Expert Opinion on Fractional Flow Reserve-Guided Full Revascularisation of ST Segment Elevation Myocardial Infarction Patients

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1 Expert Opinion on Fractional Flow Reserve-Guided Full Revascularisation of ST Segment Elevation Myocardial Infarction Patients Findings from the DANAMI-3 PRIMULTI Trial An interview with Thomas Engstrøm, MD Keywords Fractional flow reserve Acute coronary syndrome STEMI Multivessel disease Complete revascularization PRIMULTI Published: June 16 Citation: RadcliffeCardiology.com, June 16 Support: The publication of this information was supported by St. Jude Medical. Today, the interest in optimal treatment of acute coronary syndrome (ACS) has never been greater. Several factors have contributed to this including an expanding patient population, the poorer prognosis of patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease and the recent evidence from randomised trials suggesting that multivessel percutaneous coronary intervention (PCI) is not only safe but reduces major adverse cardiac events (MACEs). 1 3 In a recent publication of The Lancet, Thomas Engstrøm and his colleagues reported findings of the PRImary PCI in MULTIvessel Disease (DANAMI-3 PRIMULTI) study, which investigated whether complete revascularisation during the index admission of STEMI patients with multivessel disease reduced the risk of future events. 1 In this paper Engstrøm, the principal investigator, shares his view on this challenging patient population and the rationale and outcomes of the PRIMULTI study. Q. Why is ACS such a challenge to interventional cardiologists? Dr Engstrøm: The basic disease in atherosclerotic heart disease is the accumulation of lipids and calcium in the arteries that narrows the vessels and gives rise to ischaemia in the heart. In the case of ACS, on top of this, you also have a plaque rupture and thrombus formation, so you have a dual problem compared to stable angina patients. Q. Do you see an increase in ACS patients versus stable coronary heart disease presenting at your cath lab? Dr Engstrøm: Yes, we noted that in previous times about 3 4 % of patients were ACS patients, but they now represent more than half of our patients. Today, two out of three are ACS patients. I think that the threshold for admittance of patients with ACS is lower now so patients with very small variations in troponins are now admitted very fast for angiography. This was not the case in the past. Q. What do the European Society of Cardiology (ESC) guidelines recommend today for the treatment of STEMI patients with multivessel disease? Dr Engstrøm: The ESC guidelines recommend that you take care of the STEMI vessel and re-open the occluded vessel, for which the patient was admitted to the hospital. You only do additional PCI or revascularisation on multivessel stenoses if you have ongoing ischaemia, meaning you have ST-segment changes, continuous pain, cardiogenic shock, unstable arrhythmia and unstable haemodynamics. 4 Otherwise, if you follow the guideline recommendations, you leave the other stenoses untreated. Q. What drove you to conduct the PRIMULTI study? Dr Engstrøm: The main reason was the fact that physicians treat STEMI patients with multivessel disease quite intuitively. Some physicians perform full revascularisation, other physicians only treat the culprit lesion and others only consider severe or proximal stenoses for treatment. The field was very naïve until the Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) 2 and the Complete versus Lesion-only Primary PCI trial (CvLPRIT) 3 studies came out. The PRIMULTI investigators wanted to extend the results from PRAMI and CvLPRIT into a larger scale study, simply with more patients. Q. What methodology was used in the PRIMULTI study? Dr Engstrøm: Patients were admitted for STEMI treatment on the basis of regular indications: symptoms for more than 12 hours and ST-segment elevation on ECG. Then, primary angioplasty was performed to relieve the thrombosis and stent the vessel. If patients had another stenosis with at least % angiographic narrowing, patients were randomised either to no further treatment other than optimal medical therapy or to fractional flow reserve (FFR)- guided PCI of the noninfarct-related lesions (see Figure 1). 1 RADCLIFFE CARDIOLOGY 16

