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. For more information about PVmaps or the PVmap of the Week program, .

Aprotinin and Renal Failure (12/24/2006)
This week's PVmap highlights the recent discussion of the relationship between aprotinin, marketed as Trasylol^®, and renal failure. Aprotinin is a drug used to prevent blood loss during surgery. This safety issue was discussed in detail in a 2006 article in the New England Journal of Medicine¹. Following the disclosure of additional relevant data to the FDA, a recent letter from the lead author of the 2006 study highlighted the safety question². In late December 2006, the label for the drug was changed to reflect concern regarding renal failure.

This PVmap visually investigates whether a statistically significant number of renal failure cases in aprotinin patients had been reported to the FDA via its Adverse Event Reporting System (AERS) using data covering the period from 2001 through the first quarter of 2006. This is a Trajectory PVmap, which traces the evolution of a potential drug safety signal in the AERS database over time. There were no events under the term renal failure reported prior to the second quarter 2004. The map shows that the number of cases reported reached statistical significance in the fourth quarter of 2004, and the signal continues to increase in significance with each subsequent quarter of AERS data release. As of the first quarter of 2006, 21 cases had been reported. This is assumed to be a conservative count based simply on the adverse-event term renal failure from the MedDRA adverse event dictionary; additional cases could be found under related terms such as renal failure acute and postoperative renal failure. This map suggests that a relationship exists between the use of aprotinin and reports of renal failure contained within the AERS database during the years 2001 - Q1 2006.

Trajectory PVmap
A Trajectory PVmap traces the evolution of a potential drug safety signal over time. The horizontal axis represents the reporting ratio, which 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. Thus significant drug safety signals show an upward trajectory over time, sometimes with some small statistical fluctuation. Generally, it is important to investigate signals when they reach a Statistical Unexpectedness level of 5 or more (corresponding to a p-value of 10^-5), which is represented by the yellow and red-shaded portion of the trajectory when you move your cursor over the PVmap.

Disclaimers

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. PVmaps has been evaluated as a safety signal investigation tool for over two years.

References

1. Mangano DT, Tudor JC, Dietzel C. The Risk Associated with Aprotinin in Cardiac Surgery. N Engl J Med 2006;354:353-365.
2. Mangano DT. Judging the Safety of Aprotinin. N Engl J Med 2006;355:2261.