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Sep 30, 2004
Rofecoxib withdrawn worldwide by Merck
Whitehouse Station, NJ - Merck has withdrawn its selective COX-2 inhibitor rofecoxib (Vioxx®) from all markets worldwide, following the availability of new three-year data from the Adenomatous Polyp Prevention on VIOXX (APPROVE) trial showing an increased risk of cardiovascular events with the drug.
Rofecoxib was launched in 1999 for the treatment of arthritis and had worldwide sales last year of $2.5 billion. Merck's share price plunged on the announcement.
Multiple other studies have also suggested an increased cardiovascular risk with rofecoxib, but until now Merck has denied there was any safety issue with the drug, and the APPROVE study was conducted in part to ascertain more information on this.
The APPROVE trial, which is being stopped, was testing rofecoxib 25 mg vs placebo in the prevention of the recurrence of colorectal polyps in 2600 patients with a history of colorectal adenoma. The study showed an increased relative risk for MI and stroke with rofecoxib, which became evident after 18 months of treatment.
Raymond V Gilmartin, chair, president, and chief executive officer of Merck, said: "We are taking this action because we believe it best serves the interests of patients. Although we believe it would have been possible to continue to market Vioxx with labeling that would incorporate these new data, given the availability of alternative therapies and the questions raised by the data, we concluded that a voluntary withdrawal is the responsible course to take."
The APPROVE trial was started in 2000, following the results of the VIOXX Gastrointestinal Outcomes Research (VIGOR) study, which indicated an increased risk of cardiovascular events with rofecoxib vs naproxen. Merck argued that naproxen was exerting a protective cardiovascular effect and rofecoxib did not have a cardiac safety issue, which it claimed was supported by phase 3 studies in which no increased risk of cardiovascular events with rofecoxib were seen vs placebo or other non-naproxen NSAIDs.
Peter Kim (president of Merck Research Laboratories) said: "Merck has always believed that prospective, randomized, controlled clinical trials are the best way to evaluate the safety of medicines. APPROVE is precisely this type of studyand it has provided us with new data on the cardiovascular profile of Vioxx. While the cause of these results is uncertain at this time, they suggest an increased risk of confirmed cardiovascular events beginning after 18 months of continuous therapy."
What about the other coxibs?
While the other selective COX-2 inhibitors, such as celecoxib (Celebrex®, Pfizer) will now come under close scrutiny, they are not believed to have such a negative cardiovascular profile as rofecoxib. Merck has a second selective COX-2 inhibitor, etoricoxib (Arcoxia®), which is available in 47 countries, and the company says that the cardiovascular safety issue with rofecoxib is not necessarily applicable to others in the class but will work with regulatory authorities to assess whether changes to the prescribing information for etoricoxib is warranted. Etoricoxib is not yet available in the US, but Merck said it will continue to seek approval and will continue its clinical-trial program with this drug.
Reaction mixed from cardiologists
One cardiologist who has long maintained that rofecoxib had an unacceptable cardiovascular safety profile is Dr Eric Topol (Cleveland Clinic, OH). He commented to heartwire that "Merck has finally got it right," although it was "too bad it took so long for them to accept the truth." He added: "Ironically, the validation of our concern came from a colon polyp trial in patients without any known heart disease." He said the other COX-2 inhibitors seemed safer, but "it was hard to know."
Another high-profile cardiologist is not so forthright on this issue. Dr Robert Califf (Duke Clinical Research Institute, Durham, NC) commented to heartwire that rofecoxib caused a small but measurable increase in risk of cardiovascular events, but that other ongoing placebo controlled trials do not show the same effect. "From what we can piece together from the poor studies that are available, it looks like naproxen may be the only one that reduces riskwe just don't know about celecoxib, etc. Any chronically given drug that affects inflammation will have cardiovascular effects. Not doing long-term trials to inform the public about the balance of risks and benefits is like playing Russian rouletteyou just don't know which chambers have bullets unless you look."