2 Figure 1: Trial Profile Figure 2: Event Rates of the Combined Primary Endpoint 4,37 assessed for eligibility DANAMI-3 PRIMULTI trial (n=627) FFR-guided revascularisation during index admission (2 days after primary PCI) in non-infarct arteries with > % stenoses 3,84 STEMI confirmed 16 did not have STEMI 3 3 HR 6 (9 % CI.38.83), p= randomised 3,224 excluded* 1,9 single vessel disease 283 cardiogenic shock/unconsciousness 271 symptom duration >12h 2 linguistic problems 177 stent thrombosis 143 unwillingness to participate 138 logistic reasons 12 not eligible for first randomisation 88 indication for acute CABG 8 other reasons PCI not possible 34 short life expectancy 22 TIMI 1 after index PCI 23 heamorrhagic diathesis 9 renal impairment 7 culprit lesion in bypass graft 4 drug or contrast intolerance Event rate (%) Infarct-related artery only Complete revascularisation Follow-up (months) Infarct-related artery only Complete revascularisation Follow-up was for 44 months after primary percutaneous coronary intervention. HR = hazard ratio; other abbreviations as in Figure 1. PRImary PCI in MULTIvessel Disease (DANAMI-3 PRIMULTI) study. 33 infract-related artery revascularisation only 313 received allocated intervention 314 complete FFR-guided revascularisation 294 received allocated intervention 1 PCI failed or not feasible 1 died before PCI 2 refused subsequently 2 other reasons Figure 3: Kaplan-Meier Curves for the Primary Outcome PRAMI trial (n=46) 2 Immediate revascularisation during primary PCI in non-infarct arteries with > % stenoses lost to follow-up 1 lost to follow-up (emigration after 194 days) 313 analysed by intention to treat 314 analysed by intention to treat 1 analysed only up to emigration date CABG = coronary-artery bypass graft operation; FFR = fractional flow reserve; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infraction; TIMI = thrombolysis in myocardial infraction. * patients met two or more criteria for exclusion. FFR guidance in the PRIMULTI trial changed the initial management plan in almost one third of patients, as lesions that had appeared significant on angiography were nonsignificant based on FFR. FFR guidance meant that if the FFR was below.8, lesions were stented. If FFR was above.8, lesions were left untreated. If angiographically a stenosis was above 9 %, the physician was allowed to eliminate the FFR measurement and go directly to PCI treatment. Patients were followed for at least one year. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction and the need for ischaemia-driven repeat revascularisation. Q. What is unique about the PRIMULTI study? Dr Engstrøm: First, the PRIMULTI study is the largest study to date on this topic. Second, we now recognise that multivessel disease is more widespread than we had originally thought. It is an interesting topic; it is a big study, carried out within a contemporary framework with regard to antithrombotic therapy, second-generation drug-eluting stents, etc. Q. How is the PRIMULTI study different from previously published studies such as the PRAMI 2 and CvLPRIT 3 trials? Dr Engstrøm: The results from the three trials are quite uniform (see Figures 2, 3 and 4). In all three trials there is between 4 % and 6 % relative reduction in the primary endpoints. The outcomes all point in Preventative PCI No preventative PCI Months since randomisation Preventative PCI No preventative PCI The primary outcome was a composite of death from cardiac causes, non-fatal myocardial infarction or refractory angina. The inset graph shows the same data on a larger scale. All patients in the trial underwent infarct-artery PCI immediately before randomisation. Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial. Other abbreviations as in Figure 1. the same direction. However, there are some differences between the three studies: Patients without primary outcome (%) 1 HR.3 (9 % CI.21.8), p>.1 First, the effect on hard endpoints was quite striking in PRAMI. In the PRIMULTI trial, we could not find any effect on hard endpoints, such as death or non-fatal myocardial infarction. We believe it might be due to selection bias in the PRAMI study, since each centre only recruited 19 patients per year. On the other hand, in the PRIMULTI study, we randomised 1 patients per centre per year. The PRIMULTI lesions might have been less severe than the PRAMI lesions. The CvLPRIT trial situates somewhere in between. Second, the primary endpoint of PRAMI was death, myocardial infarction and refractory ischaemia. In the CvLPRIT study, it was death, myocardial infarction, heart failure and ischaemia-driven revascularisation. In the PRIMULTI study, it was death, myocardial infarction and ischaemia-driven revascularisation. The differences 2

