Slide 1.
Ted Feldman, MD: Hello, I'm Dr. Ted Feldman, Interventional Cardiologist from the Division of Cardiology at the Evanston Northwestern Healthcare in the Chicago north suburbs. I'd like to welcome you to our program today entitled "Optimizing Patient Outcomes in Coronary Artery Disease: Untangling Recent Drug-eluting Stent, Antiplatelet Therapy, and Medical Therapy Trial Data." I'm joined today by Dr. Dean Kereiakas, Medical Director of the Lindner Center for Research and Education, Medical Director of the Christ Hospital Heart and Vascular Center, and Chairman of the Executive Committee of the Ohio Heart and Vascular Center, Professor of Medicine Ohio State University in Cincinnati; Dr. Michael Davidson, a Clinical Professor of Medicine and Director of Preventive Cardiology at the University of Chicago Pritzker School of Medicine in Chicago; and Dr. Mike Farkouh, Associate Professor of Medicine, Director of the Clinical Trials Center at the Mount Sinai Medical Center in New York.
Slide 2. Learning objectives.
Our learning objectives today will be to discuss the role of stent technology vs medical therapy and coronary disease; to review some of the recent clinical trial results related to drug-eluting stents; and to discuss the challenges faced in treating patients with coronary disease within the broad spectrum of patients that we see in cardiology. I hope we will also discuss patient selection criteria used for choosing the optimal stent technology. I'd like to turn this over to Dean [Kereiakas] to talk about some of the recent clinical trials results.
Dean Kereiakas, MD: Thank you very much Ted. It's really a pleasure to be here. I'd like to first address an issue as to what drug-eluting stents really accomplish. For example, what might have occurred if the stents placed in a trial such as COURAGE were drug-eluting? What would we expect to have seen in the follow-up data?
Slide 3. Clinical events following BMS or DES.
Slide 4. Clinical events following BMS or DES.
Dr. Kereiakas: On the left is a graphic I've taken from the Stettler Network Analysis in over 18,000 patients, 38 clinical trials, that clearly shows a highly statistically significant reduction in target lesion revascularization by either Cypher or Taxus stent compared to bare-metal stent, shown in red, over 4 years. On the right are data that I showed for the first time at the TCT meeting in Washington. This is from the TAXUS-IV nonangiographic cohort, so it eliminates the oculo-stenotic reflex. It shows a highly statistically significant reduction in clinically driven and adjudicated target lesion revascularization through 5 years. This is very pertinent to the timeframe evaluated in the COURAGE trial. Importantly these benefits of drug-eluting stents were achieved with no penalty, no difference in death shown on the left, or the composite occurrence of death and myocardial infarction, on the right from the Stettler Network Analysis.
Slide 5. Ontario PCI Registry: 18,314 PCI at 12 centers.
Slide 6. Mortality (DES vs BMS) from 29 trials and registries.
Dr. Kereiakas: Recent data even suggest, as published by Tu and colleagues from the Ontario PCI Registry which is a closed healthcare system, that there is a relative 30% reduction over 3 years in mortality with drug-eluting stents compared with bare-metal stents and these are matched, and as shown on the bottom, there is no difference in myocardial infarction. With the help of my colleagues, I've constructed 29 trials and registries comparing DES [drug-eluting stents] vs BMS [bare-metal stents]. As shown here, DES vs BMS mortality has an odds ratio reduction of 21%. A 21% reduction in mortality with DES compared to bare-metal stent. This includes all published trials up to, but not including, what was presented by Laura Mauri, MD, from Massachusetts, here at the American Heart meeting, which showed a 20% reduction in mortality, identical to these data with drug-eluting stents compared to bare-metal stents.
Slide 7. COURAGE: the "truths and consequences."
Dr. Kereiakas: Finally to touch on the COURAGE trial, which has been one of my favorite subjects as of late, I think I will summarize several bullets taken from a recent viewpoint I published in the Journal of the American College of Cardiology. I think that the hypothesis for the study was unrealistic, it was underpowered for assessment of its primary endpoint. PCIs [percutaneous coronary interventions] performed in this trial were inadequate and incomplete and there was marked variability in PCI outcomes based on location of performance. Skewed distribution of angina was present; in fact, I'm really not entirely sure whether it's really a median of 3 or mean of 10, as published in 3 peer-review publications, but now there's an erratum that says the mean was 6. There was an excessive crossover despite highly aggressive -- and I might say unrealistic in real-world clinical practice -- medical therapy. They had a 350% greater crossover from optimal medical therapy to PCI than was prespecified by protocol. With that, Ted, I'll turn it back to you.
