Know the GI Effects Vioxx is Having on You from the FDA

Your Vioxx lawyer provides you the complete transcript of the February 16^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 vioxx information. To contact a Vioxx Lawyer, click here for a FREE case evaluation.

Gastrointestinal Effects of NSAIDs and COX-2 Specific Inhibitors

DR. CRYER: Thank you. For the purposes of full disclosure, I would first like it to be noted that I have been invited to give this presentation by the Analgesic and Anti-Inflammatory Division of the FDA. I do have relationships with sponsors of products being mentioned in today's presentation, however, I am not being paid for my participation in this meeting nor for my presentation today.

For those of you not familiar with me, I am a gastroenterologist and I am thrilled that the FDA has been begun this meeting with the focus on this subject because many of us have forgotten that the initial reason for the development of the class of the COX-2 specific inhibitors was entirely because of the gastrointestinal effects of the non-steroidal anti-inflammatory drugs and, for that reason, I think it is very appropriate that we have this review of the gastrointestinal effects of NSAIDs and what the data say from the GI perspective about the gastrointestinal effects of COX-2 specific inhibitors.

From the perspective of the NSAIDs risk, listed here are several of the known risks associated with the non-steroidal anti-inflammatory drugs, the gastrointestinal risks, the cardiorenal risks and the anti-platelet concerns. Among these, as the group knows, the adverse concerns of greatest risk historically were the gastrointestinal effects that present with features such as ulcers, perforations, bleeding, obstruction strictures and many other interesting manifestations. Over the last several years, added to this list and a focus of this meeting are cardiovascular concerns of the non-steroidal anti-inflammatory drugs but my perspective are the issues listed at the top, the gastrointestinal effects.

When looking more extensively at what the specific gastrointestinal effects of NSAIDs are, we have learned that NSAIDs have effects throughout the GI tract. The upper gastrointestinal effects are the most pronounced but there are some very interesting effects that we see throughout the GI tract, such as in the small intestine and colon. In recent years we have had an increasing focus on lower gastrointestinal effects of NSAIDs, a very interesting phenomenon. Several have been assessed by endoscopic means but there has been a lot of discussion as to what are the clinically relevant untoward major events that might happen in the lower gastrointestinal tract. While this is debated with respect to the prevalence of lower GI effects, these effects are likely somewhere in the range of 10-20 percent of total gastrointestinal effects that happen within the GI tract attributable to NSAIDs. Clearly, the major effects of NSAIDs in the GI tract are in the upper gastrointestinal tract, such as ulcers more commonly in the stomach and the duodenum, and concerns such as gastrointestinal bleeding, perforations and obstructions. So, that is really the focus upon which the strategies were developed to increase NSAID safety within the gastrointestinal tract.

With respect to the epidemiology of ulcer disease in general, some very interesting phenomena have been observed which have persisted into recent years. But the overall summary of the phenomenon that I would like to focus your attention to is that while in recent years the overall incidence of uncomplicated ulcers, both gastric and duodenal, has been markedly declining in the U.S. and worldwide, very interestingly, the incidence of complications, specifically gastrointestinal bleeding, has not declined in similar proportions and, in fact, has persisted or increased. This phenomenon, in particular the bleeding, has been felt to be a manifestation of the effects of the non-steroidal anti-inflammatory drugs within the GI tract.

This problem presents itself clearly with respect to morbidity and, unfortunately, mortality and several hundreds of thousands of hospitalizations. The costs have been debated. The actual quantified amount of mortality in the U.S. is also a number that is debated. The 16,500 estimate is probably an overestimate. But the bottom line is that NSAIDs are clearly associated with morbidity, mortality and costs in this country as well as worldwide, and this is has been the issue that has led to the discussions of the need for increasing gastrointestinal safety for NSAIDs.

So, the various ways in which these assessments have been done has ranged from studies which we have seen over the years that have been short-term evaluations of physiologic or pharmacologic effects on healthy volunteers to the more relevant studies of the gastrointestinal effects of these drugs in arthritis patients. These studies have ranged from long-term endoscopy studies to a fewer number but very important studies that have assessed clinical events such as symptomatic ulcers, GI bleeding, perforation and obstruction.

Over the years there has been extensive discussion as to the relevance of the endoscopy studies and how the endoscopic observations with NSAIDs might relate to the outcome studies. One of the criticisms of the endoscopic studies is that the endoscopic lesions are numerous. They are mostly only known from endoscopies that are done as a part of a scheduled study and they are asymptomatic. However, what we have learned from comparing the numerous endoscopic studies to observations that have been seen in the outcome studies is that the relative proportions in terms of outcomes seen in endoscopic studies tend to be predictive of what one would expect to see in an outcome study. So, we have come full circle then in our understanding of the role of endoscopic studies and, at least in the gastroenterology community, we now feel that there is some substantial value in endoscopic studies and that they are predictive of what one might expect to see in outcome trials.

Now, with respect to what we see in these types of trials, when one looks endoscopically there is a range of findings in people who are taking high doses of NSAIDs. In greater than 90 percent, if one were to look, we would see this phenomenon of NSAID gastropathy, which is this constellation of erosions and hemorrhages but it is mostly asymptomatic, mostly not clinically relevant.

