PVmap™ of the Week

ProSanos has initiated a program to publicly provide a limited set of PVmaps™ generated from the FDA's Adverse Event database. A different map will be posted each week focusing on a drug and adverse event combination that is a current topic of discussion within the industry or in the published literature. For more information about PVmaps or the PVmap of the Week program, .

Cardiac Valve Regurgitation Compared: Pergolide vs. Pramipexole (3/18/07)
The March 2007 issue of Archives of Neurology²⁷ describes a small case-control study, comparing the frequency and severity of cardiac valve regurgitation between groups of patients with Parkinson's disease who were treated with the ergot-derived dopamine agonist, pergolide, or a non-ergot-derived dopamine agonist, either pramipexole or ropinirole. The study concluded that the risk of cardiac valve regurgitation was lower for the non-ergot-derived agents. The authors refer to their study as "strengthen[ing] the conclusion that pergolide contributes to cardiac valve regurgitation." This week's PVmap of the Week further investigates this conclusion, using PVmaps to compare the similarities and differences between the adverse event profiles of the agents in the study.

Previous PVmap of the Week case studies have discussed the strong caveats (also repeated below) associated with using data mining tools such as PVmaps for comparative analysis of drug safety. However, the similar characteristics of these drugs may provide an opportunity to further corroborate (or refute) the hypothesis above. The drugs being compared are used in similar patient populations, and generally for the same indication, Parkinson's Disease. While there has been some publicity regarding cardiac regurgitation and pergolide, it only appeared in 2006, and the Trajectory PVmap (not shown) for a sentinel event, aortic valve regurgitation, does not show a surge in stimulated reports for this quarter (as in this example).

The Comparative Drug-focused PVmap above provides a visual illustration of the similarities and differences between the side effect profiles of these drugs as reflected in the reporting of adverse events in the FDA AERS database through the first quarter of 2006. Adverse events reported for pergolide are shown with red circles, and those for pramipexole are shown with green triangles. Arrows are drawn from the pergolide adverse event to the corresponding adverse event for pramipexole, thus arrows pointing down and to the left indicate adverse event signals that are stronger for pergolide. In general, dots on the map that are higher and farther to the right indicate stronger safety signals. This map therefore supports the conclusion of the Archives of Neurology paper, that cardiac valve regurgitation is more strongly associated with pergolide.

A previous PVmap of the Week from January investigated pergolide and cardiac valve regurgitation. This week's case study provides further information regarding the same signal to help put it into context. The PVmaps technology was designed to provide many different views of the data, and to help the user to synthesize those views into a comprehensive picture of a drug-safety issue. Comparative maps provide one of those views.

As mentioned in the beginning of the case study, opinions vary on whether valid drug comparisons can be made using data mining techniques. Our position at ProSanos is that data-mining-based drug-vs.-drug comparisons can be useful for hypothesis generation or corroboration, provided it is performed thoughtfully and certain conditions are met. Based on our experience, below are some of the conditions that we consider before creating a Comparative PVmap (we may also consider additional potential confounders on a case by case basis):

• The drugs being compared are used in similar patient populations.
• The drugs are generally used for the same indication or spectrum of indications.
• The drugs are generally used with the same spectrum of concomitant medications.
• There are no systematic coding differences for adverse events for one drug vs. the other. (This condition generally holds but may be an issue if there is a large amount of study data or literature data in AERS for a given drug.)
• There is no known cause of stimulated reporting (publicity, litigation) that applies to one of the drugs and not the other.
• There is no great disparity in the time that the two drugs have been on the market, which could lead to unequal reporting via the "Weber effect" (a phenomenon of enhanced safety reporting early in the market life of a drug.)

About Comparative Drug-focused PVmaps.
Above is a Comparative Drug-focused PVmap allowing you to compare two drugs in order to visualize which adverse events are most highly associated with each. In this case the drugs are pergolide and pramipexole. The red circles represent adverse events reported in the AERS database to be associated with pergolide, while the green triangles represent adverse events reported to be associated with pramipexole. On the horizontal axis of this graph is the reporting ratio that compares the number of cases of a particular adverse event with the number expected due to chance alone. The vertical axis expresses the statistical significance of the finding. Dots above the horizontal blue line and to the right of the vertical blue line represent "significant signals". The adverse events with the strongest association to a drug appear at the top and to the right on the PVmap. Arrows indicate the difference in the reporting ratio and statistical unexpectedness between the two drugs for a given designated adverse event. In this case, an arrow pointing to the right indicates a higher reporting ratio for pramipexole and an arrow pointing to the left indicates a higher reporting ratio for pergolide.

Sponsor companies have used ProSanos PVMaps for multiple therapeutic areas. To learn more about PVMaps projects in your therapeutic area or indication, please .

Disclaimers

1. ProSanos is not affiliated with the authors of cited references, and this article does not imply endorsement of their findings, content, or offerings.
2. Potential risks highlighted by drug safety analysis must be balanced against the clinical benefit attained by the use of a pharmaceutical product in a given clinical situation. Nothing in these analyses is intended to influence the practice of medicine, nor to weigh the benefits of one product over another.
3. Whether the reporting ratio of an adverse event is high enough to influence the decision to use a given product or products can only be determined by a complete analysis of the benefits, risks, and therapeutic alternatives.
4. Use of the publicly available FDA AERS data does not imply endorsement or agreement of the findings by the FDA Center for Drug Evaluation and Research.
5. There are many factors that can influence how the adverse events are reported in the AERS database and may impact the resulting safety signal. These include but are not limited to: publicity and media attention, litigation, length of time drug is on the market, whether the event in question has been previously attributed to the drug, the source of the report, etc.
6. AERS data must often be "cleaned" prior to analysis. This process may include de-duplication, reconciliation of misspelled product names, mapping of adverse events terms, and other manipulations which could introduce bias into the analysis.
7. PVmaps has been evaluated as a safety signal investigation tool for over two years.

References

27. Dewey RB, Reimold SC, and O'Suilleabhain PE. Cardiac Valve Regurgitation with Pergolide Compared with Nonergot Agonists in Parkinson Disease. Arch Neurol 2007;64:377-380.