INFUSE-AMI: Intracoronary Abciximab in STEMI Patients

The INFUSE-AMI [Intracoronary Abciximab Infusion and Aspiration Thrombectomy in Patients Undergoing Percutaneous Coronary Intervention for Anterior ST Segment Elevation Myocardial Infarction (MI)] trial, a prospective, randomized, single-blind trial conducted at 37 clinical sites in the U.S. and five European countries, enrolled 452 patients who presented within four hours of an anterior wall STEMI. Study subjects were randomized to one of four study arms:

• Intracoronary infusion of abciximab via the ClearWay RX Local Therapeutic Infusion Catheter (Atrium Medical, Hudson, New Hampshire) with thrombus aspiration;
• Intracoronary infusion of abciximab via ClearWay RX without thrombus aspiration;
• Thrombus aspiration only;
• No abciximab infusion and no thrombus aspiration (traditional PCI).

Study endpoints included impact on infarct size at 30 days as measured by cardiac MRI, ST-segment resolution, myocardial perfusion, impact on thrombus burden, and outcomes on bleeding.

The INFUSE-AMI trial was led by the Cardiovascular Research Foundation in New York.  Dr. Stone was the principal investigator and Dr. C. Michael Gibson, chief of clinical research at Beth Israel Deaconess Medical Center/Harvard Medical School in Boston, served as co-principal investigator.

What is the problem in STEMI patients that led to INFUSE-AMI?

In patients with a ST-segment myocardial infarction, we have become good at opening the infarct artery very quickly with primary angioplasty and restoring normal epicardial flow to the occluded coronary artery on the surface of the heart. However, the goal of angioplasty is to restore normal myocardial metabolism in the myocardial cells, which are experiencing ongoing injury that will lead to death if that process is not aborted. While we can restore TIMI-3 flow in >90% of patients with primary percutaneous coronary intervention (PCI), and while we can accomplish this rapidly, often we do not salvage as much of the left ventricular myocardium as we would like. This means patients end up with a large infarct and we have an increasing number of patients with heart failure, who are prone to late, sudden death or death from left ventricular failure.

In most cases, what causes a heart attack is the rupture of a thin-capped fiberatheroma overlying a necrotic core. In the necrotic core are soft cholesterol and cholesterol esters, and necrotic cells. As the fiberatheroma ruptures, the necrotic core releases its very pro-thrombotic content to the bloodstream, and that causes a thrombus to form. When the thrombus occludes the vessel, it causes a heart attack. As balloon angioplasty is performed and especially when we put a stent right in the center of the thrombus and the very soft, necrotic core, some of that material is embolized downstream. Sometimes it passes through the capillary system and then it does not do any damage, but many times this material will actually cause capillary block, decreasing myocardial reperfusion. This means even if we see epicardial reperfusion, the blood, oxygen and nutrients are not getting to the heart muscle itself, so normal metabolism cannot be restored.

Many approaches exist to try to improve myocardial salvage and reduce infarct size in patients with evolving heart attack. Two of those approaches revolve around trying to prevent distal embolization of thrombus and soft atheromatus debris from the infarct artery: thrombus aspiration and intracoronary abciximab. Thrombus aspiration uses basically a hollow catheter to extract the thrombus and other soft atheromatous debris before it embolizes (that is, before balloon angioplasty and stenting), whereas intercoronary abciximab, with a potent antiplatelet agent, is hypothesized to work by leading to a much, much higher concentration of abciximab right at the site of the thrombus than if it is given by the normal intravenous route. The concentration can be 1,000x as high in the coronary artery as intravenously, and that can directly cause disaggregation of platelets. Since the early thrombus is very platelet-rich, intracoronary abciximab may lead to less macroscopic or large embolic debris.

In the past, studies that have been done to look at these two methods have yielded conflicting results as to whether they improve microcirculatory function, reduce infarct size and improve clinical outcomes. Therefore, we undertook what was probably to date the most carefully controlled, specific trial to see if using one or both of these devices could reduce infarct size. We took patients only with a large myocardial infarction, those with the greatest clinical need — specifically, patients with anterior myocardial infarction, with occlusion of the proximal or mid left anterior descending artery. These patients had to have presented early, within 3.5 to 4 hours after the onset of their infarct, so they would undergo their angioplasty while still in the time window for effective myocardial salvage. We know that if you wait too long for revascularization, beyond 4-6 hours or so, then, in general, the patient ends up with a transmural infarct and very little chance of myocardial salvage.