With respect to incidences of asymptomatic endoscopic ulcers, gastric ulcers happen two to three times more commonly than the duodenal ulcers, with the ranges that are shown on the slide. Again, these lesions are mostly asymptomatic and don't progress in the majority of individuals to clinically untoward gastrointestinal events.

What these things look like--this is an endoscopic photograph of gastropathy demonstrating the constellation of hemorrhages and erosions that, again, are going to be mostly asymptomatic, ranging to a picture, shown here, of an endoscopic ulcer seen in the antrum of the stomach of an NSAID user.

The more clinically concerning endpoint, that being clinically significant ulcers, occurs with the non-selective NSAIDs on average about 2 percent, with a range of about 1-4 percent. This range and this mean are important numbers as benchmarks to remember because they will become relevant as we discuss some of the outcome studies that have been conducted with the COX-2 specific inhibitors.

Having reviewed what the risks are, I would now like to move the discussion to what our strategies have been to reduce the risk of the gastrointestinal complications with NSAIDs. It is a simple strategy and most experts will recommend identifying the patient population who might be at risk and this is based upon identification of risk factors. Then, once having identified susceptible populations for risk, one employs strategies that would reduce risk, such as either the use of gastroprotective drugs or the use of safer NSAIDs, and the category of safer NSAIDs clearly involves the subclass of the COX-2 specific inhibitors.

With regard to identification of risk factors, a risk factor not commonly mentioned is the NSAIDs themselves. NSAIDs clearly provide risk for gastrointestinal effects. Shown here are various NSAIDs available by class and by prescription in the United States. As you can see, they have been divided into traditional NSAIDs, non-salicylates; aspirin related, salicylate-based compounds; and then COX-2 inhibitors which are currently available, in development or previously available in the U.S.

With regard to identifying patient characteristics which may suggest risk, these have been extensively studied and they are listed here, things such as increasing age and the threshold age is widely debated but one category that has been suggested would be those greater than 65, let's say. Clearly history of GI ulceration; having had a complication; concomitant drugs such as corticosteroids or anticoagulants; cardiovascular disease, interestingly, such as CHF; and this issue of multiple NSAIDs all increase the risk.

Of this list that the group is very familiar with, the one that has probably not been as widely appreciated and one which has been highlighted from some of the outcome trials of the COX-2 specific inhibitors is this issue of multiple NSAIDs, and it is a risk factor that presents itself in the context of a patient profile, a patient who takes prescribed NSAIDs along with either low doses of aspirin of over-the-counter NSAIDs. Since we know that the risk for NSAID-related gastrointestinal events is related to dose, what one accomplishes in this group of multiple NSAIDs is essentially to increase the overall dose of NSAIDs delivered.

With regard to the strategies after having identified the susceptible population, the first category essentially is that of co-therapeutic gastroprotection. As alluded to a minute ago, it would be desirable to use the lowest effective dose of an NSAID. Then really the two prevailing gastroprotective or co-therapy strategies that we have are the use of either misoprostol or proton pump inhibitors.

Several studies have been done in either of these categories. I will just highlight for purposes of discussion two outcome trials that I think nicely demonstrate the effectiveness of these strategies. With regard to misoprostol, the most widely quoted study was the outcome trial, the MUCOSA trial in which misoprostol was given to patients who were chronically taking NSAIDs over 6 months and were demonstrated to be associated with a 40 percent or less reduction in gastrointestinal complications.

From the perspective of the PPI outcome trials, there have been fewer evaluations but there have been, in fact, some evaluations for clinically relevant outcomes for PPIs, this being one example of a trial which was actually not intended in its design to evaluate outcomes of a proton pump inhibitor in patients taking NSAIDs but, nevertheless, provided us with some insight into the potential effects from the perspective of gastrointestinal outcomes.

This was a trial that was designed with the question in mind of whether or not H. pylori eradication prior to starting an NSAID would be an effective therapy or not for the reduction potentially of NSAID-related bleeds. So, in this group of H. pylori infected NSAID users, half of them were treated for their H. pylori infections prior to being started on an NSAID and acted as a control. The other half were given a proton pump inhibitor. In this specific instance omeprazole.

What was observed, very interestingly, at the end of 6 months is that in this instance there was a 76 percent reduction in the subsequent incidence of upper gastrointestinal bleeding in the group that had received the proton pump inhibitor approach.

From the perspective of the safer NSAIDs, this is a story that is also well known. Its focus today is really to look at specifically the COX-2 specific inhibitors shown on the far right. The concept has been widely discussed and is arguably somewhat simplistic, but for the sake of today's discussion, as the group knows, it is highlighted by the observation that there are 2 COX isoforms available, COX-2 and COX-1, and that COX-1 is the isoform which is primarily responsible for the protective prostaglandins in the stomach which typically protect against injury. Once inhibited by non-selective NSAIDs, the prostaglandin products produced by COX-1 lead to an increased susceptibility for injury. The concept at least for COX-2 specific NSAIDs in that they have limited inhibitory effects on COX-1 is that they would likely not inhibit prostaglandins, likely not be associated with ulcers, and likely be associated with a reduction in clinically significant gastrointestinal untoward events with NSAIDs.

