1. Fourth draft
Jerusalem, Israel June 31, 2006
Unlucky Vioxx, Unlucky World
Summary:
Since February 2004, when an article titled “Cardiovascular Events Associated with
Rofecoxib” was published in NEJM, reporting about the APPROVe clinical study, the
deadly risks associated with Vioxx became ‘Common Knowledge’.
Recently, Merck delivered follow-up report to the FDA, adding data on 12 months,
following the termination of Vioxx.
Review of the two reports reveals that throughout the APPROVe study period of 48
months, the rate of monthly CV events, among the Vioxx group was uniform and stable,
unaffected if patients were exposed to Vioxx or not.
The rate of CV events among the Placebo group was uniform and stable on the initial 18
month period of the study, and also on the 12 months following the termination of Vioxx.
The rate of monthly CV events on the 30 months period was the same for the Vioxx and
the Placebo group.
The rate of CV events among the Placebo group was cut into less than a third, on the
second 18 month period. Such reduction cannot be attributed to the therapeutic effect of
Placebo or the nonuse of Vioxx, but to considerations related to the study’s structure, or
to pure Chance.
The conclusion from reviewing the recent APPROVe reports is clear: there is no
relationship, positive or negative, between the use of Vioxx and CV events.
Introduction:
On Sept. 24, 2004, Raymond Gilmartin, former chief executive of Merck & Co., got an
alarming message. Peter Kim, Merck's research chief, told him that the panel overseeing
the APPROVe clinical trial urged Merck to halt the trial and stop patients from taking
Vioxx.
The reason: Patients on Vioxx were twice as likely to have heart attack or stroke as
those on placebo. On September 30, Merck announced that it is withdrawing Vioxx from
the world-wide market, with huge economical and legal consequences.

2. On February, 2005, an article, titled: Cardiovascular Events Associated with Rofecoxib,
authored by Robert S. Bresalier, MD and others was published by NEJM. Since then, it
became ‘common knowledge’ that patients who took Vioxx over 18 months doubled their
risk of heart attack and stroke compared to those who took placebo. Merck relied on that
fact to support its defense, thus admitting there was a causal effect of Vioxx on CV
events.
The problem with the ‘common knowledge’ about a causal effect of Vioxx on CV events
is that the APPROVe study was not designed at all to answer questions about Vioxx’s
potential to cause heart attacks and stroke. Review of Bresalier’s February 2005 article
leaves critical questions unanswered, about the study’s validity and conclusions.
Merck followed-up for 12 more months on APPROVe, collecting data about its patients.
Findings were summarized into 108 page package sent to the FDA in the beginning of
May 2006 - reported recently on the NY Times.
The analysis hereunder is based on the facts and data reported about APPROVe on NY
Times, May 22, 2006 and NEJM, February 2005.
The participants
The February 2005 NEJM article stated:
“A total of 3,260 patients were screened for the study, of whom 2,586 were
deemed to be eligible. 1,287 of the eligible patients were randomly assigned to
receive Rofecoxib, and 1,299 to receive placebo (Fig1). The two groups were
generally similar with regard to baseline characteristics, including age, sex, use
or nouse of low-dose aspirin, and cardiovascular risk status (table 1).”

3. Table 1: Published in “Cardiovascular Events Associated
with Rofecoxib”, authored by Robert S. Bresalier, MD and
others, NEJM February 2005.
The ‘random’ selection of participants into Vioxx and Placebo groups resulted in
amazing results, that should remind the reader about the unexpected, sometime
devastating effects of Chance.
Table 2: Baseline characteristics of the Patients, measured by
% absolute numbers and difference
Rofecoxib
%
Placebo
%
Rofecoxib # Placebo
#
Difference
Patients in group 1287 1299
Use of low dose aspirin 17 16 218.79 207.84 10.95
Use of antihypertensive medication 30 29 386.10 376.71 9.39
High Cardiovascular risk 30 26 386.10 337.74 48.36
History of atherosclerotic cardiovascular
disease
9 8 115.83 103.92 11.91
History of Hypertension 36 34 463.32 441.66 21.66
History of Hypercholesterolemia 29 26 373.23 337.74 35.49
137.76
Table 2: Baseline characteristics of the patients by CV risk attributes, and difference

4. Table 1, was copied from the original February 2005 article, tabulating ‘similarity’ by key
attributes, between the Vioxx and Placebo groups. Table 2 observes the differences
between the Vioxx and Placebo groups, observed on key attributes that associate
Patients with CV risk.
The ‘Generally similar’ randomly selected groups are quite ‘different’ on attributes
associated with CV risk factor. Before single Vioxx tablet was swallowed - by Chance or
just by bad luck - there were 48 more patients subject to High CV risk in the Vioxx
group, when compared to the number in the Placebo group. That happened before even
a single Vioxx tablets was swallowed.
48 patients with high CV risk are more than double the difference in number of CV
events, between the Vioxx and Placebo groups, accumulated at the end of the 36
months of study (46 CV events occurred among the patients in the Vioxx group,
compared to 26 events among patients in the Placebo group - a difference of 20
patients).
138 patients, - the accumulated imbalance on number of patients, subject to all types of
risk factors, demonstrate the type of error that potentially would be measured, just
because of misapplying statistical analysis. (This article cannot elaborate on issues
surrounding the ‘golden rules’ of statistical methodologies, their potential error prone
disastrous conclusions, or to introduce the alternative of more reliable Statistical
Longitudinal methods.)
It suffice to state, it was ‘unlucky’ for Vioxx, Merck and the patients of the World - that the
random assignment process of candidates into groups constructed a study group
predisposed to CV event. Chance could have turned the groups just the other way
round.
The APPROVe Study:
The findings of the APPROVe study were graphically summarized, on a Kaplan-Meier
chart that plots the cumulative number of CV events that occur over the study’s time.
The absolute number of events is adjusted to the number of patients remaining in each
group at each point of time.

