Your Bextra Side Effects Lawyer - Bextra, Celebrex & Vioxx Side Effects FDA Transcript

Your Bextra side effects lawyer provides you the complete transcript of the February 17^th, 2005 joint meeting of the FDA's Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee. We have formatted the complete transcript of the three day conference for easy of navigation to provide you with the best possible bextra information. To contact a Bextra Lawyer, click here for a FREE case evaluation.

Gastrointestinal and Cardiovascular Safety of Lumiracoxib, Ibuprofen, and Naproxen - Patrice Matchaba, M.D.

DR. MATCHABA: Thank you to the Chair, thank you to the Committee, the FDA, and the public for inviting us. Just to state that for this purpose, we will be discussing the cardiovascular and GI safety data from the TARGET study, but we are certainly willing to answer any question related to an end organ, and that we have published the data in TARGET in the Lancet, two papers.

We have two of the key primary authors for the GI and other adverse events of safety profile, we have Dr. Schnitzer, and for the cardiovascular paper we have Dr. Michael Farkouh.

Before we got into the TARGET data for cardiovascular and CV, I think it is important underlie that when the TARGET study was designed, that the VIGOR study and the CLASS study had been completed, and that the discussion for the TARGET design occurred between health authorities including advice sought from the Arthritis Advisory Committee in September 2001, because there were important public health questions that were asked after the CLASS study and the VIGOR study.

Some of the key issues or principles that then drove the design of the study, the first point was that we should designing studies to detect a difference in ulcer complications because that was the COX-2 promise.

As a result, more patients were required because this event, as Dr. Cryer had discussed yesterday, is a fairly rare event, about 1 percent of patients, that the patient numbers required increased to about 18,000 patients in TARGET.

The second point was that in this population of patients that we studied in terms of osteoarthritis, that they do take low-dose aspirin, so we stratified patients to low-dose aspirin, and we managed to get a 24 percent stratification, and obviously, because of the impact of low-dose aspirin on GI outcomes, this necessitated an increase in the size of the study.

The other point that had been made from the previous two studies, that the median duration was short. If you recall, the VIGOR study had a median duration of about 9 months, and the data that we saw for CLASS was 6 months, whereas, in TARGET, we had a fixed term design of 12 months.

The other design principle that was important, and we have heard this data discussed extensively, was that not all NSAIDs are the same in terms of COX-1 and COX-2 activity and that we will see differential GI and CV effects because of that.

So, we chose two NSAIDs that should have a different impact on the GI and the CV, and addressed that question as to what is the difference between coxibs, and in this case, lumiracoxib between naproxen and ibuprofen.

Finally, there was a need to prospectively define an adjudicate all outcomes, so we had three Adjudication Committees, one for the cardiovascular outcome, the other one for the CV, and the other one for the hepatic events. In terms of the objective, it was to compare lumiracoxib at 4 times the proposed OA dose, 400 mg. to naproxen 500 mg bid, and the dose is important here, because this is the dose and the dosing frequency that people have discussed in terms of a possible anti-thrombotic effect, and ibuprofen at 800 mg 3 times a day.

Key inclusion criteria that I think are important for the endpoints is that patients who had a previous history of a cerebrovascular or ischemic event in terms of cardiac events were allowed into the study if the event occurred more than 6 months before they entered the study and if they had been on low-dose aspirin for 3 months in order to stabilize the patients, and this is the advice and the current thinking that was there in terms of patient safety if you are going to conduct a 1-year study. From a GI perspective, a key exclusion criteria was that any patients who had active GI ulcerations 30 days previously were excluded, and any patients who had a GI bleed in the previous year were excluded because the thinking again was that with the availability of PPIs and high-dose H2 antagonists, that enrolling these patients that required long-term treatment would have been an unethical thing to do.

So, the study design were 2 studies that were identical, lumiracoxib compared to naproxen in 1 study, and compared to ibuprofen in the other study. You will note that the 2 studies are of similar size, about 9,000 patients in each study, and that the studies went on to 52 weeks or 1 year with a follow-up at 56 weeks or at 1 month.

The key thing to note also is that the naproxen sub-study started recruitment 4 to 5 months before the ibuprofen sub-study, and that different centers were used for the 2 studies. So, you may see differences in the baseline risk for the endpoints that we will be discussing. For cardiovascular and for this particular discussion, as I said, we had a pre-defined and prospectively adjudicated CV endpoints that included important coronary cerebrovascular and also the peripheral events. In terms of the patient demographics, the majority were female an average age of 63. We managed the 24 percent aspirin stratification. Of importance is that within this cohort of 18,325 patients, about 12 percent of these patients had a high CV risk as defined by a previous cerebrovascular or cardiac history or by Framingham risk equations.

