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, .

Proton Pump Inhibitors & Falls (1/14/2007)
This week's map began as an investigation of a news story, and presents somewhat of a medical mystery. A recent article⁴ discussed the potential relationship between osteoporosis and the use of proton-pump inhibitors (PPI). PPI's reduce the production of gastric acid and are commonly used for treating ulcers and gastro-esophageal reflux disease. We generated Drug-focused PVmaps for three common proton-pump inhibitors, omeprazole (marketed as Prilosec^®), pantoprazole (marketed as Protonix^®), and rabeprazole (marketed as AcipHex^®), to investigate this relationship. While no fracture-related term was statistically significant, we noted an extremely strong statistical relationship between adverse events coded as fall, and all three of the proton-pump inhibitors studied.

The PVmap displayed above visually investigates the emergence of the unexpected safety signal fall in omeprazole patients which have 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. The signal crosses the threshold of statistical significance in the 2nd quarter of 2002. This is a Trajectory PVmap, which traces the evolution of a potential drug safety signal over time. The trajectory map here reflects 679 cases for omeprazole reporting fall. Maps for pantoprazole and rabeprazole contain smaller case numbers, but also show a statistically significant relationship to falls.

In a PubMed search, we found no literature discussing falls with any of the three drugs studied, so stimulated reporting (due to publicity or litigation) is unlikely. What is happening here? There are a number of possibilities including:

• The signal might be an artifact of heavy use of PPI in the elderly, who are subject to falls for other reasons. However, in this case we would expect to see signals for other events which are common in the elderly, which wasn't the case (the Drug-focused PVmap results are not shown here).
• This could be a manifestation of the relationship reported by Yang between osteoporosis and proton-pump inhibitor use. Possible scenarios include:
  1. Falls that become medically significant due to fracture, and are reported via the MedWatch system under a variety of fracture-related MedDRA codes. The individual fracture types do not become statistically significant, but falls does.
  2. Falls could be due to spontaneous hip fracture. The role of spontaneous hip fracture in falls has been discussed in the literature.⁵
• Dizziness and vertigo are reported side effects of omeprazole. These could be leading to falls. The hip fracture findings of Yang et al. may be multi-factorial, with a dizziness-related contribution and an osteoporosis-related contribution.

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

4. Yang, Y.-X. Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture. The Journal of the American Medical Association 2006;296:2947-2953.
5. Parker MJ, Twemlow TR. Spontaneous hip fractures, 44/872 in a prospective study. Acta Orthop Scand. 1997;68:325-326