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AHRQ’s Effective Health Care Program: Applying Existing Evidence to Guide Prescription Medication Use

Webcast Transcript, Monday, November 22, 2010
4:00-5:00 p.m. ET

OPERATOR:  Good day, ladies and gentlemen, and welcome to AHRQ’s Effective Health Care Program, Applying Existing Evidence to Guide Prescription Medication Use.  To submit a question or comment at any time during the Web conference, please click on the “Ask a Question” button on the bottom of your screen.  Simply type your message into the box and click on the Submit button.  If you get disconnected at any time from the Web conference, you may dial back in with 888-632-5065 or 201-604-0318, and when prompted, enter 89036596#.  Again, that code is 89036596 followed by the pound sign.

At this time, it is my pleasure to turn the floor over to Amanda Brodt.  Ma’am, the floor is yours.

AMANDA BRODT:  Good afternoon, ladies and gentlemen.  Thank you for standing by.  On behalf of the Agency for Healthcare Research and Quality, also known as AHRQ, we welcome you to today’s Web conference, Applying Existing Evidence to Guide Prescription Medication Use, held by AHRQ’s Effective Health Care Program.  My name is Amanda Brodt, and I’m a contractor for AHRQ’s Office of Communications and Knowledge Transfer, and I will be moderating today’s event.

This event is part of a series of Web conferences we are holding on the Effective Health Care Program research findings over the next few weeks, so we’re especially happy you were able to join us today and hope that you will for future events as well.  We will highlight a number of these events at the end of our call.

Before we get started, I wanted to review some information about the Web conference technology we’re using today.  If you have questions during the presentation, you may submit them electronically by entering them via the “Ask Question” button.  The “Ask Question” button is located at the bottom of your screen.  When you click on the button a box will appear, requesting that you enter your question.  Once completed, press the “Submit” button.  A selection of audience-submitted questions will be addressed during the moderated Q&A session at the end of the Web conference.

Also, if you are experiencing technical difficulties, please open the Web conference Frequently Asked Questions document under the Downloadable Files button on the bottom of your screen for troubleshooting ideas.  You can also contact technical support by submitting your issue in the “Ask Question” box.  Under the Downloadable Files button, you will also find the slides for this event, which may be helpful for reviewing the slide details and for accessing a document with speaker bio sketches.

Today’s Web conference includes closed captioning.  The captioning appears in a box below the slides; go to the Windows Media Player or Real Player buttons on the main page.  Finally, this presentation is being recorded, and it will be made available on the AHRQ Web site shortly.  So, let’s get started with the presentation.

During this Web conference, Effective Health Care investigator Dr. Michael White and I will highlight the benefits of using patient-centered outcomes research in clinical decisionmaking.  I will kick off the conference by giving you a brief overview of AHRQ’s Effective Health Care Program before I turn it over to Dr. White to share his research findings on the comparison of treatments for stable ischemic heart disease, including ACE inhibitors and ARBs.

As a reminder, you can submit questions electronically by entering them in the “Ask Question” box on the bottom of your screen.  Once you enter your question into the box, press the Submit button.  You can ask questions of either of us about comparative effectiveness research, the Effective Health Care Program, and the specific findings shared today.  Though we will hold most questions until the end of the event, I encourage you to ask them throughout the event as you think of them.  We will do our best to address as many questions as we can during the Q&A session.

To begin, I will be discussing the AHRQ Effective Health Care Program and how you can utilize patient-centered outcomes research in your practice.  Patient-centered outcomes research, also known as comparative effectiveness research, delivers unbiased, practical, evidence-based information to help you and your patients weigh different treatment options to make the most informed health care decisions.  It compares drugs, devices, procedures, tests, and methods of health care delivery.

Patient-centered outcomes research shows which treatments have been shown to work best in different clinical situations and how they compare when it comes to benefits, harms, and side effects.  It also tells us what is known and what is not.  Most importantly, patient-centered outcomes research is descriptive, not prescriptive.  It does not tell you how to practice medicine, it does not mandate a particular test or treatment for anyone, nor does it prohibit any test or treatment.  It gives you the tools, not the rules, which you and your patients can use to make the best possible decisions.

Here at AHRQ, the investment in patient-centered outcomes research has been built around the framework displayed on your screen.  The colored boxes and ovals show the different types of work involved with patient-centered outcomes research.  Underneath is the research platform that supports this work, including research infrastructure, methods, development, and training of researchers.  The research process starts with scanning the horizon to identify new and emerging clinical interventions that may impact health care in the U.S.  That leads to a systematic review and a synthesis of current medical research to compare effectiveness.  Evidence synthesis often tells us where the gaps lie between existing medical research and the needs of clinical practice.