He added that: "It's a shame the drug has to pulled from the market. It would be best to inform doctors and patients of the risk and let them make a choice, but because of the dominance of lawsuits in therapeutics, obviously Merck can't afford to do that."
Related links
1. ACR issues alert on cardiovascular complications of COX-2 inhibitors [HeartWire > News; Sep 28, 2004 ]
2. FDA-funded study shows rofecoxib doses >25 mg/day triple risk of acute MI and sudden cardiac death [HeartWire > News; Aug 26, 2004 ]
3. Largest coxib trial ever stirs more debate [HeartWire > News; Aug 19, 2004 ]
4. Rofecoxib increases risk of edema, loss of hypertension control, but not celecoxib or NSAIDs [HeartWire > Hypertension; Jun 24, 2004 ]
5. Rofecoxib, NSAIDs linked to higher CHF hospitalization rates [HeartWire > Heart failure; May 27, 2004 ]
6. Rofecoxib increases MI risk, latest study published [HeartWire > News; Apr 21, 2004 ]
7. Rofecoxib increases CV events in arthritis patients with high BP [HeartWire > Hypertension; Mar 18, 2004 ]
8. Pharmacologist wins legal battle with Merck over rofecoxib article [HeartWire > News; Feb 4, 2004 ]
9. More cardiovascular data on etoricoxib [HeartWire > News; Dec 17, 2003 ]
10. COX-2 inhibitors: No thrombotic effect but worsening of CHF? [HeartWire > News; Dec 16, 2003 ]
11. Another analysis shows increased risk of AMI with rofecoxib [HeartWire > News; Oct 29, 2003 ]
12. Experts clash again over safety of COX-2 inhibitors [HeartWire > News; Oct 16, 2003 ]
13. Concern over CV effects of COX-2 inhibitors, revisited [HeartWire > News; Nov 26, 2002 ]
14. Another study singles out rofecoxib for cardiovascular side effects [HeartWire > News; Oct 4, 2002 ]
Rofecoxib withdrawn worldwide by Merck
Whitehouse Station, NJ - Merck has withdrawn its selective COX-2 inhibitor rofecoxib (Vioxx®) from all markets worldwide, following the availability of new three-year data from the Adenomatous Polyp Prevention on VIOXX (APPROVE) trial showing an increased risk of cardiovascular events with the drug.
Rofecoxib was launched in 1999 for the treatment of arthritis and had worldwide sales last year of $2.5 billion. Merck's share price plunged on the announcement.
Multiple other studies have also suggested an increased cardiovascular risk with rofecoxib, but until now Merck has denied there was any safety issue with the drug, and the APPROVE study was conducted in part to ascertain more information on this.
The APPROVE trial, which is being stopped, was testing rofecoxib 25 mg vs placebo in the prevention of the recurrence of colorectal polyps in 2600 patients with a history of colorectal adenoma. The study showed an increased relative risk for MI and stroke with rofecoxib, which became evident after 18 months of treatment.
Raymond V Gilmartin, chair, president, and chief executive officer of Merck, said: "We are taking this action because we believe it best serves the interests of patients. Although we believe it would have been possible to continue to market Vioxx with labeling that would incorporate these new data, given the availability of alternative therapies and the questions raised by the data, we concluded that a voluntary withdrawal is the responsible course to take."
The APPROVE trial was started in 2000, following the results of the VIOXX Gastrointestinal Outcomes Research (VIGOR) study, which indicated an increased risk of cardiovascular events with rofecoxib vs naproxen. Merck argued that naproxen was exerting a protective cardiovascular effect and rofecoxib did not have a cardiac safety issue, which it claimed was supported by phase 3 studies in which no increased risk of cardiovascular events with rofecoxib were seen vs placebo or other non-naproxen NSAIDs.
