Drug for Parkinson’s Disease and Restless Leg Syndrome May Increase Heart Failure Risk

On Sept. 19, 2012, the Food and Drug Administration (FDA) issued a drug safety alert to neurologists and patients about a possible slightly increased risk of congestive heart failure with pramipexole (MIRAPEX), a drug approved for treatment of both Parkinson’s disease and restless leg syndrome.

The FDA alert was based on a pooled analysis of data from all randomized, controlled trials of pramipexole submitted to the agency by the drug’s manufacturer, Boehringer Ingelheim, and the results of two recent epidemiology studies assessing the risk of heart failure in patients taking Parkinson’s disease drugs. Although the FDA deemed the data inconclusive due to study limitations, patients taking this drug should be alert for symptoms of heart failure.

Overview of Parkinson’s disease and restless leg syndrome

Parkinson’s disease is a progressive degenerative disorder of the brain that primarily causes problems with motor (muscle) function. The disease typically strikes people older than age 50 — with an average age of 70 at the time of diagnosis — and is caused by destruction of the brain cells that make dopamine, a chemical involved in controlling movement.

Common symptoms of Parkinson’s disease include tremors (rhythmic shaking), slowness of movements, difficulty walking, rigid (stiff) muscles and impaired coordination. As the disease progresses to more severe stages, patients can develop loss of balance resulting in falls, dementia, hallucinations, depression, sleep disturbances and difficulty swallowing.

The currently available drugs for treating Parkinson’s disease only target symptoms and do not slow or reverse the underlying destruction of the dopamine-producing brain cells. These drugs can be divided into the following five categories: dopamine precursors, dopamine agonists, anticholinergic agents, monoamine oxidase inhibitors and catechol-O-methyl transferase inhibitors (see the table below).

Table: Drugs for Parkinson’s Disease Available in the U.S. by Category

* Limited Use
** Do Not Use Until 7 Years After Approval (May 2014)
*** Do Not Use

In contrast to Parkinson’s disease, which was first recognized nearly two centuries ago and has a well-established cause and underlying brain pathology, primary restless leg syndrome was first recognized relatively recently, has an unknown cause and is defined solely by subjective symptoms. The disorder has been heavily promoted by pharmaceutical industry-funded disease-awareness campaigns, which have portrayed the generally mild problem as a serious illness.

Restless leg syndrome is defined by four criteria: an urge to move the legs, onset or worsening of symptoms when at rest, relief by movement, and symptoms that can occur primarily at rest and can interfere with sleep or rest. Mild symptoms of restless leg syndrome have been reported in 5 to 15 percent of the U.S. population. While some people may experience severe, disabling symptoms, many who are labeled as “sick” may suffer more from the label than from the restlessness.

Oral iron supplements are recommended for most patients with restless leg syndrome because some patients, even those without iron deficiency, may see improvement in their symptoms. Other nonpharmacological interventions that may be helpful include:

• avoiding aggravating factors (such as caffeine, nicotine, alcohol and numerous drugs including antidepressants, antipsychotic drugs and sedating antihistamines);
• performing mild-to-moderate intensity leg exercises, particularly before bedtime; and
• engaging in brain-stimulating activities, such as video games or crossword puzzles.

Drug treatment for restless leg syndrome should be reserved for patients who have severe, incapacitating symptoms. The drugs approved by the FDA for this indication are the dopamine agonists pramipexole, ropinirole (REQUIP) and rotigotine transdermal system (NEUPRO), as well as extended-release gabapentin enacarbil (HORIZANT). Worst Pills, Best Pills News lists all of these as “limited use” drugs for the treatment of restless leg syndrome, except for rotigotine, which is listed as “do not use for seven years” (until May 2014).

The FDA’s review and approval of pramipexole

The FDA originally approved pramipexole on July 1, 1997, for treatment of the signs and symptoms of Parkinson’s disease. On Nov. 7, 2006, the agency approved the drug for treatment of moderate-to-severe primary restless leg syndrome.

The most serious risks of pramipexole identified during the FDA’s review of the clinical trials used to support these approvals included falling asleep during everyday activities, including driving, which sometimes resulted in accidents; experiencing symptomatic low blood pressure when standing (orthostatic hypotension), which can result in fainting or falls; and hallucinating. Heart failure was not identified as a risk of the drug at the time of the FDA approvals.

Other significant side effects of pramipexole identified during clinical trials of the drug included nausea, diarrhea, dry mouth, edema (swelling), fatigue and abnormal dreams.