We also promote and generate new scientific evidence and analytical tools to fill those critical gaps.  All of the information gained needs to be communicated in a way that makes sense to the health care decisionmakers.  This includes translating the research into plain language or making it accessible and useful to diverse audiences in order to improve health care.  We also have made a commitment to reach out to stakeholders and communities for input to make sure we get the research right.  If it isn’t relevant and applicable, then we can’t expect it to have impact.  The Effective Health Care Program has a cradle-to-grave research agenda that focuses on 14 priority conditions listed here.  As you can see, one of the priority conditions is cardiovascular disease, and all of them include prescription medication.

Since the inception of the Effective Health Care Program, AHRQ has funded and completed dozens of patient-centered comparative effectiveness research projects.  These projects include comprehensive reviews of diagnostic or treatment options for breast and prostate cancers, atrial fibrillation, diabetes, osteoarthritis, depression, and many other conditions.  The Effective Health Care Program creates a variety of projects that are based on these research reviews and reports.  These include executive summaries plus summary guides for clinicians, consumers, and policymakers.  We have recently added to our portfolio a number of materials to support clinician education, including continuing education modules, interactive case studies, and faculty slide sets.  We’ll soon be adding patient decision aids as well.

I would like to highlight our consumer guides that summarize the evidence in plain language and easy-to-read format.  These guides are paired with our clinician guides to promote shared decisionmaking.  Most of our consumer guides have also been translated into Spanish.  The consumer guides can be found online or are available in print.  We also have audio podcasts of the guides online as well.  Currently, the Effective Health Care Program offers various decisionmaking resources about prescription medication for hypertension, high cholesterol, breast cancer, depression, and diabetes, among others.  Today, Dr. Michael White will be discussing the research that he conducted leading to the effective health care findings presented in a clinician and consumer guide related to stable ischemic heart disease.  The other highlights can also be found on the Effective Health Care Web site.

Finally, we want to encourage you to get involved in the Effective Health Care Program.  Your participation is mutually beneficial.  There are multiple points of involvement in our program: before, during, and after the research is completed.  Before, you can nominate topics for research on our Web site.  If there is a prescription medication, health-related topic that you feel should be addressed, we will give you instructions on how to nominate this topic at the end of the conference.  During, you can give input on graphed (key) questions and reports.  This kind of involvement helps you get the type of research that will really help answer those controversial questions, and it helps us by getting the research right.  After the research is completed, you can disseminate the information to your colleagues and patients.  You can implement findings in your clinical decisions.  This helps both you and us by creating opportunities for better, more informed decisionmaking and making an impact on the quality of health care.

So let’s get started with today’s main presentation.  We now have the pleasure of hearing from Dr. Michael White.  Dr. White is an associate professor of pharmacy, director of cardiac pharmacology service, and director of the evidence-based practice center at the University of Connecticut/Hartford Hospital.  The American College of Clinical Pharmacy has approved his fellowship training program and awarded him the American College of Clinical Pharmacy’s Young Investigator Award.  Dr. White is also a University of Connecticut teaching fellow and a fellow of the American College of Clinical Pharmacists and the American College of Clinical Pharmacologists.  Dr. White’s research focuses on evidence-based practice, systematic review, and reducing drug-, herb-, and implantable device-induced diseases.

Dr. White, please begin.

C. MICHAEL WHITE:  All right, welcome, everybody, and OK.  Is my first slide there so everyone can see it?

BRODT:  No.  It’s not, Dr. White.  I don’t see it, but we can advance your slides for you if that would be more helpful.  If you just say next slide, we can move to the next slide for you.

WHITE:  OK.On the next slide, we’re going to talk about the outline of what it is we’re going to be talking about today.  And what I’m going to do is try to give you a background into the topic and what kind of things we’ve already talked about, go through some of the questions that we addressed inside our comparative effectiveness review, and then also give you some of the results for each of the key questions that we were discussing.

So, on slide number 14, what I wanted to talk about was the health impact of cardiovascular disease in the United States, where about 80 million American adults have one or more forms of cardiovascular disease and around 38 million people are estimated to be age 60 or older, so 16.8 million adults have ischemic heart disease, which is also known as coronary heart disease.

As we go on to the next slide, we’re going to talk about some standard therapies for stable ischemic heart disease, so here we’re not talking about acute coronary syndromes; we’re talking about chronic management.  Standard therapy can reduce the occurrence of cardiovascular events, and they include antiplatelet therapy; statin therapy if your LDL cholesterol is elevated; beta blocker therapy, especially for your post-myocardial infarction patients; and then aggressive modification of risk factors, so if you’re a hypertensive patient, getting good control of your blood pressure, getting good control of other modifiable risk factors.