Having said that, there have been a few gastrointestinal outcome trials that have been designed to evaluation whether or not the COX-2 inhibitors would meet this objective or not. Shown here are two of the outcome trials with rofecoxib and celecoxib.

As the group knows, there has also recently been another completed outcome trial with lumiracoxib. In general, the outcome trials have compared COX-2 specific inhibitors at higher than usual therapeutic doses for osteoarthritis to non-selective NSAIDs and evaluated the clinically significant events on average over a year. The major difference of importance between the outcome trials with celecoxib and rofecoxib was the inclusion or exclusion of low doses of aspirin. We know that low doses of aspirin are ulcerogenic. In the CLASS trial 21 percent of patients took low doses of aspirin, 325 mg/day or less, and none of the patients in the rofecoxib experience were taking low doses of aspirin.

The principal gastrointestinal observations from the CLASS trial are, as shown here in this figure, taken from the publication in the JAMA, which represents the 6-month data point from this year-long trial. In the top panel are all the patients who were evaluated in the trial who were taking either celecoxib or one of the non-selective NSAIDs, ibuprofen or diclofenac. As you note, there was a numeric but not statistically significant reduction in ulcer complications in the overall group, remembering that 21 percent of the patients in the CLASS trial were taking low doses of aspirin and that some of the ulcer effects were related to the effects of aspirin.

So, to get a better concept of the effects of a COX inhibitor compared to non-selective NSAIDs, the middle panel looks exclusively at the patients in this 6-month evaluation of the CLASS trial who were not taking aspirin, just celecoxib, ibuprofen or diclofenac. As you observe in this middle panel, there were statistically significant reductions associated for GI outcomes with celecoxib when compared to traditional NSAIDs in the absence of aspirin at 6 months.

However, for those of you who were here four years ago this month at the long-term safety evaluations of the FDA, the entire CLASS trial data set was evaluated with respect to gastrointestinal complications. When compared to either ibuprofen or diclofenac alone or combined, with respect to complications there were not statistically significant gastrointestinal reductions in events associated, as you can see, with celecoxib. With regard to the VIGOR trial, just to refresh the group's memory, this was clearly exclusively an evaluation of rofecoxib versus naproxen. There was no low dose aspirin. Their observations were straightforward in with respect to either primary or secondary event being confirmed upper GI events or complicated events. There was a statistically significant reduction associated with rofecoxib compared to naproxen.

As I have mentioned, there has also been a similar in design outcome study with lumiracoxib. The variable observations between these outcomes trials have led to extensive debate in the medical and scientific communities as to why one might have observed differences with respect to gastrointestinal endpoints between the outcome trials of COX-2 specific inhibitors.

While I don't have time to get into the nuances and specifics of that debate, one point that I would like to bring to the group's attention that I do think is worthwhile reviewing is that, to the extent that there were differences between the observations in the outcome trials, these differences may have had more to do with differences in ulcerogenic effects with the traditional NSAID comparators such as naproxen, ibuprofen and diclofenac than they may have had to do with differences with respect to ulcerogenic effects between rofecoxib and celecoxib.

The point to be highlighted is that the non-selective NSAIDs differ with regard to their ulcerogenic effects and that the delta, the difference observed between a COX-2 inhibitor and a non-selective NSAID will matter, and it will be based upon the choice of comparator being used. I am not here to speak about cardiovascular effects. Dr. Garret FitzGerald will talk about cardiovascular issues in the talk to follow. But I would like to point out that this concept of differences in COX-1 effects of non-selective NSAIDs is also applicable when we turn to a discussion of considerations of potential differences in cardiovascular observations between the trials of COX-2 inhibitors.

Having pointed out the data with the COX-2 specific inhibitors, I would like to mention that there are other potential approaches, and I would like to turn the discussion to a consideration, as shown on the bottom, of potentially older, safer NSAIDs that may be associated with gastrointestinal safety, agents such as the non-acetylated salicylates, nabumetone, diclofenac and etodolac.

I mention this because--these are not gastrointestinal events, this is a reflection of in vitro evaluations of COX-1 versus COX-2 selectivity of various NSAIDs. On the left, in the green, are NSAIDs which have increasing in vitro COX-1 selectivity and are going in the negative direction; on the right, is increasing COX-2 selectivity. When one evaluates COX-2 selectivity in vitro, there is a group of NSAIDs which fall within this mid-range category of what I would call moderately COX-2 selective, and this COX-2 selectivity of agents such as meloxicam or etodolac may be predictive of what one might see in outcome trials.

Taking etodolac as an example, when it was evaluated with respect to gastrointestinal outcomes compared to a non-selective NSAID such as naproxen, shown in the upper panel, there was a statistically significant, greater than 50 percent, reduction in gastrointestinal outcomes associated with an agent such as etodolac. So, this leads me to conclude, over here in this group of category for COX-2 specific inhibitors, that there are agents which have COX-2 selective activity which had not been widely appreciated historically.