Possible link between pramipexole and heart failure

In its Sept. 19, 2012, safety alert regarding a possible link between pramipexole and heart failure, the FDA referenced data from three sources. The first was a pooled analysis of data from all randomized, placebo-controlled phase trials of pramipexole. This pooled analysis was first submitted to the agency by the drug’s manufacturer in 2008 and later updated in 2010. The data showed that the occurrence of new-onset heart failure was more frequent in study subjects treated with pramipexole (12 of 4,157 subjects, or 0.29 percent) than study subjects treated with placebo (4 of 2,820 subjects, or 0.14 percent). Although the absolute increase in the risk of newly diagnosed heart failure was very small (increasing by roughly 2 cases per 1,000 subjects taking the drug compared to those on placebo), the relative increase in risk was 2.6-fold. However, the FDA noted that this difference was not statistically significant.

The second data source referenced by the FDA was an epidemiology cohort study published in Pharmacoepidemiology and Drug Safety in January 2012. The study researchers used a large computerized records database, known as the General Practice Research Database (GPRD), which includes medical records for more than 10 million patients from more than 500 general medical practices in the U.K.

The researchers identified all patients in the GPRD from ages 40 to 89 who used any Parkinson’s disease drug between January 1997 and June 2009. Patients were excluded from the study if they had previously been diagnosed with heart failure or were taking prescription drugs suggestive of heart failure at the time of initial registration in the GPRD. The study included 26,814 patients meeting these criteria.

During an average follow-up period of 3.4 years, 783 of these patients developed probable or possible heart failure. For each case, 10 control patients without heart failure, matched for various demographic and clinical factors, were randomly selected from the cohort. Patients using a particular Parkinson’s disease drug were then compared to patients not taking that drug, and the relative risk of developing heart failure was determined after adjusting for numerous potentially confounding factors.

The investigators found that the incidence of heart failure was 1.6 times greater in patients who were current users of any dopamine agonist compared to patients not taking these drugs. The increased risk was greatest for current users of pramipexole (1.9-fold increased risk) and pergolide, a drug no longer available in the U.S. (1.4-fold increased risk). These relative increases in risk were statistically significant. In discussing their results, the authors of the study noted that the mechanism by which dopamine agonists could increase the risk of heart failure is uncertain.

The final data source referenced by the FDA was another epidemiology cohort study published in Pharmacological Research in March 2012. For this study, researchers obtained data from four large, population-based health care databases in the U.K., Netherlands and Italy containing medical information from more than 6.6 million patients.

From this population, the researchers identified all new users of either dopamine agonists or levodopa (LODOSYN, PARCOPA, SINEMET, SINEMET CR) for Parkinson’s disease between January 1996 and December 2007. New users were defined as those patients who had not used these drugs for one year prior to enrollment in the study cohort. Patients were excluded from the study if they had previously been diagnosed with heart failure or diseases that could cause heart failure, such as rheumatic heart disease, valvular disease and congenital heart disease. Using these criteria, the researchers identified a cohort of 25,459 patients, 44 percent of whom were new users of dopamine agonists. Fifty-six percent were new users of levodopa.

After an average follow-up period of approximately three years, 527 cases of newly diagnosed definite or probable heart failure were identified. Of these, 518 heart failure patients were compared to 38,641 matched controls who did not have heart failure. (Nine of the cases were not used because of a lack of matched control patients.) Only patients using pramipexole were found to have a statistically significant increase in the risk of heart failure compared to those using levodopa (1.6-fold higher risk after adjusting for numerous potentially confounding factors). Further analysis revealed that this increased risk was seen only during the first three months of pramipexole use.

In discussing the findings of the two epidemiology studies, the FDA noted several factors that may have biased the results. For example, the GPRD study investigators did not validate each heart failure diagnosis by reviewing the patients’ primary medical charts. Also, in both studies, the heart failure patients had a higher prevalence of risk factors for cardiovascular disease than the control patients. Finally, because pramipexole can cause peripheral edema, which can be a sign of heart failure, there may have been a bias toward detecting heart failure in patients taking this drug in both studies.

What You Can Do

The data discussed above do not prove that pramipexole increases the risk of heart failure, and any increase, if real, appears to be small in absolute terms. However, you should be aware of signs and symptoms of heart failure if you are taking this drug for Parkinson’s disease, restless leg syndrome or any other disorder.

You should promptly contact your primary health care provider if you develop any of the following symptoms of heart failure while taking pramipexole:

• shortness of breath, either with exertion or at rest;
• nighttime waking with shortness of breath that is relieved by sitting up;
• edema of the feet, ankles, legs or abdomen;
• fatigue and weakness;
• rapid or irregular heart beat;
• chest pain; and
• persistent wheezing or coughing with production of white or pink-tinged sputum.

Because edema can be caused by pramipexole, development of this symptom alone does not mean you definitely have heart failure. Nevertheless, you should be evaluated by your physician if significant edema develops while taking this drug.

Because there are other dopamine agonists that can be used to treat both Parkinson’s disease and severe restless leg syndrome unresponsive to other measures, you should discuss switching to a different drug if you develop evidence of heart failure or significant edema.

Do not discontinue the use of any medication without first consulting your prescribing doctor.