The patients were fairly representative of an OA population. We had hypertensive patients, diabetics, and patients with dyslipidemia. Very importantly, because it was fixed term design, 60 percent of the patients finished the 12 months, a total of about 11,000 taking treatment for 12 months.

For the primary endpoint, which was ulcer complications, or perforations, obstruction, and bleeds in the non-aspirin population, it was a relative risk of 0.21 or a 79 percent reduction if you compared lumiracoxib to all NSAIDs.

If you made that comparison by sub-study, it was an 83 percent reduction compared to ibuprofen, and 76 percent reduction compared to naproxen.

So, although we have 2 different NSAIDs with different COX-1 and COX-2 activities, this the first GI outcome study that looked at ulcer complications as a primary endpoint and shows definitively a reduction in ulcer complications for lumiracoxib compared to the NSAID studied.

A lot of the discussion, because if you recall, we have stratified patients to low-dose aspirin in the 24 percent of patients, about 4,000, and the question was, and is, what is the impact of low-dose aspirin on this outcome, and we will also discuss the CV outcome.

Now, if you look at the ulcer complications in the low-dose aspirin population, and I have tried to show you an analytic figure here, is that for the upper GI ulcer complications, there was a relative risk of 0.79 with wide confidence intervals crossing the line of no difference with a point estimate showing a 21 percent reduction.

What we have done, however, for this discussion is to say when we consider more events, ulcer complications and symptomatic ulcers, is the point estimate still favoring lumiracoxib and does the confidence interval tighten in terms of the precision, and you can see that the reduction increases to 27 percent, but the confidence interval certainly still crosses one.

In this context, it is important to remember that the TARGET study wasn't designed to show a difference in the low-dose aspirin population, but was designed to show a difference in the non-aspirin population, and it cascaded to the overall population if the first result was positive.

But what is encouraging is the consistent trend that we see in this population.

There was discussion yesterday about do coxibs, in this case lumiracoxib, does it still show benefit in patients who have a high GI risk, and this was prespecified in the TARGET analysis, and high GI risk, there were 5 categories of risk defined, age greater than 65, low-dose aspirin use, a history of ulcers or bleeds in H. pylori-positive patients. When we do the analysis, taking one risk into consideration, you see that the magnitude of about a 3-fold reduction in favor of lumiracoxib for ulcer complications is maintained. If we have time later on, we can also show you the data for patients greater than 65, for patients who were H. pylori-positive, but because of the exclusion criteria that I outlined beforehand for patients who had a previous bleed, the numbers become smaller and smaller when we look at further increasing risk for these patients.

So, in summary, for the GI data, the TARGET study definitively shows benefit for patients taking lumiracoxib compared to these 2 different NSAIDs, ulcer complications in the non-aspirin population. We have seen the high risk or high GI population as defined in TARGET, and we see a consistent trend although it is not significant because of the numbers in the patients taking low-dose aspirin.

The cardiovascular endpoint that was chosen at that time was the APTC endpoint. Certainly, all the other cardiovascular events were also adjudicated, peripheral events, pulmonary embolism, deep vein thrombosis.

At the time we published the data, and as prespecified in the protocol, the plan was to compare lumiracoxib to all NSAIDs for the APTC endpoint, but for the purpose of this discussion, if we do that, we fail to disaggregate the relative results for lumiracoxib compared to naproxen and compared to ibuprofen.

So, we will discuss the separate studies, but, first, you will see that when you compare lumiracoxib and NSAIDs, that there is no difference in the APTC endpoint throughout the 12-month period, but there is greater data and more insight to be mined when you look at the 2 studies separately. That is the current debate.

Before we look at the data, look at the baseline demographics. If you recall, these were 2 parallel studies, recruiting at different centers, different time points, identical in design, but what you can see is that for the endpoint that may have an impact on the rate of cardiovascular events in the 2 studies, that there seems to be differences in the low-dose aspirin use, for the naproxen sub-study, patients who were high CV risk and patients with baseline hypertension.

For the high CV risk patients, in terms of patient numbers, this translates to about 140 patients difference. Now, this may or may not be a factor in terms of looking at the differences in rates, and there are other factors certainly that we may not have measured that could impact on the differences in rates.

So, we will look at the ibuprofen sub-study first and look at the APTC endpoints, myocardial infarcts, look at stroke, look at the cardiorenal complications, congestive heart failure, and a combined endpoint, and just to state that in terms of all-cause mortality, there were 29 patients who passed away in the lumiracoxib study arm and 30 patients in the NSAIDs, and when you split it up between the 2, there was essentially no difference.

