The introduction of bias in the design and analysis of studies likely explains a reported reduction of mortality with antacid therapy in patients with idiopathic pulmonary fibrosis (IPF), according to a new Canadian review study.
The research, “The effect of anti-acid therapy on survival in idiopathic pulmonary fibrosis: a methodological review of observational studies,” was published in the European Respiratory Journal.
In addition to the approved anti-fibrotic therapies Ofev (nintedanib), from Boehringer Ingelheim, and Esbriet (pirfenidone), from Genentech, antacid therapy also is recommended for patients with IPF. Antacids normally are indicated for gastroesophageal reflux disease, a common occurrence in IPF. However, evidence supporting the use of antacids in IPF is controversial, with reported results ranging from a marked decrease in mortality to no effect at all.
The research team in the current study suspected that the large benefits of antacids seen in observational studies of IPF are probably the result of immortal time bias, which may occur when a period of time is used in a study in which the outcome of a particular interest, such as death, cannot occur.
Immortal time bias is typically seen when the determination of an individual’s exposure or treatment status involves a delay or waiting period, such as when a patient waits for a medication to be dispensed after starting follow-up. This wait is considered “immortal” because subjects who end up in the treated group survive until the treatment definition is met.
Therefore, bias results from the misclassification of treatment status or exclusion from the analysis. Immortal time bias is frequent in observational studies and reduces the rate of events in the treated group, thereby artificially favoring the studied treatment.
Now, scientists reviewed observational studies assessing the link between antacid treatment and mortality in IPF, with the goal of identifying research that was affected by immortal time bias.
Their analysis included 10 studies published from 2011 to 2017. Specifically, they included seven cohort studies — a type of study that follows participants to assess the risk of disease, the incidence rate, and the relative risks — and three retrospective observational studies using data from other clinical trials.
The results revealed that five of the cohort studies reported an association between antacids and a reduced risk of mortality in IPF, four of which introduced immortal time bias in their design and analysis. The existence of bias in the fifth study was inconclusive.
“It would be imperative to reanalyse the data from the four studies affected by immortal time bias using proper methods that avoid this bias,” the researchers wrote.
According to the team, bias was introduced by a required minimum duration of antacid use to define exposure status. The exposed group had to survive that period, thereby being “immortal,” while the unexposed group was at risk of death right after study’s start.
In contrast, the studies avoiding immortal time bias did not find a link between antacid therapy and mortality.
Therefore, the researchers suggested that “the apparent beneficial effects of anti-acid therapy on mortality in patients with IPF result from observational studies affected by immortal time bias.”
They added: “Thus, the effectiveness of anti-acid therapy in IPF remains uncertain and needs to be reassessed with more accurate observational study methods and randomized trials.”