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. On a regular basis, we will post a map 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, .

Angiotensin II Antagonists, ACE inhibitors, and Hyperkalemia (10/15/2007)
An article in the latest Archives of Internal Medicine⁵⁶ raises safety concerns with regard to the growing interest in combining angiotensin II receptor blockers (ARB) with angiotensin-converting enzyme (ACE) inhibitors for symptomatic left ventricular dysfunction. While the effectiveness of this regimen has been demonstrated, the authors conclude that the regimen increases the rate of adverse drug effects compared to the use of drugs of either class alone. Adverse events of particular concern included hyperkalemia, worsening renal function, and symptomatic hypotension. Their study was based on a meta-analysis of randomized clinical trial data in which an ARB / ACE inhibitor combination was compared to a single drug.

We investigated whether the adverse events associated with these drug combinations led to a signal of disproportionate reporting in the FDA Adverse Event Reporting System (AERS) database, using PVmaps as the tool for this investigation. We focused on hyperkalemia (MedDRA Preferred Term hyperkalaemia; to focus on the symptomatic clinical condition as much as possible, the Investigations term blood potassium increased was not used). We took advantage of the WHO Anatomic Therapeutic Chemical classification system to study the chemical class "angiotensin II antagonists, Plain". We produced a Potential Interactions PVmap for the combination of angiotensin II antagonists and hyperkalemia, in order to see whether ACE inhibitors were disproportionately associated with this drug-event combination:

While a number of other ATC Chemical groups appear, "ace inhibitors, plain" appears as the ninth-ranked Chemical group, with a total of 185 cases of hyperkalemia in the AERS database in combination with angiotensin II antagonists. Summary information for these cases appears below:

One would expect some bias in this data compared to prospectively-measured hyperkalemia in a controlled study where potassium is routinely monitored: only symptomatic cases—serious enough to motivate someone to report them to the FDA—will appear in the AERS database. We note that more than half of the reported cases were age 65 or older. For half of the cases, the outcome was categorized as "requiring hospitalization". Forty-eight cases record an outcome of "life-threatening", and 22 record "death". Only a minority of the reports (36) list "Study" as their source, so most of this data is presumably independent of that studied by the authors of the Archives of Internal Medicine paper.

An investigation of the AERS database in this manner cannot generate the kind of conclusive, quantitative data that can be obtained from a randomized trial. However, it can serve to show that the concerns of Drs. Phillips et al are reflected in real-world postmarketing data as well as in the clinical-research environment. With the ability to apply PVMaps to flexibly defined drug groups as well as individual drugs, the relationship between antiotensin II antagonists, ACE inhibitors, and hyperkalemia in the AERS data was easily illustrated.

Potential Interactions PVmaps
Above is a Potential Interactions PVmap, allowing you to visualize what concomitant drugs are significantly associated with a specified drug/adverse event combination. In this case, the drug/adverse event combination involves angiotensin II antagonists reported with hyperkalaemia. The red dots on the first map represent concomitant drugs in use when the drug / adverse event combination occurred. On the horizontal axis of this graph is the reporting ratio, which compares the use of the concomitant drug with an angiotensin II antagonist in a case of hyperkalemia, with the use of the concomitant drug 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 concomitant drugs that are most highly associated with the drug/event combination of interest appear at the top and to the right of the PVmap.

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. 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

56. Phillips CO, Kashani A, Ko DK, et al. Adverse Effects of Combination Angiotensin II Receptor Blockers Plus Angiotensin-Converting Enzyme Inhibitors for Left Ventricular Dysfunction. Arch Intern Med 2007;167(18):1930-1936.