Dr. Feldman: That's great, and we're going to hear from Mike Davidson about that very subject, optimal medical therapy, which is clearly key in the management of all of these patients.
Slide 8. Medical management.
Michael Davidson, MD: Thanks Ted. I think that for clinicians the important consideration is that when they have somebody with coronary disease, we have proven risk factor-modifying therapies that can reduce events in general, and I specifically want to focus on LDL [low-density lipoprotein] reduction with statins. I think right now the goal is < 100 mg/dL, but there is a consideration for < 70 mg/dL for high-risk patients. The American Heart Association has said < 70 mg/dL is reasonable. As more evidence accumulates I think we can feel more and more comfortable with < 70 mg/dL being both effective in improving outcomes and safety. It's very safe to have your LDL < 70 mg/dL. In fact I was thinking about pushing for lower LDLs in general in trials underway looking at about LDL 70 vs 50 mg/dL in an acute coronary syndrome population.
So I think that one of the primary things to do in a clinical setting is aggressive risk factor modification, control lipids (LDL, non-HDL [high-density lipoprotein]), consider combination therapy that can improve lipids and other targets beyond LDL, hypertensive management, smoking cessation, and in a diabetic patient you need more aggressive control to achieve the A1C targets that have been established. With that in mind we do have medical management to consider for our patients with angina or ischemia on noninvasive testing, and I think the COURAGE trial gives us some comfort in a subset of patients. We can discuss how big that subset is and how to manage our patient with coronary disease when it comes to interventions. In a subset of patients, medical management is appropriate and we can reserve interventions once we see how patients are progressing with their treatment.
Dr. Feldman: You've touched on one of the biggest problems we have in managing coronary disease across the board and that's the diabetic patient, and Mike Farkouh is going to talk to us a little bit about that particular subset and some of our challenges with that group.
Slide 9. AHA/ACC/ADA goals of treatment.
Michael Farkouh, MD: Thank you, Ted. I think that the diabetics really are an example of the patients for which we have to be the most aggressive and for which there is the most evidence. As Michael alluded to we have targets now of hemoglobin A1C of < 7% in most of our trials and there is the upcoming ACCORD trial, which will test even a more aggressive strategy of < 6% for hemoglobin A1C. Our European colleagues actually feel that we're not aggressive enough. Blood pressure now in diabetics I must alert everyone is 130/80 mm Hg is the target and there is some talk to lower the systolic blood pressure even to 120 mm Hg. LDL cholesterol is accepted in a diabetic with coronary disease, < 70 mg/dL is the accepted target, and we are approaching trials now of even going lower than that.
Slide 10. Room for improvement.
Dr. Farkouh: One of the things I want to talk a little bit about because we see this in our FREEDOM trial, which I'll introduce in a moment, is the fact that smoking cessation is so important, particularly in countries for which smoking is an epidemic. Moving forward I just want to tell everyone where we are now. Where are we in terms of the data from registries? From the National Registry of the NHANES database, both from the early and late 1990s (and actually will have other data coming forward in the next couple of years), you'll see on this slide that for hemoglobin A1C, blood pressure control, and total cholesterol being a surrogate for LDL, that blood pressure control, LDL targets, and hemoglobin A1C are only reached in about 40% of patients individually and overall only 10% of patients remain in good control. So if we look at this backdrop we have so much room to move to optimize medical management and also optimize the results of coronary revascularization.
Slide 11. Diabetes & PCI -- effect of intensive risk factor control on MACE.
Dr. Farkouh: This slide illustrates a single-center experience from Dr. Columbo's group in Milan where we can see that MACE [major adverse cardiac event] rates are posted on the Y axis and poorly controlled patients are those for which the hemoglobin A1C and LDL targets have not been met, suboptimal is where only 1 of the targets is met, and optimal is where both are met. You can see a very, very significant finding of a decreased MACE rate in the optimally-treated patient. This gives us some advantage for our patients to get them to the full maximal medical therapy before we move on perhaps to coronary revascularization in patients who are stable. I'll leave that as a controversial issue.
Slide 12. BARI 2D: evaluating treatment options for CAD and DM in type 2 DM.
Dr. Farkouh: I want to just let you know about 2 studies that are coming down the road, the first is the BARI 2D trial in patients with stable disease who are only mildly symptomatic at best and usually have single-vessel disease. They are randomized in a 2-by-2 fashion to either aggressive medical therapy alone vs revascularization and medical therapy combined. Then there is a second randomization to an insulin-providing regimen vs an insulin-sensitizing regimen. Now this issue of insulin sensitizing has been clouded somewhat with the rosiglitazone controversy. We may have time to discuss that, but just to point out that even in the sensitizing arm, to get patients to target 50% are requiring insulin, so more and more patients are on insulin. This issue of whether patients are requiring insulin is really linked very tightly to the targets that we set for ourselves.