So, for the APTC endpoint, looking at lumiracoxib versus ibuprofen, if you start off with the overall result, in other words, all patients including those who took low-dose aspirin, you can see that the hazard ratio for all populations studied are consistently less than 1.

The other point that I want you to see is that in the non-aspirin population, the number of events are the same with a hazard ratio of 0.94. There is certainly a lot of discussion and this was thought to be part of the value of looking at the TARGET data to ask what happens in the low-dose aspirin population where you have this possible interaction with ibuprofen.

You see in this population that there were 6 events in lumiracoxib and 10 in ibuprofen. This difference, however, was not significant, and you will see when we look at myocardial infarct, that the number of events in this population when you look down to myocardial infarcts, are not enough to definitively contribute to this debate about the interaction of low-dose aspirin and ibuprofen, but certainly all the data in this 8,600 patients studied do not indicate that lumiracoxib is any different from ibuprofen in terms of the APTC endpoint or cardiovascular risk.

For myocardial infarcts, going through the same analysis, the overall population, 5 versus 7, again, you see the hazard ratio of consistently less than 1. The number of events are low. In the non-aspirin population, 4 versus 5, and as I pointed out, in this aspirin population, 1 versus 2, so difficult to comment and to contribute to the debate about myocardial infarct and ibuprofen interaction.

For stroke, again the number of events were low, 8 versus 9, no real difference, 6 versus 5, and 2 versus 4 in the aspirin population, lumiracoxib 2 events, and ibuprofen 4 events. So, again from this data, 8,600 patients treated for 1 year, no indication that lumiracoxib is any different from ibuprofen in this robust data set.

I think it is important to recall that this study, in terms of patient exposure and patient numbers, is larger than the VIGOR or the CLASS study in itself in terms of exposure.

The real differences we see in the TARGET study is in hypertension, and there has been a lot of debate yesterday about the possible impact of hypertension as a risk factor in contributing to an increase in strokes and myocardial infarct, and cardiovascular morbidity.

If we look at the cumulative incidence of new onset hypertension or de novo hypertension, you can see that over the study period, 360 days, that the patients taking ibuprofen have a significantly higher incidence of new onset hypertension compared to the patients taking lumiracoxib. This is percentages, number of patients.

So, it is about 10 percent of patients with new onset hypertension with about 6 percent of patients.

For a similar analysis looking at aggravated hypertension, if you recall in our demographic analysis, about 45 percent of the patients in the TARGET study were hypertensive. In terms of aggravation or worsening of the hypertension, you see exactly the same trend between lumiracoxib and ibuprofen, which was significant.

If we look at the mean difference over the entire study period, again comparing lumiracoxib and ibuprofen for blood pressure, we see a systolic of 2.7 for patients taking ibuprofen compared to 0.7, and we see almost a 1 millimeter increase in blood pressure for patients taking ibuprofen with a zero mean increase for patients on lumiracoxib, and these differences again are statistically significant.

There was a lot of debate yesterday as to the possible cardiorenal implications of this in terms of edema, congestive heart failure, and weight gain, and if you look at the data in TARGET for this sub-study in terms of edema, no significant differences between the comparators, but for edema and congestive heart failure, you see that there are more patients taking lumiracoxib with edema, congestive heart failure, but no difference for weight gain.

There was discussion previously about how do we assess benefit-risk. There was discussion also yesterday that any advantage that was shown in terms of GI ulcer complication reduction with rofecoxib in VIGOR was negated by an increase in CV events.

We prespecified, and this is not a validated way of analyzing benefit or risk, but at least we prespecified this outcome to say if we combine ulcer complications as defined by perforation, obstruction, and bleeds, and combine them with the primary cardiovascular endpoint, of the APTC endpoint, what is the trend compared to the lumiracoxib and ibuprofen, and this is the endpoint that I am showing you for the non-aspirin population, that patients taking ibuprofen are significantly worse for this combination of the 2 endpoints of GI ulcer complications and APTC.

Certainly, this is the first time that this has been done in an outcome study in arthritis, but we hope that this will contribute to the discussion in terms of getting an overall assessment for benefit for the patients with osteoarthritis.

If you look at the overall population, this difference is still significant with a 50 percent reduction, but if you look at the aspirin population alone, the significance disappears as would be expected.

So, in summary, in this patient population of more than 8,500 treated and randomized to treatment for 1 year with these doses of lumiracoxib and ibuprofen, if we look at the APTC endpoints, myocardial infarcts, and stroke, the hazard ratios are consistently less than 1.

We see significant differences in hypertension, and obviously, hypertension in the long term, as discussed yesterday and today, may be an impact on CV adverse events for patients with osteoarthritis.

