A New Standard of Care: Dr. Gregg Stone Discusses CADILLAC

Stenting alone (with the Multi-Link and Duet stents from Guidant Corporation, Santa Clara, CA); Stenting plus abciximab; Angioplasty; Angioplasty plus abciximab. Stenting significantly improved the outcomes of balloon angioplasty alone, especially at 12 months. In addition, abciximab improved the short-term (30-day) safety profile of the procedure. Outcomes for patients in the study in general were the best ever described for patients with AMI, with a successful procedure in approximately 95% of patients. At the end of 12 months, 96% of patients had survived. Cath Lab Digest spoke with Dr. Stone after his return from the March American College of Cardiology meeting, where he presented CADILLAC trial data. Is there a message you hope facilities will take from the CADILLAC trial results? I think that there’s several, actually. The first is that there’s a new standard for the treatment of patients with acute myocardial infarction. Patients need to get as quickly as possible to a center with invasive facilities and a center that performs primary angioplasty on a 24-hour, 7-day a week basis. A skilled invasive cardiology team needs to get to the cath lab, define the patient’s coronary anatomy, open the occluded or nearly occluded coronary vessel, and implant a stent. With that kind of approach, in most patients, we can expect about 96% survival at 6 to 12 months, and about 90% survival free of any adverse events. This really creates a new standard of care for excellent outcomes that can be expected in patients with AMI. What were some of the patient inclusion criteria? We meant for the CADILLAC trial to be very non-restrictive and all-inclusive. We took patients of any age experiencing an AMI up to 12 hours in duration, with any electrocardiographic pattern of MI. Basically, the only exclusion criteria, clinically, was the presence of cardiogenic shock. These data do not apply to this very high-risk subgroup, which is usually about 5% of the patients. We brought 2,681 consented patients to the cath lab, defined their anatomy, and found that 2,082 had the appropriate anatomy for coronary stenting. That is, a native coronary artery lesion that was up to approximately 64mm long that could be covered by two long stents, in a 2.5 to 4mm diameter vessel, not too tortuous, not too calcified, etc. We randomized those patients to either balloon angioplasty or stenting, and then each group was further randomized to abciximab (ReoPro®, Eli Lilly & Company, Indianapolis, Indiana) versus placebo. You found that abciximab plus stenting led to greater TIMI three flow. The addition of abciximab to either the balloon angioplasty-only arm or to the stent arm improved the results at 30 days. The procedures were a little safer, the TIMI flow was a little better and there was less stent thrombosis. By 6 months, restenosis basically took over, and the primary determinant at 6 months was whether or not you put a stent in not use of abciximab. How many patients had single versus multi-vessel disease? Approximately half the patients had multi-vessel disease. It’s a very powerful predictor of adverse outcomes, especially triple vessel disease. However, the benefits of stenting applied to the patients with multi-vessel disease just as well as single-vessel disease. In the study, you utilized the Guidant Multi-Link and Duet stents. What were the advantages of using these stents? This was really the first trial of any size that used those stents in myocardial infarction. Our previous study, Primary Angioplasty in Myocardial Infarction (PAMI) Stent, which before CADILLAC was the largest study of interventional therapy in AMI, was a 900 patient study in which we compared balloon angioplasty to a Palmaz-Schatz® stent (Cordis Endovascular, Warren, NJ). That was a big, relatively bulky sheathed stent. The stent actually led to decreased blood flow and a trend toward increased mortality. Even though stenting in the PAMI Stent trial led to less restenosis and less infarct artery reocclusion, it also led to increased mortality and decreased TIMI flow. As a result of that study, stenting was not routinely considered the standard of care in patients with acute MI. What we did in CADILLAC, (which was more than twice as large as PAMI Stent) was to use the lower profile, much more flexible sheathless Multi-Link and Multi-Link Duet stent, which allowed us to treat a much broader cross-section of patients. We also hoped it would be less traumatic to the vessel and because of its smaller profile, cause less embolization of thrombus. Sure enough, for a variety of reasons (a smaller profile may have been one of them), in the stent alone versus the PTCA alone group, we did not find the same adverse effect of decreased blood flow and increased mortality. If anything, it was the opposite. With aspirin, Plavix and heparin, and with the ability to cross over to abciximab, we found that the lower profile enhanced Multi-Link stent did not have the same kind of problems we found in the earlier PAMI Stent study. One of the trial results was that primary stenting optimizes the outcome of women with AMI. That’s from data I presented at the ACC. Women are known to be a high-risk group with myocardial infarction. In the CADILLAC trial, about 27% of the patients were women, and they of course were randomized to the same four groups: either balloon angioplasty, with or without abciximab, or stenting, with or without abciximab. Stenting continued to improve outcomes with women, but unfortunately, the mortality was 2.5 times higher in women than in men. Despite the fact that stents improve outcomes, stenting improves outcomes mostly by reducing restenosis. It doesn’t reduce death, reinfarction, or disabling stroke. Women had, by multivariate analysis, independent risk for mortality in heart attack. We have found that in all of our studies. You’re going to be working on a cost-effective analysis as well as safety and efficacy data. Any advance thoughts on what they might reveal? No, we don’t have the analysis done yet, though I suspect stenting will be shown to be cost-effective. What do you think the next step is in light of the CADILLAC results? The overall best outcomes were a combination of stents and the glycoprotein IIb/IIIa antagonist abciximab. However, there’s a lot more that needs to be done: First, from an educational perspective, we need to get people with heart attack symptoms into the hospitals earlier. Second, the whole question about facilitated angioplasty remains open. Given that there’s at least a two-hour delay to angioplasty in most centers, should we be treating patients with thrombolytic therapy first, and then getting them to the cath lab? That’s a real question we need to answer. Third, there are other strategies being developed to try and save even more heart muscle. We’re doing a study right now called the EMERALD study, which is randomizing 500 patients with heart attacks to either stenting or stenting plus distal protection of the distal microcirculation with the Medtronic PercuSurge® device (Miami, FL). That’s going to be very important to see if we can further decrease infarct size. There are other devices that are looking at cooling the myocardium, and supersaturated oxygen delivery. All of these devices hold a lot of promise that we may be able to reduce infarct size as well.