Timing, technique and the challenges in non-culprit vessel revascularisation: a critical look at the iMODERN Trial

Over 50% of patients with ST-elevation myocardial infarction (STEMI) have multivessel disease (1,2). The optimal strategy for the management of these patients is a constantly evolving subject with many levels of decision-making.

The first question pertains to the need for complete revascularisation (CR) compared to culprit-lesion-only revascularisation. Large randomised controlled trials (RCTs) conducted in the last decade now provide us with sufficient evidence to support CR (3-5). The COMPLETE trial is the largest RCT comparing CR with culprit-lesion-only revascularisation in STEMI. It showed a 26% lower risk of the primary composite endpoint, comprising of cardiovascular death or myocardial infarction (MI), [hazard ratio (HR), 0.74; 95% confidence interval (CI): 0.60 to 0.91; P=0.004] in patients who underwent CR—a difference which was primarily due to a lower risk of MI. The CR group was also observed to have 82% lower rate of ischemia-driven revascularisations (4). Subsequently, Bainey et al. confirmed these findings and showed a 31% relative risk reduction in cardiovascular death with the strategy of CR in a meta-analysis including 10 RCTs with a total of 7,030 patients (6). The latest European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) guidelines acknowledge this with a class 1A recommendation for CR in hemodynamically stable patients presenting with STEMI (7,8).

Secondly, should the non-culprit vessel revascularisation be guided by anatomy or by physiologic testing? In chronic coronary syndromes, there is robust evidence to demonstrate that fractional flow reserve (FFR) guided revascularisation significantly reduces the risk of death, nonfatal MI and repeat revascularisation compared to angiography-guided revascularisation, while also resulting in lesser number of treated lesions (9). Non-hyperaemic physiologic testing using instantaneous wave-free ratio (iFR) has also been demonstrated to be non-inferior to FFR in large RCTs like DEFINE-FLAIR and iFR-SWEDEHEART (10,11). Consequently, the use of FFR or iFR to guide lesion selection for revascularisation in chronic coronary syndrome is endorsed by both of the latest guidelines with a class IA recommendation (12,13). However, in the scenario of acute coronary syndromes (ACS), there is both conceptual as well as evidentiary equipoise regarding the use of physiologic testing. Only two RCTs have conducted a head-to-head comparison of FFR-guided CR strategy with an angiography-guided strategy in patients with STEMI, and have yielded discordant results (14,15). A network meta-analysis, including 20 RCTs amounting to a total of 13,000 patients, showed no significant differences between angiography and physiology-guided CR in the risk of major adverse cardiovascular events (MACEs) or other efficacy or safety endpoints (16).

The third level of decision-making in the management of patients with STEMI with multivessel disease is the timing of CR. Existing literature comparing immediate CR strategy with staged CR strategy have, more often than not, clubbed together patients with STEMI and non-ST-elevation MI (NSTEMI). Since distinguishing culprit lesions from non-culprit lesions can be difficult in patients with NSTEMI (17), enrolling NSTEMI and STEMI patients together may tip the scales in favour of immediate CR. The recent 2025 ACC/AHA guidelines stated an updated preference for immediate non-culprit lesion revascularisation over a staged approach to reduce the risk of cardiovascular events in selected patients, based on two RCTs (BIOVASC and MULTISTARS AMI) and a meta-analysis (16,18,19). However, the 44% reduction in the composite of cardiovascular death or MI with immediate CR observed in the BIOVASC trial occurred in a trial population consisting of 60% NSTEMI patients (18). In addition, the 43% reduction in the primary composite endpoint observed in the MULTISTARS AMI trial was driven by a reduction in unplanned revascularisations, which may be considered a subjective endpoint (19).

Nijveldt et al. sought to answer this uncertainty regarding the preferred timing of non-culprit lesion revascularization by designing a much-needed superiority trial consisting solely of STEMI patients (20). This investigator-initiated, open-label, multicenter trial randomized 1,146 STEMI patients with at least one non-culprit lesion, after successful primary percutaneous coronary intervention (PCI), to an immediate iFR-guided revascularisation strategy or a deferred cardiac stress magnetic resonance imaging (MRI)-guided revascularisation strategy within 6 weeks. The mean age of the population was 63 years. Both arms were similar in terms of most cardiovascular risk factors except obesity and a history of smoking, which were more common in the immediate revascularisation arm. In both arms, approximately 87% of the patients had an estimated glomerular filtration rate (eGFR) of >60 mL/min/1.73 m², and 83% had no or mild left ventricular dysfunction. The residual SYNTAX score after culprit lesion revascularisation was also similar in both arms. The primary endpoint, a composite of death, recurrent MI, or heart failure hospitalization (HFH) at 3-year follow-up, occurred in 9.3% of patients in the immediate revascularisation group and in 9.8% of patients in the deferred strategy group (HR, 0.95; 95% CI: 0.65 to 1.4; P=0.81), showing that an immediate iFR-guided revascularisation strategy was not superior to a deferred stress MRI-guided revascularisation strategy. The immediate revascularisation arm also had a lower rate of HFH at 6 months, 12 months, and 3 years, although the trial was not adequately powered to evaluate this. This is in accordance with the results of the recently published OPTION-STEMI trial, another multicenter RCT with 994 patients, which failed to demonstrate the non-inferiority of immediate CR strategy to a staged CR strategy (21).

