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CME

Clinical Counterpoints: New Techniques in Total Knee Arthroplasty and Pain Management

  • Authors: Faculty: Evan F. Ekman, MD; Peter M. Bonutti, MD, FAAOS, FACS; Kirby D. Hitt, MD; William J. Hozack, MD
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Target Audience and Goal Statement

This program was designed to meet the educational needs of orthopedic surgeons and other physicians involved in the surgical management of joint pain and postoperative pain management.

Upon completion of this activity, participants will be able to:

  1. Identify predictors for improved patient satisfaction after orthopedic surgery.
  2. Explain the concept of multi-modal analgesic therapy, and discuss its place in pain management.
  3. Discuss different surgical and navigational approaches for TKA.

 


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Postgraduate Institute for Medicine has a conflict of interest policy that requires course faculty to disclose any real or apparent commercial financial affiliations related to the content of their presentations/materials. It is not assumed that these financial interests or affiliations will have an adverse impact on faculty presentations; they are simply noted here to fully inform participants.



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CME

Clinical Counterpoints: New Techniques in Total Knee Arthroplasty and Pain Management

Authors: Faculty: Evan F. Ekman, MD; Peter M. Bonutti, MD, FAAOS, FACS; Kirby D. Hitt, MD; William J. Hozack, MDFaculty and Disclosures
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Welcome and Introductory Remarks; Case Presentation: State of the Art in Total Knee Arthroplasty (TKA) , Presented by Evan F. Ekman, MD

Goals of Pain Management

  • I know that people are still coming in the door, but for the sake of time, we'll try to go ahead and get forward at least with some of the housekeeping information. My name is Evan Ekman; I'm an orthopedic surgeon. I practice orthopedic sports medicine in Columbia, South Carolina, and I am absolutely thrilled that you all are here. This turnout is great and I think certainly it speaks to your desire for education and your interest in the topic, and the topic overlaps into a couple of arenas, both of which I think are very, very timely and we're looking forward to sharing some information with you.

    Let me talk just briefly about a couple of housekeeping items and let me also mention that there are still some seats; there are several right up at this table and up here towards the front, there are some seats. First of all, this is for CME activity; it's for 2 credit hours. And to get your 2 credit hours of CME, first of all, you have to be here -- thank you! -- and second, you have to fill out your evaluation form. We have done this course in the past and I would also tell you that evaluation form is very useful in planning for the future. Also, there is a CD-ROM that will be made available of tonight's program; if you check at the registration desk, they will make certain that you get that CD-ROM. As well, there are some handouts that are available in folders at all of the tables; should there not be enough for everyone, please, again, leave your business card at the registration table and they will be more than happy to mail that information to you. Counting myself, there will be four speakers and I truly am excited to hear the next three speakers. At the end, there will be an opportunity for questions; if you would prefer rather than ask your question, please write it down on one of the question cards that's in your folder and hold it. Someone will come get that question card from you and bring it up here to me. So I think that's just about all of our housekeeping except to say that this CME activity is co-sponsored by Pfizer and also by Stryker, so thanks to our sponsors. And if you get an opportunity on the way out, be certain and thank our sponsors as well.

    Well, now with that, let me just say the number 1 most common reason a patient comes to seek out healthcare, whether you practice in Malaysia, the United States, Canada, Korea, the number 1 reason a patient comes to see you is for pain relief. As orthopedic surgeons, we're somewhat unique in not only that do we treat pain, at times we create pain and the pain due to surgery, and our ultimate goal obviously is facilitation of getting people back to full activity and doing it in a timely fashion. So the entire focus of this evening is on getting people back to activity in an appropriate and timely fashion, using a strategy that maximizes patient satisfaction.

  • Welcome and Introductory Remarks. Case Presentation: State of the Art in Total Knee Arthroplasty

    Slide 1.

