Risks seen even with short treatment duration

In patients with first myocardial infarction (MI), prescription non-steroidal anti-inflammatory drug (NSAID) treatment over a mean follow-up of 2.3 years significantly increased the risk for cardiovascular events and bleeding, an observational study in Korea found.

In those receiving prescription NSAIDs, risk for cardiovascular events climbed by nearly sevenfold (HR 6.96, 95% CI 6.24-7.77; P < 0.001), while bleeding events rose fourfold (HR 4.08, 95% CI 3.51-4.73; P < 0.001) over those with no NSAID treatment, reported Cheol Ung Choi, MD, PhD, of the Korea University College of Medicine in Seoul, and co-authors.

Risks were apparent even with treatment duration of 1 week. Risks for both bleeding and cardiovascular events were lowest — though still elevated — with celecoxib and meloxicam.

“The concomitant use of NSAIDs and post-MI antithrombotic medications was closely associated with increased risk for cardiovascular and bleeding events in this study, which is the largest contemporary cohort of patients with MI,” Choi and colleagues wrote in Journal of the American College of Cardiology.

When NSAID use is unavoidable, they suggested “selective and relative COX-2 inhibitors could be considered a primary choice on the basis of their observed relative safety profile in patients with MI.”

Because celecoxib and meloxicam showed the least increase in adverse outcomes, “they may deserve a more central place in the anti-inflammatory armamentarium,” noted Juan Badimon, PhD, and Carlos Santos-Gallego, MD, both of Icahn School of Medicine in New York City, in an accompanying editorial.

“There is no free lunch in medicine, so if NSAID therapy in patients post-MI is inevitable, we have to understand which price we are paying for pain relief,” they added.

Most individual NSAIDs have been reported to increase the risk for adverse cardiovascular events, and recent guidelines have discouraged the use of NSAIDs in patients with established cardiovascular disease, particularly given recommendations for dual antiplatelet therapy for 6 to 12 months followed by lifelong single agent therapy in some situations. Despite this, patients with cardiovascular disease are frequently exposed to NSAIDs because of medical comorbidities, with an estimated 5-year exposure rate of NSAIDs in this setting of up to 44%.

Evidence that NSAID treatment after MI is associated with bleeding and cardiovascular risk has been studied in Western populations: a 2015 study in Denmark found increased risk of bleeding and cardiovascular events with concomitant use of NSAIDs after MI, regardless of antithrombotic treatment, type of NSAID, or duration of use.

In the present study, Choi and colleagues analyzed data from 108,232 Korean patients with first MI (mean age 64.2, 72.1% men) using the Health Insurance Review and Assessment Service database in Korea between January 2009 and December 2013. Patients were followed from the date of the index MI to first thromboembolic cardiovascular or bleeding event or end of follow-up in December 2014.

Prescription claims for celecoxib, meloxicam, aceclofenac, diclofenac, naproxen, ibuprofen, dexibuprofen, and zaltoprofen were identified through pharmacy records. Non-prescription NSAID use was not included in the analysis.

Patients were divided into groups on the basis of the prescribed antithrombotic medications, including dual antiplatelet (DAPT) and single antiplatelet therapy (SAPT) as well as anticoagulation. The primary and secondary outcomes were thromboembolic cardiovascular and clinically relevant bleeding events. NSAID use was determined by prescriptions filled.

DAPT (87.9%) was the most frequently prescribed antithrombotic regimen within the first 30 days after index MI, followed by SAPT (8.0%), triple antithrombotic therapy (2.9%), and oral anticoagulant with dual-antithrombotic therapy (0.3%).

Cardiovascular events developed in 26,202 patients (24.2%) and bleeding developed in 25,358 people (23.4%). Those with these events were prescribed one or more NSAIDs for at least 4 weeks in 1,909 (1.8%) and 2,052 (1.9%), respectively.

Among NSAID subtypes, the risk for cardiovascular and bleeding events overall was lowest with the use of celecoxib (HR 4.65 and HR 3.44, respectively) and meloxicam (HR 3.03 and 2.80, respectively).

Subgroup analysis for those on DAPT or SAPT showed concomitant NSAIDs increased risk for cardiovascular events (DAPT HR: 6.93; 95% CI 6.15-7.80; P< 0.001; SAPT HR: 7.05 95% CI 4.03-12.33; P < 0.001).

Similar results were seen for bleeding: increased risk for bleeding events in the DAPT and SAPT groups was HR 4.05 (95% CI 3.44-4.75; P < 0.001) and HR 4.43 (95% CI 1.97-9.96; P < 0.001), respectively.

Diclofenac was the most frequently prescribed in those with cardiovascular events (71.8% of NSAIDs) and also for those with bleeding (68.9% of overall NSAIDs). Celecoxib was prescribed in 12.8% of those with cardiovascular events and 12.7% of those with bleeding events.

Limitations include substantial group differences at baseline. NSAID treatment was based solely on prescription claims, so over-the-counter NSAID use was not included in the analysis, which may have underestimated NSAID exposure. Also, mortality outcomes were not included in the database and the effect of NSAID treatment in patients receiving potent P2Y12 inhibitors, such as ticagrelor or prasugrel, or direct oral anticoagulants was not assessed. Other adverse events of NSAIDs, such as renal failure, were not included in the analysis.

  1. After first myocardial infarction, prescription NSAID use increased risk for cardiovascular events and bleeding events, even with short treatment duration.

  2. Of eight NSAIDs in the study, risks for both bleeding and cardiovascular events were lowest with celecoxib and meloxicam, though they still were significantly elevated.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The researchers reported they have no relationships relevant to the contents of this paper to disclose.

The editorialists reported they have no relationships relevant to the contents of this paper to disclose.

Cat ID: 358

Topic ID: 74,358,730,358,142,192,925