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, .

Dexamethasone as a Bystander in Thrombocytopenia (2/5/2007)
One of the many investigator groups focused on the challenges of understanding drug safety is the group working under Dr. James N. George at the University of Oklahoma Health Sciences Center. Dr. George's group hosts a website devoted platelet-related diseases¹⁰, including a review database of all English language reports which reference a single adverse event: Drug-Induced Thrombocytopenia. This week, they announced an update to their review database, with a brief correspondence in the journal Drug Safety¹¹.

This article prompted us to examine the "Event-focused PVmap™" for the adverse event thrombocytopenia. In an Event-focused PVmap, we use the flexibility of PVmaps to reverse the usual paradigm and ask "what drugs are most strongly associated with a particular adverse event". We used the publicly-available data from the FDA via its Adverse Event Reporting System (AERS), using data covering the period from 2001 through the first quarter of 2006.

A comparison of our Event-focused PVmap results to the review database revealed that most of the drugs on the PVmap were either noted in the database, or were in one of their excluded categories (e.g. cytotoxic chemotherapy drugs due to their mechanism of action). However, we noted an extremely strong signal for one drug that was not in their database, dexamethasone: 309 individual safety reports, with a reporting ratio of 3.67, and a Statistical Unexpectedness of 80.99.

To further investigate this signal, we created a "Potential Interactions PVmap" for dexamethasone and thrombocytopenia. A Potential Interactions PVmap answers the question: "For a given drug/adverse event combination, what other drugs are reported as being taken at the time of that adverse event". It can be used to suggest potential drug interactions as well as bystander effects. A 'bystander effect' is a case where a drug does not necessarily have a causal relationship to a particular adverse event, but is frequently co-prescribed along with other drugs that do.

The map above visually illustrates that patients who experience thrombocytopenia while on dexamethasone are often also on a number of concomitant cytotoxic cancer chemotherapy agents at the same time. Thrombocytopenia is a known and expected consequence of many of these cytotoxic agents. This map strongly suggests that the relationship between dexamethasone and thrombocytopenia is not a causal one, but rather is a bystander effect.

Dexamethasone is often prescribed as an anti-nausea agent to reduce the harmful effects of cancer chemotherapy. For this example, many experienced drug safety investigators would likely be able to make the determination of a likely bystander effect without generating a PVmap. However in other cases, the potential bystander effect is less well-known, and the Potential Interactions PVmap can be a useful aid in guiding the subsequent steps of the investigation for a particular drug-event combination. In addition, having the evidence to substantiate and validate decisions, even in obvious cases, may be helpful in the investigation process.

Event-focused PVmaps
The first map shown in the case study above is an Event-focused PVmap, allowing you to visualize which drugs are most highly associated with a particular adverse event (rather than the other way around). In this case, the adverse event is the MedDRA term thrombocytopenia, and the red dots represent drugs reported in the AERS database to be associated with thrombocytopenia. On the horizontal axis of this graph is the reporting ratio, which compares the number of times that a drug is reported with the specified adverse event to 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 drugs with the strongest association to thrombocytopenia appear at the top and to the right on the PVmap.

Potential Interaction PVmaps
The second Pvmap shown in the case study above is a Potential Interactions PVmap, allowing you to visualize which concomitant drugs are most highly associated with a particular drug-event combination. In this case, the drug is dexamethasone, the adverse event is the MedDRA term thrombocytopenia. The red dots represent other drugs reported in the AERS database to have been co-prescribed along with dexamethasone when thrombocytopenia was reported as an adverse event. On the horizontal axis of this graph is the reporting ratio, which compares the number of times that a co-prescribed drug is reported with the specified drug-event combination, compared to 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 drugs with the strongest association to dexamethasone and thrombocytopenia appear at the top and to the right on the PVmap.

To learn more about PVMaps projects in your therapeutic area or indication, please .

Disclaimers

1. ProSanos is not affiliated with Dr. George's group at the University of Oklahoma Health Sciences Center, 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

10. Platelets on the Internet. http://moon.ouhsc.edu/jgeorge. Accessed 31 January 2007.
11. Li X, Swisher KK, Vesely SK, George JN. Drug-Induced Thrombocytopenia: An Updated Systematic Review, 2006. Drug Safety 2007:30;185-186.