Studying additive interaction in a healthcare database: Case study of NSAIDs, cardiovascular profiles, and acute myocardial infarction

Abstract

PurposeThere are clinical trial data on risk of acute myocardial infarction (MI) with nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at increased cardiovascular (CV) risk requiring chronic daily treatment. This study investigated whether risks of acute MI with real-world prescription NSAIDs, such as low-dose or intermittent use, vary according to an individual’s CV profile.MethodsNested case-control analyses were carried out on an administrative health cohort from Quebec, Canada by randomly selecting 10 controls per case matched on age ± 1 year, sex, and month and year of cohort entry. We measured the additive joint effects on acute MI of current NSAID use and presence of hypertension, coronary heart disease (CHD), history of previous MI, or concomitant use of cardioprotective aspirin. The endpoint was the relative excess risk due to interaction (RERI). To verify the robustness of interaction findings, we performed sensitivity analyses with varying specifications of NSAID exposure-related variables.ResultsThe cohort consisted of 233 816 elderly individuals, including 21 256 acute MI cases. For hypertension, CHD, and previous MI, we identified additive interactions on MI risk with some but not all NSAIDs, which also depended on the definition of NSAID exposure. Hypertension was sub-additive with naproxen but not with the other NSAIDs. Celecoxib and CHD were sub-additive in the primary analysis only (modelling NSAID dose on index date or up to 7 days before–best-fitting base model) whereas celecoxib and rofecoxib were super-additive with a history of previous MI in the secondary analysis only (modelling NSAID use on index date). For cardioprotective aspirin we found no evidence for an additive interaction with any of the NSAIDs.ConclusionsAlternative specifications of NSAID exposure concurred in finding that concomitant use of cardioprotective aspirin does not attenuate the risks of acute MI with NSAIDs. However we were unable to demonstrate consistent interactions between an individual’s cardiovascular comorbidities and NSAID-associated acute MI. Our study highlights challenges of studying additive interactions in a healthcare database and underscores the need for sensitivity analyses.

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“…Similarly, it has long been recognized that additive interaction is more relevant for clinicians, public health practitioners, and policy makers because it highlights the individuals in the population who would benefit most from an intervention . Based on the interpretation of superadditive interaction from our results, the number of deaths in aging women who have high BMI is greater than the number of deaths expected from either high BMI or increasing age independently . Ultimately, whether additive or multiplicative interaction is most relevant depends on the question that the researchers are trying to answer.…”

U.S. Adults With Pain, a Group Increasingly Vulnerable to Nonmedical Cannabis Use and Cannabis Use Disorder: 2001–2002 and 2012–2013

“…Estimates for ratios of risk ratios and 95% confidence intervals were obtained using Fieller's method incorporating predicted marginal prevalences and standard errors from SUDAAN. Interactions on the additive scale are of particular interest from a public health perspective, as they point to groups that experience the greatest population-level risk (or shifts in risk) and thus may represent important targets for prevention and intervention (see the Supplemental Material section and Table S6 in the online supplement) (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). To yield estimates representative of the U.S. adult population, we incorporated the survey weights, and used SUDAAN 11.0.1 (46) to adjust for the complex sampling designs.…”

Non-steroidal anti-inflammatory drugs in the pharmacological management of osteoarthritis in the very old: prescribe or proscribe?

“… 40 Concomitant use of cardioprotective aspirin does not appear to reduce the risk of acute MI with NSAIDs. 41 A subsequent analysis using data from the Quebec administrative health cohort confirmed that all five NSAIDs, including naproxen, are associated with increased risk of MI. This increased risk exists for celecoxib after continuous use for more than 30 days, whereas, for the other four NSAIDs, it occurs within 7 days of use.…”

“…The ORs for the five NSAIDs studied were 1.24 (0.91-1.82) for celecoxib, 1.48 (1.00-2.26) for ibuprofen, 1.50 (1.06-2.04) for diclofenac, 1.53 (1.07-2.33) for naproxen, and 1.58 (1.07-2.17) for rofecoxib 40. Concomitant use of cardioprotective aspirin does not appear to reduce the risk of acute MI with NSAIDs 41. A subsequent analysis using data from the Quebec administrative health cohort confirmed that all five NSAIDs, including naproxen, are associated with increased risk of MI.…”