3 Figure 4: Kaplan-Meier Curves CvLPRIT trial (n=296) 3 Immediate revascularisation recommended during primary PCI in non-infarct arteries with > 7 % stenoses (otherwise during the index admission) Complete IRA only MACE (%) between primary endpoints were more subtle but nevertheless, primary endpoints were different between studies.third, in PRAMI and CvLPRIT, the decision to do PCI in the noninfarct-related arteries was based on angiographic judgement of lesion severity. In the PRIMULTI study, a more physiological assessment was preferred, with FFR measurements as part of the protocol. FFR guidance in the PRIMULTI trial changed the initial management plan in almost one third of patients, as lesions that had appeared significant on angiography were nonsignificant based on FFR. Finally, another difference was the strategy for noninfarctrelated artery PCI. This was done immediately in the PRAMI study, meaning at the time of the primary PCI. In the PRIMULTI study, however, PCI was staged within two days after admission for STEMI treatment. 2 Q. What is a realistic complete revascularisation strategy in real-world practice? What is the best timing for a complete revascularisation strategy? Dr Engstrøm: We do not yet have sufficient data to support one strategy over another. Physicians in favour of acute full revascularisation believe you relieve all ischaemia at once, which potentially benefits the left ventricle. However, if you treat all ischaemic lesions acutely, the patient is exposed to more stress, more contrast and longer procedures. In that context, within two days after the primary PCI you have time to prepare your additional PCI, and you have less stressful operations on the patient because the treatment is done over two sessions. You also have the ability to do precise FFR measurements because the jeopardised microcirculation may influence the FFR unpredictably in the acute phase. There are a number of unanswered questions in this regard, but we believe assessment of noninfarct-related arteries within two days is safe in STEMI patients. This is our strategy moving forward. This is applied to all patients without ongoing ischemia during the primary procedure. If there is continuous ischaemia, I believe we should immediately treat all ischaemic lesions Hazard ratio (9 % CI):.4 (.24,.84), p=.9 Month Complete revascularisation IRA only Cumulative events rate for infarct-related artery (IRA)-only versus complete revascularisation groups. CI = confidence interval; other abbreviations as in Figure 1. Complete versus Lesiononly Primary PCI trial (CvLPRIT). Q. Does angiographic assessment of stenosis in the noninfarct-related arteries offer sufficient information to select lesions for additional treatment? Dr Engstrøm: We don t think so. We do think that the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) studies show clearly that FFR is superior to angiographic assessment. In the acute phase, it is even more difficult to do an angiographic assessment correctly. For example, high adrenaline levels in the blood could contract the arteries and can provide false impressions about the stenosis severity. We definitely think a physiological assessment with FFR is better. Q. In the article published in The Lancet, you state the following, Our results show that it is safe to do a complete revascularisation in this particular patient population. Although complete revascularisation should be recommended, any condition that makes complex PCI unattractive may support a more conservative strategy for the infarct-related artery PCI only. Under what conditions would a more conservative approach be recommended? Dr Engstrøm: Our study clearly showed that if you do full revascularisation, you can avoid the need for later revascularisation. However, in cases where you have a complex lesion that is only suitable for an unacceptable complex PCI, then the result and outcome of the PCI may be inferior. In those cases, you can leave these types of lesions alone since full revascularisation in our study had no effect on hard endpoints. We believe assessment of noninfarct-related arteries within two days is safe in STEMI patients. This is our strategy moving forward. Q. Does the PRIMULTI study show that FFR further improves outcomes in STEMI when FFR is used as part of a multivessel PCI approach? Dr Engstrøm: We may not yet be able to make that statement, but we can say that FFR-directed full revascularisations are safe, feasible and can prevent the need for further revascularisation. Some of the patients who were randomised to actually had no additional PCI because FFR was above.8 in all lesions. And of course, these patients do not face the risk for stent thrombosis in those lesions. In this context, I think you can say FFR further improved outcomes. Q. How confident are you that measuring FFR in STEMI patients is safe? Dr Engstrøm: I am quite confident FFR is safe if it is done after some hours or one to two days after the primary PCI. A recent publication from Ahmed et al. 6 describes the largest study to date showing FFR is feasible and safe in STEMI and NSTEMI patients. As the study included both academic and regional hospitals, without a track record in coronary physiology, the observations are representative of real-world clinical practice. 3