Now, ACE inhibitors and angiotensin receptor blockers have established benefits, and the American Heart Association and the American College of Cardiology both agree on these benefits in patients who have heart failure or people who have had myocardial infarction and also have left ventricular dysfunction.  However, right now, they–there had been more limited information on their benefits in patients who had a myocardial infarction or other form of stable ischemic heart disease, but did not have left ventricular dysfunction, so their ejection fraction was greater than 40 percent.  And that’s one of the areas that we wanted to hone in on because that was a practice gap.

On the next slide, we’re going to talk about the rationale for additional therapies in this patient population, so, despite standard medical therapy, these patients continue to experience considerable morbidity and mortality.  Now, ACE inhibitors and angiotensin receptor blockers have established benefit in those other two populations, but the evidence for prophylactic use of ACEs and ARBs in patients without heart failure and post-myocardial infarction patients who had preserved left ventricular (LV) function was less clear.

But, as we go to this diagram, this just kind of shows you where ACE inhibitors and angiotensin receptor blockers work, and one of the things that I wanted you to realize is that, even though they both work on the rennin angiotensin aldosterone system, they don’t work in exactly the same place.  Where ACE inhibitors are blocking angiotensin-converting enzyme, trying to prevent angiotensin I from turning into the biologically active angiotensin II, where angiotensin receptor blockers block the angiotensin II type I receptor, which are the receptors that cause that pharmacologic effect.

Now, a couple of quick caveats, and that is that even though angiotensin-converting enzyme can convert angiotensin I into angiotensin II, the heart and the vascular have non–ACE enzymes that can also generate angiotensin II.  One may think that maybe an angiotensin receptor blocker might have some advantages over an ACE inhibitor because it blocks that final common pathway when the angiotensin II hits the receptors, regardless of where it was made; however, ACE inhibitors have something else that’s pretty unique, and that is that they are also a blocker of kininase and kininase II takes bradykinin, which is a vasodilator, and end up turning it into inactive products, so that when you use an ACE inhibitor, you actually get these two effects, and when you use an angiotensin receptor blocker, you get one effect, but that effect is magnified.  So, they’re different, but they’re very similar, and they’re working in a similar system.

Here’s the development process for our project.  The topic was nominated in a process, so you know it was identified that this was an important question and that this was going to improve patient care, you know, to have an evidence-based idea about what’s happening in this area.  We put together a technical expert panel; from Boston we had JoAnne Foody, we—as a practicing cardiologist and researcher—we had Paul Thompson as a researcher from Hartford Hospital.  We had a variety of practicing clinicians, we had, you know, the health-payers’ perspective, we had the patient perspective.

We brought these people together, and what we did is we developed key questions, questions that we thought would be important to all of our key stakeholders: to the clinician, to the health care decisionmaker, and to the patient.  We didn’t want to leave out any of those important stakeholders.  Now, what happened when we had those key questions is that we ended up posting them on the AHRQ Web site, so that anybody who had an interest in the area could log in, could see what the proposed key questions were, and then could make—could ask questions or could post comments or alterations of things for us to think about.  We reviewed all of those.  We made some changes where they were appropriate.  We identified where some differences may be and ended up getting those key questions that were approved.

At that point, we put together the methodology for being able to answer questions with that technical expert panel.  And then our evidence-based practice center went through and answered the questions.  Now, after the answering of those questions, they sent it out to, I believe, 12 peer-reviewers and people who had different stakeholders—patient advocates, clinicians, health policy decisionmakers—and we got comments from them.  But it also went back out for public comments so that anyone with an interest in this area could go on and could also post other comments.  We had to go through and respond to all of those comments and, at that point, the final report was approved and is available on the Effective Health Care Web site.

Now, after it was approved, one of the groups within AHRQ called the Eisenberg Center ended up coming up with a slide set.  And on the Effective Health Care Web site right now, there is one hour of continuing education based on that slide set with voice-over PowerPoint, and there are also slides that you can download.  If there are certain slides from this presentation that you would like to add to some of your own presentations, they’re available for general consumption from the public.

OK, so on to the next slide, rating the strength of evidence.  It isn’t valuable enough just to summarize what the evidence is and to say that this is significant or that’s not significant.  It’s also important to grade the strength of the evidence because something may be significant, but it might be significant based on a study that had a lot of flaws.  Or maybe something is not significant, but the problem is that it hasn’t really been analyzed very much, so you don’t know whether or not it’s not significant because it doesn’t really exist or whether that’s an effect that’s just due to being underpowered, so you’d be able to show that it has that effect.

