Which NSAID Has the Least CV Risk? An Overview of Cardiovascular Safety

October 16, 2025 •

5 min read

According to the Food and Drug Administration (FDA), all non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) carry a boxed warning about an increased risk of heart attack and stroke. This warning has led many to question: which NSAID has the least CV risk? The answer is complex, as it depends on factors like dose, duration, and a patient's individual health profile.

Quick Summary

All non-aspirin NSAIDs carry some cardiovascular risk, but the magnitude varies by drug, dose, and treatment duration. Factors influencing risk include the NSAID's effect on blood pressure and the balance of anti-clotting factors. Naproxen, celecoxib, and low-dose ibuprofen are generally considered lower risk, but patient health is critical.

Key Points

All NSAIDs have CV risk: The FDA warns that all non-aspirin NSAIDs increase the risk of heart attack and stroke, with the risk starting early and increasing with higher doses and longer duration of use.
Naproxen's perceived safety is challenged: While once thought safest among traditional NSAIDs, large studies like PRECISION have shown naproxen's cardiovascular risk to be comparable to ibuprofen at the doses studied, particularly for those at high CV risk.
Celecoxib is non-inferior for CV events: The FDA-mandated PRECISION trial found that moderate-dose celecoxib was non-inferior to naproxen or ibuprofen regarding cardiovascular safety, while causing fewer gastrointestinal and renal events.
Ibuprofen affects blood pressure more: A substudy of the PRECISION trial showed that ibuprofen significantly increased systolic blood pressure compared to celecoxib and naproxen, an important consideration for patients with hypertension.
Safest choice depends on the patient: For minimizing overall risk, particularly concerning blood pressure and GI issues, celecoxib at moderate doses appears favorable based on recent trial data, but the best choice depends on individual risk factors and a healthcare provider's guidance.
Prioritize alternatives and lowest dose: For patients with cardiovascular concerns, the primary recommendation is to avoid NSAIDs entirely if possible. If necessary, use the lowest effective dose for the shortest duration, and consider safer alternatives like acetaminophen or topical NSAIDs.

Understanding NSAID Cardiovascular Risk

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of medications widely used to treat pain, inflammation, and fever. They work by inhibiting cyclooxygenase (COX) enzymes, which are responsible for producing prostaglandins that mediate these effects. There are two main types of NSAIDs: nonselective NSAIDs, which block both COX-1 and COX-2 enzymes, and COX-2 selective inhibitors, or "coxibs," which primarily target COX-2.

The Role of COX Enzymes in Cardiovascular Health

The COX-1 enzyme, which is active in platelets, promotes the production of thromboxane A2, a substance that helps blood clot. The COX-2 enzyme, expressed in the lining of blood vessels, produces prostacyclin, which helps prevent blood clots. When selective COX-2 inhibitors are used, they suppress prostacyclin production without inhibiting thromboxane. This imbalance can lead to an increased risk of thrombotic events like heart attack and stroke. Nonselective NSAIDs inhibit both enzymes but with varying degrees of selectivity, explaining the differing cardiovascular risks within the class.

Other Cardiovascular Effects of NSAIDs

Beyond the risk of blood clots, NSAIDs can also increase cardiovascular risk through other mechanisms:

Blood Pressure Elevation: NSAIDs can cause sodium and water retention by affecting kidney function, which can increase blood pressure. This effect is particularly concerning for individuals with pre-existing hypertension. A study involving patients with arthritis found that ibuprofen significantly increased systolic blood pressure compared to celecoxib.
Heart Failure: Due to the risk of fluid retention, NSAIDs can worsen pre-existing heart failure and potentially increase the risk of hospitalization. This appears to be a class effect, with studies showing an increased risk for both traditional NSAIDs and coxibs.

Comparative Safety of Key NSAIDs

For years, medical professionals have debated the comparative cardiovascular safety of different NSAIDs. Recent large-scale studies have provided clearer insights, though the recommendations remain nuanced.

Naproxen

Historically, naproxen was often considered to have one of the most favorable cardiovascular risk profiles among non-selective NSAIDs. This perception was partly based on the VIGOR trial, which showed a lower risk of myocardial infarction in naproxen users compared to those taking the now-withdrawn COX-2 inhibitor rofecoxib. However, later meta-analyses and trials like PRECISION revealed that naproxen, especially at higher doses, is also associated with an increased risk of acute myocardial infarction. The American Academy of Family Physicians notes that naproxen and low-dose ibuprofen appear to have lower CV risk among non-selective NSAIDs, but emphasizes using the lowest effective dose for the shortest duration.

Ibuprofen

Ibuprofen's cardiovascular risk appears to be dose-dependent, with studies suggesting lower risks at lower doses. The FDA also highlighted the interference between ibuprofen and the cardioprotective effects of low-dose aspirin, recommending patients take ibuprofen at least 30 minutes after or 8 hours before aspirin. The PRECISION trial also shed new light on ibuprofen's cardiovascular and blood pressure effects, as discussed below.

Celecoxib

As a COX-2 selective inhibitor, celecoxib (Celebrex) has been under scrutiny for cardiovascular risk since the withdrawal of rofecoxib (Vioxx). However, research has consistently shown that celecoxib's risk is lower than rofecoxib and is not necessarily higher than traditional NSAIDs. In a significant randomized trial mandated by the FDA, celecoxib's cardiovascular safety at moderate doses was found to be non-inferior to naproxen or ibuprofen.

The PRECISION Trial: A Landmark Study

The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial was a major clinical study designed to compare the long-term cardiovascular safety of celecoxib, ibuprofen, and naproxen in patients with arthritis who were at increased cardiovascular risk.