4 Q. There are concerns that FFR may not be reliable in STEMI patients. Is that a valid concern? Dr Engstrøm: It is a valid concern, but it is only relevant in the acute phase if the microcirculation is jeopardised. In that case, you are not able to create sufficient hyperaemia and get the true FFR. There are data and papers that suggest the concern is a bit overrated. However, as it cannot be fully excluded, we believe it is not a problem to postpone the FFR measurement until two days after the STEMI treatment. You might consider IMR as a tool to stratify patients with heavy damage on the microcirculation This means that there could indeed be a future role for a combined FFR plus IMR approach in this group of patients. Q. Research has shown that microcirculation can provide valuable prognostic information in acute myocardial infarction patients. Is there a place for the index of microcirculatory resistance (IMR) in this newly recommended treatment approach for STEMI patients? Dr Engstrøm: Definitely, IMR could be very attractive and interesting. An increased IMR means that there is an increased resistance in the microcirculation and could indicate that the microcirculation is compromised. It corresponds to the size of the infarct and therefore may have a prognostic value. You might consider IMR as a tool to stratify patients with heavy damage on the microcirculation. In the acute phase, you can imagine that those patients are treated, for instance, with more aggressive medications or using alternative methods instead of just conventional primary PCI. There could be a future role for a combined FFR plus IMR approach in this group of patients. Q. When you presented the PRIMULTI data around the world, what questions from your colleagues about the study or about treating this particular patient population came up that you did not anticipate? Dr Engstrøm: One important criticism is the risk for unneeded repeat revascularisation. When a patient with an additional stenosis is randomised to the arm that doesn t receive full revascularisation, the physician may be biased if the patient is re-admitted to the hospital afterward. This might lead to subsequent revascularisations that may not be needed. Having said that, we have looked into the two treatment groups and there was no difference between the two groups with regard to the frequency of readmission or the suspicion of angina. So we were able to address the question but we acknowledge there might be a bias. Q. Where do we go from here in terms of understanding the need to assess the noninfarctrelated arteries during STEMI? Dr Engstrøm: In a large-scale trial, we need to find out whether there is an effect of full revascularisation on hard endpoints. The Scandinavian FULL-REVASC (FFR-Guidance for ST Elevation Myocardial Infarction Revascularization) study will be initiated within the next six months. In this study, 4, patients will be randomised to FFR-guided full revascularisation versus revascularisation of the culprit lesion only. This study should be powered sufficiently to identify hard endpoints such as death and non-fatal myocardial infarction. n Thomas Engstrøm MD is currently head of interventional cardiology at Rigshospital in Copenhagen. Engstrøm studied at the University of Copenhagen and trained at Gentofte University Hospital, Skejby University Hospital and Rigshospitalet in Denmark. He is the author of more than 1 scientific articles in peer-reviewed journals. Figure : Fractional Flow Reserve and PressureWire Guidewire Standard of Care and Scientific Advancement,7 19 The PRIMULTI Study Key Takeaways Complete FFR-guided revascularisation of multivessel disease in STEMI patients, resulted in a lower risk of the primary composite endpoint (all-cause death, nonfatal MI and ischaemia-driven revascularisation [PCI or CABG] as compared to the standard care. ACS CAGB Stable CAD FFR method validation FFR versus stress testing Safety and effectiveness DEFER versus angiography alone FAME ESC 1A guidelines Class I, Level of Evidence A versus medical therapy alone FAME 2 FFR in the real world RIPCORD R3F ASAN POST-IT Multiple registries versus CABG FAME 3 initiated of Non-Culprit in ACS FAMOUS NSTEMI DANAMI-3 PRIMULTI Percutaneous Coronary Intervention of Functionally Non-significant Stenosis (DEFER); Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) study; PRImary PCI in MULTIvessel Disease (PRIMULTI) study. ACS = acute coronary syndrome; CABG = coronary-artery bypass graft operation; CAD = Coronary Artery Disease; FFR = fractional flow reserve; MI = myocardial infarction; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction. 4