However, there are some other important observations from the study that trigger a thorough vetting of the methods used. In the iFR group, 43.7% of the patients had a functionally significant non-culprit lesion compared to 21.8% in the stress MRI group. In the context of the observed low event rates in both groups, this may point towards a high false-positive rate in the iFR group. The investigators therefore suggest that the difference may be related to the inherent technical aspects of the modalities in evaluating ischemia, pointing out that the proportion of functionally significant lesions in the immediate iFR group and in the deferred group who underwent iFR as bailout appeared similar. However, the cohort that underwent deferred iFR bailout only consisted of 65 patients and may not be sufficient to draw meaningful conclusions. The authors also suggested that this difference could be due to the lower sensitivity of stress MRI, as smaller ischemic territories may be undetected. However, as the observed event rates were similar, these small territories were likely clinically irrelevant. The accuracy of using iFR in the ACS setting has not been well studied and is not supported by robust evidence. The authors mentioned the validation of iFR measurements in patients with STEMI in a recent trial. The trial assessed the level of agreement between acute iFR measured across 157 non-culprit lesions in 120 patients with STEMI and follow-up iFR measured at a staged follow-up procedure (22). In this study, acute iFR showed a good sensitivity, detecting 87% of the stenoses with follow-up iFR <0.90. However, around one-third of the lesions showing an acute iFR <0.90 had follow-up iFR >0.90, reflecting a high false positive rate. Interestingly, the interval between the acute and follow-up iFR affected classification agreement, with the observed agreement decreasing to 70% when the time interval was 16 days or more. This suggests that acute physiological disturbances due to STEMI may result in false-positive iFR recordings. With each new study, our understanding of how to manage this subset of patients grows. However, the complexity of non-culprit lesion assessment is yet to be resolved. In the setting of STEMI, physiology testing may be mechanistically flawed due to microvascular dysfunction. Several studies have shown that acute microvascular dysfunction is not just confined to the culprit vessel, but also involves remote myocardium (23). Microvascular dysfunction limits maximal achievable blood flow resulting in a lower pressure drop across the lesion and thus, falsely elevated FFR. Existing literature shows that around 22% of non-culprit vessels demonstrate microvascular dysfunction when diagnosed on the basis of index of microvascular resistance (IMR), and around 15% when diagnosed by coronary flow reserve (24).

The expected benefit due to immediate CR in patients with STEMI is from a reduction in recurrent MI conferred by the tackling of other high-risk unstable plaques that could rupture, leading to a clinically significant ACS. Since plaque morphology, rather than physiological significance, may be more closely linked to the fate of lesions, deferral of some physiologically insignificant lesions that contain high-risk morphological features, such as thin-capped fibroatheromas and signs of plaque inflammation, could result in missed future culprit lesions. Hence, the probability of attaining a significant benefit from an immediate CR strategy is linked to our ability to accurately assess and identify the appropriate non-culprit lesions. More well-designed trials with adequate statistical power are needed to augment our understanding of non-culprit lesion assessment. The ongoing COMPLETE-2 trial is comparing angiography-guided CR with physiology-guided CR in more than 5,100 patients, followed for a median of 3 years. It includes a prospective, observational optical coherence tomography (OCT) imaging sub-study of 1,500 eligible patients. Future trial designs incorporating integrated imaging and physiology-guided non-culprit lesion revascularisation strategies could provide us with a new dimension of information. Until data from COMPLETE-2 provide definitive answers on the role of physiology and imaging, the iMODERN results suggest caution. The reliance on acute physiological indices may lead to overtreatment without clinical benefit. For now, the results of the iMODERN study add on to the confidence of interventionists who support a deferred approach for non-culprit vessel revascularisation guided by coronary physiology.

Acknowledgments

None.

