Clinical Context

Clinicians commonly prescribe nonsteroidal anti-inflammatory drugs (NSAIDs) for symptom relief in acute respiratory infections (ARIs). However, some previous research suggests that individually, ARI and NSAID use may each increase risk for acute myocardial infarction (AMI).

NSAID use during ARI episodes might act synergistically to compound the risk for AMI, but no previous research has tested this hypothesis. The goal of this nationwide case-crossover study by Wen and colleagues was to evaluate the potential simultaneous effect of ARI and NSAID use on AMI risk using the National Health Insurance Research Database in Taiwan.

Study Synopsis and Perspective

Use of NSAIDs during ARIs increases the risk for AMI 3.4-fold if taken by mouth and 7.2-fold with parenteral dosing compared with baseline risk without NSAID use or ARI, according to a report published online February 2 in the Journal of Infectious Diseases.^[1]

Experts agree that clinicians should consider patient history and the potential risks before prescribing the drugs to patients with an ARI.

Several studies have shown an increased risk for AMI during an ARI, as well as an increased risk for AMI with NSAID use.

Since 2005, the US Food and Drug Administration has required manufacturers of over-the-counter NSAIDs to include warning labels about elevated risk for cardiac effects; the agency strengthened^[2] the warning for MI and stroke in 2015.

However, studies have not previously examined the effect of combined NSAID and ARI exposure.

Therefore, Yao-Chun Wen, MA, from National Taiwan University Hospital, Taipei, and colleagues investigated the possible combined effect of an ARI and NSAID use with a case-crossover study that included 9793 patients with hospitalization for AMI between 2007 and 2011. Using claims data from Taiwan's National Health Insurance Program, the authors compared AMI risk among patients with ARI and NSAID exposure, ARI without NSAID exposure, NSAID exposure only, or no exposure (neither ARI nor NSAID use).

The index date for AMI was the first day of hospitalization, and the case period for AMI extended back 7 days. The matched control period was between 366 and 372 days before the index date. The index date for an ARI was the date of an outpatient visit.

Compared with no exposure, NSAID use during an ARI was associated with a 3.4-fold increased risk for AMI (adjusted odds ratio [aOR], 3.41; 95% confidence interval [CI], 2.80-4.16), ARI without NSAIDs was associated with a 2.7-fold increased risk for AMI (aOR, 2.65; 95% CI, 2.29-3.06), and NSAID use alone was associated with a 1.5-fold increased risk (aOR, 1.47; 95% CI, 1.33-1.62).

Parenteral NSAID delivery in patients with ARI introduced an even greater risk for AMI (aOR, 7.22; 95% CI, 4.07-12.81).

NSAID dosing also made a difference in AMI risk. Low-dose oral NSAIDs to treat ARI symptoms were associated with a 3-fold increased risk for AMI (aOR, 2.95; 95% CI, 2.31-3.75), whereas high-dose oral NSAIDs were associated with a 3.3-fold increased risk for AMI (aOR, 3.32; 95% CI, 2.34-4.93).

"[W]e determined that NSAIDs use during ARI episodes, particularly parenteral NSAIDs use, was associated with a further increased risk of AMI," the researchers conclude.

The "potential joint effect of ARI and NSAIDs" is consistent with increases in cytokine production, accumulation of macrophages in atherosclerotic lesions, and heightened inflammation and coagulation during an ARI, the researchers note. NSAIDs could elevate blood pressure through increased sodium and water retention, which could rupture plaque deposits, and enhance the synthesis of leukotrienes, leading to platelet aggregation, and lower levels of antithrombotic prostaglandin I₂.

Charlotte Warren-Gash, PhD, from the London School of Hygiene and Tropical Medicine, London, United Kingdom, and Jacob A. Udell, MD, MPH, from the University of Toronto, Toronto, Ontario, Canada, agree with the researchers that the procoagulation and proinflammatory effects of ARI and NSAIDs may set up a perfect storm of conditions for a cardiac event.

"It is certainly plausible that interaction between these deleterious mechanisms may, in part, explain the greater risk of AMI seen in individuals with ARIs treated with NSAIDs compared with those with untreated ARIs or those with NSAID use alone," they write in an accompanying commentary.^[3]

"The report by Wen and colleagues contributes to the evidence for dual effects of AMI triggers and highlights the need for cautious use of NSAIDs in the context of ARI; clinicians should consider both medical conditions and existing medications when prescribing NSAIDs for symptomatic ARI relief," Dr Warren-Gash and Dr Udell conclude.

Limitations of the study include not considering the severity of the ARI (preliminary findings indicate that symptoms that blossom into influenza increase the risk for AMI further), not evaluating individual NSAIDs, and inability to tell whether patients actually took the NSAIDs indicated in their records.

The researchers and commentators have disclosed no relevant financial relationships.

J Infect Dis. Published online February 2, 2017.

Clinical Implications

• A Taiwanese nationwide case-crossover study showed that NSAID use, particularly parenteral NSAID use, during ARI episodes yielded an increased risk for AMI greater than that associated with either exposure alone.
• Because NSAIDs use during ARI episodes is highly common in real-world settings, the findings should raise clinical concern regarding this practice.
• Implications for the Healthcare Team: Before prescribing NSAIDs to patients with ARI, clinicians should consider patient cardiovascular and gastrointestinal history and weigh the risks against the potential benefits.

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