1

Giving the MI data the best face possible

For all comparisons except mortality and MI, Merck used:Vioxx event rate PUBs: Vioxx 2.1/100pyr RR 0.5Naproxen event rate Naproxen 4.5/100pry

But with MIs, Merck flipped the conventional method:Vioxx event rate MIs: Naproxen 4 RR 0.2Naproxen event rate Vioxx 17

•Additionally, Merck used the number of patients as the denominator for calculating the MI rates but used patient-years for calculating the all other rates.

•Merck’s top scientist on Vioxx, Alise Reicin, commented that “we prefer to flip the data and say it was reduced on naproxen.”

•Merck’s statitician, Joshua Chen admitted, under oath, that flipping the rates is confusing.

2

Giving the MI data the best face possible

Merck used patient-years to calculate most rates, including the GI PUB rate. However, they calculated the MI rate for aspirin sub-group analysis differently – using patients instead of patient years. This inappropriate calculation misleadingly diminished the statistical significance.A Merck reviewer of the VIGOR draft paper complained about this:

“Should you not mention that for general safety analyses CL’s on absolute differences rather than proportional differences were used to look for potential factors – the authors should be prepared to respond to referee queries on why relative risk estimates are being used for GI events but risk differences are being used for the CV comparisons.”

3

Because Merck used Total-Patients (rather than Patient-Years) to calculate the rate difference for MI, they had to use Total-Patients to make the Aspirin Sub-Group Calculations, BUT EXCLUDING 3 MIs FROM THE NON-ASA-INDICATED GROUP ALLOWED MERCK TO AVOID STATISTICAL SIGNIFICANCE FOR THE NON-ASA-INDICATED PATIENTS.

Comparison of Non-ASA patients (with the 3 extra MIs)

7715769916Totals

383838344Naproxen

3877386512Vioxx

TotalsNo MIMI

Chi-square = 3.93 p < 0.05

Comparison of Non-ASA patients (without the 3 extra MIs)

MI No MI Total

Vioxx 9 3868 3877

Naproxen 4 3834 3838

Total 13 7702 7715

Chi-square = 1.876 0.05 < p < 0.20.

4

Giving the MI data the best face possible

To support the Naproxen hypothesis (that naproxen prevented MIs, rather than Vioxx causing excess MIs) Merck claimed that the risk difference in MI rates was not statistically significant in low risk (non-ASA-indicated patients). A internal Merck reviewer cautioned the Vigor authors:

“If you are going to go down this path [you] need to give number of events in each of the subgroups either in the text or in table 5.”

The Vigor authors ignored these comments and left the subgroup number of events out of the paper. The review continued:

“I think that this is a stretch for a post hoc analysis- there is considerable overlap in the CI’s- Clearly the difference on an absolute scale has to appear less pronounced in the low risk group vs the high risk group-was there less or more overlap of CI’s on the proportional scale- if one looked at the absolute scale for GI events I would venture that similar findings would hold (eg steroid vs non- steroid use- in fact the CI’s on the RR for the steroid subgroup exhibit a similar pattern to this and yet the authors conclude ‘similarity’”

5

Merck’s internal reviewer criticized Merck’s post-hoc distinction between

ASA and non-ASA patientsCommenting on the difference in MI rates between the high risk and low risk for MI patients, the internal reviewer said:

“give me a break one barely has enough power (with just 21 events) to detect an overall difference with so few events so you probably have high “power” to see a non-significant result in the low risk

group when you break up the overall results into a high risk and low risk group).”

6

What data did Dr. Laine omit when he said they were “cagey” ?

ON VIOXX: Statistically significant increase in discontinuances due to hypertension (RR 4.67, 95% CL 1.93- 11.28) Large and important differences in congestive heart failure (RR 2.11, 95% CL 0.96-4.67) Edema-related discontinuances (RR 1.92, 95% CL 0.98-3.57) Tripled the rate for CHF for those remaining in the trial (RR 3, p<0.05) Nine fold increase in hypertension (9 on Vioxx, 0 on Naproxen, p<0.025) Statistically significant increase in edema events (RR 1.5, p<0.01) Discontinuations for edema were borderline significant but were significant for a trend (p<0.1) Total edema rates were elevated (5.4% vs. 3.6%) and this rate ratio was statistically significant (p<.001).