography in all patients at follow-up, and within 3 months of discharge. None of the patients were administered corticosteroids. Although there was no information about aspirin administration in the nationwide surveys, we considered that aspirin was an anchor drug and it was administered to all controls with KD. There was no report of dalteparin administration in the nationwide surveys and therefore it was assumed that dalteparin was not administered to controls with KD.
Definition of coronary artery lesions
The coronary arteries of patients were regularly assessed by pediatricians using two-dimensional echography. Acute cardiac lesions were defined as those that developed within 1 month of onset (acute lesions); cardiac sequelae were defined as those that persisted beyond 1 month after onset [
17].
We reviewed these records within 3 months from the onset of KD. CAL was diagnosed in patients in accordance with the following Japanese Ministry of Health criteria: an internal lumen diameter > 3.0 mm in children < 5 years of age or > 4.0 mm in children ≥ 5 years of age, an internal segment diameter at least 1.5 times larger than that of an adjacent segment, or an irregular lumen [
18]. Although some KD patients present with CAL at diagnosis [
19], we did not find any cases before initial treatment in either cohort.
Statistical analysis
We calculated the required sample size based on the assumption that IVIG plus dalteparin would lower the prevalence of acute-phase CAL from 12.0% to 4.0% (first cohort) and from 9.0% to 2.0% (second cohort). With a two-sided test, an α value of 0.05, a power of 80%, and a total sample of 101 (first cohort) and 94 patients (second cohort) would be needed.
Data are presented as a percentage for categorical variables. Baseline characteristics and components of treatment were compared between the dalteparin group and the control group using the chi-square test for categorical variables. For all analyses, a two-sided p < 0.05 was considered indicative of statistical significance. The odds ratio was calculated as crude odds. The adjusted odds ratio for dosage of initial IVIG therapy in both groups was obtained using the Mantel-Haenstzel method, while the adjusted odds ratio for acute-phase CAL, cardiac sequelae, and additional IVIG therapy was not analyzed because the nationwide surveys contained no dosage information for the various initial IVIG treatments.
Coagulation parameters
Monitoring of prothrombin time and activated partial thromboplastin time was not necessary. Monitoring of dalteparin therapy is only possible using an anti-factor Xa assay. Anti-Xa levels might be useful to monitor effects in patients with severe renal dysfunction, abnormal coagulation parameters, or bleeding. We did not monitor anti-factor Xa levels in our cohort studies.