5 1. Engstrøm T, Kelbæk H, DANAMI-3 PRIMULTI Investigators. Complete revascularization versus treatment of the culprit lesion only in patients with STEMI and multivessel disease (DANAMI-3 PRIMULTI): an open-label, randomised controlled trial. Lancet 1;386: PMID: Wald DS, Morris JK, PRAMI Investigators. Randomized trial of preventive angioplasty in myocardial infarction. N Eng J Med 13;369: DOI: 1.16/NEJMoa13; PMID: Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary PCI for STEMI and MVD. The CvLPRIT trial. J Am Coll Cardiol 1;6: DOI: 1.116/j. jacc ; PMID: ; PMCID: PMC Windecker S, Kolh P, Alfonso F, et al. 14 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 14;3: DOI: 1.193/eurheartj/ehu278; PMID: Tonino PA, De Bruyne B, FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 9;36: DOI: 1.16/NEJMoa87611; PMID: Ahmed N, Layland J, Carrick D, et al. Safety of guidewirebased measurement of fractional flow reserve and the index of microvascular resistance using intravenous adenosine in patients with acute or recent myocardial infarction. Int J Cardiol 16;2:3 1. DOI: 1.116/j.ijcard ; PMID: ; PMCID: PMC De Bruyne B, Fearon WF, FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med 14;371: DOI: 1.16/NEJMoa14878; PMID: Pijls NH, van Schaardenburgh P, Manoharan G. Percutaneous coronary intervention of functionally nonsignificant stenosis: -year follow-up of the DEFER Study. J Am Coll Cardiol 7;49: PMID: Layland J, Oldroyd KG, FAMOUS-NSTEMI investigators. Fractional flow reserve vs. angiography in guiding management to optimize outcomes in non-st-segment elevation myocardial infarction: the British Heart Foundation FAMOUS NSTEMI randomized trial. Eur Heart J 1;36:1 11. DOI: 1.193/eurheartj/ehu338; PMID: ; PMCID: PMC Engstrom T. The third Danish study of optimal acute treatment of patients with ST-segment elevation myocardial infarction primary PCI in multivessel disease DANAMI-3 PRIMULTI. FAME 3. Late-breaking clinical trial presented at ACC 1, San Diego, California. Am Heart J 1;169: DOI: 1.116/j.ahj.1.2.4; PMID: FAME 3 study. NCT show/nct21722?term=nct21722&rank=1; last accessed online March Pijls NH, De Bruyne B, Peels K. Measurement of fractional flow reserve to assess the functional severity of coronaryartery stenoses. N Engl J Med 1996;334: Fearon WF, Bornschein B, Tonino PA. Economic evaluation of fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease. Circulation 1;122:24. DOI: / CIRCULATIONAHA ; PMID: Wijns W, Kolh P, Danchin N. Guidelines on myocardial revascularization: The task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 1;31:21. DOI: 1.193/eurheartj/ ehq277; PMID: Curzen N, Rana O, Nicholas Z, et al. Does routine pressure wire assessment influence management strategy at coronary angiography for diagnosis of chest pain? The RIPCORD study. Circ Cardiovasc Interv 14;7:248. DOI: / CIRCINTERVENTIONS ; PMID: Van Belle E, Rioufol G, Investigators of the Registre Francais de la FFR-R3F. Outcome impact of coronary revascularization strategy reclassification with fractional flow reserve at time of diagnostic angiography: Insights from a large French multicenter fractional flow reserve registry. Circulation 14;129: doi: /CIRCULATIONAHA ; PMID: Park SJ, Ahn JM, Park GM. Trends in the outcomes of percutaneous coronary intervention with the routine incorporation of fractional flow reserve in real practice. Eur Heart J 13;34: DOI: 1.193/eurheartj/eht44; PMID: Toth G, De Bruyne B, Casselman F, et al. Fractional flow reserve-guided versus angiography-guided coronary artery bypass graft surgery. Circulation 13;128: DOI: /CIRCULATIONAHA ; PMID: Li J, Elrashidi MY, Flammer AJ, Lennon, RJ. Long-term outcomes of fractional flow reserve-guided vs. angiographyguided percutaneous coronary intervention in contemporary practice. Eur Heart J 13;34: DOI: 1.193/eurheartj/ eht; PMID: ; PMCID: PMC Rx Only Rx Only Brief Summary: Prior to using these devices, please review the Instructions for Use for a complete listing of indications, contraindications, warnings, precautions, potential adverse events and directions for use. Unless otherwise noted, indicates that the name is a trademark of, or licensed to, St. Jude Medical or one of its subsidiaries. St. Jude Medical and the nine-squares symbol are trademarks and service marks of St. Jude Medical, Inc. and its related companies. 16 St. Jude Medical, Inc. All Rights Reserved. (SJM-FFR a) Item approved for global use.