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Fractional flow reserve in acute coronary syndromes

Fractional flow reserve is an invaluable tool in the assessment of coronary stenoses with prognostic value in stable patients. Randomised studies are required to assess its potential in patients with NSTEMI
Jamie Layland MBChB MRCP FRACP 
Department of Cardiology, St Vincent’s Hospital, Melbourne, Australia
Keith G Oldroyd MD FSCAI FRCP
Department of Cardiology,
Western Infirmary, Glasgow, UK
Unstable angina (UA), non-ST segment elevation myocardial infarction (non-STEMI) and ST segment elevation myocardial infarction (STEMI) are a triad of disorders that are collectively referred to as acute coronary syndromes (ACS) and reflect varying degrees of coronary artery obstruction and microvascular damage.(1–5) ACS is a common cause of cardiovascular morbidity and mortality accounting for up to 50% of all deaths due to cardiovascular disease and resulting in a large economic burden to global health care. In the UK, the estimated total economic impact of ACS, including health care expenditure and disability-adjusted life years lost, is £10 billion. Therefore, strategies aimed at improving outcomes in this population are of critical importance. 
Early invasive management is generally recommended in patients with ACS in order to acutely restore myocardial perfusion (as is the case with STEMI) or identify patients who may benefit from revascularisation.(6) Contemporary diagnostic management of ACS patients is therefore primarily based on a visual interpretation of coronary disease severity revealed by the coronary angiogram since functional information from stress testing, mandated for most patients with stable angina,(7) is rarely available in the acute setting.
A new paradigm
Recent data from studies in patients with stable angina have challenged the paradigm of determining revascularisation strategies solely on the angiographic appearance of coronary stenoses. It has been clearly shown that judgments made by individual cardiologists regarding the assessment of the haemodynamic severity of coronary stenoses are subjective and inaccurate, potentially leading to misdiagnosis and incorrect treatment decisions which can be of prognostic significance.(8-10) 
This is more of an issue in patients with multivessel coronary disease who present a particular challenge since identifying the culprit stenosis (or stenoses) and discriminating flow limiting from non-culprit disease can be difficult.(6,11,12) This is of importance for NSTEMI patients because up to 50% of the population will have multivessel coronary disease. Treatment decisions guided by interpretation of the angiogram include medical therapy, percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). Thus, decisions based solely on the angiogram may potentially lead to sub-optimal health outcomes.(13) Consequently, there is an urgent need to assess and validate new strategies that can aid decision-making in ACS patients.
Assessing haemodynamic significance of coronary stenoses
Unlike stable angina, the demonstration of reversible ischaemia through non-invasive testing is not always appropriate or practical in patients with ACS. Recent studies in patients with stable chronic coronary artery disease have utilised guidewire-based pressure measurement across a coronary stenosis to calculate fractional flow reserve (FFR), a robust method to ascertain lesion level ischaemia.(14,15)
Measuring FFR
The technique involves the use of a specialised wire that possesses a distal pressure sensor. The wire (and pressure sensor) is placed beyond a coronary stenosis so that distal coronary pressure (Pd) can be recorded. Proximal aortic pressure (Pa) is recorded simultaneously from the guide catheter. Hyperaemia is then induced most commonly with intravenous or intracoronary adenosine. At peak hyperemia there is a linear relationship between coronary pressure and flow such that the ratio of Pd to Pa is proportional to flow (Figure 1). FFR can be performed at the time of initial angiography and, if significant, the stenosis can be stented using the pressure wire as the principle coronary guidewire.
The pivotal clinical trials DEFER(14) and FAME(15) highlighted the ability of FFR measurement in patients with stable angina to more accurately identify flow-limiting stenoses and guide PCI leading to improved outcomes and reduced costs compared to angiography alone(16) (Figure 2). DeBruyne and colleagues demonstrated that FFR measurement can be used to identify and exclude obstructive CAD with high diagnostic accuracy both in stable patients(17) and in patients with prior myocardial infarction (> six days).(18) However, the validity and accuracy of FFR in patients with more recent acute myocardial infarction is still debated.(19)
Concerns regarding the use of FFR
Culprit vessels
In the setting of emergency primary PCI for acute STEMI there is no role for FFR in the culprit artery. In the NSTEMI setting, angiography is often performed more than 24 hours after initial presentation. However, even at this later timepoint, it may not be possible to achieve maximal hyperaemia and establish the critical linear relationship between pressure and flow necessary for the assessment of FFR.(20) The attainment of maximal hyperaemia is based on the assumption of a normal distal microvascular bed. However, using PET, Uren and colleagues showed impaired microcirculatory function in the infarcted region compared with healthy controls up to six months following AMI. Thus, in patients with recent MI microvascular injury, stunning and oedema can result in a failure to achieve minimal resistance and FFR values may be falsely elevated.(21) Tamita and colleagues highlighted this by demonstrating a higher post PCI FFR in patients with STEMI compared with patients with stable angina despite similar intravascular ultrasound parameters. Patients with TIMI II flow also had a higher FFR compared with those patients with TIMI III flow. Thus in patients with microvascular dysfunction, the assessment of FFR may be unreliable.(22)
Non-culprit vessels
Several studies have clearly demonstrated altered blood flow patterns and impaired vasodilator response in territories remote from the culprit vessel.(21,23) As discussed above, this could potentially have implications for the assessment of FFR in non-culprit vessels in patients presenting with ACS.
