Dr Nick Palmer (Liverpool Heart and Chest Hospital, Liverpool, UK) discusses the large multinational COMPLETE trial.
The aim of this comparative-effectiveness study was to determine whether routine angiographically-guided percutaneous coronary intervention (PCI) would prevent CV death or MI, compared with optimum guideline-directed medical therapy alone.
Filmed in London at BCIS ACI 2020.
Interviewer: Leiah Norcott
Videographer: Natacha Wienand / Dominic Woodruff
Transcript Below :
Question 1 : What was the COMPLETE study design and what did it aim to assess?
So the COMPLETE study is a multinational, multicenter, comparative trial. Which essentially is used to assess the difference between culprit-only PCI following successful management of STEMI against a complete revascularization of all suitable lesions. The study design is essentially that patients who have a successful PCI for STEMI, are then randomised to stratigiphy the complete revascularization of culprit-only PCI. And one of the really important aspects of this trial is at the point of randomization, the operator had to state whether they were going to undertake a further procedure to a non-culprit vessel. And the definition of a non-culprit lesion is an angiographic stenosis of over 70%, or a more modest lesion associated with a low FFR assessment. And the operator had to state whether they were going to undertake that procedure on the same admission, or undertake it in a time course following their procedure after discharge, up to a maximum of 45 days. So, the trial design is really looking to see if there's a difference between complete revascularization in culprit lesion only. And it was powered particularly to look for more hard endpoints. So, those of cardiovascular death, myocardial infarction, as well as ischaemia-driven revascularization, which is a new feature because of the size of the trial which has enabled us to answer some questions which previous trials haven't been able to answer totally.
Question 2 : What were the key outcomes from the study?
So, the key outcomes of the trial were that firstly, as a median follow-up of three years, there was a consistently demonstrated 26% reduction in cardiovascular death and MI endpoint, a combined, what's called co-primary endpoint, of the COMPLETE revascularization group compared to culprit-only PCI. When you look at the second co-primary endpoint which adds in ischaemia-driven revascularization, there's a 49% risk reduction in that group, and this is consistent out to the follow-up of median three years, but also right out to five years in smaller numbers of patients. So, a very clear difference between the two treatment groups.
Question 3 : Where there any limitations with COMPLETE?
The limitations with COMPLETE, it actually answered a lot of the limitations of previous trials, to be honest. So essentially, it was a larger trial of over 4,000 patients. It was appropriately randomised. It did seek to answer whether there was a difference between undertaking revascularization during admission or following discharge. And really, because this wasn't a specifically randomised part of the trial, it was more operator choice, it was subject to confounding factors. So whilst this trial does help answer the question around reducing cardiovascular death or MI, it actually doesn't tell us when we should be performing the second procedure on the basis of this. So the statement that it's actually safer or just as safe to undertake PCI in the weeks following the index PCI for STEMI, that question really isn't answered in this trial, even though the trial sort of states that there is no difference between either approach. I think that other thing that is important to note about the COMPLETE trial is that a large part of the outcome is driven by ischaemia-driven revascularization and MI, which was obvious in other trials. And they're actually, some would argue, that it's a concern, that actually, when you look at the endpoint alone of cardiovascular death, there's no difference between the groups, and also there's no difference in all-cause mortality between the two groups.
Question 4 : What did the additional timing and OCT sub-analyses add to the story?
The additional timing, issues around the timing of the procedure. So essentially, this was whether the procedure is undertaken during the admission or whether the non-culprit lesion procedure is undertaken in a time course after the procedure. What the data demonstrated is that it would seem to be safe, that you could actually defer a procedure to a further admission, a few weeks down the line, a mean of 23 days, or a median, sorry, of 23 days down the line, and it's still safe, and it still confers similar outcomes out to four or five years. However, this was a non-randomized aspect of the trial, so we still really don't know the answer as to whether we can keep these patients waiting for a procedure, or whether they need to be done on the same admission. In terms of the OCT sub-study, this was a very observational study. And basically, they looked at about 93 patients, all were the patients in the COMPLETE revascularization group, and they carried out OCT before successful PCI was undertaken, and what this trial, in simply an observational way, is showing is that we're demonstrating that about 40% of significant lesions have what's called a thin-cap fibroatheroma which is a marker of high risk type of lesion. So it just helps postulate that actually some of the benefits we're seeing from the COMPLETE trial are that we're actually reducing inflammation or we're pacifying a severe lesion with a stent, and reducing the risk of further events as a result of that. But it is very observational. It's more hypothesis-generating than anything else, and I think a lot more work needs to be done to examine that side of things before we can make firm conclusions about the role of inflammation in this outcome data.
Question 5 : How should COMPLETE influence practice?
So the COMPLETE trial, the data that's been produced, tells us a couple of things. The first thing it tells us is that there's definite indication that complete revascularization improves outcomes. We may criticise the endpoints to a degree, but it gives more data in an appropriately proud trial that we can reduce endpoints of cardiovascular mortality and MI. So it gives us confidence that we actually are benefiting patients and may not necessarily need to investigate them for ischaemia or treat them medically, as we conventionally do. It doesn't answer the question as to when we should do the procedure, whether we should do it on the same admission or after discharge. But I think that most importantly, it's telling us that complete revascularization would seem to be safe, over and above, complete culprit lesion PCI. Even though more procedures are done, there doesn't appear to be a signal that we are subjecting the patient to greater risk by undertaking further procedures.
Question 6 : What questions remain unanswered that require further research?
The first question that remains unanswered is the idea of the timing of when we should do the non-culprit PCI. Should it be same admission? Should it be in a time frame following? And I think that needs a randomised study, looking at that area specifically. The second issue is, we obviously carry out physiological assessment of coronary lesions with fractional flow reserve, and what is the role of fractional flow reserve in assessing modest and even severe lesions, angiographically? And does the use of FFR influence the amount of revascularization that we undertake and would it influence the outcome of COMPLETE? And the final thing is that the OCT data suggests that there may be an inflammatory role that is actually driving the reduction in events that is seen consistently out to a median of three years but out to five years. And it might be that more explanation of whether there's an inflammatory element to treating these non-culprit lesions that actually is having an influence on the overall outcome and assessing the size of that influence overall.