In this issue of the Journal, Liu et al. report a study from Taiwan, which indicates that angiotensin-converting enzyme inhibitors (ACEIs) reduce the risk of pneumonia in patients who have had a stroke. The purported mechanism behind this effect is that ACEIs, by stimulating the cough reflex, prevent aspiration into the lungs of content from the upper gastrointestinal tract. Pneumonia is a frequent and potentially serious adverse event following stroke, and ACEIs are relevant drugs for a large proportion of these patients, for a number of indications. If these drugs can be found to have an effect on the risk of pneumonia this might have implications for the choice of drugs in patients who have had a stroke, for indications like hypertension .
The interest in this question is expressed in the high number of studies on the same topic, including a secondary analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) . The results of these studies are somewhat conflicting, but several studies indicate that at least in elderly people who have had a stroke, and particularly in Asian populations, ACEIs have a protective effect against pneumonia, and, based on these studies, the Japanese Society of Hypertension has suggested that ACEIs should be the choice of treatment for patients with hypertension that repeatedly develop aspiration pneumonia .
The study presented by Liu et al. used a case crossover design to ascertain the effect of ACEIs on the risk of pneumonia. Cases were identified in a large and comprehensive Taiwanese database of hospitalized patients, and drug exposure immediately prior to the pneumonia (case period) was compared with drug exposure at earlier times, when patients were known not to have pneumonia (control periods). This design allows each patient to serve as his/her own control, which avoids many important sources of bias that can arise when different people are compared. The study encompassed nearly all individuals living in Taiwan at the time, and data have been correctly analyzed with conditional logistic regression, adjusting for key time-varying confounding factors, such as concomitant medication. The key message from the study is that patients who used ACEIs before the stroke were found to have a highly statistically significant 23% lower risk of pneumonia. The credibility of this result was strengthened by the finding of a clear dose-risk relationship, of a high level of consistency of the findings in different subgroup and sensitivity analyses, and of the finding that angiotensin receptor blockers (which have no effect on the cough reflex) had no effect on pneumonia risk. In addition, the hypothesis that pneumonia is caused by aspiration was strengthened by the finding that proton pump inhibitors (which reduce the secretion of gastric acid and can weaken the barrier against bacterial growth in the upper gastrointestinal tract) were associated with an increased risk of pneumonia, as has been shown in other studies .
As in all observational studies, there are of course a number of alternative explanations for the observed association. Importantly, as mentioned by the authors, there is a possibility that patients who developed cough in the early phase of pneumonia, stopped using ACEIs simply because the cough was mistaken as a side effect of the ACEIs. If that was the case, fewer patients with pneumonia would have used ACEIs immediately prior to the pneumonia, and cough due to pneumonia would be a factor confounding the association between ACEIs and pneumonia. Other sources of bias are possible, and the crude nature of data from a nation-wide registry of this kind make it difficult to adjust for all relevant confounding factors. It is not plausible, however, that the observed association represents a chance finding (type I error), given the large effect and the precise effect estimate.
This study does not provide a definite answer to the question of whether ACEIs prevent pneumonia, and it should not on its own lead to changes to the way we treat patients who have had a stroke. Still, it provides interesting hypotheses, which are worth pursuing. At the least, it provides a strong case for including pneumonia as an important endpoint in clinical trials of ACEIs, in particular in patients at high risk of pneumonia, such as patients who have had a stroke. In addition, this study is a nice demonstration of the value of registry data, using a good and probably underused study design.
Conflicts of interest
There are no conflicts of interest.
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