INFUSE-AMI screened more than 3,600 patients, at 37 sites in 6 countries around the world, and we only enrolled patients with anterior myocardial infarction, proximal or mid left anterior descending coronary artery occlusion, 3.5 to 4 hours within their infarct time, no prior myocardial infarction and some other contraindications, to enroll a total of 452 patients. We randomized them in a 2 x 2 factorial design, to either aspiration, yes vs. no, and each of those groups was sub-randomized to intracoronary abciximab, yes vs. no. All patients were treated with bivalirudin as the foundation anticoagulant. In the intracoronary abciximab arm, since no patient received a 12-hour infusion of abciximab, patients were treated only with a bolus of intracoronary abciximab versus no intracoronary abciximab, allowing us to isolate its effects. Finally, the primary endpoint was infarct size measured by cardiac magnetic resonance imaging (cardiac MRI) at 30 days. A unique aspect of the trial was the choice of a 30-day endpoint. Most studies would have a cardiac MRI endpoint at 2 to 4 days, but that leads to a much larger infarct size, because cardiac MRI at 2 to 7 days misclassifies myocardial edema as infarct. There is a great deal of edema early on which resolves over the first 30 days in particular, but then even ongoing probably for the entire year. By waiting to 30 days, we hoped to gain a more accurate impression of infarct size by having probably a 60-70% resolution of myocardial edema.

The primary endpoint of cardiac MRI at 30 days showed intracoronary abciximab “significantly but modestly” reduced the infarct size.

We hypothesized at the beginning and powered the trial for an infarct size of approximately 24% of the left ventricle. So 24% of the entire 100% of the left ventricle would be involved with an infarct in the control group, and we thought it would be clinically relevant if we could reduce that by a relative 25% or an absolute 6% down to an infarct size of 18%. Since we did the study with an endpoint at 30 days instead of earlier, the infarcts were slightly smaller than anticipated in the control group, at about 17.9% of the left ventricle, which is still a very large infarct. We reduced it to 15.1% with intracoronary abciximab, which is approximately a 3% reduction of myocardial size. That is about half the size that we had pre-specified would be clinically relevant. It was a real reduction, it was statistically significant, but the real question is, what would a 3% reduction in infarct size mean to a single patient or 1,000 patients? That can only be answered in a large-scale, randomized trial. The current trial was underpowered for clinical events. We never expected to see differences in clinical events, nor did we, and while we did not see any statistically significant harm from abciximab, which would primarily be bleeding or thrombocytopenia, we would need a large-scale trial to see if the bolus-only would make a significant difference.

What did we learn about manual aspiration?

Well, it had a neutral effect. There was no effect, basically, on reducing infarct size or improving microcirculatory function with aspiration thrombectomy in this carefully controlled study.

What can clinicians take away from that for their daily practice?

If manual aspiration does not reduce infarct size, there is no valid mechanistic reason to believe that it would reduce mortality, reduce heart failure or otherwise improve clinical outcomes. However, these were the results in all comers who met the inclusion criteria, and we did not specify the amount of thrombus that had to be present. We have not yet performed an analysis based on how much thrombus was present, but will do so in the future. I still think that aspiration thrombectomy, from a practical point of view, has a role for patients with a very large amount of thrombus in the coronary artery. From experience, we know the results will not be satisfactory if you only directly balloon and stent in these patients. For most lesions that cause acute myocardial infarction, it does not appear that aspiration thrombectomy is at all beneficial. And of course, there is some cost associated with it.

The trial also showed a lack of significant decrease in abnormal wall motion in the intracoronary abciximab group.

The study was underpowered to show that and there was a strong trend toward reduction in abnormal wall motion with abciximab. P-value was .08. There was also a trend, but more non-significant, for about a 1.3% improvement in global left ventricular ejection fraction at 30 days. Again, if a larger study was performed, if we had randomized 800 patients instead of 452, it’s likely that both of those numbers would have been significant.

What about other secondary endpoints, such as ST-segment resolution and myocardial perfusion?

With both therapies, intracoronary abciximab and aspiration thrombectomy, other measures, such as angiographic myocardial blush, an angiographic surrogate of blood getting into the myocardium, and ST-segment resolution, which means, did we stop the ongoing injury, were both neutral. That was a little bit surprising, especially in the intracoronary abciximab arm, where we would have expected that to track along with the decreased infarct size at 30 days. We will be doing more studies to try to figure out why there was discordance in those outcome measures. But most people would ascribe infarct size to be the more powerful surrogate of clinical outcomes.

Any final thoughts?

The results clearly demonstrate that in high-risk patients presenting early in the course of a large evolving anterior MI undergoing primary PCI with bivalirudin anticoagulation, bolus intracoronary abciximab delivered to the infarct lesion site via the ClearWay Rx Infusion Catheter results in a significant reduction in infarct size at 30 days. A randomized trial powered for clinical and safety endpoints is thus warranted to determine the role of local abciximab delivery in STEMI. In contrast, manual thrombus aspiration did not reduce infarct size. The final word on aspiration in STEMI awaits the ongoing results from two large randomized trials ongoing in Sweden and Canada.

Dr. Stone can be contacted at gs2184@columbia.edu.

Disclosure: Dr. Stone reports he is a consultant to Abbott Vascular, Boston Scientific, Medtronic, Atrium, BMS-Sanofi, Merck, Janssen, Eli Lilly, Daiichi Sankyo, The Medicines Company, and Astra Zeneca.