FDA Drug Safety Communication: Ongoing Safety Review of Stalevo and possible increased cardiovascular risk
Safety Announcement
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary
Safety Announcement
[08-20-2010] The U.S. Food and Drug Administration (FDA) is evaluating clinical trial data that suggest patients taking Stalevo (a combination of carbidopa/levodopa and entacapone) may be at an increased risk for cardiovascular events (heart attack, stroke, and cardiovascular death) compared to those taking carbidopa/levodopa (sold as the combination product, Sinemet).
Both Stalevo and Sinemet have been shown to be effective treatments for the symptoms of Parkinson's disease. The addition of entacapone to carbidopa/levodopa has been shown to lead to a greater degree of improvement in some of the symptoms of Parkinson's disease than treatment with carbidopa/levodopa alone.
Entacapone is also available as a single-ingredient product (sold under the brand name Comtan) to be always administered in association with carbidopa/levodopa (entacapone has no antiparkinsonian effect of its own).
It is estimated that 154,000 patients were dispensed a prescription for Stalevo from its approval in June 2003 through October 2009.
At this time, FDA's review of the potential cardiovascular risk with Stalevo is ongoing.
Healthcare professionals should regularly evaluate the cardiovascular status of patients who are taking Stalevo, especially if they have a history of cardiovascular disease.
Patients should not stop taking Stalevo unless told to do so by their healthcare professional.
FDA is exploring additional ways to assess whether Stalevo increases the risk of cardiovascular events, and will update the public when this review is complete.
The data being evaluated are from a meta-analysis that combined the cardiovascular-related findings from 15 clinical trials comparing Stalevo to carbidopa/levodopa; that is, examining the effect of adding entacapone to carbidopa/levodopa. In the meta-analysis, a small increased risk of cardiovascular events in the Stalevo group was found. However, several factors make evaluation of these findings difficult. First, the clinical trials in the meta-analysis were not specifically designed to evaluate cardiovascular safety. In addition, the majority of patients had preexisting risk factors for cardiovascular disease, so that even small differences in the level of these risks could affect the outcome markedly. Moreover, many of the events occurred in a single trial. It should also be noted that cardiovascular events are not uncommon in people with Parkinson's disease in the age range studied in these trials.
Additional Information for Patients
FDA has not concluded that Stalevo increases your risk of heart attack, strokes, or cardiovascular death. The Agency is still reviewing the available information about this safety concern.
Do not stop taking your Stalevo or Comtan unless told to do so by your healthcare professional.
Make sure your healthcare professional knows if you have a history of cardiovascular disease.
Talk to your healthcare professional if you have concerns about Stalevo or Comtan.
Additional Information for Healthcare Professionals
In a meta-analysis that included 15 clinical trials comparing entacapone/carbidopa/levodopa to carbidopa/levodopa alone, a small increase in the risk of heart attack, stroke, or cardiovascular death was found in the group treated with entacapone/carbidopa/levodopa.
FDA is still reviewing the available information and has not concluded that Stalevo increases a patient's risk for cardiovascular events.
Follow the recommendations in the drug label when prescribing Stalevo or Comtan.
Regular evaluation of the cardiovascular status of patients who are taking Stalevo is recommended.
Data Summary
FDA's decision to conduct a meta-analysis was based on findings from the Stalevo Reduction In Dyskinesia Evaluation - Parkinson's Disease or STRIDE-PD trial, which reported an imbalance in the number of myocardial infarctions in patients treated with Stalevo compared to those receiving only carbidopa/levodopa. Although myocardial infarction, cardiac irregularities, hypertension, and palpitations have been reported with levodopa, previous clinical trials with Stalevo did not show an imbalance in myocardial infarction, stroke, and cardiovascular death. The majority of these trials, however, were of 6 months duration or less and had relatively few events.
In STRIDE-PD, 373 patients received Stalevo and 372 received carbidopa/levodopa. Treatment lasted between 2.6 years and 4 years (mean duration: 2.7 years). The average age of patients in the trial was approximately 60 years. Seven myocardial infarctions and one cardiovascular death were reported in the Stalevo group and no myocardial infarctions or cardiovascular deaths were reported in the carbidopa/levodopa group.
Based on the findings from the STRIDE-PD trial, FDA conducted a meta-analysis that combined the cardiovascular findings from 15 clinical trials in approximately 4,800 patients comparing entacapone/carbidopa/levodopa to carbidopa/levodopa without entacapone. A composite endpoint of myocardial infarction, stroke, and cardiovascular death was used to represent cardiovascular events. Twenty-seven cardiovascular events were reported in the entacapone/carbidopa/levodopa group compared to 10 in the carbidopa/levodopa group. This resulted in a relative risk of 2.46 (95% Confidence Interval: 1.19, 5.09). When the STRIDE-PD trial was removed from the analysis, the relative risk was 1.67 (95% Confidence Interval: 0.77, 3.61), i.e., a finding that was no longer statistically significant.
Although there was a statistically significant increased risk of cardiovascular events in the entacapone/carbidopa/levodopa group compared to carbidopa/levodopa group when STRIDE-PD is included, the following factors make it difficult to draw sound conclusions based on this finding:
Trials included in the meta-analysis were not specifically designed to evaluate Stalevo's cardiovascular safety.
Most patients had preexisting risk factors for cardiovascular disease.
Eleven of the trials had a duration of fewer than six months, possibly not long enough to evaluate cardiovascular risk (7 of the 8 events in the STRIDE-PD trial occurred after 6 months of Stalevo treatment).
The safety signal is largely driven by one trial, STRIDE-PD, with a relative risk of 2.46 (95% Confidence Interval: 1.19, 5.09) when STRIDE-PD is included and a relative risk of 1.67 (95% Confidence Interval: 0.77, 3.61) when STRIDE-PD is not included.
Adverse event narratives were poor and cardiovascular event validation was difficult in many cases.
An assumption of the meta-analysis was that covariates were balanced through randomization in the 15 trials.
No data was available on treatment discontinuation or trial discontinuation. It is assumed that any discontinuation was independent from the risk of adverse events in both treatment groups.
There was no access to detailed data at the level of individual patients to allow for an exploration of the potential effect of covariates on the finding and a better assessment of the causal relationship between Stalevo and cardiovascular events.
FDA is exploring additional ways to assess whether Stalevo increases the risk of cardiovascular events, and will update the public when this review is complete.