One of the things we do is that we synthesize and summarize the data, but then we need to grade the strength of that evidence.  And when we graded it, we used a standardized system called the GRADE system, and here we looked at four main domains. The domains consider at risk biases within the different studies, but consistency between those studies; the directness of those studies, were they actually measuring final health outcomes or were they measuring more surrogate endpoints or what they call intermediate health outcome; and then the precision of some of those studies.  And, based on those different factors, we ended up rating the evidence as either being high evidence, moderate evidence, or low evidence.

It was kind of similar to what the American Heart Association and American College of Cardiology do when they grade different bodies for, you know, the evidence and the strength of the evidence that we were finding, where high evidence says there are consistent results from good-quality clinical trials and that further research is unlikely to change the conclusions.  Now, moderate evidence means that the findings are supported.  We have reasonable confidence in these findings, but further research could change the conclusion.  And then low-quality evidence means that there are very few clinical trials or the trials are very small or, within these existing trials, there are important flaws that—so that we don’t have a lot of confidence in the results.

On to the next slide, where we’re addressing clinical questions.  We wanted to look at the comparative effectiveness of different combination treatments; ACE inhibitor or ARB in addition to standard therapy versus standard therapy alone, so those ACE inhibitors and beta blockers and cholesterol-control medications, with or without an ACE inhibitor or ARB.  Now, remember the population we’re talking about, patients with stable ischemic heart disease and preserved left ventricular function.

The second question we wanted to ask was, would adding an ACE inhibitor and ARB together plus standard therapy be better than just using an ACE inhibitor plus standard therapy?  And one of the reasons why this question is important is that they know that, in patients who have congestive heart failure, when you use an ACE inhibitor and an angiotensin receptor blocker together that you get more benefits than when you use either of those two agents alone.  But in the VALIANT Trial, in patients with left ventricular dysfunction, post-myocardial infarction, adding those two agents together, an ACE inhibitor and an ARB, was no better than using an ACE inhibitor alone, but was associated with greater adverse effects, so what was the evidence here for combination therapy with two rennin angiotensin aldosterone system blockers versus only one of those, but again, in addition to standard medical therapy?

The last question was an ACE inhibitor or an ARB plus standard medical therapy versus standard medical therapy alone, but here we’re looking at a very select population--those people who are in proximity to a revascularization procedure.  So, within a few days of a revascularization procedure or at the same time of a revascularization procedure, if you gave them an ACE or you gave them an ARB, what are these short- to moderate-term benefits that you would be likely to expect from therapy?  And we looked at the benefits and the harms, and this is one of those things that they do in the Effective Health Care Program that’s very, very important.

Now, a lot of clinical trials are designed specifically to look at benefits, but not to look at harms.  Some of those trials have run-in periods, where they put people in the clinical trial; they will put them on either an ACE inhibitor or an ARB and, over the course of a few weeks, they’ll get rid of people who are noncompliant, they’ll get rid of people who have adverse effects, and, at the end, it looks like the benefits are there, but that some of the harms are underpowered.  And very rarely in clinical trials do they power them for harms, but by combining the results of this trial, through statistical pooling, with the results from several other trials, you can get a good handle on some of those harms, so not only looking at the benefits and harms, but also looking at some of those benefits in various subpopulations of people because not everybody is the average.

On to the next slide, where we’re talking about outcomes of interest; you can see that there’s a myriad of outcomes that we were looking at.  For benefits, we were looking at important final health outcomes, like total mortality, cardiovascular death, non-fatal myocardial infarctions, stroke, the composite endpoint of cardiovascular death, nonfatal MI, or stroke;, and the need for a revascularization procedure and its impact on quality of life.  When we looked at harms, we were looking at the important harms that you would expect from ACE inhibitor and ARB therapy: hyperkalemia, cough, angioedema, hypotension, rash, blood dyscrasias, syncope, and then withdrawal from the trial.

On to the next slide; here we’re talking about trials that evaluate the addition of an ACE inhibitor or ARB to standard medical therapy for stable ischemic heart disease and preserved left ventricular function.  So, here we’re looking at the trials that ended up making it into this evaluation, and what you see is that there were only two angiotensin receptor blocker trials that were compared versus standard medical therapy and that the TRANSCEND Trial with telmisartan and then also this Kondo trial.  And what you see when you look at that is that virtually all the patients in that analysis are really coming from the TRANSCEND Trial.

