Anatomy vs. Physiology: Achieving Revascularization in ACS

Abstract and Introduction

Abstract

Graphical Abstract

Comparison of trial characteristics between the FRAME-AMI and FLOWER-MI trial.

Introduction

Since the inception of primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI), there has been debate on how best to manage patients with multivessel coronary artery disease (CAD). Over the last decade, several randomized trials have demonstrated that achieving complete revascularization with PCI of non-culprit lesions is beneficial in reducing clinical outcomes, mainly non-culprit lesion ischaemia-driven revascularization.^[1–4] The multinational COMPLETE trial of >4000 patients showed that complete revascularization with staged angiography-guided non-culprit lesion PCI reduced the hard outcomes of cardiovascular death or new MI, in addition to its known benefit in reducing ischaemia-driven revascularization.^[5] Based on these results, the 2021 AHA/ACC/SCAI Revascularization Guidelines elevated the recommendation for complete revascularization in patients with STEMI and multivessel CAD from a Class 3 recommendation in prior guidelines to the very highest level recommendation, Class 1A.^[6] One of the most important questions now is: 'how can we best identify which non-culprit lesions to revascularize?' Traditionally there have been two approaches: an angiography-guided approach where non-culprit lesions suitable for PCI are identified based on their visual stenosis severity or a physiology-guided approach where non-culprit lesions suitable for PCI are identified based on their functional significance. An angiography-guided strategy is most commonly used because it is widely available and simple, and now shown in the COMPLETE trial to reduce hard outcomes. However, a disadvantage of this approach is that, by opening all angiographically significant non-culprit lesions, it may lead to unnecessary PCI procedures. In a recent analysis from the COMPLETE trial angiographic core lab, the entire benefit of complete revascularization appeared to be confined to the two-thirds of patients with more severe non-culprit lesions [≥60% by quantitative coronary angiography (QCA) or ~80% visual stenosis], with no apparent benefit in the one-third of patients with less severe lesions.^[7] A downside to visusal estimation is that it has poor interobserver reliability, and QCA is not practical in most catheterization labs. One way to identify suitable non-culprit lesions is with a physiology-guided approach using a hyperaemic index such as fractional flow reserve (FFR) or a non-hyperaemic index such as the resting full-cycle ratio (RFR) or instantaneous wave-free ratio (iFR), where only lesions that are deemed to be functionally significant are treated with PCI; those that are not functionally significant are treated with medical therapy alone. These indices are measured by inserting a pressure wire across a lesion and comparing the pressure distal to the stenosis with aortic pressure. This approach is well established in patients with stable CAD where it has been shown to be superior to an angiography-guided strategy.^[8,9] However, in the acute coronary syndrome (ACS) setting, the role of a physiology-guided strategy is much less clear because, while in stable CAD most plaques are fibro-calcific with a low propensity to plaque rupture, in ACS about one-half of all plaques are inflamed lipid-rich thin-capped fibroatheromas with a higher propensity for plaque rupture.^[10–12] The fate of these non-culprit lesions may be more closely linked to plaque morphology than to physiological significance, implying that deferral of some physiologically insignificant lesions that contain high-risk morphological features such as inflammation and thin-capped fibroatheromas could still be associated with increased cardiovascular events. This raises the question of whether a physiology-guided strategy in the setting of ACS will allow safe deferral of non-culprit lesions as in stable CAD.

A meta-analysis of randomized trials of complete vs. culprit lesion-only PCI support the physiology-guided approach by demonstrating no heterogeneity in the trials that used an angiography-guided approach and the trials that used a physiology-guided approach.^[13] Recently, two randomized trials directly compared physiology-guided vs. angiography-guided complete revascularization strategies in patients with ACS (Graphical Abstract). In the FLOWER-MI trial of 1171 STEMI patients with multivessel CAD, non-culprit lesion PCI was reduced substantially in the physiology-guided arm as compared with the angiography-guided arm (66% vs. 97%).^[14] At 1 year, there was no difference between the two strategies on the primary outcome of death, MI, or urgent revascularization [5.5% FFR-guided vs. 4.2% angiography-guided, hazard ratio (HR) 1.32; 95% confidence interval 0.78–2.23; P = 0.31]. The Kaplan–Meier curves appeared to separate late in favour of an angiography-guided strategy.

In this issue of the European Heart Journal, the FRAME-AMI investigators publish the results of a 562 patient trial of patients with STEMI or non-STEMI (NSTEMI) and multivessel disease randomized to FFR-guided or angiography-guided complete revascularization.^[15] The original sample size was 1292 patients, but the trial was terminated prematurely by the executive committee, with <50% of the originally planned enrolment due to slow recruitment because of the COVID-19 pandemic. Of those randomized, 60% underwent immediate non-culprit lesion PCI and 40% had a staged procedure. Non-culprit lesion PCI was performed in 64% in the FFR-guided arm and 97% in the angiography-guided arm. At a median follow-up of 3.5 years, the primary endpoint of death, MI, or repeat revascularization was reduced with the FFR-guided strategy compared with the angiography-guided strategy (7.4% vs. 19.7%, HR 0.43, P = 0.003). The time-to-event curves diverged early, on Day 1, suggesting that a significant proportion of the excess events in the angiography-guided group may have been procedure related. Death (5 vs. 16 patients), MI (7 vs. 21 patients), and unplanned revascularization (10 vs. 16) were also lower in the FFR-guided PCI group.