    Welcome and Introductory Remarks. Case Presentation: State of the Art in Total Knee Arthroplasty (TKA)

    (Enlarge Slide)
  • And certainly we could present any case that you would like, but this is just to kind of give you a thought of where we are heading with the evening and that's this particular patient. It's a 51-year-old female with a long history of osteoarthritis in her knee. She has had appropriate and nonoperative treatment, including anti-inflammatories, acetaminophen or paracetamol. She's had physical rehabilitation, has spent some time walking with a cane. Her therapist had had difficulty normalizing her gait. Her past medical history is fairly benign except for just a bit of hypertension. So for all intents and purposes, we can agree that this patient is going to need surgery and the rest of the evening is going to focus on the surgery -- some of the preoperative considerations, perioperative considerations, strategies in decision-making, and also postoperative pain relief.

  • Case: 51-yo Female Requires Knee Replacement

    Slide 2.

    Case: 51-yo Female Requires Knee Replacement

    (Enlarge Slide)
  • Now my charge this evening is concepts in pain relief and the things that we can do to maximize satisfaction and get people comfortable so they can go home and get back to a normal life. Well, since September 30, 2004, there have been a number of news-related events and even as recent as last Friday with the conclusion of the FDA subcommittee meeting, more news has come out. And so, as not a last minute but in the last week, I have made the decision to really focus my talk on some of these most recent cardiovascular events, and that's because those are the questions I'm getting most commonly from my orthopedic surgeon colleagues. So we'll spend a considerable amount of time going over these events and I will also give you the conclusions of the FDA subcommittee and some of the data they looked at to make these conclusions.

  • Improving Postsurgical Patient Satisfaction and Performance: Perioperative Pain Management

    Slide 3.

    Improving Postsurgical Patient Satisfaction and Performance: Perioperative Pain Management and Surgical Technique

    (Enlarge Slide)
  • Now look at this gentleman on the right. That was a perfect example of what the World Health Organization in 1976 said our goals for pain management were, to meet the humanitarian need for pain relief, and that's what that athlete laying on the floor is thinking about right now, but also to facilitate rehabilitation and return to function. And I can think of no better starting slide than the information that is contained here that really summarizes all of the strategies that will be presented tonight. Now I want to share with you some pain strategies; I've had a chance for about the past 5 or so years to teach our Academy's instructional course lecture on orthopedic pain management and I would also reference a review article that was in the Journal of Bone and Joint Surgery in the summer for many of this information and it's all in the peer-reviewed literature.

  • The Goals of Pain Management

    Slide 4.

    The Goals of Pain Management

    (Enlarge Slide)

Analgesia Strategies

  • But it's important as orthopedic surgeons we understand and hopefully embrace some of these strategies, and the first one is multimodal analgesia. Well, the pain process can be modulated at multiple sites. Multimodal analgesia takes advantage of the notion that we are going to affect these multiple sites with the ultimate goal of decreasing opioid utilization, and by decreasing opioid utilization, decreasing opioid-related adverse events. Now multimodal analgesia doesn't mean just adding a coxib or just adding an anti-inflammatory; it may mean adding Marcaine to a joint, regional anesthesia, cryotherapy or ice. So all of these things are considered, but clearly with the advent of coxibs and their lack of effect on platelet aggregation, it opened up an opportunity for you and I to affect the prostaglandin production in the perioperative environment.

  • Multimodal Analgesia

    Slide 5.

    Multimodal Analgesia

    (Enlarge Slide)
  • Now the next concept that I want to get across is pre-emptive analgesia, and that means that the timing of dose makes a difference. So, yes, there are things you should do before surgery that are going to help pain relief after surgery, and one of those things is pre-emptive analgesia. So let me give you sort of a cartoon here that's going to help us understand that, but keep in mind prostaglandin production, inducible prostaglandin production, which creates pain, begins not when the patient wakes up but when the knife drops. And the concept is, well, what if we completely inhibit or stop prostaglandin production before the stimulus? And that's why we dose before surgery.

  • Sensitization/Preemptive Analgesia

    Slide 6.

    Sensitization/Preemptive Analgesia

    (Enlarge Slide)
  • Here's this pain curve; the greater the stimulus, the more the pain and that's rather obvious. I'll give you a few examples to think of. The first one is knee replacement surgery, a minimally invasive knee replacement surgery. The second one, bumping my toe against this podium. The third one: A sunburn.