Peter Kim (president of Merck Research Laboratories) said: "Merck has always believed that prospective, randomized, controlled clinical trials are the best way to evaluate the safety of medicines. APPROVE is precisely this type of studyand it has provided us with new data on the cardiovascular profile of Vioxx. While the cause of these results is uncertain at this time, they suggest an increased risk of confirmed cardiovascular events beginning after 18 months of continuous therapy."
What about the other coxibs?
While the other selective COX-2 inhibitors, such as celecoxib (Celebrex®, Pfizer) will now come under close scrutiny, they are not believed to have such a negative cardiovascular profile as rofecoxib. Merck has a second selective COX-2 inhibitor, etoricoxib (Arcoxia®), which is available in 47 countries, and the company says that the cardiovascular safety issue with rofecoxib is not necessarily applicable to others in the class but will work with regulatory authorities to assess whether changes to the prescribing information for etoricoxib is warranted. Etoricoxib is not yet available in the US, but Merck said it will continue to seek approval and will continue its clinical-trial program with this drug.
Reaction mixed from cardiologists
One cardiologist who has long maintained that rofecoxib had an unacceptable cardiovascular safety profile is Dr Eric Topol (Cleveland Clinic, OH). He commented to heartwire that "Merck has finally got it right," although it was "too bad it took so long for them to accept the truth." He added: "Ironically, the validation of our concern came from a colon polyp trial in patients without any known heart disease." He said the other COX-2 inhibitors seemed safer, but "it was hard to know."
Another high-profile cardiologist is not so forthright on this issue. Dr Robert Califf (Duke Clinical Research Institute, Durham, NC) commented to heartwire that rofecoxib caused a small but measurable increase in risk of cardiovascular events, but that other ongoing placebo controlled trials do not show the same effect. "From what we can piece together from the poor studies that are available, it looks like naproxen may be the only one that reduces riskwe just don't know about celecoxib, etc. Any chronically given drug that affects inflammation will have cardiovascular effects. Not doing long-term trials to inform the public about the balance of risks and benefits is like playing Russian rouletteyou just don't know which chambers have bullets unless you look."
He added that: "It's a shame the drug has to pulled from the market. It would be best to inform doctors and patients of the risk and let them make a choice, but because of the dominance of lawsuits in therapeutics, obviously Merck can't afford to do that."
Related links
1. ACR issues alert on cardiovascular complications of COX-2 inhibitors [HeartWire > News; Sep 28, 2004 ]
2. FDA-funded study shows rofecoxib doses >25 mg/day triple risk of acute MI and sudden cardiac death [HeartWire > News; Aug 26, 2004 ]
3. Largest coxib trial ever stirs more debate [HeartWire > News; Aug 19, 2004 ]
4. Rofecoxib increases risk of edema, loss of hypertension control, but not celecoxib or NSAIDs [HeartWire > Hypertension; Jun 24, 2004 ]
5. Rofecoxib, NSAIDs linked to higher CHF hospitalization rates [HeartWire > Heart failure; May 27, 2004 ]
6. Rofecoxib increases MI risk, latest study published [HeartWire > News; Apr 21, 2004 ]
7. Rofecoxib increases CV events in arthritis patients with high BP [HeartWire > Hypertension; Mar 18, 2004 ]
8. Pharmacologist wins legal battle with Merck over rofecoxib article [HeartWire > News; Feb 4, 2004 ]
9. More cardiovascular data on etoricoxib [HeartWire > News; Dec 17, 2003 ]
10. COX-2 inhibitors: No thrombotic effect but worsening of CHF? [HeartWire > News; Dec 16, 2003 ]
11. Another analysis shows increased risk of AMI with rofecoxib [HeartWire > News; Oct 29, 2003 ]
12. Experts clash again over safety of COX-2 inhibitors [HeartWire > News; Oct 16, 2003 ]
13. Concern over CV effects of COX-2 inhibitors, revisited [HeartWire > News; Nov 26, 2002 ]
14. Another study singles out rofecoxib for cardiovascular side effects [HeartWire > News; Oct 4, 2002 ]
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