Since aspirin was such and important phenomenon in outcome trials, I think it is relevant to review the gastrointestinal effects of low doses of aspirin. This has been looked at mostly from an epidemiologic perspective, and trials such as this have tended to show a dose-response relationship. Although not statistically significant in this case, clearly lower doses, at least numerically, of aspirin such as 75 mg were associated with a lower rate of clinically relevant gastrointestinal bleeding than higher doses such as 300 mg. In this instance, at least numerically from 75 to 300 mg, the odds ratio of clinically relevant upper gastrointestinal bleed doubled.

Because of the risk associated with very low doses of aspirin such as 75 mg, doses of aspirin that have been quite low, such as 10 mg, have been evaluated in human studies to assess the question of whether or not there would be any daily orally administered dose of aspirin which would be without gastrointestinal effects.

When measured by use of an intermediate marker that would be of COX inhibition or measurement of gastrointestinal prostaglandins, daily doses of aspirin given out to 3 months, as low as 10 mg, were associated with as great of a reduction of gastrointestinal COX as seen with 320, and gastric ulcerations were observed with a dose of aspirin that was as low as 10 mg, suggesting that there is likely not a dose of aspirin that would be effective that would be daily administered that would be without gastrointestinal risk.

Another commonly asked question would be the potential benefit of an enteric coating or buffered preparation of aspirin. When assessed in this cohort from the Framingham trial of patients who were taking various formulations of low dose aspirin, as one sees that there was no appreciable reduction in gastrointestinal bleeding associated with either enteric coating of aspirin or buffered aspirin when compared to plain, non-enteric, non-buffered aspirin preparations. Coming back to the risk factor which I mentioned had been not widely appreciated, the risk factor of multiple NSAID use, that is, combining low dose aspirin with a non-selective NSAID or COX-2 specific inhibitor, I think it is valuable to appreciate for a moment the actual risk, numerical risk, contributed by the addition of aspirin to another prescribed NSAID.

From this population study in Denmark, it was apparent that when one combines the use of low dose aspirin and a non-selective NSAID the risk of having a clinically significant bleed, upper gastrointestinal bleed, more than doubled, such that several people would feel that the risk of a 6-fold increase in the combination of a non-selective NSAID plus aspirin is sufficiently high that this population of users would need to be further risk reduced.

These are data with non-selective NSAIDs. The data with respect to COX-2 specific inhibitors have come primarily from a few sources. In this previous figure in which we saw earlier the 6-month data from the CLASS trial we stopped with the middle panel and had events in individuals taking celecoxib or non-selective NSAIDs in the absence of aspirin.

But when one looks at the bottom panel, rates of events, complications or symptomatic ulcers and ulcer complications in individuals who were taking one of these agents in the face of low doses of aspirin, it is clear that the use of low dose aspirin in the face of a COX-2 specific inhibitor markedly increased the rates of gastrointestinal events.

But a point that I would like you to focus your attention on is the actual incidence of events in the patients who were taking either aspirin in combination with a COX inhibitor or non-selective NSAID. You will remember that the problem that led to really the focus and development of classes of safer NSAIDs is an incidence of ulcer complications of 1-4 percent in the population that takes non-selective NSAIDs. When one looks at the incidence of events that occurs annualized in patients who take aspirin, at least derived from the data in the CLASS trial, it is clear that the incidence that was observed of 2-6 percent is higher than the original problem.

So, I would like to summarize with respect to the effects of low dose aspirin that low dose aspirin clearly increases the risk and mitigates the potential gastrointestinal beneficial effects of a COX-2 specific inhibitor. These observations have been seen in other experiences with regard to the total lack of outcome data which I previously showed you, where we stopped on the top panel. When looking at the observations in patients taking low doses of aspirin, the beneficial effects of total lack disappear.

In endoscopic trials recently we have also seen this effect of aspirin in this trial over 12 weeks in which either aspirin was given alone or in combination with rofecoxib and compared to ibuprofen. Focusing on the rofecoxib plus aspirin comparison, rofecoxib plus aspirin users have a similar, equivalent incidence of endoscopic ulcerations to non-selective NSAIDs such as ibuprofen. So, the short conceptual way of summarizing this is a COX-2 specific inhibitor plus aspirin equals the effects of a non-selective traditional NSAID.

The gastrointestinal discussion that we have had so far has pointed out some of the potential gastrointestinal effect benefits of a safer class of agents such as a COX-2 specific inhibitor. Clearly, the gastrointestinal benefit does not exist in the face of aspirin and what we have recently learned is that the gastrointestinal benefit derived from a class of safer agents in the GI tract might be mitigated by adverse events in other areas, and other areas for consideration for this week's meeting are potential cardiovascular effects.

Given the limitations of COX-2 specific inhibitors and low dose aspirin users or when there may be potential cardiovascular concerns, one question that we have been asked to address would be in a potential world of no COX-2 specific inhibitors would we return to the problem of several gastrointestinal bleeds, hospitalizations or mortality?