  • Sensitization/Preemptive Analgesia

    Slide 7.

    Sensitization/Preemptive Analgesia

    (Enlarge Slide)
  • And I'll do this quickly, but certainly if I bump my toe the first time, you'll see that the pain may not be much, at the bottom of the curve on the right.

  • Sensitization/Preemptive Analgesia

    Slide 8.

    Sensitization/Preemptive Analgesia

    (Enlarge Slide)
  • If I bump it a second time, it will certainly hurt worse; that's a painful stimulus that's become more painful and that's hyperalgesia. That's why it would hurt if you bump a knee that's been replaced in the perioperative environment.

  • Sensitization/Preemptive Analgesia

    Slide 9.

    Sensitization/Preemptive Analgesia

    (Enlarge Slide)
  • Well, what about the sunburn? As you sit there and listen to me talk, the shirt on your shoulders isn't painful; if you had a sunburn, it might be and that's allodynia. So our charge in pain management is to get that curve to shift back to the right. Our charge in pre-emptive analgesia is to never let that curve shift. So keep these things in the back of your mind.

  • Sensitization/Preemptive Analgesia

    Slide 10.

    Sensitization/Preemptive Analgesia

    (Enlarge Slide)

Celecoxib Multicenter Efficacy Study

  • Well, let's put this to a real-world task and I'm going to share just a little bit of clinical data in efficacy. This was a big multicenter study I had an opportunity to present this summer at the Sports Medicine Society.

  • Efficacy of Celecoxib Used Pre- and Postoperatively for Knee Arthroscopy

    Slide 11.

    Efficacy of Celecoxib Used Pre- and Postoperatively for Knee Arthroscopy

    (Enlarge Slide)
  • It takes advantage of both of these, pre-emptive analgesia and multimodal analgesia, and the second most common operation in the world, which is knee arthroscopy with meniscectomy. And a multicenter group of investigators got together to define the standard of care and we decided it was an opioid combined with paracetamol or acetaminophen plus Marcaine in the joints. So we standardized that; everyone got 20 cc of Marcaine and prn utilization of Vicodin, the trade name in the United States. Half the patients got a 400 mg pill of celecoxib preoperatively; one 200 mg pill postoperatively at their first request for medication, and the other group got placebo in those two spots. The simple question was: Will you take less opioid if you're in the celecoxib group?

  • Slide 12.

    (Enlarge Slide)
  • Now the question you all may have for me is who cares? Does it matter? And I will show you that it does, in fact. And the answer to the first question is yes, the group taking celecoxib took less opioid in the 24-hour postoperative period; the placebo group of course took more opioids. So, yes, less opioid was used.

  • Total Analgesic Use at 24 Hours (24-hr mITT)

    Slide 13.

    Total Analgesic Use at 24 Hours (24-hr mITT)

    (Enlarge Slide)
  • Now here's a bit of the surprise: The group taking placebo and taking more opioid reported more pain; the celecoxib group taking less opioid had less pain. You'll notice here in the first 6 hours, there are no statistical differences and that's simply because everyone has Marcaine in their joint, so they're not experiencing a lot of pain. The Marcaine wears off; the statistical differences in this multicenter study are rather compelling. And then at some point, we certainly expect just with these two doses that those points are going to come back together and certainly they do; there's no statistical difference by 24 hours.

  • Patient's Assessment of Pain at Rest (VAS, mm) (mITT)

    Slide 14.

    Patient's Assessment of Pain at Rest (VAS, mm) (mITT)

    (Enlarge Slide)
  • Here's the so what. So we've seen so far less opioid utilization, better pain relief, and what I think is important is fewer opioid-related adverse events. And the numbers are pretty considerable: 36% and 18%. So whether it's respiratory depression, sedation, confusion, urinary retention, somnolence, or the most common things, which are nausea and vomiting, these issues are important to the patient and they affect patient satisfaction. So therefore they should be important to us. Well, efficacy seen with this strategy.

  • Treatment-Emergent Adverse Events (All Causalities)

    Slide 15.

