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 or in the published literature. For more
information about PVmaps
or the PVmap of the Week program, .
Drug-Associated Thrombocytopenia (3/11/07)
The New England Journal of Medicine recently carried a research article25
and a commentary26 on the subject of drug-induced, immune-mediated
thrombocytopenia. The articles focus on vancomycin, but they discuss the fact
that severe, immune-mediated thrombocytopenia can be induced by many different
drugs.
Oftentimes, a drug-safety investigation begins with a particular drug and
involves asking the question, "What adverse events are associated with this
drug?". We presented this type of investigation for dexamethasone and
thrombocytopenia in our February 4, 2007 PVmap of the
Week. However, as in the case of severe thrombocytopenia, there are some
events that are known to be drug-related. For these "suspect" events,
an important question to ask is, "What drug, if any, could be causing this
suspect adverse event?" PVmaps flexibility supports this paradigm shift
through Event-focused PVmaps, which quickly identify the drugs most highly
associated with a user-specified adverse event. In this week's case study, we
present an Event-focused PVmap investigation of Thrombocytopenia.
The Event-focused PVmap above was generated using the MedDRA term
thrombocytopenia, using publicly-available data from the FDA via its
Adverse Event Reporting System (AERS) covering the period from 2001 through the
first quarter of 2006. The visual display above lists the top 12 drugs out of
a total of 406 drugs above the statistical significance limit for an association
with thrombocytopenia (the number of drugs labels to display on the PVmap is
user specified, and the statistical significance limit is shown as the blue
dotted horizontal line at a Statistical Unexpectedness of 5.3.) This list
includes causative agents with a variety of mechanisms, as well as statistical
"bystanders", which appear because they are commonly prescribed
alongside causative agents.
Not surprisingly, Heparin tops the list due to its well-documented ability to
induce immune-mediated thrombocytopenia. The glycoprotein IIb/IIIa antagonist
abciximab (marketed as ReoPro®) also figures prominently, as
discussed in the article in NEJM. Some of the other drugs high on the list,
such as cisplatin, act on platelets through non-immune-mediated mechanisms and
are either generally cytotoxic or are bystanders of cytotoxic agents.
Vancomycin, the main topic of the NEJM article, is #22 on the list. Established
causative agents appear further down the list as well; eptifibatide, also
mentioned in the article, is #325.
To more fully investigate the entire list of statistically significant drugs
associated with thrombocytopenia we can also choose the Results Detail View of
the Event-focused PVmap which allows the drugs that appear on a Drug-focused
PVmap to be examined one-by-one in table form. Results on this view can be
filtered to easily locate specific drugs of interest. Below we show an example
of filtering on "eptifib" to locate eptifibatide on the list. This
capability makes it easy to check a list of drugs for a particular case report
to see if any of them are statistically associated with the adverse event being
investigated.
Event-focused PVmaps
The PVmap 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.
Sponsor companies have used ProSanos PVMaps for multiple therapeutic areas.
To learn more about PVMaps projects in your therapeutic area or indication,
please .
Disclaimers
- ProSanos is not affiliated with the authors of cited
references, and this article does not imply endorsement of their findings,
content, or offerings.
- 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.
- 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.
- 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.
- 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.
- 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.
- PVmaps has been evaluated as a safety signal investigation tool for over two years.
References
- Von Drygalski A, Curtis BR, Bougie DW, et
al. Vancomycin-Induced Immune Thrombocytopenia. N Engl J Med 2007 ; 356 : 904-910.
- Warkentin TE. Drug-Induced Immune-Mediated Thrombocytopenia-from Purpura to
Thrombosis. N Engl J Med 2007; 356:891-893.