Well, this brings us back to the question of what might be the other approaches to accomplish the objective of reductions in GI events. We have discussed some of the older, safer NSAIDs. There are NSAIDs in development such as nitric oxide NSAIDs or phosphatidylcholine NSAIDs, the effects of which we are unsure of now and they are currently being evaluated. But the other prevailing strategy to accomplish this objective would be the consideration of a non-selective NSAID plus co-therapy with either a proton pump inhibitor or misoprostol.

Data in support of the proton inhibitor approach have been looked at in several trials, one example of which is shown here, endoscopic ulceration in NSAID users receiving co-therapy with either placebo, a proton pump inhibitor or misoprostol. What the data pretty consistently say is that proton pump inhibitors have similar ability to misoprostol to prevent recurrent ulceration in NSAID users.

Given that there are two prevailing approaches to accomplishing GI safety, either COX-2 specific inhibitor alone or a non-selective NSAID plus a PPI, an important question which has presented itself for evaluation has been how might these two approaches compare directly and this is an important question to consider when considering the alternatives to having a world potentially in which there might not be COX-2 specific inhibitors available. Could GI safety be accomplished?

Well, this question has been asked at least in two trials or similar design in which high risk NSAID users--high risk being defined as people who previously had a history of bleeding ulcers. Once the ulcers were healed, they were then placed on either of the combination of non-selective NSAID plus a proton pump inhibitor or a COX-2 specific inhibitor, and then were followed for 6 months for rates of recurrent gastrointestinal bleeding. The results of one of these trials has been fully published in a peer reviewed journals, shown here.

The two endpoints being looked at--on the right are outcomes such as upper gastrointestinal bleeding; on the left are the results of endoscopic ulceration. Either of these endpoints tells us that the approach of a non-selective NSAID plus a PPI appears comparable to the COX-2 specific inhibitor approach for achieving the objective of reductions in GI safety. However, two important points that I would like to point out to the group are, one, we have endoscopy on the left and outcomes, GI bleeding, on the right. Again, the endoscopic ulcerations that are seen in the trials generally predict what one would see in an outcomes study but, more importantly, if one looks at the actual rates of events which occurred, on the right, 5 percent and 6 percent with either approach in a group of individuals at high risk, meaning they previously had a history of gastrointestinal bleed, it is clear that either approach, either NSAID plus PPI or COX-2 specific inhibitor, is sufficiently adequate to reduce the rates of events back to a comfortable range. The rates of events seen here in a high risk population are similar to the initial problem for which these approaches were developed.

In conclusion I have several observations. The untoward gastrointestinal effects of NSAIDs, as we know, cause considerable morbidity, mortality and cost. Secondly, COX-2 specific inhibitors were developed principally to achieve a reduction in NSAID gastrointestinal toxicity. That was a very desirable objective to be reached. But very interestingly, as we just reviewed, this objective has been partially reached. It seems that the risk reduction may not be achieved to the extent that we would have liked in patients who are at high risk for gastrointestinal bleeding, and the reason this is important is that that is clinically the target group of interest for risk reduction.

Paradoxically, I did not mention that if one looks at subgroup analyses of outcome studies it appears that people who are at lower baseline gastrointestinal risk do have a benefit from receiving a COX-2 specific inhibitor. However, the low risk group has a low prevalence of this problem of NSAID-related gastrointestinal events in the population.

So COX-2 inhibitors, it appears, have been widely used by patients who are not at high risk for GI effects, and we have reviewed over the last several minutes that there are some limitations with COX inhibitors. In my opinion, there is no great clinical need for COX-2 specific inhibitors in patients who are at baseline at low GI risk. It is also clear that there is no GI benefit in patients who are concurrently taking aspirin. We are here to discuss the possibility that cardiovascular concerns may exist for some groups of patients.

So, the strategies to reduce the gastrointestinal effects of NSAIDs should focus on patients at greatest risk. Just to reiterate, the patients at greatest risk may not be sufficiently risk reduced by either of the prevailing strategies which we currently have available clinically. For such patients, COX-2 specific inhibitors may be an attractive option but it looks like the target group of interest may not have the anticipated benefit.

For patients who are taking low dose aspirin or, if cardiovascular concerns were to exist, we have been asked to consider that if there were a world without COX-2 specific inhibitors how might we accomplish this objective, and it is clear that there are other strategies available that may lead to a reduction in NSAID GI effects. Thank you very much.

DR. WOOD: Thank you very much. Byron, could you just stay there in case there are specific questions for you while the slides are up? I have one. Could you put up slide 4 again? That shows data through 1990.

DR. CRYER: Yes.

DR. WOOD: What surprised me is Jim Freis has updated that data through 2000, and that dramatically changes what that slide looks like. In fact, he found a 67 percent decline since 1990 in complicated ulcers, the vast majority of which occurred actually before COX-2 specific inhibitors went on the market. So, I am interested, first of all, in why you chose to present 15-year old data when there is new data out there that contradicts that, and whether you would like to comment on his publications from which this data came as well.