    Treatment-Emergent Adverse Events (All Causalities)

    (Enlarge Slide)

Cardiovascular/Cerebrovascular Safety Issues

  • But tonight those aren't your questions, I'm sure. Your questions are: Well, what's going on in the world of cardiovascular safety? I've heard so much, I'm becoming fatigued by the constant questions my patients have about this and I'm becoming fatigued about having to defend my position. Well, we're in a unique opportunity as orthopedic surgeons; the FDA meeting concluded on Friday (February 18, 2005), and we are the first major meeting in medicine to be able to disseminate this information. So I'd tell you as orthopedic surgeons, we're leaders and if I'm not mistaken, this might be the first chance in the world that this information has been disseminated from the podium.

  • Cardiovascular Safety

    Slide 16.

    Cardiovascular Safety

    (Enlarge Slide)
  • Well, here's a little timeline of what has happened. September 30 is the day that you and I heard that rofecoxib was being withdrawn from the worldwide market and that was because they had a prevention trial, if you will, on polyp disease that demonstrated a 2-fold increase in the incidence of significant cardiovascular events in a group taking rofecoxib at a 25 mg dose compared to the placebo group. Well, so they took the drug off the market.

    Next data point: November 2004, the US package labeling for valdecoxib changes. The relevant piece of information here is in that change, it reflected that there were two studies in coronary artery bypass grafting that demonstrated an increased incidence of cardiovascular events. None were seen in any studies in osteoarthritis and rheumatoid arthritis or in fact in any of the other surgery or pain studies as well, and the orthopedic community in fact has participated in many of these. These were exclusive to the highest risk population, those patients immediately having undergone coronary artery bypass grafting and this medication being used in the postoperative period. So this was reflected with a label change.

    Then on December 17, the National Cancer Institute announced that they were stopping another prevention trial called the APC trial; in fact, they were stopping two trials because one of the trials showed an increase in cardiovascular events on patients with celecoxib. And to date to that point, we had never ever seen any signal at any dose of cardiovascular events with celecoxib, so those studies were stopped.

    Then December 20, there was another prevention, an Alzheimer's prevention trial called the ADAPT trial -- all these letters become a little bit confusing at some point. But this trial was stopped based on IRB considerations from the data from these trials, but when they looked at the data, what they found was there was a statistical increase in cardiovascular events in a treatment group, but it was not the celecoxib group. The patients taking the lowest possible dose of naproxen -- by the way, that's the over-the-counter dose in the United States, 220 mg twice a day; you're using considerably more than that in your patients -- had a 2 times increase in cardiovascular events. So now the question becomes: Well, what is the safety of a traditional nonselective anti-inflammatory, that option we commonly turn to?

  • Developments Leading to FDA Advisory Committee

    Slide 17.

    Developments Leading to FDA Advisory Committee

    (Enlarge Slide)
  • So just to look a little bit deeper, here's this first study I mentioned, the APPROVe trial with rofecoxib, rofecoxib being compared to placebo for polyp prevention. Here's 36 months and you can see a rather compelling statistical increase and the break-off point appeared to be at about 18 months.

  • APPROVe: Confirmed Serious Thrombotic Cardiovascular Events

    Slide 18.

    APPROVe: Confirmed Serious Thrombotic Cardiovascular Events

    (Enlarge Slide)
  • So here are these polyp trials that I mentioned, polyp prevention trials. One goes by APC, the other goes by preSAP and I'll show them to you side to side. The theory behind these is that celecoxib will reduce polyp recurrence and somehow the primary endpoints of the study have certainly not been highlighted with all of these other issues. So here's the one that raised the concern for celecoxib; you see at 400 mg twice a day or at an 800 mg dose -- that's four times the FDA approved dose for osteoarthritis and rheumatoid arthritis -- an increase in cardiovascular events compared to the placebo group. Even in the 200 mg twice a day, or 400 mg total daily dose, it's certainly approaching statistical significance and we hadn't seen this before, as I said. Well, here's the preSAP trial ongoing at the same time and celecoxib and placebo are perfectly paralleling each other, but they were both stopped -- so no statistical differences, no numeric differences in that study.

