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Non-steroidal anti-inflammatory drugs (NSAIDs) are currently the most widely used and most commonly used analgesic and anti-inflammatory drugs, including cyclooxygenase (COX) non-selective inhibitors and cyclooxygenase-2 (COX-2) selective inhibitors.

Since the first synthesis of aspirin in 1898, NSAIDs have been listed on thousands of brands so far, which is “the king of innocence.”

 

However, it is also a troublesome “king”.

Figure 1: FDA strengthens safety warnings for NSAIDs

  • October 2004: Merck Corporation announced that it has taken the initiative to withdraw Wolo (Rofecoxib) from the global market;
  • April 2005: The US Food and Drug Administration (FDA) issued a statement that NSAIDs (except aspirin) have potentially serious cardiovascular risks;
  • July 2015: FDA strengthens cardiovascular warnings for NSAIDs: NSAIDs (except aspirin) can cause heart attack and stroke risk, both of which can cause death.

For cardiovascular doctors, the risk of bleeding from NSAIDs has always been a “troublesome”.

When NSAIDs encounter anticoagulants, especially new oral anticoagulants that are more and more widely used, will the bleeding risk increase compared with anticoagulants alone? In addition to the risk of bleeding, is there any other “trap”?

01

NSAIDs+ anticoagulant, facing double troubles of bleeding and stroke

Recently, the Journal of the American College of Cardiology (JACC) published a new study from Professor Anthony P. Kent and others in the United States. It was found that the simultaneous use of NSAIDs and anticoagulants increased bleeding, stroke, and stroke in patients with atrial fibrillation. Hospitalization risk.

Figure 2: JACC article title map

The study was a reanalysis of the RE-LY study, the world’s first non-valve AF prognostic clinical trial with positive results, involving 18,113 patients with atrial fibrillation at risk of stroke, randomized to receive fixation. A dose of dabigatran etexilate (110 mg or 150 mg bid), or a modified dose of warfarin.

In this article, the investigators divided 18113 participants who used anticoagulants according to whether they used NSAIDs, the NSAIDs group (n = 2,279) (used at least once in the RE-LY trial) and the non-NSAIDs group (n =15834), comparing the differences in bleeding, stroke or embolism, myocardial infarction, and hospitalization rates. turn out:

  • Increased bleeding risk: AF patients with NSAIDs had a 68% increased risk of major bleeding (HR=1.68, 95% CI: 1.40-2.02, P<0.0001), and an increase of 81% in gastrointestinal bleeding events (HR=1.81, 95% CI: 1.35~2.43, P<0.0001).
  • Increased risk of stroke or systemic embolism: 50% increase in stroke or systemic embolism (HR=1.50, 95% CI: 1.12–2.01, P=0.007), and a 55% increase in the risk of ischemic stroke (HR=1.55, 95CI: 1.11-2.16, P=0.01).
  • The NSAIDs group was hospitalized more frequently (HR=1.64, 95% CI: 1.51-1.77, P<0.0001). In addition, there was no significant difference in risk of myocardial infarction and all-cause mortality between the two groups.

It appears that patients with AF using NSAIDs not only increase the risk of bleeding from 60% to 80%, but also increase the risk of stroke (including ischemic stroke) by 50%!

Then, there is another question, are these risks related to what anticoagulants are used?

Afterwards, the researchers compared bleeding and stroke between dabigatran etexilate and dabigatran etexilate, respectively, when combined with NSAIDs and non-NSAIDs, compared with warfarin, and dabigatran etexilate 100 mg, 150 mg of three anticoagulants. / Embolism risk difference. The results showed that the use of NSAIDs did not affect the difference in bleeding and stroke risk between dabigatran etexilate and warfarin.

 

This suggests that the risk of stroke caused by NSAIDs + anticoagulants is independent of the type of anticoagulant. It seems that whether it is warfarin or a new oral anticoagulant, be careful when using NSAIDs together!

However, the study also has limitations. For example, RE-LY studies included non-selective NSAIDs that included only ibuprofen, naproxen, meloxicam, diclofenac, and ketones, and lack of specific types of non-selective NSAIDs, doses, and NSAIDs. The reason for the data. Second, the study did not analyze the baseline prevalence of osteoarthritis, rheumatoid arthritis, or other inflammatory conditions in the NSAIDs use group at baseline.

02

How to deal with the dilemma of NSAIDs+ anticoagulants?

For patients with atrial fibrillation who have osteoarthritis or other oral anticoagulants, how to deal with the dilemma of NSAIDs seems to be an unavoidable problem. The discussion of NSAIDs has not stopped. Many scholars have also made many suggestions on this issue.

So, is there any way to reduce the risk? Let’s take a look at these proposals~

• Proposal 1: Can I use acetaminophen instead of NSAIDs?

Answer: Acetaminophen has poor anti-inflammatory effects and is not of great significance for patients with osteoarthritis.

• Proposal 2: Can I use the proton pump inhibitor stomach to reduce the risk of bleeding?

Answer: Proton pump inhibitors can only protect the stomach and prevent bleeding in the intestines and other parts. It is not a panacea.

• Proposal 3: Is it possible to consider the use of selective COX-2 inhibitors such as celecoxib instead of ordinary NSAIDs? These drugs have less bleeding and do not reduce platelet function, but still have anti-inflammatory effects.

Answer: There is currently no research on the combination of selective COX-2 inhibitors and anticoagulants. Recent studies, such as the SCOT study published at the 2015 European Cardiovascular Annual Meeting and the PRECISION study published at the 2016 American Heart Association Annual Meeting. However, the results of the study showed that the cardiovascular risk difference between celecoxib and naproxen was not obvious, and it is worth noting that ibuprofen has a relatively high incidence of cardiovascular adverse events.

In addition, both trials reported poor adherence to the celecoxib group and high exit rates.

Just like many questions that don’t have a perfect answer, the best solution for NSAIDs with anticoagulants is still on the way.

Before the emergence of safe and effective NSAIDs, we had to repeatedly measure how to manage the risk of oral anticoagulant patients with atrial fibrillation patients and cardiovascular patients with NSAIDs. After all, doing the right monitoring and vigilance is the most important thing!

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