Opinion: The value of FAME

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By Dr Ascan Warnholtz

The recently published results of the COURAGE1 trial have questioned the advances and benefits of percutaneous coronary intervention (PCI). Since the publication of this trial the interventional community has responded globally with more defensive strategies and a slight reduction of the number of performed PCI. However, subanalyses have revealed that patients with a significant extent of stress-induced myocardial ischaemia still benefit from the percutaneous coronary intervention of an ischaemia inducing coronary stenosis. Therefore, the results of the COURAGE trial do not argue against the value of percutaneous coronary intervention but emphasise the importance of obtaining evidence of myocardial ischaemia prior to PCI. Among the non-invasive stress tests available, electrocardiographic or nuclear stress tests lack sufficient specificity and/or sensitivity as well as spatial resolution. This is especially true for multivessel coronary disease. Stress echocardiography is mostly applied to enhance specificity, sensitivity and spatial resolution. The accuracy of stress echocardiography is highly dependent on the skills of the sonographer, it is time consuming and in some settings not cost effective, a major drawback.


The determination of myocardial fractional flow reserve (FFR) by using a coronary pressure guidewire is an invasive test to detect inducible myocardial ischaemia. This method is validated and increasingly applied for more than a decade. The spatial resolution of FFR, its reproducibility and independence of the patient’s haemodynamics are unrivalled by other stress tests. It is characterised by high specificity and sensitivity depending on the applied cut-off value of .75 or .8 for proven ischaemia. The controlled pressure wire pullback allows a clear discrimination of ischaemia-inducing lesions from nonischaemic lesions in a multiple stenosed coronary artery. Furthermore, the gradual increase in the ratio of distal to aortal pressure after pullback of the pressure wire in a diffusely diseased coronary artery provides evidence that this vessel will not benefit from revascularisation despite proven ischaemia. Despite the advantages of the FFR test, the invasive character of fractional flow reserve still precludes the application of FFR as a standard test for myocardial ischaemia in all patients with the suspect of coronary artery disease. Currently, fractional flow reserve should be considered in patients with a clinical indication for a coronary angiography and intermediate coronary artery stenoses of unknown significance. It provides also valuable information if discrepancies between the angiographical and non-invasive pretest findings and/or the clinical picture occur during the coronary angiography. Instead of taking the patient off the cath lab table for non-invasive stress tests, FFR can answer questions right away.


The prognostic value of fractional flow reserve measurement was ascertained in single-vessel coronary disease by the DEFER2 trial. The recently published FAME3 trial has evaluated the prognostic significance of FFR in patients with coronary multi-vessel disease. In a multicentre trial with 20 participating sites throughout the USA and Europe, 1,005 patients with multivessel coronary artery disease were randomised to either angiographically driven percutaneous coronary intervention or fractional flow reserve guided revascularisation. Patients in the angiography-guided group underwent stenting of all lesions of at least 50% diameter stenosis that were indicated prior to randomisation to require PCI based on angiographic appearance and clinical data. Patients assigned to the fractional flow reserve group underwent FFR measurement of all indicated lesions based on the same criteria as in the angiography group but received PCI only in lesions with fractional flow reserve of .8 or less. Percutaneous coronary intervention was performed exclusively with drug-eluting stents. Approximately one-third of the patients presented an acute coronary syndrome. Patients with ST-segment elevation within the last five days were excluded. A mean of close to three lesions per patient were a priori indicated in each group. Fractional flow reserve measurements identified close to two lesions as being haemodynamically significant. Accordingly, a mean of 1.9 stents were implanted in the FFR group while 2.7 stents were used in the angiography group. Procedure time did not differ between groups. The volume of contrast agent used was lower in the fractional flow reserve group. After one year of follow-up, the composite endpoint of death, myocardial infarction and the need for revascularisation was significantly reduced in the FFR group compared to the angiography group. The reduction of major adverse cardiac events was predominantly caused by a reduction of early myocardial infarction and late reduction of required revascularisation procedures. The frequency of anginal attacks and the concomitant use of antianginal medication were comparable in both groups. Based on the American market, material costs were reduced in the FFR group compared to the angiography group.


Taken together, the FAME trial adds valuable prognostic information for patients with multivessel disease. At least, for the selected patient population investigated in the FAME trial, the FFR guided approach is preferable to the angiography guided approach. It may not only save patients’ lives by reducing major adverse cardiac events rates, but also alleviate the health care-related economic burden of the interventional treatment of coronary artery disease. The results of the FAME trial emphasise the superiority of “functional complete revascularisation” to “angiographically complete revascularisation”. Of note, the angiography guided complete revascularisation of patients with symptomatic multivessel coronary artery disease recently failed to be non-inferior to surgical treatment by aortocoronary bypass grafting in the SYNTAX4 trial. Interestingly, analysing major adverse cardiac and cerebrovascular events of a comparable subset of patients of the FFR guided treatment arm of the FAME trial with the surgical arm of the SYNTAX trial has revealed almost identical major adverse cardiac and cerebrovascular events rates. Therefore, fractional flow reserve guidance of interventional treatment may abrogate the disequilibrium of PCI compared to bypass surgery in patients with multi-vessel disease. My recommendation is to conduct a prospective clinical trial to compare “functional complete revascularisation” by FFR guided treatment with “complete revascularisation” by bypass surgery in patients with multivessel coronary disease to retest the comparability of the interventional versus surgical approach in these patients.


Dr Ascan Warnholtz is Assistant Professor of cardiology and Head of the Emergency Department and Chest Pain Unit at the University of Mainz, Germany.

 

References
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2. Pijls NH, van Schaardenburgh P, Manoharan G, Boersma E, Bech JW, van’t Veer M, Bär F, Hoorntje J, Koolen J, Wijns W, de Bruyne B. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol. 2007 May 29;49(21):2105-11.

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4. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, Ståhle E, Feldman TE, van den Brand M, Bass EJ, Van Dyck N, Leadley K, Dawkins KD, Mohr FW; SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009 Mar 5;360(10):961-72.

 

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