We have also seen that there isn't an increase compared to ibuprofen for congestive heart failure and for edema, and as for the combined safety endpoint, there is a significant benefit for patients taking lumiracoxib.

So, we will now look at the naproxen sub-study and go through the same analysis, APTC endpoint, myocardial infarct, stroke, cardiorenal, the combined endpoint.

What you see immediately is that for this sub-study, that the number of events is much greater than the ibuprofen sub-study. Also, what you see is that the hazard ratios are now in favor of naproxen, and there are more events with the lumiracoxib compared to naproxen.

You will see when we look at the next slide, and we look at myocardial infarcts, you will see that this is driven by the differences in myocardial infarcts particularly in the non-aspirin population.

So, if we look at the non-aspirin population, patients taking lumiracoxib, 10 myocardial infarcts, clinical and silent, compared to 4 in the naproxen population, a hazard ratio of 2.37, but which is not significant over the 12-month treatment period.

But the robustness and I think the value that TARGET adds to the debate is that because we stratified 24 percent of the population to low-dose aspirin, when you look at the aspirin population, you see the numeric difference or the hazard ratio decreases in this population.

Now, low-dose aspirin we all agree has COX-1 activity, irreversibly binds to the platelet, and it may contribute to 10 to 30 reduction in myocardial infarcts.

The question then was asked when we look at this data, and this is the data that we present to you, is that if it's COX-1 activity of low-dose aspirin that is negating the differences in terms of myocardial infarct, the implication therefore that naproxen at 500 mg dose taken twice daily in a clinical trial situation to ensure compliance, and there is certainly pharmacological data that shows that this dose has got anti-thrombotic and platelet aggregation activity, that naproxen must have significant COX-1 activity.

There has been extensive debate this morning about observational studies, the merits of them, and looking at the naproxen and non-naproxen data, but this paper published by June in Lancet last year, looking at all the studies, observational studies, and this is not the rofecoxib analysis, but just the observation studies looking at naproxen.

We can see that when you combine all the data, that the diamond at the end here shows a 14 percent reduction in myocardial infarcts with a confidence interval that doesn't cross the line of no difference or 1.

The point I think was made by a member of the panel that in observational studies, that the dose that is taken could be less than the 500 mg dose, and that the dosing interval would not be the regular dosing interval that you see in clinical trial situation.

I think Dr. Graham also made the point that in that case, you would see the point estimates moving closer to 1 in terms of the real effect that you would see if it had anti-thrombotic activity.

So, you go back to the sub-study of naproxen and look at strokes, you see that in the non-aspirin population, small numbers, and the same thing in the aspirin population, so no significant differences, and the confidence intervals are crossing 1.

Now, again when we do the analysis for blood pressure, we see that there is significant difference in favor of lumiracoxib compared to naproxen. Now, if you recall in the VIGOR study, where they compared rofecoxib to naproxen, that the differences in blood pressure were the reverse, and that rofecoxib increased systolic and diastolic blood pressures, systolic by about 3 to 4 millimeters of mercury, and diastolic for this same comparator.

The caveats are there that these are different patient populations. The RA population is a high-risk population, this is an OA population, but without the studies that compared directly COX-2s, this is the only way that we can make a cross-study comparison.

Again, hypertension may be significant as discussed in terms of long-term morbidity and mortality.

For the same analysis we did with the ibuprofen sub-study for de novo hypertension, and for new aggravated hypertension, no significant difference between lumiracoxib and naproxen although consistently, the lumiracoxib patients have less events over the 12 months.

This is again a revealing analysis if we look at the cardiorenal complications. For edema, slightly more patients having edema, 4.5 versus 4.2 percent, but we think what is encouraging is the no increase compared to naproxen for congestive heart failure.

Again, we saw in VIGOR, or if you look at the VIGOR data, that rofecoxib had more patients with congestive heart failure or pulmonary edema compared to the same comparator, and we have not seen this is the naproxen sub-study, and weight gain, 8.1 percent versus 9 in favor of lumiracoxib.

For the same analysis we did for ibuprofen looking at this safety endpoint that we introduced and prespecified in TARGET, for ulcer complications and APTC in the non-aspirin population, again we see over time that notwithstanding the reduction that you get with myocardial infarcts with naproxen or when you add the 2 combined, that over time for patients with osteoarthritis, at the doses that we tested, that there is a significant reduction and benefit for patients taking lumiracoxib in the yellow line there.

