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, .

Warfarin Interactions as Reflected in AERS (7/30/2007)
An interesting recent article in Archives of Internal Medicine reminds us of the need for vigilance regarding the safety profiles of older drugs as well as newer ones. This article describes the studies and analysis behind the decision to add a black box warning to the labeling for warfarin regarding bleeding complications.⁵⁴

The anticoagulant warfarin was first approved for use in humans in 1954 and has been widely used to prevent and treat venous thrombosis and thromboembolic complications of atrial fibrillation or valve replacement, as well as to reduce the risk of death from recurrent myocardial infarction. Its bleeding complications have been well known since its first use, and are discussed in the labeling for the drug. The paper describes the steps taken by FDA to ascertain that a stronger form of warning was required to ensure that patients on this drug are adequately monitored to avoid bleeding complications.

In this Map of the Week, we decided to focus on another well-established property of warfarin, namely, its tendency to interact with a wide range of other drugs. The paper does not discuss this issue, except to note that "Drug Interaction NOS" is the third most-frequent adverse event reported for warfarin, with 2179 case reports sent to FDA from 1993 to 2006.

The label for warfarin (marketed as COUMADIN^®) lists 136 individual drugs, in addition to long lists of drug classes and botanicals, which can interact with warfarin. Some of these interactions are commonly observed, while others are rare or hypothetical. Using PVmaps, we can determine which drug interactions with warfarin currently occur with the greatest statistical significance in the AERS database.

In order to do this, we create a Potential Interactions PVmap for warfarin (including trade names) using data from the FDA Adverse Event Reporting System (AERS) for 2003 to 2006. To detect bleeding events, we use the Standardized MedDRA^® Query (SMQ) designated "Haemorrhage terms (excl laboratory terms)", to study actual events rather than laboratory abnormalities.

Based on this data, the top ten drugs associated with warfarin and bleeding events are:

1. digoxin
2. furosemide
3. aspirin
4. amiodarone
5. simvastatin
6. omeprazole
7. diltiazem
8. hydrochlorothiazide
9. isosorbide
10. heparin

In order to interpret this data, we need to produce a Co-Prescribed Drugs PVmap:

We note that digoxin and furosemide are very commonly co-prescribed with warfarin for underlying cardiovascular disease, and this is the most likely explanation for their appearance on the "top ten" list, while they do not appear on the label for warfarin. This raises the likelihood of a "bystander effect" rather than a drug interaction. Likewise, diltiazem most likely appears because of its role in treating atrial fibrillation rather than as a truly interacting drug, though this cannot be determined definitively from a data-mining study alone. Hydrochlorothiazide is an interesting case: the label for warfarin refers to "diuretics" as a class, in the context of both increases and decreases in prothrombin time and INR, but it does not list this particular drug. Medline yields no specific references to a hydrochlorothiazide-warfarin interaction. The remaining drugs on the "top ten" list-aspirin, amiodarone, simvastatin, omeprazole, isosorbide, and heparin-all appear on the label as potentially interacting with warfarin. The presence of aspirin on the list is a good reminder of the need to consider tracking the use of this nonprescription drug in connection with warfarin.

Here we have shown an application of PVmaps to identify which of the potential drug interactions of warfarin occur with the greatest statistical significance in actual practice. This approach could obviously be extended past the top ten. Information of this kind can be very useful in planning the data collection for safety studies or in the design of case-control studies, and can also be used in the development of risk management plans, and for the generation of manual or automated checking rules in pharmacy systems, to help prevent harmful drug interactions.

Potential Interactions PVmaps
Above is a Potential Interactions PVmap that allows you to visualize what concomitant drugs are significantly associated with a specified drug/adverse event combination. In this case, the drug/adverse event combination is the drug warfarin reported with hemorrhage-related MedDRA terms. The red dots on the map represent concomitant drugs in use when the drug / adverse event combination warfarin / hemorrhage occurred. On the horizontal axis of this graph is the reporting ratio, which compares the use of the concomitant drug during warfarin / hemorrhage 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.

Co-Prescribed Drug PVmaps
The second map is a Co-Prescribed Drug PVmap that allows you to visualize what concomitant drugs are most frequently co-prescribed with a particular drug. In this case, the drug is warfarin. The red dots on the map represent concomitant drugs. On the horizontal axis of this graph is the reporting ratio, which compares the use of the concomitant drug in combination with warfarin vs. 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 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. 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

54. Wysowski DK, Nourjah P, Swartz L. Bleeding Complications With Warfarin Use: A Prevalent Adverse Effect Resulting in Regulatory Action. Arch Intern Med 2007;167:1414-1419.