DR. CRYER: Sure. It is correct that there are newer data available that have demonstrated a reduction in gastrointestinal bleeds on a population basis. On the other hand, it is also very true that this problem of gastrointestinal bleeding with NSAIDs continues to be a significant problem despite its more recent decline. But, more importantly, he also highlighted a very important observation which is that the declines in gastrointestinal bleeding that have been seen in populations preceded the introduction of COX-2 specific inhibitors, and there are some data sets to suggest, at least in the U.S., that hospitalizations for gastrointestinal bleeding since the introduction of COX-2 specific inhibitors have not markedly declined compared to hospitalizations prior to their introduction.

DR. WOOD: Right. So, most of the 67 percent decline occurred before these drugs went to the market, and that 67 percent occurs from the points on your slide here.

DR. CRYER: Point well taken.

DR. WOOD: And one other point of clarification I guess, the data you showed from CLASS, was that data from the predefined endpoint of the study at 18 months or the 6-month analysis that was published?

DR. CRYER: Just for sake of review, I have pointed out both time-dependent endpoints. The endpoint that was published and shown here, in the JAMA, was the predefined 6-month data and the endpoints that are shown here represent an evaluation of the entire data set. There are clearly differences in the conclusions about the effects of celecoxib which varied by time and varied by whether one evaluates the data at 6 months or evaluates the entire data set.

DR. WOOD: Just remind us, at 18 months what did the data set show?

DR. CRYER: At 13 months the data, with respect to complications, indicate that there was no statistically significant reduction in upper gastrointestinal complications associated with celecoxib, at a dose of 400 twice daily, when compared to either diclofenac or ibuprofen individually or when compared to both of them together. I will point out for the sake of fair balance that this data does include the 21 percent of individuals who were taking low doses of aspirin.

DR. WOOD: Other questions from the committee? Dr. Nissen?

DR. NISSEN: Yes, this 1-4 percent rate, I am interested in understanding the time-dependent hazard. If a patient is put on a non-selective NSAID and, let's say, for the first year has no GI events, is the risk in the second and third and fourth years the same as it is in the first year? In other words, once you know that a patient is tolerating an NSAID are they no longer at high risk?

DR. CRYER: There are a few answers, sub-answers to that question. It is a complicated discussion. What is clear that risk persists, that even in the individual who did not develop a complication in year one, that individual continues to have risk in subsequent years--two, three, four, etc. There are data sets that suggest that the period of highest susceptibility, highest risk is within the first three months of administration. Having said that, there are other data sets to the contrary. This incidence of gastrointestinal events that are time-dependent in individuals has been difficult to assess primarily based upon a concept of selection of susceptible individuals. People drop out because of other reasons such as dyspepsia. So, it is difficult to get a firm estimate on that. But it is clear, in summary, that the risk after one year or after any period of time is always persistent as long as the NSAID exposure is present.

DR. NISSEN: Two more quick questions. I didn't see any analysis of COX-2 plus low dose aspirin versus a non-selective NSAID plus low dose aspirin. The reason I am asking that is that, as a cardiologist, in my patients who are taking conventional NSAIDs, if they need aspirin for cardiovascular prophylaxis I give them aspirin. So, the question is are there any studies looking at NSAID plus aspirin versus COX-2 specific inhibitor plus aspirin?

DR. CRYER: Well, the CLASS trial addressed that question in a subpopulation of individuals which was under-powered statistically to give a definitive answer to that question. That is an ongoing debate within the medical communities. I will say, however, that while the debate continues what is clear is that with either approach COX-2 specific inhibitor plus aspirin or non-selective inhibitor plus aspirin the ensuing rates of gastrointestinal events are too high for us to feel comfortable that we have risk-reduced those patients sufficiently.

DR. NISSEN: And a final question, symptoms of dyspepsia are obviously one of the issues as well, and I want to make sure I understand what fraction of the population, let's say an osteoarthritis population, simply cannot tolerate NSAIDs because of GI discomfort. Do we have data on that?

DR. CRYER: Sure. A couple of comments about dyspepsia which I didn't mention, NSAID dyspepsia is common. Its prevalence varies depending on how dyspepsia has been defined in trials, and because there have been variable definitions of dyspepsia, its reported rates have varied anywhere from 10-30 percent of NSAID users, but it is clearly more common than complications.

In the patient who has dyspepsia, the presence of dyspepsia is not predictive of the patient who might have risk. In most of these studies dyspepsia, in my way of thinking, is considered more of a nuisance issue that can be controlled symptomatically with acid reduction rather than something that presents significant gastrointestinal concern.

DR. WOOD: Dr. Gibofsky?

DR. GIBOFSKY: You commented extensively on the upper GI risk but in your second slide you correctly pointed out that there are problems with traditional medications affecting the structures of the GI tract below the ligament of triads. Could you comment somewhat on the data comparing the effect of COX-2 specific inhibitors versus traditional non-steroidals with or without proton pump inhibitor protection on the lower GI tract?

DR. CRYER: There have been fewer data sets which have assessed the lower gastrointestinal events with NSAIDs. A few comments on the types of studies that have been done, there have been studies using pill endoscopy which have indicated that lesions, endoscopic ulcers and erosions occur in the lower gastrointestinal tract contributed to by non-selective NSAIDs, an effect which can be reduced by a COX-2 specific inhibitor, an effect which is not reduced by the co-therapy approach of adding a PPI to a non-selective NSAID. I am speaking of the lower gastrointestinal effects.

