AVICA

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Sheehan WJ, Mauger DT, Paul IM, et al, for the NIH/NHLBI AsthmaNet. "Acetaminophen versus ibuprofen in young children with mild persistent asthma". New England Journal of Medicine. 2016. 375(7):619-630.
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Clinical Question

In young children with mild persistent asthma, does treatment of pain or fever with acetaminophen lead to a greater number of asthma exacerbations requiring treatment with systemic glucocorticoids compared to treatment with ibuprofen?

Bottom Line

The study found no significant difference in serious asthma exacerbations requiring systemic glucocorticoid treatment in children from 12-59 months with mild persistent asthma between those treated with acetaminophen and ibuprofen.

Major Points

There is a suggested association between frequent acetaminophen use and asthma-related complications in children, but evidence evaluating this association are lacking. Acetaminophen is one of the most commonly used pediatric medications in the United States. In adults with asthma an association was seen observationally.[1] Its safety in children with asthma has become controversial since a post hoc analysis of a randomized trial on the safety of short-term use of acetaminophen versus ibuprofen for febrile illnesses in children showed significantly higher unscheduled visits for asthma in the acetaminophen group.[2] The AVICA trial sought to investigate whether the use of acetaminophen is associated with higher morbidity related to asthma than ibuprofen in young children with mild persistent asthma. This trial was run in concert with the INFANT trial [3] which is awaiting publication.

The AVICA trial randomized 300 patients aged 12-59 months at 18 sites across the US, designating acetaminophen (150) or ibuprofen (150) use when needed for antipyretic or analgesic effects over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both treatment groups received standardized asthma-controller therapies that were used in a simultaneous, factorially-linked trial. There was no significant difference in the primary outcome (relative rate of asthma exacerbations for acetaminophen (0.81) vs ibuprofen (0.87), RR 0.94; 95% CI 0.69-1.28). There was also no significant difference detected with respect to the percentage of asthma-control days, use of albuterol/salbutamol rescue inhaler, unscheduled health care utilization for asthma, or adverse events.

Some limitations of this trial should be noted. These results may not be generalizable to other age groups or to patients with more severe asthma. Adherence to asthma-controller medications was strictly monitored and these results may not apply to patients who are non-adherent or are not taking any medications for their asthma. Without a placebo group, which would be unethical being given to a child with fever, malaise, and pain, the possibility that both ibuprofen and acetaminophen use may cause parallel increases in asthma exacerbations or symptoms cannot be excluded.

Guidelines

As of April 2017, no guidelines have been published that addresses the use of acetaminophen or ibuprofen in asthmatic children.

Design

  • Multicenter, randomized, double-blind, parallel trial
  • N=300
    • Acetaminophen (n=150)
    • Ibuprofen (n=150)
  • Setting: 18 sites in USA
  • Enrollment: March 2013 - April 2015
  • Follow-up: 48 weeks
  • Analysis: Modified Intention-to-treat
  • Primary Outcome: Number of asthma exacerbations requiring systemic glucocorticoids

Population

Inclusion Criteria:

  • 12-59 months old
  • mild persistent asthma
    • symptoms on more than two days per week, but not daily
  • Eligible for receiving long-term step 2 asthma-controller therapy[3]
    • low-dose inhaled glucocorticoids
    • montelukast
    • cromolyn

Exclusion Criteria:

  • History of adverse reaction to any trial medications
  • Evidence participants might show poor adherence to the trial medication or study procedures

Baseline Characteristics:

Displayed Acetaminophen group (N=150)

There are no significant differences between the two groups that are clinically relevant.

  • Age (months): 40.3±12.9
  • Male: 57%
  • Race:
    • White: 49%
    • Black: 31%
    • Hispanic or Latino: 23%
  • Age at onset of asthma (months): 13.1±9.4
  • Parent with history of asthma: 58%
  • Asthma measure at time of randomization
    • Oral glucocorticoid courses in the previous 6 months: 1.01±1.06
    • Urgent care or ED visits in the previous year: 3.13±2.45
    • Hospitalizations in the previous year: 0.29±0.57
    • Asthma-control days (full control days without the use of rescue medications for asthma, daytime asthma symptoms, nocturnal asthma symptoms, and unscheduled health care visits for asthma): 85.5% ± 18.7
    • Albuterol/Salbutamol inhalations per week: 1.81±3.49
    • Use of inhaled glucocorticoids in the previous year: 61%
    • Use of leukotriene receptor antagonist in the previous year: 15%
  • Measure of atopy at time of randomization
    • Median IgE (kU/liter): 64
    • Median blood absolute eosinophil count (cells/mm3): 259.6
    • Positive aeroallergen test: 43%

Interventions

Following 2 to 8 weeks run-in, patients were randomly assigned to:

  • Acetaminophen (160mg/5ml) at a dose of 15 mg per kilogram of body weight every 6 hours as needed
  • Ibuprofen (100mg/5ml) at a dose of 9.4 mg per kilogram of body weight every 6 hours as needed

Outcomes

Presented as acetaminophen vs. ibuprofen group

Primary Outcome

Number of asthma exacerbations per participant requiring systemic glucocorticoid treatment

n=298 total population
0.81(0.65-1.02) vs. 0.87(0.69-1.10), (RR 0.94, 95% CI 0.69-1.28; P=0.67)
n=226 completed trial
0.74(0.58-0.93) vs. 0.70(0.55-0.90), (RR 1.05, 95% CI 0.75-1.45; P=0.79)
n=200 completed trial and ≥1 dose study medication
0.74 (0.58-0.94) vs. 0.77(0.60-1.00), (RR 0.95, 95% CI 0.68-1.32; P=0.76)

Secondary Outcomes

Asthma-control days (Mean full calendar days without use of rescue medications or asthma symptoms)
85.8% vs. 86.8%, RR-1.01(95%CI -3.94-1.92; P=0.50)
Mean number of albuterol/salbutamol rescue inhalations per week
2.8 vs. 3.0 (RR -0.2; 95%CI -0.9 to 0.6; P=0.69)
Unscheduled health care utilization for asthma per participant
0.75 vs 0.76 (RR 0.99; 95%CI 0.72 to 1.37; P=0.94)

Adverse Effects

No significant between-group differences were observed with respect to adverse events or serious adverse events (SAE: acetaminophen 4.0% vs ibuprofen 8.1%).

Criticisms

  • The generalizability may be limited:
    • children with severe asthma not included
    • only included children between 12-59 months of age
    • high medication adherence to asthma-controller medications was strictly monitored, may not apply to patients with low adherence or those without medical management
    • study did not address environmental factors that could exacerbate asthma. (e.g. exposure to cigarette smoke, pollen)
  • Treatment effect may be masked if ibuprofen causes similar rates of exacerbation to acetaminophen.
    • This cannot be determined without a placebo group, which would be unethical when dealing with febrile conditions.
  • Affects of the medications from the INFANT trial[3] cannot be excluded

Funding

  • Funded by the Asthma Network (AsthmaNet) of the National Heart, Lung, and Blood Institute (NHLBI)
  • NHLBI independent data and safety monitoring board which also reviewed the primary analyses

Further Readings

  1. Shaheen SO et al. Frequent paracetamol use and asthma in adults. Thorax 2000. 55:266-70.
  2. Lesko SM et al. Asthma morbidity after the short-term use of ibuprofen in children. Pediatrics 2002. 109:E20.
  3. 3.0 3.1 3.2 Individualized Therapy For Asthma in Toddlers [1]