Now, for ACE inhibitors, you can see that there are a lot of very large clinical trials, so we have a lot of power to be able to evaluate some of those differences, if those differences were true, and the length of followup for these very large trials was also very long, which, you know, would increase your confidence in some of the results that we came up with.

On to the next slide, where we’re talking about drugs and target doses.  Here you can see, for the ACE inhibitors, that in some of the larger trials they looked at ramipril.  In some of the other trials, they looked at enalapril, they looked at perindopril, they looked at trandolapril, and then they also looked at zofenopril.  So, they have one sulphydryl group containing ACE inhibitors, a couple of carboxyl groups containing ACE inhibitors, so that we had a good mix of some different types of ACE inhibitors.  Some of the ACE inhibitors had good tissue specificity; some had less tissue specificity, so overall a good mix to be able to look at.

The TRANSCEND Trial, which virtually all the data in the ARB comparison came from, was with telmisartan, and then the Kondo trial was with candesartan.  Then you can look at the target doses.  And, you know, these are reasonable, modest doses of these therapies.

So, what were the benefits with a high level of evidence from adding an ACE inhibitor to standard medical therapy for stable ischemic heart disease with preserved left ventricular function?  What we can say is that total mortality was reduced, and the number needed to treat was 91, so you would need to treat 91 patients in order to be able to prevent one extra patient from dying.  That was about the same level that you would have to have for nonfatal myocardial infarction.  You can see also that heart failure-related hospitalizations were significantly reduced, as was the need for revascularization.

Even these relative risk reductions, which ranged from 10 percent to 22 percent, depending on the outcome, were the same, pretty much, as the studies that were done in patients who had a myocardial infarction who had left ventricular dysfunction; what everyone already knew.  The numbers needed to treat are higher here, and that’s because this population is not as at high risk of having subsequent events as people with a decreased left ventricular function.

The relative risks are the same, but you need to treat more people because the number of events that you can expect to see within the population is a little bit less.  But what you can see when you’re looking at all this data is that, with a high level of evidence, adding an ACE inhibitor to standard medical therapy in these patients with preserved LV function is a beneficial thing to do.  On the next slide, when you combine those things together, of course you also have a relative risk reduction, and you’d have to treat 56 people in order to have one fewer patient have a combined risk of death from a heart-related cause, suffering a nonfatal MI, or having a stroke.

So, those are the benefits, but what about the harms of adding these in therapy?  And what we see is that there was an increased risk of syncope.  There was an increased risk of ACE inhibitor-induced cough.  There was really no big effect on angioedema, and the risk of hyperkalemia was elevated.  However, in these studies, the level of evidence was low because a lot of these major clinical trials did have those run-in periods that I was telling you about before, where people who would be at higher risk for adverse effects would be eliminated at that point in the trial.  Knowing what we know about this disease state, plus what we know from the use of ACE inhibitors and ARBs in other disease states, when you put it together and you’re trying to look at the balance of benefits to harms, it looks like the balance of benefits to harms is favorable.

Now, on to the next slide, where we’re looking at the ACE/ARB combination versus ACE inhibitor alone.  And with this trial, what we found was that there was one very large trial called the ONTARGET Trial, and in this trial there was no evidence of greater clinical benefit with the addition of an ACE inhibitor and ARB versus an ACE inhibitor alone, in addition to standard medical therapy.  However, there was a third arm in this trial which looked at angiotensin receptor blocker therapy alone.  And, in this trial, what they found was that angiotensin receptor blocker therapy provided similar benefits to ACE inhibitor therapy.

So, that is important information also.  You start with an ACE inhibitor, because that’s where the greatest evidence of benefit resides, but if your patient can’t take an ACE inhibitor because of an ACE inhibitor-induced cough, an angiotensin receptor blocker seems to be a reasonable therapeutic alternative for your patient.

So, no additional benefits from the combination of an ACE and ARB, but look at the harms associated with the combination: increased number of discontinuations, increased hypotension, increased risk of syncope, increased risk of renal impairment, and increased risk of diabetes.  When you look at the balance of benefits to harms, they’re not favorable in this case, with a moderate level of evidence.

On to the next slide; here we’re looking at the addition of an ACE inhibitor or an ARB to standard medical therapy versus standard medical therapy alone, in proximity to a revascularization procedure.  There was a thought that, if you gave an ACE inhibitor really close to a revascularization procedure, it might decrease subsequent need for revascularization or improve other endpoints.  There were a number of trials that were conducted in order to be able to evaluate that.  As we look down, you see that only one of those really had looked at ARB therapy there,