Downside of Long-term NSAID Use

Though NSAIDs have long been linked to GI bleeding, they are commonly used long-term in the elderly to treat various conditions and decrease cardiovascular risk, especially among those with diabetes.  Now, a new study has suggested that NSAIDs can increase the risk of CV events, including ischemic stroke, and that these risks differ by type of NSAID.

“[E]lderly patients with diabetes using NSAIDs were at a higher risk of both GIB [gastrointestinal bleed] and CV [cardiovascular] events compared to non-users, and these risks differed among different NSAIDs in a way that did not correspond directly to COX-2 selectivity,” wrote lead author Byung-Joo Park and colleagues at Seoul National University College of Medicine (Seoul, Republic of Korea).

The study included over 117,000 people and was conducted in Korea. It was published online in BMJOpen Diabetes Research Care.

The results regarding NSAIDs other than aspirin are intriguing. While aspirin has long been known to increase bleeding risk and cause GI complications, the CV risks associated with NSAIDs other than aspirin-such as those with stronger COX-2 selectivity like meloxicam, and newer agents like etoricoxib-are unclear, according to the authors.

In the nationwide cohort study, researchers used the Korean national health insurance database, which covers claims for the years 2008-2012, to identify NSAID users and NSAID non-users (58,805 in each group) with diabetes and aged ≥ 65 years. Then they propensity score matched NSAID users and non-users on a one-to-one basis, allowing them to compare similar patients in the user vs non-user groups. They also looked at recent use of antihypertensives, anticoagulants, antiplatelet agents, aspirin, proton pump inhibitors (PPIs), gastroprotective agents (GPAs), corticosteroids, and serotonin reuptake inhibitors (SSRIs). Follow-up occurred for about three years.

The study could not adjust for several potential confounders, such as diagnostic laboratory findings, family history, and lifestyle factors like smoking or obesity, because these were not available in the database.

Key results showed:

• 2184 (1.86%) cases of first GI bleeds (1354 in NSAID users, 830 in non-users)

• 9333 (7.94%) cases of MI or stroke (5043 in the NSAID group, 4290 among non-users)

• Compared to non-users, NSAID users had 68% increased risk of GI bleed, after adjusting for age, sex, comorbidities, and recent medications (adjusted HR [aHR] of 1.68 [95% CI 1.54 to 1.83])

• Compared to non-users, NSAID users had 20% increased risk of MI/ischemic stroke (aHR of 1.20 [95% CI 1.15 to 1.25])

• Patients on anticoagulants, antiplatelet agents, aspirin and selective serotonin reuptake inhibitors had higher risk of CV events

• Compared to celecoxib, users of ketorolac had higher risk of CV events (aHR 3.13)

• Patients on PPIs and GPAs had:

♦ Increased risk of GI bleeds (PPI: IRR 2.09 [1.60-2.73], GPAs: 1.60 [1.43-1.79])

♦ Increased risk of MI/ischemic stroke (PPI: IRR 1.31 [1.12-1.52]; GPA: 1.18 [1.12-1.25])

• Similar risks for GI bleed for celecoxib (aHR 1.09 (95% CI 0.79 to 1.50]) and PPI + NSAID (aHR 1.10 [95% CI 0.93 to 1.31])

“PPI users eventually became more vulnerable to NSAID toxicity,” the authors wrote.

Guidelines recommend adding a PPI or choosing a COX-2 inhibitor for patients at high CV risk, the authors explained, and past studies have suggested that COX-2 inhibitors may have a protective effective against GI bleeds, compared to PPIs.  These data, though, do not support such a conclusion, the authors pointed out.

COX mechanisms are characterized by diversity, and different agents have different IC50 values-the concentration of an inhibitor which decreases the response by half.

 “Prescribing NSAIDs only by the COX-2 selectivity determined in vitro by the IC50 ratios of COX-1 and COX-2 should be avoided since COX-2 selectivity is not directly correlated with risky outcomes in real life,” the authors emphasized.

Take-home Points

• A Korean study has shown that NSAID users have increased risk of GI bleeds and MI/ischemic stroke.

• These risks differ by type of NSAIDs and do not correspond directly to COX-2 selectivity.

• Compared to celecoxib, users of ketorolac had higher risk of CV events.

• PPI users may eventually experience NSAID toxicity.

Reference: Kim J, et al. Risk of gastrointestinal bleeding and cardiovascular events due to NSAIDs in the diabetic elderly population. BMJ Open Diabetes Res Care. 2015 Dec 18;3(1):e000133.