Slide 13. FREEDOM design.
Dr. Farkouh: Finally the FREEDOM trial, which is the trial that has now recruited 1000 patients, will address the question of optimal revascularization -- the patient who is very symptomatic with multivessel disease. This comes on the heels of the BARI 1 trial diabetes finding and is addressing the question of optimal PCI management with drug-eluting stents in multiple vessels compared to contemporary bypass either on- or off-pump but with aggressive background medical therapy. Just to point out the differences; in the BARI 1 trial the mean LDL cholesterol going into the trial was 145 mg/dL and coming out of the trial was over 140 mg/dL. In FREEDOM, the mean LDL cholesterol going into the trial is 90 mg/dL and at 1 year, we have a mean LDL of 77 mg/dL. That tells you that that is a new era and we will be able to address the combination of optimal revascularization on top of optimal medical management.
Dr. Feldman: We've covered a substantial breadth of material here and where do you begin to talk about this? I think optimal medical therapy without defining it is like saying you're in favor of world peace, everybody gets optimal medical therapy. The controversy that I think has loomed largest over the last year is out of the pool of coronary patients, who do you revascularize? And I think that has become kind of clouded and confused. So Dean you might want to even mention some of the new COURAGE data that was presented here at the American Heart Association meeting in terms of what is the real value of revascularization when we're getting medical therapy that is this effective?
Slide 14. Proportion of patients in each group with ischemia reduction ≥ 5% of myocardium in the COURAGE nuclear substudy.
Dr. Kereiakas: Yes, that's a great point. I find it intriguing personally and actually for one of the first times you look at a trial and you say this really makes sense. PCI plus OMT [optimal medical therapy] resulted in greater delta reduction in ischemic defect which is quantitative in a subset of patients of the COURAGE trial that had ischemic objective defects on their SPECT nuclear studies. PCI plus OMT had a greater percentage of primary endpoint achieved which is ≥ 5% reduction in ischemic defect from baseline to follow-up that was performed anywhere from 6 to 18 months, greater than OMT alone. OMT alone did not result in the same magnitude of improvement in ischemic defect.
Slide 15. Exploratory analysis, outcomes by extent of residual ischemia (% of myocardium with ischemia at follow-up MPI).
Dr. Kereiakas: Then intriguingly, probably the most interesting and fascinating slide that I saw presented, was the correlation between the level of ischemic defect and the composite occurrence of death or myocardial infarction over time. Although you would say intuitively that makes sense, too often we don't see that in a population of patients. So larger ischemic defects equals higher death and myocardial infarction over time, larger ischemic defects probably should be treated with a combination of OMT plus PCI because it will result in a greater degree of reduction in ischemic defect.
Dr. Davidson: I think in light of the CORONA study, which also came out at the American Heart Association meeting, which found that statin therapy in a congestive heart failure patient with ischemic cardiac disease was not that beneficial. It prevented nonfatal MI [myocardial infarction] and stroke, but the overall death was so overwhelming from sudden death and pump failure that the benefit was not significant. I think that it is very important for my colleagues on the interventional side to know when to intervene with intervention, using this information about the size of the profusion defect as a key driver -- when to intervene vs when I can be comfortable with medical management. This is very important.
Slide 16. Recommendations.
Dr. Feldman: So for you, particularly with a focus on prevention, you see patients with stable angina or with asymptomatic ischemia who come into the office maybe for the first time to a cardiologist. Has the last year's data suggesting the tremendous power of medical therapy driven you away from getting an angiogram on those patients as an early step? You know they have ischemia, you know you're going to treat them with optimal medical therapy, do you get the cath?
Dr. Davidson: Yes, honestly, I still do. The reason why is because I do want to identify what I'm dealing with. Will we intervene with a procedure? Not necessarily. I think we have stepped back and said "let's be more conservative and see what we're dealing with," but I think that trying to understand what you're dealing with from a risk perspective is more comforting to me and the patient and that's why I think taking a look is important. Unfortunately we have to try to make sure that we don't necessarily use that automatic reflex to dilate or to put a stent in if necessary but we do have to, I think, get a good understanding of what we're dealing with from a patient perspective.
Dr. Feldman: You're talking about dilate and stent and Dean and I are shaking our heads left main, left main, those are the patients that we have to identify first.