Footnote

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References

1. Park DW, Clare RM, Schulte PJ, et al. Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction. JAMA 2014;312:2019-27. [Crossref] [PubMed]
2. Dziewierz A, Siudak Z, Rakowski T, et al. Impact of multivessel coronary artery disease and noninfarct-related artery revascularization on outcome of patients with ST-elevation myocardial infarction transferred for primary percutaneous coronary intervention (from the EUROTRANSFER Registry). Am J Cardiol 2010;106:342-7. [Crossref] [PubMed]
3. Smits PC, Abdel-Wahab M, Neumann FJ, et al. Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction. N Engl J Med 2017;376:1234-44. [Crossref] [PubMed]
4. Mehta SR, Wood DA, Storey RF, et al. Complete Revascularization with Multivessel PCI for Myocardial Infarction. N Engl J Med 2019;381:1411-21. [Crossref] [PubMed]
5. Biscaglia S, Guiducci V, Escaned J, et al. Complete or Culprit-Only PCI in Older Patients with Myocardial Infarction. N Engl J Med 2023;389:889-98. [Crossref] [PubMed]
6. Bainey KR, Engstrøm T, Smits PC, et al. Complete vs Culprit-Lesion-Only Revascularization for ST-Segment Elevation Myocardial Infarction: A Systematic Review and Meta-analysis. JAMA Cardiol 2020;5:881-8. [Crossref] [PubMed]
7. Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J 2023;44:3720-3826. [Crossref] [PubMed]
8. Rao SV, O'Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2025;151:e771-862. [Crossref] [PubMed]
9. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213-24. [Crossref] [PubMed]
10. Götberg M, Christiansen EH, Gudmundsdottir IJ, et al. Instantaneous Wave-free Ratio versus Fractional Flow Reserve to Guide PCI. N Engl J Med 2017;376:1813-23. [Crossref] [PubMed]
11. Davies JE, Sen S, Dehbi HM, et al. Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI. N Engl J Med 2017;376:1824-34. [Crossref] [PubMed]
12. Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation 2023;148:e9-e119. [Crossref] [PubMed]
13. Vrints C, Andreotti F, Koskinas KC, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J 2024;45:3415-537. [Crossref] [PubMed]
14. Puymirat E, Cayla G, Simon T, et al. Multivessel PCI Guided by FFR or Angiography for Myocardial Infarction. N Engl J Med 2021;385:297-308. [Crossref] [PubMed]
15. Lee JM, Kim HK, Park KH, et al. Fractional flow reserve versus angiography-guided strategy in acute myocardial infarction with multivessel disease: a randomized trial. Eur Heart J 2023;44:473-84. [Crossref] [PubMed]
16. Ueyama HA, Akita K, Kiyohara Y, et al. Optimal Strategy for Complete Revascularization in ST-Segment Elevation Myocardial Infarction and Multivessel Disease: A Network Meta-Analysis. J Am Coll Cardiol 2025;85:19-38. [Crossref] [PubMed]
17. Heitner JF, Senthilkumar A, Harrison JK, et al. Identifying the Infarct-Related Artery in Patients With Non-ST-Segment-Elevation Myocardial Infarction. Circ Cardiovasc Interv 2019;12:e007305. [Crossref] [PubMed]
18. Diletti R, den Dekker WK, Bennett J, et al. Immediate versus staged complete revascularisation in patients presenting with acute coronary syndrome and multivessel coronary disease (BIOVASC): a prospective, open-label, non-inferiority, randomised trial. Lancet 2023;401:1172-82. [Crossref] [PubMed]
19. Stähli BE, Varbella F, Linke A, et al. Timing of Complete Revascularization with Multivessel PCI for Myocardial Infarction. N Engl J Med 2023;389:1368-79. [Crossref] [PubMed]
20. Nijveldt R, Maeng M, Beijnink CWH, et al. Immediate or Deferred Nonculprit-Lesion PCI in Myocardial Infarction. N Engl J Med 2026;394:958-68. [Crossref] [PubMed]
21. Kim MC, Ahn JH, Hyun DY, et al. Immediate versus staged complete revascularisation during index admission in patients with ST-segment elevation myocardial infarction and multivessel disease (OPTION-STEMI): a multicentre, non-inferiority, open-label, randomised trial. Lancet 2025;406:1032-43. [Crossref] [PubMed]
22. Thim T, Götberg M, Fröbert O, et al. Nonculprit Stenosis Evaluation Using Instantaneous Wave-Free Ratio in Patients With ST-Segment Elevation Myocardial Infarction. JACC Cardiovasc Interv 2017;10:2528-35. [Crossref] [PubMed]
23. Bax M, de Winter RJ, Koch KT, et al. Time course of microvascular resistance of the infarct and noninfarct coronary artery following an anterior wall acute myocardial infarction. Am J Cardiol 2006;97:1131-6. [Crossref] [PubMed]
24. Everaars H, van der Hoeven NW, Janssens GN, et al. Cardiac Magnetic Resonance for Evaluating Nonculprit Lesions After Myocardial Infarction: Comparison With Fractional Flow Reserve. JACC Cardiovasc Imaging 2020;13:715-28. [Crossref] [PubMed]