FFR thresholds in ACS
An FFR ≤0.80 derived from the pressure wire is an evidence-based physiological threshold indicative of obstructive CAD potentially amenable for revascularisation.(20) By contrast, an FFR >0.80 implies that revascularisation is not indicated as the lesion is of no significant haemodynamic consequence. The original validation studies that determined the FFR threshold for ischaemia were all performed in stable patients. However, there have been several studies that have aimed to establish and validate FFR thresholds for ischaemia in patients with ACS.
In 48 stabilised patients with recent MI, Samady and colleagues compared FFR in the infarct related artery to non-invasive findings using SPECT and myocardial contrast echocardiography (MCE). Patients had a mean time to angiography of 3.7 days with 73% of patients with STEMI. The group demonstrated that an FFR ≤0.75 had 91% sensitivity, 93% specificity and a diagnostic accuracy of 92% for detecting reversible ischaemia. They provided an optimal cut off FFR value of ≤0.78 for detecting reversible ischaemia using ROC analysis.(24) De Bruyne et al demonstrated that an FFR ≤0.75 in a culprit vessel ≥six days following an AMI was still predictive of reversible ischaemia shown on non-invasive SPECT imaging.(18) Thus, there is some evidence for the use of FFR to determine ischaemia in the culprit territory four to six days following ACS. 
Current evidence for benefit of FFR in ACS
The FAME trial included patients with NSTEMI/UA; however these patients were generally stable without symptoms in the five days prior to the study.(15,25) Nevertheless the FAME investigators have confirmed that the use of FFR to guide revascularisation remained superior to angiographic-guided strategies in patients with recent NSTEMI/UA and multivessel disease. However, the pooling of patients with unstable angina and NSTEMI, the failure to report the date of index infarction or troponin values as well as the lack of high-risk acute cases limits the applicability of the study to the general, more acute NSTEMI population seen in clinical practice.(25) 
The only randomised study to date specifically addressing the utility of FFR guided decision-making in NSTEMI was performed by Leesar et al.(26)
They undertook a small single-centre randomised study of treatment decisions guided by FFR versus stress perfusion myocardial scintigraphy in 70 selected patients with a history of unstable CAD and a single coronary stenosis. They found that FFR-guided treatment reduced the duration and cost of the index hospitalisation. However, the study only had 35 patients per group, none of whom had multivessel CAD and only 60% had a diagnosis of MI. Again, the group included patients who were medically stable for at least 48 hours prior to admission.
In accordance with this study, Potvin et al demonstrated that in 201 unselected patients presenting to the cath lab the use of an FFR threshold of ≤0.75 was safe to allow deferral of stenting. However, only 21% of patients had a recent STEMI/NSTEMI and the use of FFR was not randomised or blinded. Thus, although helpful, these studies were in relatively stable patients and not powered to detect any impact of FFR-guided management on health outcomes or to determine the clinical utility of FFR in patients with ACS.(27)
Lopez-Palop et al have recently published the results of an observational non-randomised cohort of 107 NSTEMI patients who had FFR evaluation of non-culprit stenoses.(28) They demonstrated no difference in outcome between patients who had revascularisation deferred on the basis of FFR compared with those who underwent angiographically guided revascularisation.
In addition, Ntalianis et al evaluated the assessment of non-culprit stenoses in 26 patients with an acute NSTEMI (within 72 hours) and 126 patients with STEMI and showed that FFR values in the non-culprit vessel were unchanged when measured again approximately five weeks later.(29) Thus the use of FFR to evaluate non-culprit stenoses has been shown to be accurate in a small subset of patients but the clinical utility of this approach is yet to be validated in a larger, randomised patient population.
Benefits of FFR 
Contemporary guidelines recommend making revascularisation decisions for culprit lesions in patients with convalescent STEMI and NSTEMI/UA in the same manner as stable angina. This strategy appears to improve symptoms and reduce rates of death and non-fatal MI at long-term follow up.(3) However, there has been discordance in the literature with some authors suggesting a lack of prognostic benefit of revascularisation over modern medical therapy in NSTEMI.(30)
Current revascularisation guidelines for stable angina recommend the use of non-invasive stress testing/FFR for lesions that are angiographically intermediate in severity.(7,31) However, as eluded to earlier, this strategy, while appropriate in stable angina, is problematic in patients with ACS, not only because stress testing is not recommended but also because FFR has not been extensively validated in this population. If such validation was available, then using FFR in the assessment of culprit and non-culprit stenoses in ACS may afford the same prognostic advantage as it does in stable angina with additional potential for cost savings. 
FFR is an invaluable tool in the assessment of coronary stenoses for patients being assessed in the catheter laboratory. Its prognostic value has been clearly shown in patients with stable angina and in stabilised patients with NSTEMI/UA. There have been several, small studies examining the utility of FFR in ACS patients but we still lack large randomised studies addressing its utility in this setting. Such studies are ongoing and we must await their results before routinely using FFR in the ACS population.
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