  • Celecoxib Colon Polyp Prevention Trials

    Slide 19.

    Celecoxib Colon Polyp Prevention Trials

    (Enlarge Slide)
  • And here's the ADAPT, this Alzheimer's prevention trial that I also mentioned, and this ADAPT trial, again, the signal that was of concern was one with naproxen, raising the question about the cardiovascular safety of nonselective anti-inflammatories.

  • Alzheimer's Disease Prevention Trial (ADAPT)

    Slide 20.

    Alzheimer's Disease Prevention Trial (ADAPT)

    (Enlarge Slide)
  • So the FDA says: You know, we've got a lot of question marks; there's a lot of concerns, public concerns, physician concerns, and personal concerns and we want to get everybody together and figure this issue out a little bit deeper.

  • ADAPT

    Slide 21.

    ADAPT

    (Enlarge Slide)

Celecoxib Cardiovascular Safety: Meta-analysis Findings

  • So they invited presentations from all the relevant industry players -- Pfizer, Merck, Novartis, Bayer -- and also some selected people from the community who were expert in the field to make some comments and some presentations as well, and there are 32 members of this panel who are going to vote. These things were started last Wednesday and finished on Friday, so this is hot off the press.

  • FDA Advisory Committee Hearing on Safety of Coxibs and NSAIDs: February 16-18, 2005

    Slide 22.

    FDA Advisory Committee Hearing on Safety of Coxibs and NSAIDs: February 16-18, 2005

    (Enlarge Slide)
  • So how do we take these little bits of data and try to make sense out of them in a bigger picture? And that's probably with reasonable sound, adjudicated meta-analysis. There are also some rather enormous epidemiology studies with celecoxib and these are two of the main pieces that were presented to the FDA. So I'll go over these and I think it's important for you and I to look at these to answer personally our own questions. So in these meta-analysis of prospective, randomized controlled trials, here's what we see. First, there were I believe there were over 44,000 patients represented; there were I believe over 20 clinical trials and I may be underestimating that number. The number of patients that this data represents in the randomized controlled trials is absolutely extraordinary, particularly when you think of it against the information we have as orthopedic surgeons and how we do our clinical trials.

  • Celecoxib Cardiovascular Safety

    Slide 23.

    Celecoxib Cardiovascular Safety

    (Enlarge Slide)
  • So this is a summary of everything that's out there and I've broken it down in a few different ways. I'll compare celecoxib to placebo and then I'll compare celecoxib to the traditional nonselective anti-inflammatories. And I'm going to present it to you in terms of odds ratios, okay? So if your odds ratio is 1.0, the two groups are the same; if your odds ratio is less than 1, your chances are less of having an event in the celecoxib group than the placebo group, and the opposite if you're greater than 1. And you can see the confidence intervals overlap 1 on every single case; I won't read these to you, but they're broken down by relevant cardiovascular events. But we can conclude on this that celecoxib in all of these clinical trials was absolutely no different than the placebo group. These, you might point out and I will point out to you as well, they are numerically different in myocardial events and myocardial infarction, but not statistically speaking.

  • Meta-analysis: Relative Risk (95% CI): Celecoxib vs Placebo

    Slide 24.

    Meta-analysis: Relative Risk (95% CI): Celecoxib vs Placebo

    (Enlarge Slide)
  • Well, if you have a concern about celecoxib today, what's your decision? You put them on a nonselective anti-inflammatory. If I can get anything across tonight, it's this – that that decision is unfortunately being made with a lack of science behind it. There is no data to support that conclusion and actually the data that I will show you probably would even refute it. Celecoxib vs traditional nonselective anti-inflammatories, no differences in both of these. There are statistical differences in favor of celecoxib in terms of cerebrovascular events and strokes.

  • Meta-analysis: Relative Risk (95% CI): Celecoxib vs NSAIDs

    Slide 25.