Having said that, again similar to the endoscopic ulcer story, these endoscopically detected lesions in the lower gastrointestinal tract probably have very limited clinical relevance. When lower gastrointestinal clinically significant events have been assessed from the prospective trials, the one noted most commonly in the literature is an assessment of the VIGOR trial looking at the effects of rofecoxib compared to naproxen, in which case a 40-50 percent reduction was seen in lower gastrointestinal events with rofecoxib compared to naproxen, again to reiterate, a reduction which would not be expected to be observed with the proton pump inhibitor approach. Having said that, in that assessment of the rofecoxib experience there was an inclusion in the definition of lower GI events of individuals who had had reductions in hemoglobin and hematocrit and who did not otherwise have clinically apparent gastrointestinal bleeding.

Probably the best assessment in terms of the risk of lower gastrointestinal events on NSAIDs comes from population-based observational studies. While there is variance in that estimate, it looks like the lower gastrointestinal events probably contribute 10-20 percent of clinically relevant events when compared to all GI events that might happen on NSAIDs.

DR. GIBOFSKY: One last quick point, would your recognize that there might well be a population of patients whom you would stratify as low GI risk who, nevertheless because of either intolerance, as the last speaker asked, or lack of efficacy to traditional non-steroidals, would be candidates for another class of agents?

DR. CRYER: Sure. Their NSAID dyspepsia is a common phenomenon. I will say that when dyspepsia has been carefully evaluated in the prospective trials of COX-2 specific inhibitors in general there tends to be a reduction in the rates of dyspepsia associated with the COX-2 specific inhibitors. However, when one evaluates the absolute reduction in rates of dyspepsia in the trials it generally tends to be a few percentage points. Finally, some of the other strategies that were mentioned to accomplish risk reduction, for reduction in GI events in patients on NSAIDs, also accomplished reductions in dyspepsia in patients who might experience NSAID-related dyspepsia.

DR. WOOD: Dr. Cush?

DR. CUSH: Byron, two time questions. One, is there a time point at which peptic ulcerations and bleeds plateau over time in NSAID users or COX-2 users? Second, what is the longest data set that we have as far as the use of a COX-2 agent in a clinical trial where observation is carried out? Do we have two-year data; five-year data?

DR. CRYER: Right. There does appear to be some plateau-ing of the effect. The data sets do suggest that after long-term exposure the rates of events with longer-term exposure are not as great as rates of events with initial exposure to NSAIDs but, again, that may be attributable to the phenomenon of dropping out of susceptibles. The second portion of your question, Jack, was?

DR. CUSH: What is the longest data set we have on COX-2 agents?

DR. CRYER: Well, when one looks at the trials, the prospectively defined outcome trials--we have CLASS, TARGET, VIGOR--there are periods of observation out to 13 months. Having said that, we certainly have longer periods of observations of COX-2 specific inhibitors for trials in which the specific outcome of interest was defined for an endpoint that was other than upper GI bleeding, so specific polyp reduction, Alzheimer's disease, other trials that we certainly will hear about over the course of the next few days, many of which have gone out to periods as much as 3 years.

DR. WOOD: Is there anyone else who has a question that specifically addresses something on a slide that the speaker could show again? If not, we will come back to these questions and ask you, Byron, if you would, to be available this afternoon.

DR. CRYER: Yes.

DR. WOOD: Are there any questions that somebody has specifically? Tom?

DR. FLEMING: Yes, could we go back to the slide that showed the CLASS trial with the time to complicated ulcer?

DR. CRYER: There were two. You can tell me which one you are referring to, this or the next?

DR. FLEMING: Both, this and the next. Basically, here what you are showing us is that in the presence of aspirin there doesn't seem to be a reduction in the complicated ulcers although in those that are not taking aspirin there is this reduction of about two-thirds. If you go to the next slide, that is at 6 months. Hence, we see at 6 months this reduction in the rate in the celecoxib group that is driven by those patients who are not on aspirin. But that effect, as you noted, has disappeared out at a year.

I know that is making a lot of a single data set but is this suggestive of the possibility that, in response to Steve Nissen's question, there could be a group that is more susceptible and what you are doing, in the presence of aspirin, is achieving not effect; in the absence of aspirin you are achieving a delayed effect but, in essence, you are going to have the same overall incidence by a year even with the COX-2 specific inhibitor?

DR. CRYER: Sure, your point is that there are likely subgroups of susceptibility for GI risk on NSAIDs or on COX-2 specific inhibitors. But I would say also that underlying that argument, which I think is accurate, is the observation which confounds the whole discussion, which I have mentioned previously, which is that early on in any of these trials you are going to remove the most susceptible of the individuals and those who actually persist in the trial tend to be the least susceptible subpopulation.

DR. FLEMING: Indeed, but that is the essence of what I am saying, and this would be consistent then with the theory that if there is a particular susceptible group, that group is going to have a higher risk and it is, in fact, going to have complicated ulcers. They just occur somewhat sooner with the non-specific NSAIDs. The COX-2s are not preventing that, they are just delaying the time to the occurrence.