5. Graph 1: Published in NEJM, February 2005
Graph 1 was generally interpreted as proving that patient in the Vioxx group had twice
the risk of CV event than patient assigned to the Placebo group. The endpoint for the
Vioxx group curve, on the 36th
month, at about 4% height, is twice the accumulated rate
at the end point for the Placebo group, at about 2%. The difference is statistically
significant.
This graph and its stark message prompted Merck to withdraw Vioxx from the market,
with all dire consequences.
Graph 2: Updated Kaplan – Meier graph Published in NY
Times, May 22, 2006

6. Graph 2 is the Updated Kaplan – Meier graph, plotting the cumulative number of CV
events that occur over the 48 months for the Vioxx and the Placebo groups.
The vertical lines indicates 95 percent confidence intervals. The width of the confidence
interval gives us some idea about how uncertain we are about the conclusion.
Analysis:
Three distinct periods are presented on the X axis of graph 2:
• ‘Opening period’ – months 0-18;
• ‘Second period’ – months 18-36;
• ‘Follow up’ period – months 36-48.
Graph 3 presents a simplified summary of the trends for CV events, for the Placebo and
Vioxx groups:
Kaplan-Meier Estimates of Cumulative CV events
0
1
2
3
4
5
6
7
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
Month
CumulativeIncidenceofCVevents(%)
Placebo Vioxx Vioxx trend
1.5%
Vioxx Line
Vioxx 48 month
trend line 1.8% 1.2%
0 33%
Placebo Line1.2%
Graph 3: Simplified Kaplan-Meier Estimates of the Cumulative Incidence of CV
events.
The Placebo line (blue) presents three periods:
• The initial 18 months period, where the rate of CV annual events is 1.2%. The
line overlays over the Vioxx line for the same period.

7. • The second 18 months period, month 18-36, where the rate of CV annual events
drops to 0.33%, for no reason that can be related to Vioxx.
• The third 12 months period, month 36-48, where the rate of CV annual events
returns to the same 1.2% annually, for no reason that can be related to Vioxx.
The Vioxx line (pink) presents three periods:
• The initial 18 months period, where the rate of CV annual events is 1.2%. The
line overlays over the Placebo line, for the same period.
• The second 18 months period, month 18-36, where the rate of CV annual events
increases somewhat, to 1.8%.
• The third 12 months period, month 36-48, where the rate of CV annual events
goes down to 1.5%, which is equal to the average annual rate for the initial and
second period (presented by a yellow line).
• The difference in the rates is statistically insignificant.
Conclusion:
The rate of annual CV events for the Vioxx group is statistically constant, at 1.5% annual
rate over the three periods.
The rate of CV events for the Placebo group remains statistically constant, at 1.2% for
the first and third period, when the group was not exposed to Vioxx. The rate of monthly
CV events for the Placebo group on the Opening and Follow up periods is statistically
the same (1.5%) as the rate of CV monthly events for the 48 months, for patients in the
Vioxx group.
The rate of annual CV events, for the Placebo group, goes down dramatically (from
1.2% down to 0.33%) on the ‘Second period’ between the 18th
and the 36th
month, for
reasons that are not related to the use of Vioxx, probably due to an effective exclusion
from the study of patients at CV event risk, who were exposed to pain with no relief, or
just Chance or Bad Luck. The rate of monthly CV events, for the Placebo group, returns
to normal (1.2% annually) on the ‘Follow up’ period’, for reasons that are not related to
Vioxx, to the normal rate experienced on the ‘Opening Period’.
Thus it is concluded positively that there is no increased risk of CV events with the short
term and long term use of Vioxx.
Avi Shatz is the founder CTO of EdenBase Ltd. Avi authored white papers on the Vioxx recall,
available at:
http://www.edenbase.com/intercon/products_dynatrack.htm
Find earlier press releases:
http://www.medicalnewstoday.com/medicalnews.php?newsid=16502
www.kdnuggets.com/news/2004/n22/3i.html

8. http://www.kdnuggets.com/news/2005/n09/7i.html
Disclaimer.
EdenBase has not received or been promised any compensation by Merck, Pfizer or any other
major participant in the discussed controversy. None of its officers or employees owns any equity
or derivatives in those same companies.
For Further Information contact: Avi Shatz, in Jerusalem, ISRAEL
US toll free:
Office 1-888-202 9801 Cellular 1-877-271-7330
or by email: avi.shatz@edenbase.com