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NSAIDs, Respiratory Infection Together Raise MI Risk

  • Authors: News Author: Ricki Lewis, PhD; CME Author: Laurie Barclay, MD
  • CME / ABIM MOC / CE Released: 3/16/2017
  • Valid for credit through: 3/16/2018
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Target Audience and Goal Statement

This article is intended for primary care clinicians, cardiologists, pulmonologists, allergist/immunologists, critical care specialists, nurses, pharmacists, public health officials, and other members of the healthcare team caring for patients receiving nonsteroidal anti-inflammatory drugs for acute respiratory infection who may be at increased risk for acute myocardial infarction.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Evaluate the association of acute respiratory infections (ARIs) and use of nonsteroidal anti-inflammatory drugs (NSAIDs) with the risk for acute myocardial infarction (AMI), based on a Taiwanese nationwide case-crossover study
  2. Determine the clinical implications regarding the association of ARIs and NSAID use with AMI risk


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  • Ricki Lewis, PhD

    Freelance writer, Medscape


    Disclosure: Ricki Lewis, PhD, has disclosed no relevant financial relationships.


  • Robert Morris, PharmD

    Associate CME Clinical Director, Medscape, LLC


    Disclosure: Robert Morris, PharmD, has disclosed no relevant financial relationships.

CME Author(s)

  • Laurie Barclay, MD

    Freelance writer and reviewer, Medscape, LLC


    Disclosure: Laurie Barclay, MD, has disclosed the following relevant financial relationships:
    Owns stock, stock options, or bonds from: Alnylam; Biogen; Pfizer Inc.

CME Reviewer/Nurse Planner

  • Amy Bernard, MS, BSN, RN-BC

    Lead Nurse Planner, Medscape, LLC


    Disclosure: Amy Bernard, MS, BSN, RN-BC, has disclosed no relevant financial relationships.

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NSAIDs, Respiratory Infection Together Raise MI Risk

Authors: News Author: Ricki Lewis, PhD; CME Author: Laurie Barclay, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 3/16/2017

Valid for credit through: 3/16/2018


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.

Study Highlights

  • This Taiwanese nationwide case-crossover study included 9793 patients hospitalized for AMI (index date=first day of hospitalization) between 2007 and 2011.
  • For ARI, the index date was the date of the outpatient visit.
  • The investigators compared exposure status between the case (1-7 days before index date) and matched control period (366-372 days before index date) for NSAID use during ARI episodes, ARI episodes without NSAID use, NSAID use only, or no exposure to ARI or NSAIDs.
  • ORs adjusted for potential confounders (aORs) were estimated with multivariable conditional logistic regression models.
  • The risk for AMI was increased 3.4-fold for any NSAID use during an ARI (aOR, 3.41; 95% CI, 2.80-4.16) and 7-fold for parenteral NSAID use (aOR, 7.22; 95% CI, 4.07-12.81).
  • For oral NSAIDs used during ARI episodes, a high NSAID dose was associated with a higher risk for AMI (aOR, 3.32; 95% CI, 2.34-4.93) than a low NSAID dose (aOR, 2.95; 95% CI, 2.31-3.75).
  • The risk for AMI was increased 2.7-fold for ARI without NSAID use (aOR, 2.65; 95% CI, 2.29-3.06) and 1.5-fold for NSAID use only (aOR, 1.47; 95% CI, 1.33-1.62).
  • For NSAID use without ARI, high-dose NSAIDs were not highly associated with a higher risk for AMI than low-dose NSAIDs.
  • On the basis of these findings, the investigators concluded that NSAID use, particularly parenteral NSAID use, during ARI episodes was associated with an increased risk for AMI greater than that associated with either exposure alone.
  • Because NSAID use during ARI episodes is highly common in real-world settings, the findings should raise clinical concern regarding this practice.
  • Potential mechanisms underlying the simultaneous effect of ARI and NSAIDs on the risk for AMI include the effects of ARI on increasing biosynthesis of proinflammatory and prothrombotic cytokines, macrophage accumulation in atherosclerotic lesions, and systemic inflammation and coagulation resulting in thrombosis.
  • Despite the anti-inflammatory effect of NSAIDs, cyclooxygenase inhibition decreases levels of antithrombotic prostaglandin I2 and enhances leukotriene synthesis, leading to platelet aggregation and vasoconstriction.
  • NSAIDs can also increase sodium and water retention, resulting in blood pressure elevation that could lead to plaque rupture.
  • Study limitations include inability to determine ARI severity; possible misclassification or protopathic bias; and possible uncontrolled confounding, including confounding by indication.
  • An accompanying commentary recommends that before prescribing NSAIDs to patients with ARI, clinicians consider patient cardiovascular and gastrointestinal history and weigh the risks against the potential benefits.
  • Clinicians should also use the lowest effective dose for the shortest duration needed for symptom control and prescribe naproxen or low-dose ibuprofen instead of other NSAIDs for their more favorable thrombotic cardiovascular safety profile.

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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