DR. CRYER: I think we are in agreement there.

DR. WOOD: Richard?

DR. PLATT: To extend that, on slide 13 you list some risk factors for NSAID-associated GI toxicity. Can you tell us how well those discriminate low risk individuals from high risk individuals? And, if they do, what fraction of the population falls into low risk, medium risk, high risk? And, quantitatively what are those risks?

DR. CRYER: That is a complicated question but it is an important one. When people like myself have shown these risks we commonly lead to the assumption that these risk are numerically equivalent, which they are not. There are certain risk factors which clearly place one individual at higher risk than others. The highest risk most consistently seen in trials would be that of having had a previous history of a gastrointestinal bleeding ulcer. But not far behind that would be the risk of taking an anticoagulant, such as Coumadin, in association with a non-selective NSAID. Age as a risk factor is a variable one. Although we suggest in our discussions of this that there may be a threshold of age below which one may be not at risk and above which at risk for having it. In fact, it is a continuum. In fact, the risk contributed by age is about a 2 percent increase in risk per decade of life, such that people who are in their 80s are at very high risk, much higher risk than people who are in their 40s.

With respect to your question of quantifying the risk in a population, that is a difficult issue because all of these risk factors do not individually present themselves in any one patient. The more risk factors one has--two risk factors present greater risk than one; three greater than two. I would say, having said that and trying to give you a reasonable estimate, in my opinion the percentage of NSAID users who would likely be candidates for this is probably somewhere on the order of 20-25 percent, depending on how one assesses that. If one looks at an OA or RA population and concludes that age in and of itself is a risk factor, then you are close to 80 or 90 percent of the population that might be at risk based upon that risk factor of age. So, it really depends on which risk factor, and it really depends on the quantitative contribution of the risk factor being described. But, certainly, I would say the one that most clearly and consistently has presented itself as highest risk in the various trials has been the risk factor of having had a previous bleeding ulcer, and it is the one that I would like to underscore which does not appear to be sufficiently risk-reduced by either of the strategies which we have available.

DR. WOOD: Any other questions that are so burning that they have to be asked now and not in the discussion? Ralph? Burning? And let's try and make the answers as brief as we can.

DR. D'AGOSTINO: What are the consequences of complicated ulcers in, say, the CLASS trial where you do see this differential and this catching up? Do they follow to see the consequences of these ulcers? Were they different over the time period?

DR. CRYER: I am sorry, I don't understand.

DR. D'AGOSTINO: What are the consequences? What happened to these subjects after? Were they reversible, the ulcer? Does it lead to mortality?

DR. CRYER: Right, what I assume is driving your question is whether there are differences in mortality--

DR. D'AGOSTINO: Well, morbidity, mortality, what happens.

DR. CRYER: Well, clearly, morbid effects are hospitalization and the complications of them having a massive gastrointestinal bleed, which can be several. The ultimate complication or consequence of these morbid effects is mortality and in these outcome trials there were no differences in the level of mortality. With regard to the various other consequences, most of them are clearly going to be reversible after having suffered a significant hospitalization.

DR. WOOD: Any other smoking questions? Peter?

DR. GROSS: A question on the third to last slide, on recurrent ulcer bleeding in high risk patients, the so-called non-selective NSAIDs selected diclofenac to compare with celecoxib.

DR. CRYER: Yes.

DR. GROSS: Diclofenac is roughly comparable in COX-2 selectivity. Is that the right drug to test with PPI to show that the PPI plus a non-selective NSAID is comparable to a COX-2 inhibitor like celecoxib? Should they have picked a non-selective NSAID that was less selective for COX-2?

DR. CRYER: Sure. Your point is very well taken and it is one which I tried to underscore throughout the talk, which is that there are clearly differences in the COX-1, i.e., ulcerogenic, effects of non-selective NSAIDs. Diclofenac clearly is an agent which is associated with a lower rate of gastrointestinal ulceration and complications than non-selective NSAIDs. So, in this evaluation of the comparison of diclofenac plus omeprazole compared to celecoxib there is a valid discussion that the results may have been biased in favor of the diclofenac plus omeprazole approach.

The reason I showed that is that that was a fully published paper. There are, however, other trials not yet fully peer reviewed, which have been presented in the gastrointestinal community, looking at other NSAIDs, such as naproxen plus a proton pump inhibitor compared to the COX-2 specific inhibitor approach, and the results of those observations again are comparable endpoints between the two strategies.

DR. WOOD: I am going to move us on now and we will come back after the next talk. Dr. Cryer, we would like you to come back up if there are questions at that time as well. The next speaker is Dr. Garret FitzGerald. Garret?

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see also:

Q & A Your Vioxx Lawyer - Vioxx, Celebrex & Bextra FDA Transcript - Q&A
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Questions Safety Concerns - The Vioxx Questions the Doctors are Asking
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FDA Transcript - Day 1 Conference for Safety - Vioxx, Celebrex & Bextra FDA Transcript
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