So, in summary, these two studies, huge studies, 8- to 9,000 patients, randomized to 1 year, show interesting data, and the naproxen sub-study shows no significant increase compared to naproxen/lumiracoxib for the APTC endpoint, but we see these differences in myocardial infarcts with more events in lumiracoxib, but of key importance that when you consider the low-dose aspirin population and you add COX-1 activity, that the numeric difference disappears.

From a public health perspective, still significant differences in blood pressure, no increase in cardiorenal or congestive heart failure with lumiracoxib as we saw in the other study, and the combined safety endpoint still significantly favor lumiracoxib.

Now, because the study included a certain number of high-risk CV patients, it allows us to look at a high-risk cohort within the TARGET study and follow them over the 12 months, and asked in this sensitive high-risk cohort of patients, what are the outcomes in terms of APTC and myocardial infarct, and we will discuss only the myocardial infarct for this high risk.

A total of over 2,200 patients, and these are patients who had a history of either coronary artery disease, a previous myocardial infarct, and other vascular events, and we added these patients to those who had a high Framingham, high risk, so over 2,200 patients treated for 1 year.

We look at the myocardial infarct data because we will probably glean more from looking at this specific endpoint than looking at APTC, but if you have questions, we will address those questions.

But if you look at the overall population, these 2,200 patients, including those who were not taking aspirin and those who were taking aspirin, the naproxen sub-study, there were 7 myocardial infarcts in the lumiracoxib population compared to 5. Obviously, the number of events low, nonsignificant, and if you look at the ibuprofen sub-study, 1 in the lumiracoxib and 2 in the ibuprofen sub-study.

The question, and certainly there has been debate that by adding low-dose aspirin, which I think everybody thought it was a good idea in the year 2001 in terms of answering some of these biological questions on the impact of low-dose aspirin--

DR. WOOD: Hang on. You are getting well over time, so you can try and speed it up a bit.

If you look at the APTC endpoint, and notwithstanding all the discussion and comment that has come forth including from Dr. FitzGerald, that combining all comparisons is probably not the right thing to do, we did a comparison against all comparators.

Now, this is a cumulative meta-analysis and I will just quickly run through it. These are the studies that we have done from 2001 to 2004.

These are the cumulative patients you can see as we have added a trial, over 34,000. These are the events as events have occurred for APTC, 156, and we have added the events to try and get an estimate as they have occurred, and you can see that the relative risk of 1.2 with a confidence interval crossing 1. This is against all comparators for the APTC.

We do the same analysis and we subtract naproxen, and when you do the same analysis without naproxen, you see the relative risk changes to 0.94, over 24,000 patients with cumulative event of 0.88. What you also see is that at no time in our development program have we seen a significant increase in risk.

If we look at myocardial infarct, same analysis against all controls, a relative risk of 1.28 crossing the line of no difference. A similar analysis minus naproxen again, and you see the relative risk goes to 1, 24,000 patients and 34 events.

For strokes, all controls comparison, a

relative risk of 1.02, 62 events, and when we remove naproxen for the analysis, a relative risk of 0.84.

Now, this reduction that we are seeing in the more robust data set with the meta-analysis is certainly within the bounds of the 10 to 30 percent benefit that you would expect from aspirin in the idea situation.

A specific question and the comparison has

been made for the 2 studies, the naproxen sub-study versus the VIGOR, but just to point out, and we can have discussion if time permits, that the half-lives are different of this compound and the structure. Lumiracoxib has got a short half-life, and if the hypothesis that continuous prostacyclin inhibitor is important, this may be an important factor.

A median 9-month versus 12 months, seeing a significant difference with the caveats of the different populations, but not seeing it in a similar population not taking low-dose aspirin, and we have commented about the differences in the congestive heart failure and the hypertension, which we think plays a significant role with time.

The final slide I think has been discussed before in terms of prostacyclin, and if the Chair and the committee decides we can discuss that more in detail, but the fact that the other NSAIDs also show a prostacyclin inhibition compared to the COX-2s.

So, in summary, we have seen that the meta-analysis is supportive of the data that we are seeing in TARGET. It's a robust meta-analysis, 34,000 patient. We are seeing that each time you removed naproxen from the comparison, you are getting your 10 to 30 percent difference and that at no time point during our development program have we seen a significant increase for the APTC endpoint.

Importantly, we are seeing no increase with lumiracoxib with congestive heart failure and hypertension.

The question was asked, and this obviously is the subject to further debate as to what do we think as a company going forward.

Thank you, Mr. Chair, and thank you, committee.

DR. WOOD: Great. Thanks very much.

We are going to break for lunch and I have to remind the members to turn in their dinner reservation form I guess to Kimberly, and we have a table reserved for the committee members in the restaurant. We will be back here and start at 1 o'clock, so you had better grab it and eat.

(Lunch recess.)