Cardiovascular and cerebrovascular risks associated with the use of cyclo-oxygenase-2 selective (COX2) non-steroidal anti-inflammatory drugs (NSAIDs) have received substantial attention. COX2 medications are associated with increased risk of heart attacks and strokes, which resulted in withdrawal of rofecoxib. However, much less attention has been given to cardiovascular and cerebrovascular safety of non-COX2 NSAIDs. There are some indications that the risk of heart attacks and strokes is increased with exposure to any NSAID and overall risk to the patient may be modified by baseline cardiovascular risk. Because cardiovascular risk varies based on patient characteristics it is important to understand if the risks associated with NSAID use are similar across diverse patient subgroups.
The objective of this study is to evaluate the risk of NSAID-related adverse events in patients exposed to NSAIDs. The specific aims of the project are: 1) examine whether pre-existing cardiovascular disease risk factors modify the risk for NSAID-related cardiovascular events; 2) Determine whether decreased kidney function modifies the risk of cardiovascular events in patients with osteoarthritis taking NSAIDs; and 3) Evaluate the impact of impaired drug metabolism by comparing risk in those exposed to NSAIDs with and without impaired liver function.
We conducted an observational cohort study of VA patients with a diagnosis of osteoarthritis, in order to identify a group of patients appropriate for long-term NSAID use, that were at least 65 years of age. We used VA healthcare encounter data in conducting this analysis. The patient cohort was identified using national inpatient and outpatient data. Medication exposure was identified from the DSS Pharmacy Extract databases. Patients were followed from their initial eligible diagnosis date until date of event, the end of the study period or until they were lost to follow-up. Deaths were identified using the VA Vital Status File data. Clinical information was obtained from the DSS Laboratory Results Extracts to characterize clinical factors of patients during the follow-up period.
A total of 813,228 patients were identified for inclusion in the cohort with an average age of 73.7 years (sd 6.0). The average follow-up period was 2.73 years in the cohort. Within the cohort, 45% of the patients were exposed to an NSAID during the follow-up period. The two most prevalently used NSAIDs were naproxen and ibuprofen. Amongst those that were exposed at some point during the follow-up period nearly half of them had at least one prescription dispensing for ibuprofen (47%). A total of 102,031 (12.6%) patients experienced a cerebrovascular or cardiovascular event and there were 109,231 deaths (13.4%) occurring during follow-up. When CAD groups were defined based on those considered high risk and all others considered non-high risk, exposure to any NSAID during the follow-up period was associated with an adjusted odds ratio of 1.14 (1.08 to 1.21) for cardiovascular or cerebrovascular events in the non-high risk group and 1.18 (1.11 to 1.27) in the high risk group. When exposure was stratified by COX-2 and non-selective NSAIDs, the association between exposure and events remained similar for the non-selective NSAIDs as with the NSAIDs overall. There was an association with increased risk for cardiovascular or cerebrovascular events in both non-high risk and high risk groups and a decreased risk for overall mortality.
Our study demonstrated an increased risk of non-fatal cardiovascular and cerebrovascular events consistent with previous reports. We found that risks may differ for events based on pre-existing coronary artery disease, and, importantly, that there may be some degree of protective effect of NSAIDs on all-cause mortality. This study, when added to the rapidly increasing literature of NSAID exposure, suggests the need for better understanding of mechanisms related to major adverse events.
- Lee TA, Bartle B, Weiss KB. Impact of NSAIDS on mortality and the effect of preexisting coronary artery disease in US veterans. The American journal of medicine. 2007 Jan 1; 120(1):98.e9-16.