    Meta-analysis: Relative Risk (95% CI): Celecoxib vs NSAIDs

    (Enlarge Slide)
  • Just to dig a little deeper, is there a dose-related effect with celecoxib? It's clearly been seen that we've seen it with rofecoxib and I will tell you, by the way, and I'm not showing rofecoxib data, I think the FDA would agree that rofecoxib clearly behaves differently than the other coxibs. Here we are all the way up to an 800 mg a day dose and in these meta-analysis, it was not at all statistically or numerically different than the control group, that for traditional nonselective anti-inflammatories.

  • Celecoxib vs NSAIDs: Any Thromboembolic CV Event -- Dose

    Slide 26.

    Celecoxib vs NSAIDs: Any Thromboembolic CV Event -- Dose

    (Enlarge Slide)

Celecoxib Cardiovascular Safety: Epidemiologic Data

  • So quickly moving into this epidemiology data, and basically these are very, very large population databases that use a match control strategy to look at extraordinary numbers of patients in the real world setting.

  • Celecoxib Cardiovascular Safety

    Slide 27.

    Celecoxib Cardiovascular Safety

    (Enlarge Slide)
  • And here's really what's out there in the peer-reviewed literature. And if you just sort of look down on the number of people, the groups are very, very big and I don't have time to go over all of these; I certainly won't hide any data. I want you to get a clear understanding of the good, the bad, and the ugly, as they say, but I'm going to show you the biggest one and one that I think is very important, a ton of information in this.

  • Risk of MI and Use of Coxibs

    Slide 28.

    Risk of MI and Use of Coxibs

    (Enlarge Slide)
  • This is an FDA-sponsored study done through Kaiser; Dr. Graham is a member of the FDA and he's actually on this subcommittee. There are 1.4 million patients in this trial. The primary endpoints were acute MI and sudden cardiac death, okay, and we'll use an odds ratio strategy again.

  • FDA-Sponsored Kaiser Permanente Study

    Slide 29.

    FDA-Sponsored Kaiser Permanente Study

    (Enlarge Slide)
  • If you are in one of these groups, what are your chances of getting an MI or sudden cardiac death? And as you can see here, celecoxib has an odds ratio that is not statistically different than 1; it doesn't increase your incidence of cardiovascular events in this big epidemiology study. Well, clearly there were some issues with rofecoxib; at the higher doses, it was probably a 215% increase. But look at naproxen again; there was a statistical increase in cardiovascular events in patients on naproxen. Other traditional nonselective anti-inflammatories, a statistical increase. Indomethacin, a statistical increase. So not to try to sugar-coat everything, but in looking critically at the data, especially in the large, large numbers of patients, we just don't see this information with celecoxib.

  • Risk of AMI and SCD With Current Use of COX-2-Specific and NS-NSAIDs vs Remote NSAID Use

    Slide 30.

    Risk of AMI and SCD With Current Use of COX-2-Specific and NS-NSAIDs vs Remote NSAID Use

    (Enlarge Slide)

Valdecoxib Cardiovascular Safety: Meta-analysis Findings

  • Well, I don't have as much data to share with you about valdecoxib because not as much data exists, but certainly we're going to use the same strategy here. We'll use a meta-analysis of existing randomized, controlled trials; there aren't any big population data based epidemiology studies.

  • Valdecoxib Cardiovascular Safety

    Slide 31.

    Valdecoxib Cardiovascular Safety

    (Enlarge Slide)
  • Actually Dr. Graham just had a very recent one and its findings are exactly consistent with this. But here we see we've got 19 controlled trials, over 12,000 patients, the doses go up to 80 mg.

  • Cardiovascular Safety of Valdecoxib: Meta-analysis

    Slide 32.

    Cardiovascular Safety of Valdecoxib: Meta-analysis

    (Enlarge Slide)
  • And here I think you might recognize a trend. While there are no statistical differences comparing valdecoxib to placebo in cardiovascular events, numerically every one of these things falls to the right of that line -- not statistically different, but something that I think any judicious physician would recognize.

  • Meta-analysis: Relative Risk (95% CI): Valdecoxib vs Placebo -- All Patients

    Slide 33.

