The April 28, 2004, report quoted the lead researcher, Dr Richard Dewey Jr, an associate professor from the University of Texas Southwestern Medical Center, as saying he believed the drug should be taken off the market.
Permax (pergolide) belongs to a class of drugs known as dopamine agonists. Dopamine helps regulate movement and balance. People with Parkinson's suffer from a shortage of dopamine and Permax stimulates nerves in the brain that would normally be stimulated by dopamine. The drug has also been prescribed to treat restless leg syndrome.
Two years earlier, in December 2002, doctors at the Mayo Clinic reported heart valve disease in three patients who had been taking Permax for several years, similar to the damage found in patients who took the Fen-Phen diet drugs.
The 3 cases involved women aged 61, 72, and 74, with no history of heart disease, who had been taking Permax for between three and seven years to treat Parkinson's symptoms. They were all diagnosed with serious valve disease and two required replacement surgery.
As a follow-up to the earlier reports of valve damage in Permax patients, Dr Dewey, and his fellow researchers sent out 200 letters to people who were known to be taking Permax for Parkinson's to determine whether the reports were isolated cases or a common side effect of the drug, and to suggest that patients should switch to anther drug. Patients who wanted to continue taking Permax were urged to have an echocardiogram, to check for heart valve damage.
For the Dewey study, echocardiograms were performed on 46 patients, and then compared the test results from a similarly-aged healthy comparison group. The study found that 89% of the patients receiving Permax had evidence of leaky heart valves, called valvular insufficiency, and Permax patients were up to 18 times more likely to have significant leakage in at least one valve, than patients in the comparison group.
Blood is pumped through the heart in only one direction, according to the Texas Heart Institute. Heart valves play a key role in this one-way blood flow, opening and closing with each heartbeat. Pressure changes on either side of the valves cause them to open their flap-like "doors" at just the right time, then close tightly to prevent a backflow of blood. There are 4 valves in the heart:
- Tricuspid valve
- Pulmonary valve
- Mitral valve
- Aortic valve
- Shortness of breath and/or difficulty breathing
- Weakness or dizziness
- Chest pain or pressure
- Heart palpitations
- Swelling of ankles, feet, or abdomen
- Rapid weight gain
In one study titled, "Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation," researchers led by Dr Renzo Zanettini, in Milan, Italy obtained echocardiograms from 155 patients taking various Parkinson's drugs, and 90 healthy patients for a comparison group.
The study found moderate to severe valve problems in more than 23% of the patients receiving Permax compared to less than 6% of the patients in the comparison group.
The second study found that Permax users were five to seven times more likely to have leaky heart valves than patients taking other types of Parkinson's drugs, and patients taking the highest doses of Permax had a 37 times greater risk of valve damage. In this study, Dr Rene Schade and colleagues in Berlin and Montreal reviewed records from over 11,400 patients with Parkinson's disease in the UK.
"This is not a rare side effect," says Dr Bryan Roth, a pharmacology professor at the University of North Carolina, who wrote an editorial accompanying the reports in the NEJM. "That's an extraordinarily high incidence," he warns. "That makes this a serious problem."
Experts note that there are no medications that can be used to reverse valve damage and replacement surgery is the only solution.
Dr Roth published a paper several years ago warning that Permax appeared to trigger the same heart valve problems as the Fen-Phen combination of the drugs, Pondimin and Redux, which were pulled off the market in 1997, after they were linked to valve disease.
The findings of the new Permax studies could potentially represent a public health crisis. The drugs, available in generic form from a variety of producers, "have been around a long time, and a large number of people have potentially been exposed to them," said Dr Michael Okun, medical director of the National Parkinson Foundation, in the January 4, 2007 LA Times.
Permax came on the market in the US about 14 years ago, and an estimated half million people had already taken the drug by the time its maker, Eli Lilly, added valve damage to the side effects listed on the labeling in late 2003. The warning included the statement: "Some patients have required valve replacement, and deaths have been reported," but at the same time, Lilly claimed that the problem only occurred in five out of every 100,000 Permax users.
The drug is now marketed in the US by Valeant Pharmaceuticals.
Heart valve damage is an extremely serious medical condition that is both life-threatening and costly to treat. During valve replacement surgery, the breastbone is divided, the heart is stopped, and blood is sent through a heart-lung machine. Because the heart or aorta must be opened, it requires open heart surgery, according to the Texas Heart Institute.
The two kinds of valves used for replacement surgery are mechanical valves made from materials such as plastic or metal, and biological valves made from animal tissue or human tissue from a donated heart.
Mechanical valves are stronger and last longer but because blood tends to stick to them and create blood clots, patients need to take blood-thinning drugs for the rest of their lives. And because these medicines increase the risk of bleeding within the body, patients must always wear a medical alert bracelet so medical professionals will know they are taking a blood-thinning medication.
Patients with biological valves usually do not have to take blood-thinning drugs but because the valves are not as strong as mechanical valves patients may need have the valve replaced every 10 years.
Following surgery, a patient can expect to stay in the hospital for about a week, including at least 1 to 3 days in the Intensive Care Unit, the Texas Institute says. Patients with an office job, can usually go back to work in 4 to 6 weeks but those with more physically demanding jobs may need to be off work longer.
In addition to switching to another drug to treat Parkinson's disease, medical experts are advising all Permax patients to undergo testing to check for heart valve damage.