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, .
Tegaserod and Cholecystectomy (8/20/07)
A recent report in Drug Safety, by authors at the FDA and the Center for
Health Care Policy and Evaluation, uses medical claims data to investigate the
relationship between tegaserod and the rate of Cholecystectomy.55
Tegaserod (marketed as ZELNORM®), a treatment for irritable bowel
syndrome (IBS), was recently taken off the market in the US due to an unrelated
safety concern, but is being reintroduced for patients meeting appropriate
criteria. The study by Brinker et al. reported a rate of cholecystectomy in the
months following the initiation of tegaserod that was 2.9 times higher than the
corresponding rate for patients not using the drug.
We used PVmaps to investigate the relationship between tegaserod and
cholecystectomy in FDA Adverse Event Reporting System (AERS) data from the fourth
quarter of 1997 through the fourth quarter of 2006, starting with a Drug-Focused
PVmap for tegaserod. The signal for cholecystectomy is highlighted in
yellow, and appears well above the threshold for statistical significance
(horizontal dashed line). It is actually the twelfth-ranked signal for the drug,
with a reporting ratio of 28.06, and a Statistical Unexpectedness of 43.95.
There are 41 cases of this drug-event combination in AERS.
To gain further perspective on the size of this signal, we produced an
Event-Focused PVmap for the MedDRA Preferred Term (PT) cholecystectomy.
We note that tegaserod is the drug most strongly associated in the AERS database
with this somewhat unusual adverse event, i.e., it is ranked #1 for
cholecystectomy. The rank of a particular drug on an Event-Focused PVmap can
provide useful perspective as to the relative strength of a signal of
disproportionate reporting:
It is noteworthy that the adverse event under study here is a medical
procedure, cholecystectomy, rather than a symptom, condition, or disease.
This raises questions about the mechanism of the potential relationship between
the drug and the medical procedure, since a drug cannot "cause" a
procedure in the same way that it can cause a symptom or medical condition.
Brinker et al consider three potential mechanisms for this drug-event association:
1) Tegaserod increases gallbladder motility, unmasking symptoms of
previously-asymptomatic cholelithiasis as biliary colic; 2) Misdiagnosis of
symptomatic gallstones as IBS, leading to tegaserod treatment; 3) empiric
cholecystectomy for tegaserod-resistant abdominal pain. In order to provide
evidence supporting or refuting these possibilities, it would be interesting to
know what MedDRA terms related to gallbladder pathology were reported among the
patients having cholecystectomy with tegaserod. For this, we can use a
Potential Syndrome PVmap, designed to examine the co-occurrence of adverse events
related to a particular drug. Of the 41 cases of tegaserod/cholecystectomy,
twelve list cholelithiasis as a co-occurring event. This confirms that,
at least in a substantial fraction of the patients, the presence of gallstones
was reported. A total of nine cases list cholecystitis or
cholecystitis acute. It would be helpful to know if these terms came from
a pathologist's report or a presumptive clinical diagnosis, but this information
is not available in the public release of the AERS database.
Here we have shown the use of a number of different map types-Drug-Focused,
Event-Focused, and Potential Syndromes—to paint a picture of a drug-event
relationship. In this particular case, we were able to rapidly corroborate that
the signal for tegaserod and cholecystectomy, derived from claims data
and discussed in the article by Brinker et al., has a counterpart in the FDA
Adverse Event Reporting System database.
About Drug-focused PVmaps
Above is a Drug-focused PVmap, allowing you to visualize which adverse events are
most highly associated with a particular drug of interest. In the map directly
above, the drug is tegaserod and the red dots represent Adverse Events reported
in the AERS database to be associated with tegaserod. On the horizontal axis of
this graph is the reporting ratio that 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. Dots above
the horizontal blue line and to the right of the vertical blue line represent
"significant signals". The adverse events with the strongest association
to tegaserod appear at the top and to the right on the PVmap.
About Event-focused PVmaps
The second PVmap shown in the case study above is an Event-focused PVmap that
allows 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 cholecystectomy and the red dots represent drugs
reported in the AERS database to be associated with this condition. On the
horizontal axis of this graph is the reporting ratio, which compares the number
of times 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 cholecystectomy appear at the top and to the
right on the PVmap.
About Potential Syndrome PVmaps
The third map in the example above is a Potential Syndrome PVmap, which allows
you to visualize what co-occurring events are significantly associated with a
specified drug/adverse event combination. In this case, the drug/adverse event
combination is the drug tegaserod reported in association with cholecystectomy.
The red dots on the first map represent additional events (MedDRA preferred terms)
reported for patients who took tegaserod and reported cholecystectomy.
On the horizontal axis of this graph is the reporting ratio, which compares the
actual rate of occurrence of each event in patients with
tegaserod/cholecystectomy compared to the event rate 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 co-occurring events 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
- 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
- Brinker A, Schech SD, Burgess M, Avigan M.
An Observational Study of Cholecystectomy in Patients Receiving Tegaserod.
Drug Safety 2007;30(7):581-588.