Key findings from the PRECISION trial and its blood pressure substudy (PRECISION-ABPM) include:

Cardiovascular Safety: At moderate doses, celecoxib was non-inferior to both naproxen and ibuprofen regarding the composite primary outcome of cardiovascular death, heart attack, or stroke. This dispelled the notion that naproxen was definitively the safest non-selective NSAID.
Blood Pressure Effects: The PRECISION-ABPM substudy found that ibuprofen treatment was associated with a significant increase in systolic blood pressure compared to celecoxib. The blood pressure increase with naproxen was also noted, but was not significantly different from celecoxib in this study.
Gastrointestinal and Renal Events: Celecoxib was associated with fewer gastrointestinal and renal adverse events than both ibuprofen and naproxen.

Despite the clear data, limitations exist, such as a high rate of patient and study-drug discontinuation. Nevertheless, the study provides valuable comparative data for these three commonly used NSAIDs.

A Comparison of NSAID Cardiovascular Profiles


Feature	Naproxen (Aleve)	Ibuprofen (Advil, Motrin)	Celecoxib (Celebrex)
Drug Class	Non-selective NSAID	Non-selective NSAID	COX-2 selective inhibitor
CV Risk	Historically considered lower, but recent studies show risk, especially at higher doses.	Risk is dose-dependent; higher doses associated with higher risk.	At moderate doses, non-inferior to naproxen and ibuprofen; overall risk appears comparable to non-selectives at therapeutic doses.
Blood Pressure	Can increase BP; showed a smaller increase than ibuprofen in PRECISION-ABPM.	Caused a significant increase in systolic BP in the PRECISION-ABPM study.	Minimal effect on blood pressure compared to ibuprofen and naproxen in PRECISION-ABPM.
GI Risk	Higher risk of gastrointestinal bleeding than celecoxib.	Higher risk of gastrointestinal bleeding than celecoxib.	Lower risk of gastrointestinal bleeding than non-selective NSAIDs.
Aspirin Interaction	Can interfere with aspirin's anti-platelet effect.	Can interfere with aspirin's anti-platelet effect.	No significant interference with aspirin's anti-platelet effect.

Recommendations for Minimizing Risk

For patients who need to use NSAIDs, especially those with pre-existing cardiovascular conditions, a cautious approach is critical. The following strategies are essential for minimizing risk:

Lowest Effective Dose, Shortest Duration: Always use the lowest dose that is effective for pain relief and for the shortest time possible.
Consider Alternatives: For many people, particularly those with heart disease or other risk factors, alternatives to oral NSAIDs should be the first choice. Acetaminophen (Tylenol) is often recommended as a first-line treatment for pain that doesn't have a significant inflammatory component, as it does not carry the same cardiovascular or gastrointestinal risks as NSAIDs. Topical NSAIDs, such as diclofenac gel, offer another option for localized pain with minimal systemic absorption.
Check for Drug Interactions: Be aware that some NSAIDs, like ibuprofen and naproxen, can interfere with the anti-clotting effect of low-dose aspirin.
Monitor Your Health: Patients using NSAIDs should be monitored for increases in blood pressure, fluid retention, and changes in kidney function.
Consult Your Healthcare Provider: The most crucial step is to discuss your specific health profile and pain management needs with a healthcare professional. They can help weigh the risks and benefits to determine the safest and most effective option for you.

Conclusion

Determining which NSAID has the least CV risk is not straightforward, as all non-aspirin NSAIDs have some associated risk. Landmark studies like PRECISION have shown that at moderate doses, celecoxib's cardiovascular risk profile is comparable to ibuprofen and naproxen, while offering a better safety profile for gastrointestinal and blood pressure concerns. Ultimately, the safest approach for individuals with or at risk of cardiovascular disease is to avoid NSAIDs whenever possible, opt for the lowest effective dose for the shortest duration if necessary, and prioritize alternatives like acetaminophen or topical pain relievers. This decision should always be made in consultation with a healthcare provider who can assess the individual patient's total health picture.

Frequently Asked Questions

If you have heart disease, you should avoid NSAIDs whenever possible. All non-aspirin NSAIDs carry a risk of increasing heart attack and stroke, especially with long-term or high-dose use. Alternatives like acetaminophen or topical pain relievers should be considered first, and any NSAID use must be discussed with your healthcare provider.

No, taking low-dose aspirin does not reliably counteract the cardiovascular risk of other NSAIDs. Furthermore, some NSAIDs like ibuprofen and naproxen can interfere with aspirin's anti-platelet effect, making aspirin less effective.

A substudy of the PRECISION trial found that celecoxib had a minimal effect on blood pressure compared to ibuprofen, which caused a significant increase in systolic blood pressure. Naproxen's effect was smaller than ibuprofen but still present.

Topical NSAIDs, such as diclofenac gel, are absorbed systemically in much smaller amounts than oral NSAIDs and therefore carry a lower risk. However, they are not entirely without risk, and it is still recommended to discuss their use with a healthcare professional, especially for those with existing heart conditions.

According to the PRECISION trial, moderate-dose celecoxib was non-inferior to naproxen and ibuprofen concerning cardiovascular safety. While all carry some risk, celecoxib demonstrated a lower risk for gastrointestinal and blood pressure side effects.

NSAIDs are associated with an increased risk of fluid retention and worsening heart failure. Therefore, they should be avoided in patients with heart failure. Acetaminophen is often the safest alternative, though it has risks related to liver toxicity at high doses, and any medication choice should be made in consultation with a doctor.

Yes, celecoxib (Celebrex) is still on the market. While it belongs to the same class of drugs as the withdrawn Vioxx, studies have shown that celecoxib's cardiovascular risk profile is lower than Vioxx and comparable to traditional NSAIDs at therapeutic doses.