Why do Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) increase cardiovascular risk?

From the Guidelines

NSAIDs increase cardiovascular risk primarily through their effects on the balance between thromboxane and prostacyclin in the body, with COX-2 selective inhibitors like celecoxib and diclofenac carrying higher risks, while naproxen appears to have a more neutral cardiovascular profile 1. When NSAIDs inhibit cyclooxygenase (COX) enzymes, particularly COX-2, they reduce the production of prostacyclin, which normally helps dilate blood vessels and prevent platelet aggregation. However, many NSAIDs (especially COX-2 selective inhibitors like celecoxib) don't equally suppress thromboxane, which promotes blood clotting and vasoconstriction. This imbalance creates a prothrombotic state that increases the risk of heart attacks and strokes. The risk varies among different NSAIDs, with diclofenac and high-dose ibuprofen (>2400mg daily) carrying higher risks, while naproxen appears to have a more neutral cardiovascular profile 1. Some key points to consider:

• The risk is dose-dependent and increases with longer duration of use 1.
• Patients with existing cardiovascular disease, hypertension, or risk factors should use NSAIDs cautiously, at the lowest effective dose for the shortest duration possible 1.
• For those requiring long-term pain management with significant cardiovascular risk, alternatives like acetaminophen or topical NSAIDs might be safer options, though they should discuss specific recommendations with their healthcare provider 1. It's also important to note that the selective COX-2 inhibitors and other nonselective NSAIDs have been associated with increased cardiovascular risk, with the risk appearing to be amplified in patients with established cardiovascular disease 1. A study by Gislason et al. analyzed the risk of rehospitalization for MI and death related to the use of NSAIDs, including selective COX-2 inhibitors, in patients with prior MI, and found that the risk of death and rehospitalization for MI associated with the use of selective COX-2 inhibitors and nonselective NSAIDs was increased 1. In summary, NSAIDs should be used with caution in patients with cardiovascular risk factors, and the lowest effective dose should be used for the shortest duration possible, with alternatives like acetaminophen or topical NSAIDs considered for long-term pain management 1.

From the FDA Drug Label

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal.

Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal.

BOXED WARNING Cardiovascular Risk NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal.

The NSAIDs increase cardiovascular risk because they cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal 2, 3, 4.

• The risk may occur early in treatment and may increase with duration of use.
• Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

From the Research

Mechanisms of Increased Cardiovascular Risk

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) increase cardiovascular risk by antagonizing the platelet-vascular homeostasis of metabolites of COX-thromboxane A2 and prostaglandin I2 (prostacyclin) 5
• The balance between COX-1 mediated prothrombotic thromboxane and COX-2 mediated antithrombotic prostacyclin is important for thrombotic risk, and COX-2 inhibitors can disrupt this balance, leading to an increased risk of myocardial infarction and death 6

Comparative Risks of Different NSAIDs

• Naproxen and low-dose ibuprofen appear to have lower increased cardiovascular risk among NSAIDs 7, 8
• Diclofenac, celecoxib, and rofecoxib have been shown to increase cardiovascular risk, with diclofenac being as COX-2 selective as celecoxib and increasing cardiovascular risk dose dependently 9, 7, 6
• Etoricoxib has been shown to have a higher risk than ibuprofen and naproxen, with a ratio of relative risks (RRR) of 1.68 and 1.75, respectively 7
• Indomethacin has been shown to have a high risk of cardiovascular events, with a relative risk of 1.30, and its use has been questioned due to its toxicity and cardiovascular risk 7

Factors Influencing Cardiovascular Risk

• Treatment dose and duration can influence cardiovascular risk, with higher doses and longer durations of treatment increasing the risk of adverse cardiovascular events 8, 6
• Baseline patient risk is also an important factor, with patients having a higher baseline risk of cardiovascular disease being more likely to experience adverse cardiovascular events when taking NSAIDs 8
• The use of NSAIDs can increase cardiovascular risk within weeks of treatment, highlighting the need for careful consideration and monitoring when prescribing these medications 7, 6