Dr. Kereiakas: Almost 1000 patients in the COURAGE trial that were excluded because of significant left main disease, 947 to be exact. So without the angiogram those patients would have been ignored.
Dr. Feldman: Mike there's another layer to all of this and that is within this population of patients we have our average risk, garden variety coronary disease patients and we have diabetic patients. So what do you do differently when the diabetic patient walks into your office?
Dr. Farkouh: Well Ted, one of the interesting things about the diabetics is how we recommend screening for coronary disease and it's interesting that the American Diabetes Association advocates that we screen patients routinely at either 1- to 2-year intervals with a stress test and so on. The American Heart Association has taken a more conservative approach and says, "look let's manage them maximally and medically, patients will declare themselves." It's interesting in New York what I find for my patients is when they climb the subway steps, one of the most common symptoms I find is patients will say "I can't make it to the top of the subway steps" and that's when I know that I have to act quickly. But I think that for most of us in the field we are screening our patients routinely with a noninvasive study to document ischemia, as Dean has pointed out, and then of course using the right judgment as to when to go to the cath lab. I think that's the way we're using a different approach for diabetics than we might in other patients.
Dr. Feldman: Do you use coronary calcium scoring? I would be interested in how much faith you put into that, particularly a diabetic person and a nondiabetic.
Dr. Farkouh: They tend to have higher calcium scores and I'm starting to be more of a believer in our younger diabetics. At Mount Sinai we are using CT [computed tomography] angiography more commonly now to screen patients, but the calcium score has been relegated to second or third line.
Dr. Davidson: I think as this becomes more and more advocated based on better technology, we are going to get patients early in the disease process who have little or no symptoms and have evidence of preclinical disease. So I think trying to establish some algorithm and I think I really appreciate the comments on determining the size of ischemic defect as a critical driver, when to refer in for an invasive diagnostic test and a potential procedure.
Dr. Feldman: So it's funny that we've taken this last year of controversy, huge trials, and conflicting meta-analysis basically to come back to the 1993 PCI guidelines that say that if a patient has moderate to large ischemic territory on a noninvasive test that they should be revascularized. Again we could go down this path for quite a while, but now we've got the patient who has greater than 10% of their myocardium with a reversible defect. They are going to be revascularized and now the decision we're facing today on a daily basis: do they get a bare-metal stent or a drug-eluting stent? Let's run the table here and start with Mike.
Dr. Farkouh: Well I've always said that for patients with diabetes, the drug-eluting stent was made for my patients. I can tell you my practice in the bare-metal stent era I had about an 80% over the long-term occurrence of clinical restenosis. It was very, very impressive. So I've found the drug-eluting stents have made a tremendous difference in quality of life for our patients and I'm very reassured by the data that's emerged now as to some of the safety but we never had any misconceptions as to what we were expecting of drug-eluting stents.
One of the things that we're very aggressive on with our diabetics is to use long-term dual antiplatelet therapy with aspirin and clopidogrel. We tend to treat them beyond 1 year and we hope that there are no bleeding events, but that seems to be the stop gap down the road. So we have treated our patients with very aggressive dual antiplatelet therapy.
Dr. Davidson: I think I defer to the interventional cardiologist for that type of decision about bare-metal vs drug-eluting stents. I think the issue for me in taking care of the patient afterward is the length of the time of the antiplatelet therapy or the better potential agents out there. We've heard about them at this meeting -- although the risk-benefit is a concern. I think we're going to be able to solve the thrombotic complication as we get better and better antiplatelet drugs as well.
Dr. Kereiakas: I think in patients with no contraindication to protracted dual antiplatelet therapy, it's DES, that's the highly, highly significant reduction in clinical and angiographic restenosis. I'm intrigued by the prasugrel story and TRITON here at the meetings that reported a 52% reduction in stent thrombosis with use of both bare-metal and drug-eluting stent thrombosis compared to clopidogrel.
Dr. Feldman: What I'm seeing literally every day, and it's because we're asking -- and you ask every patient now before you even start on the diagnostic cath -- "do you have any elective surgery planned in the next year: cataracts, gallbladder, hips, knees?" And I think that's the biggest challenge we have right now and hopefully short-acting intravenous antiplatelet drugs will give us a way to manage the drug-eluting stent patient in a manner analogous to the mechanical heart valve patient with Coumadin, heparin, back to Coumadin. But we certainly do have plenty of challenges ahead.
I think we've accomplished our goals and touched on the objectives for the program and I want to thank you for taking time to join us today. Thanks very much and good day.
Supported by an independent educational grant from Boston Scientific.
