Which of the following is the most cardiotoxic: Rofecoxib, Diclofenac, or Celecoxib?

From the Guidelines

Diclofenac is generally considered the most cardiotoxic among the three options, with a higher risk of cardiovascular events, including myocardial infarction and stroke, compared to celecoxib and rofecoxib. The cardiotoxicity of diclofenac is related to its COX-2 selectivity combined with its effects on the COX-1 enzyme, which creates an unfavorable cardiovascular risk profile 1. According to a study published in Circulation, the use of nonsteroidal anti-inflammatory drugs, including diclofenac, increases the risk of cardiovascular events, with a hazard ratio of 2.40 (2.09 to 2.80) for death compared to other NSAIDs 1.

Some key points to consider when evaluating the cardiotoxicity of these NSAIDs include:

• The risk of cardiovascular events is proportional to COX-2 selectivity and the underlying risk in the patient 1
• Diclofenac inhibits both COX-1 and COX-2 enzymes, but has a higher selectivity for COX-2, which reduces protective prostacyclin production while not adequately inhibiting thromboxane, potentially creating a prothrombotic state 1
• Celecoxib at lower doses (200mg daily) is generally considered to have a more favorable cardiovascular safety profile among these options, but should be used with caution in patients with cardiovascular risk factors 1
• When prescribing NSAIDs to patients with cardiovascular concerns, it's essential to use the lowest effective dose for the shortest duration possible and to consider alternative pain management strategies when appropriate 1

In terms of specific data, a study published in the Journal of the American College of Cardiology found that the hazard ratio for death associated with diclofenac use was 2.40 (2.09 to 2.80), compared to 2.57 (2.15 to 3.08) for celecoxib and 2.80 (2.41 to 3.25) for rofecoxib 1. These findings suggest that diclofenac is associated with a higher risk of cardiovascular events, including myocardial infarction and stroke, compared to celecoxib and rofecoxib.

From the FDA Drug Label

Cardiovascular safety outcomes were also evaluated in the CLASS trial Kaplan-Meier cumulative rates for investigator-reported serious cardiovascular thromboembolic adverse events (including MI, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischemic attacks, and ischemic cerebrovascular accidents) demonstrated no differences between the celecoxib capsules, diclofenac, or ibuprofen treatment groups The cumulative rates in all patients at nine months for celecoxib capsules, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The most cardiotoxic of the three options, Rofecoxib, is not mentioned in the provided text in relation to the other two options, Diclofenac and Celecoxib. However, based on the provided information, Diclofenac has a slightly higher cumulative rate of cardiovascular thromboembolic adverse events (1.4%) compared to Celecoxib (1.2%) and Ibuprofen (1.1%) in the CLASS trial 2. It is essential to note that Rofecoxib is not included in this comparison, and its cardiotoxicity cannot be directly assessed from the given data. Therefore, among Celecoxib and Diclofenac, Diclofenac appears to have a slightly higher cardiotoxic risk based on the CLASS trial results.

From the Research

Comparison of Cardiotoxicity

• The cardiotoxicity of Rofecoxib, Diclofenac, and Celecoxib has been studied in various research papers 3, 4, 5, 6, 7.
• Rofecoxib has been shown to have a higher risk of myocardial infarction and cardiovascular events compared to other NSAIDs, including Diclofenac and Celecoxib 4, 5, 7.
• Diclofenac has been found to have a similar risk of myocardial infarction as Rofecoxib, but recent studies suggest that this risk may be decreased in patients with high cardiovascular risk 6.
• Celecoxib has been shown to have a lower risk of cardiovascular events compared to Rofecoxib and Diclofenac, and may even have a protective effect against myocardial infarction and stroke 5.

Key Findings

• Rofecoxib was withdrawn from the market due to its increased risk of cardiovascular events 3, 4.
• The use of Rofecoxib has been associated with a higher risk of acute myocardial infarction, particularly at higher doses 7.
• Aspirin use may mitigate the risk associated with low-dose Rofecoxib, but not high-dose Rofecoxib 7.
• The risk of cardiovascular events with Diclofenac and Celecoxib is lower than with Rofecoxib, but may still be present, particularly with high doses or long-term use 3, 5, 6.