Why was Vioxx taken off the market? The story behind the 2004 recall

October 8, 2025 •

3 min read

In one of the largest voluntary drug recalls in history, Merck & Co. withdrew its blockbuster arthritis drug Vioxx (rofecoxib) from the worldwide market on September 30, 2004. The recall followed concerns and clinical trial data indicating Vioxx increased the risk of heart attack and stroke.

Quick Summary

The arthritis drug Vioxx was withdrawn in 2004 due to evidence confirming its link to an increased risk of heart attacks and strokes. A clinical trial revealed elevated cardiovascular events in patients using the medication long-term, leading to legal issues and scrutiny.

Key Points

Cardiovascular Risks: A large clinical trial (APPROVe) showed that long-term Vioxx use increased the risk of heart attack and stroke compared to placebo.
Pharmacological Imbalance: As a selective COX-2 inhibitor, Vioxx suppressed protective prostacyclin without affecting pro-clotting thromboxane, potentially increasing blood clot risk.
Recall Trigger: The findings from the APPROVe study led directly to Merck's worldwide withdrawal of Vioxx on September 30, 2004.
Corporate Conduct: Evidence from litigation suggested Merck may have had early indications of risks and potentially downplayed findings.
Legal and Financial Impact: Merck faced significant litigation and paid substantial settlements and penalties related to harm claims and marketing.
Regulatory Changes: The recall prompted stricter FDA regulations regarding post-market drug safety and industry research scrutiny.

From Blockbuster Drug to Safety Disaster

First approved by the FDA in 1999, Vioxx was a selective cyclooxygenase-2 (COX-2) inhibitor, a new class of non-steroidal anti-inflammatory drugs (NSAIDs). It was marketed as a potentially safer alternative to traditional NSAIDs like ibuprofen and naproxen, which were known to cause gastrointestinal side effects such as stomach bleeding and ulcers. The drug was prescribed for conditions including osteoarthritis, rheumatoid arthritis, acute pain, and menstrual symptoms. With sales topping $2.5 billion in 2003, Vioxx quickly became a pharmaceutical giant for its manufacturer, Merck & Co. However, concerns regarding potential cardiovascular risks emerged early in the drug's history, despite being submitted to the FDA without specific cardiovascular safety trials.

The First Warning Signs and Clinical Trial Controversies

Early studies began to hint at Vioxx's potential cardiovascular issues. The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial, which compared Vioxx to naproxen, showed fewer gastrointestinal side effects but indicated an increased risk of heart attack among Vioxx users. Merck was criticized for potentially understating these findings. This was followed by an FDA warning in 2001 regarding promotional practices.

The Study That Prompted the Recall

The definitive evidence came from the Adenomatous Polyp Prevention on Vioxx (APPROVe) study, which began in 2001. This study, investigating Vioxx's effect on colorectal polyps, was halted early in 2004 when data revealed a greater risk of serious cardiovascular events, including heart attack and stroke, in patients taking Vioxx for over 18 months, compared to those on a placebo. These results directly led to Merck's decision to withdraw Vioxx globally.

Unveiling the Mechanism and Consequences

The cardiovascular risks of Vioxx are linked to its action as a selective COX-2 inhibitor.

The Role of COX Enzymes

COX-1: Involved in protecting the stomach lining and blood clotting.
COX-2: Produced during inflammation, contributing to pain and swelling.

By blocking only COX-2, Vioxx aimed to reduce pain without the gastrointestinal side effects of traditional NSAIDs that block both enzymes. However, this selectivity suppressed prostacyclin (which prevents clots) while not affecting thromboxane A2 (which promotes clotting), creating an imbalance favoring clot formation and increasing the risk of heart attack and stroke.

The Fallout and Legal Ramifications The Vioxx recall had significant repercussions:

Extensive Litigation: Merck faced numerous lawsuits from patients claiming harm.
Massive Settlements: Merck paid $4.85 billion to settle around 27,000 personal injury lawsuits in 2007.
Government Scrutiny: In 2011, Merck paid $950 million to settle charges related to illegal marketing, including promoting Vioxx for unapproved uses.
Regulatory Reform: The FDA introduced stricter post-marketing surveillance requirements.

The Impact on Patients and Public Trust

The recall eroded public trust in the pharmaceutical industry and regulators. Many patients who relied on Vioxx for pain relief were unknowingly exposed to serious cardiovascular risks. This event emphasized the need for transparency, comprehensive clinical trials, and clear communication of safety information by drug manufacturers.


Comparison Aspect	Vioxx (Rofecoxib)	Other NSAIDs (e.g., Ibuprofen)
Mechanism	Selective COX-2 inhibitor, blocks only COX-2 enzyme.	Non-selective COX-1 and COX-2 inhibitor, blocks both enzymes.
Cardiovascular Risk	Significantly increased risk of heart attack and stroke due to unbalanced suppression of prostacyclin.	Lower or comparable cardiovascular risk, with some, like naproxen, potentially having cardioprotective effects.
Gastrointestinal Risk	Lower risk of stomach bleeding and ulcers compared to non-selective NSAIDs.	Higher risk of gastrointestinal side effects due to inhibition of protective COX-1 enzyme.
Recall Status	Voluntarily withdrawn from the worldwide market in 2004 due to cardiovascular risks.	Still widely available and commonly used for pain relief.

Conclusion

The Vioxx recall in 2004 was a significant event in drug safety, triggered by clear evidence of increased cardiovascular risks. The drug's selective mechanism, intended to protect the stomach, inadvertently contributed to a cardiovascular imbalance. The incident highlighted issues in corporate conduct and regulatory oversight, leading to legal actions and changes in drug safety procedures.

Frequently Asked Questions

Vioxx (rofecoxib) was a prescription non-steroidal anti-inflammatory drug (NSAID) known as a selective COX-2 inhibitor. It was used to treat pain and inflammation from conditions like osteoarthritis and rheumatoid arthritis.

Vioxx was voluntarily withdrawn from the worldwide market by its manufacturer, Merck & Co., on September 30, 2004, after a clinical trial showed an increased risk of cardiovascular events.

The primary health risks associated with Vioxx were an increased risk of serious cardiovascular events, including heart attack and stroke, especially with long-term use.

Evidence uncovered during litigation suggested that Merck executives and scientists may have had early indications of Vioxx's cardiovascular risks, but some internal communications and public statements downplayed or obscured the findings.

Traditional NSAIDs inhibit both COX-1 (stomach protection) and COX-2 (pain and inflammation) enzymes. Vioxx was designed to selectively inhibit only COX-2 to reduce pain without causing as many gastrointestinal side effects. However, this led to an imbalance in the cardiovascular system.

The APPROVe study, a large, placebo-controlled trial, provided evidence that long-term Vioxx use (more than 18 months) increased the risk of heart attack and stroke compared to a placebo, directly prompting the recall.

Yes. The Vioxx recall led to widespread scrutiny of all COX-2 inhibitors. Another drug in the class, Bextra (valdecoxib), was also voluntarily withdrawn in 2005 due to cardiovascular risks, while Celebrex (celecoxib) remains on the market with strengthened cardiovascular risk warnings.