    Meta-analysis: Relative Risk (95% CI): Valdecoxib vs Placebo -- All Patients

    (Enlarge Slide)
  • But we don't treat patients with placebo; placebo isn't our option if we take somebody off of valdecoxib; traditional nonselective anti-inflammatories are, or at least one of them. So when we compare valdecoxib in these meta-analyses to traditional anti-inflammatories, you will see here that there are no statistical differences. MIs were in fact less, but the trend almost flips over comparing it to traditional anti-inflammatories.

  • Meta-analysis: Relative Risk (95% CI): Valdecoxib vs NSAIDs -- All Patients

    Slide 34.

    Meta-analysis: Relative Risk (95% CI): Valdecoxib vs NSAIDs -- All Patients

    (Enlarge Slide)

Conclusions

  • Well, so that's a lot of information for the FDA to cull through. What I felt was relevant to present to you was the largest numbers of patients and I did it in meta-analysis, then epidemiological surveys. Here were the conclusions on Friday of the Food and Drug Administration, and I think this is very, very critical. First of all, the committee pointed out that COX-2 pain medicines are important treatment options for arthritis patients in the United States. Second of all, the committee voted that overall risk vs benefit profile for celecoxib, valdecoxib, and rofecoxib supported marketing in the US. And importantly, a preponderance of data demonstrated that the cardiovascular risk associated with celecoxib is similar to nonselective anti-inflammatories, and you know, at the end of the day, they put all this stuff to a vote and the vote was rather overwhelmingly in favor of celecoxib at 31:1 to keep it on the market. And these last two points revolve around the same thing, but they're critical, and that's that there are a tremendous number of unanswered questions and the unanswered questions revolve around traditional nonselective anti-inflammatories. We simply do not have the data; despite the fact they've been around for a long, long time, we don't have the data about their cardiovascular safety. And in my opinion, the data that we have seen certainly raises a question. And as a final conclusion, they said: We need to do rigorous trials looking at the cardiovascular safety of traditional nonselective anti-inflammatories. So no surprise to you as a believer in the science and the technology of COX-2 specific inhibitors, I felt this was a validation of what you and I as physicians have understood. And it's interesting how the media has had an impact on the things that you and I do from day to day, on a day-to-day basis. But you know the media doesn't seem to get too excited about good news and I'm sure I don't have to convince anyone of that.

  • Conclusions From the FDA Advisory Committee Meeting

    Slide 35.

    Conclusions From the FDA Advisory Committee Meeting

    (Enlarge Slide)
  • Here's probably a bigger picture, and I'm not going to talk about ulcer safety here, but that's why these drugs came about, right? Look what's happened to the incidence of GI hospitalization since the launch of celecoxib. It has continued to drop down and I've marked two important hallmarks here -- one was the development of the understanding of H. pylori but also the launch of COX-2 specific inhibitors. And so this picture is the benefit when they're speaking of the relative risk. And I can tell you it's really kind of exciting to be able to share this information with you all; I face the same issues as you. Our patients have concerns and this is not going to be an overnight process, I think, of having this pendulum swing.

  • Celecoxib and GI Hospitalizations

    Slide 36.

    Celecoxib and GI Hospitalizations

    (Enlarge Slide)
  • To shift this now that we've discussed the risk-related issues and these recent events, let me bring it back to where we're headed tonight, and that's joint replacement surgery. This is a study done by Dr. Camu in hip replacement surgery that looks at the same question that I posed with the knee arthroscopy trial and that's, given a scheduled dose of a coxib with a preoperative dose, will you take less opioid? And in total hip replacement, the answer was yes. If you were on one of these two groups, you took 41% or 43% less opioid than the opioid-only group -- fairly compelling number. And once again, keep in mind this group is taking more opioid; despite the fact they're taking more opioid, they're having more pain.

    Well, I hope that that is useful; I hope that that's some information that perhaps you can share with your patients and share with your colleagues. I would be happy to entertain any questions at the end, but at this point, we're going to hold all of the questions until the end. And if for any reason you don't get to them all, feel free to grab me and I'll stay as long as we need to, to discuss these issues.

  • Hip Arthroplasty Study: Postoperative Morphine Consumption

    Slide 37.

    Hip Arthroplasty Study: Postoperative Morphine Consumption

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