The use of low-dose aspirin in conjunction with a single dose of intravenous immunoglobulin (IVIG) among children with Kawasaki disease was associated with three times the risk of requiring a second IVIG dose compared with high-dose aspirin, a retrospective chart review in two Canadian centers concluded.
In one hospital where low-dose acetylsalicylic acid (ASA; 3 to 5 mg/kg/day) was routinely used, 23% of patients were given a second infusion of IVIG, compared with 8.7% of those treated in another hospital where high-dose ASA (80 to 100 mg/kg/day) was used (P=0.003), according to Anita Dhanrajani, MBBS, of British Columbia Children’s Hospital in Vancouver, and colleagues.
In a multivariable analysis that adjusted for potential confounders including platelet count, age, and C-reactive protein (CRP), the odds ratio for a second IVIG dose with low-dose ASA was 3.2 (95% CI 1.1-9.1, P=0.03), the researchers reported online in Arthritis Care & Research.
Kawasaki disease is an acute vasculitis predominantly affecting children younger than age 5 years, and currently is the most common form of acquired heart disease in developed countries, especially among those of Asian ancestry. The disease is associated with potentially severe cardiac outcomes, particularly the development of coronary artery aneurysms.
The American Heart Association (AHA) first published recommendations for diagnosis and treatment of Kawasaki disease in 1993; these have been revised, most recently in 2017. The recommendations, which favor high-dose aspirin, have been developed to assist clinicians in decision-making regarding treatment with IVIG, ASA, and corticosteroids, but have not been uniformly adopted. While an IVIG dosage of 2 g/kg is standard, the aspirin dose has been varied, with high doses possibly having greater anti-inflammatory effects but low doses being assumed to have better gastrointestinal tolerability.
In addition, IVIG can be costly and should be judiciously used, according to Dhanrajani’s group.
The standard approach used at British Columbia Children’s Hospital (center 1) involves a single IVIG infusion plus aspirin, 3 to 5 mg/kg/day, for 6 weeks, while at Stollery Children’s Hospital in Edmonton (center 2), the aspirin dose is 80 to 100 mg/kg/day until 24 to 48 hours after defervescence.
Some 10% to 20% of children with Kawasaki disease fail to respond to the initial IVIG dose, which is referred to as IVIG resistance. These patients usually are given a second dose, but are at increased risk of coronary complications and may have longer hospital stays and adverse events such as hemolytic anemia.
Therefore, to see if IVIG resistance is influenced by ASA dose, the researchers reviewed 122 charts from the years 2009 to 2014 at center 1 and from 127 at center 2 from 2005 to 2014.
At baseline, patient ages ranged from 33 to 36 months, and almost two-thirds were boys. Asians were significantly more common in center 1 (53.3% versus 13.4%, P<0.001).
The brand of IVIG most often used in center 1 was Gamunex, and a local formulation of 10% IVIG was the most common in center 2.
To determine whether the different time frames in the two centers influenced the results, the researchers conducted a secondary analysis that included patients only seen from 2009 to 2014, finding an incidence of IVIG resistance of 23% in center 1 and 7.3% in center 2.
Among patients requiring a second infusion of IVIG, time between infusions ranged from 25 to 66 hours.
In the main multivariate analysis, ethnicity was not included, because it was assigned based on family name, which can be unreliable because of marriage and mixed ethnicity. However, when Asian ethnicity was added to the analysis, 19.5% of Asian children had IVIG resistance compared with 13.8% of non-Asians, which was not a significant difference, and the odds ratio for low-dose ASA and IVIG resistance was 3.7 (95% CI 1.2-11.6, P=0.02).
The mean hospital stay was 4.1 days in center 1 and 4.7 in center 2. “It is surprising that despite the difference in IVIG resistance, we could not document a difference in length of hospital stay between the two centers. This may be due to differences between the centers in usual practices regarding discharge of patients with Kawasaki disease,” the researchers noted.
Coronary artery aneurysms developed in two patients from center 1 and in six patients from center 2, which was not significantly different. The study was not powered to detect a difference in this outcome, however.
The three times increased odds of a second IVIG dose seen with low-dose ASA represented a 14% absolute increase, and the number needed to treat was seven.
“Until there is better evidence from randomized controlled trials, it seems reasonable to adhere to AHA guidelines and prescribe high-dose ASA in the initial phase of Kawasaki disease,” Dhanrajani’s group concluded.
Among the limitations of the study were its retrospective design and a lack of information about adverse events associated with ASA.
Dhanrajani and co-authors disclosed no relevant relationships with industry.
F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner