Usefulness of Fractional Flow Reserve during Routine Clinical Procedures in All-Comer Coronary Artery Disease Patients

Background: Fractional flow reserve (FFR)-guided interventions, though proved to be safe, continue to be a much-underutilized modality in determining treatment strategy, and data is lacking in Indian population. Objective: We aimed to determine the use of FFR-guided PCI and assess the overall impact on treatment decisions and clinical outcomes in patients with acute coronary syndrome (ACS) or chronic coronary syndromes (CCS). Methods: In this single-center retrospective and prospective observational study, FFR had been performed for the evaluation of treatment reclassification and clinical outcomes, as per physician’s clinical practice. Results: Data was obtained for 250 subjects (mean age 60.45 ± 9.6 years) with 324 lesions. The treatment plan based on angiography alone changed in 28% of lesions post-hyperemic FFR. The initial treatment plan based on angiography vs. the final treatment plan post-FFR (>0.80) was medical management 56.5% vs. 66.0%; CABG 11.1% vs. 7.7%; and PCI 32.4% vs. 26.2%. In subjects initially assigned to medical management, 14% had changed to PCI, and for subjects initially assigned to PCI, 44% had changed to medical therapy. Receiver operating characteristics (ROC) curve analysis revealed a good correlation between a resting FFR value of <0.87 and hyperemic FFR value of <0.80. The rate of 2-year major adverse cardiovascular events (MACE) was 0.9%. Conclusion: This study supports the use of FFR in determining treatment strategy in ACS or CCS patients with low MACE. Resting FFR value of <0.87 may be an alterna-tive to intracoronary nitroglycerine/adenosine/Nikorandil-induced FFR in predicting positive FFR particularly in hemodynamically unstable patients, and who are intolerant to hyperemic drugs.


Introduction
Coronary angiography (CA) is considered the standard technique for guiding percutaneous coronary intervention (PCI) in patients with myocardial ischemia.
Myocardial ischemia is a crucial risk factor among patients with multi-vessel coronary artery diseases [1] [2]. Evidence shows that decisions pertaining to coronary stenoses revascularization should be taken not only based on angiographic results but also considering non-invasive or invasive indication of reversible myocardial ischemia [3]. Controversies still exist about performing PCI in angiographically significant but functionally non-significant stenosis [4].
Fractional flow reserve (FFR) has been considered an effective index and gold standard to assess the physiological lesions and detect myocardial ischemia [1].
It is defined as the ratio of maximum blood flow in a stenotic coronary artery to maximum blood flow in a normal artery without stenosis as measured using a coronary pressure wire during invasive coronary angiography [2]. The FFR value in a normal coronary artery is 1.0. An FFR value of 0.80 implies coronary stenosis probability to trigger myocardial ischemia with greater than 90% accuracy [5]. The FFR provides more specific information and has a better spatial resolution. In FFR, every artery is examined individually, and masking of one ischemic zone by another is avoided. Some observational studies have suggested that worse clinical outcomes associated with stenosis deferred revascularization with lower FFR values than higher FFR values [6] [7].
The European Society of Cardiology guidelines (2010) have incorporated FFR as a class I recommendation into current PCI techniques [8]. The American Heart Association/American College of Cardiology guidelines (2011) have given class IIa recommendation for FFR [9]. The American College of Cardiology (2017) has recommended FFR among patients with stable ischemic heart disease (SIHD) for revascularization [10]. In the FAME (Fractional Flow Reserve Versus Angiography in multi-vessel Evaluation) study, there was a significant reduction in the mortality and myocardial infarction (MI) rates at two years in the FFR-guided group (8.4%) compared with the angiography-guided group (12.9%) (p = 0.02) [1]. The RIPCORD study revealed that after FFR, there was a 26% change in the management plan (medical management, coronary artery bypass grafting [CABG], and percutaneous coronary intervention [PCI]) among stable coronary artery disease (CAD) population. Furthermore, the number of vessels with significant coronary disease changed in 32% of the cases after FFR disclosure [11].
For patients with multivessel disease (MVD), minimal use of stents through the PCI intervention needs to be achieved for complete relief of myocardial ischemic symptoms. Improved health and economic outcomes in terms of qual-World Journal of Cardiovascular Diseases ity of life and treatment expenditure have been demonstrated in patients undergoing FFR by deferring PCI and other surgical revascularization treatments [12].
However, multiple studies have reported conflicting decisions between the usage of angiography and FFR-guided interventions with the significant reclassification of treatment plans in patients with MVD. Although FFR-guided revascularization is backed by a substantial body of evidence and is cost-effective, it remains underutilized due to a combination of factors such as added procedural time and operator unfamiliarity. In addition, limited studies have been published to understand the treatment plan changes using coronary angiography and FFR in India. The purpose of this study is to understand the routine use of FFR in clinical practice. The study aimed to determine the reclassification rates of coronary revascularization strategy after performing FFR in addition to diagnostic angiography. The study also assessed the impact of FFR-guided intervention on treatment decisions and clinical outcomes.

Study Design and Population
This study was a single-center, open-label, retrospective and prospective observational study. The data were collected between October 2015 and March 2020 with a median follow-up of 27 months. Patients included in the study were as follows: 1) patients aged eighteen years or older at the time of procedure; 2) non-culprit vessel assessment of patients presenting with ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), unstable angina, or stable coronary artery diseases; and 3) patients planned to undergo FFR for further PCI consideration, or those who underwent cardiac catheterization. Patients with extremely tortuous or calcified coronary arteries, and with a patent coronary artery bypass graft at the target vessel were not considered for analysis.

Procedure
Baseline characteristics, including demographics (age, gender), clinical parameters (comorbidities, clinical presentation), and routine laboratory tests before the procedures, were recorded.
Angiography was performed according to standard practices. The FFR procedure was performed after the recording of angiographic parameters. In the FFR procedure, a coronary pressure wire (Radi, St Jude Medical, Uppsala, Sweden) was advanced through the coronary artery, distal to the lesion, adequately.
The pressure was equalized with the sensor at the tip of the guiding catheter.
Maximal coronary hyperemia was triggered with adenosine (140 μg/kg per min) through a central venous infusion. For all participants, aspirin and clopidogrel were continued for one year.
The treating physicians recorded prior revascularization strategy on angiography before performing the FFR measurements. Then, the final patient revas-World Journal of Cardiovascular Diseases cularization strategy was recorded after performing FFR measurements. The treatment plan established was medical management (MM), coronary artery bypass surgery (CABG), and PCI. Medical management was considered for an FFR value of >0.80, and revascularization was recommended if FFR was less than 0.80. The cutoff value of 0.80 was selected in line with contemporary guidelines and previous findings [13] [14]. Reclassification of the treatment decision was regarded as "changed" if there was at least one decision change based on FFR for multiple lesions; if none of the decisions have been changed for multiple lesions, the treatment decision was defined as "unchanged".

Endpoints and Definitions
The endpoints determined in the present study were cardiac events, target vessel revascularization (TVR), and target lesion revascularization (TLR). Cardiac death was defined as any death because of a proximate cardiac cause, including cardiac arrest, myocardial infarction, low-output failure, or fatal arrhythmia. Both TVR and TLR were defined according to latest ARC consensus statement [15].

Statistical Analysis
Frequency and percentage change in treatment decisions were presented at the subject level and per lesion level. The following cutoff values were used to categorize a continuous variable into a binary variable. FFR group was defined as "low FFR" if it was equal to or below 0.80. Continuous variables were expressed as mean ± SD; categorical variables were expressed as absolute numbers and percentages (%). The receiver-operating characteristic (ROC) area under the curve analysis was used to estimate the diagnostic efficiency of resting FFR value of <0.87 in patients with resting FFR value of >0.80, and to identify the most appropriate cut-off value corresponding to hyperemic FFR value of <0.80.
The diagnostic performance of resting FFR was assessed using sensitivity and specificity.

Demographics and Baseline Characteristics
Two hundred and fifty subjects underwent FFR between October 2015 and March 2020. The mean age was 60.45 ± 9.6 years; and 199 (79.6%) were males. Majority  Table 1.
S. Kasturi et al.

Change in Treatment Strategy
The treatment plan based on angiography alone changed following resting FFR  Figure 1.

Clinical Outcomes
Major adverse cardiac events (MACE) were defined as a composite, including all-cause death, non-fatal myocardial infarction, and TLR/TVR. The MACE for the overall population at 24 months was 0.9%: death occurred in 3 patients including one patient who was changed to MM from PCI after FFR. There were no cases of TVR, TLR, MI, and cardiac death immediately after intervention or during the follow-up.

Discussion
This retrospective study demonstrated the safety and feasibility of FFR-guided management in CAD patients with multiple vessel disease and intermediary lesions. Majority of the patients were ACS. The FFR-guided management resulted in a considerably higher change in treatment post FFR.  Previous studies reported adverse events with adenosine with no significant difference between intracoronary and intravenous administration [11] [22]. We did not find any major clinically significant adverse events with adenosine except few minor side effects like bradycardia and hypotension which were managed with IV atropine, IV fluids and in some patients IV inotropes. Moreover, we found that whenever a resting FFR value is <0.87 it usually predicts hyperemic FFR value <0.80 with intracoronary nitroglycerine/adenosine/Nikorandil in majority of patients, and this may be considered as one of the indicators to predict positive FFR test. We feel this finding would be an additional parameter to make decision in patients with clinically unstable status, and who are intolerant to hyperemic drugs which might save time and cost. However, this should be confirmed in future multiple randomized trials.
Several real-world studies noted that FFR-guided treatment was associated with a positive long-term outcome with a decreased reduction in MACE events [23] [24]. The overall 24-month clinical outcome (MACE) rate is shown to be 4.7% which is comparable to the previous findings from historical studies [25] [26]. Similar to our study, an observational study in Indian setting showed that at 21-median follow-up, the composite endpoint of cardiac death, nonfatal MI, objective evidence of ischemia, and ischemia-driven revascularization in the vessels assessed by FFR occurred were observed in 0.9% of patients [21].

Conclusion
In conclusion, the use of FFR in this observational study considerably changed the treatment plan compared to only angiogram. Based on the outcomes, it can be suggested that FFR-guided management is safe and feasible to guide revascularization decisions of both ACS and stable CAD patients and might benefit Indian patients with multiple vessel disease and intermediate/borderline lesions.
Further, long-term prospective studies are needed to establish the safety and feasibility of FFR-guided revascularization in ACS and stable CAD patients.

Limitations
Though our study included larger population with ACS compared to other studies in Indian settings, our study is limited by observational design without control arm.

Funding
The study has been funded by St Jude Medical India Pvt Ltd (now Abbott). The funding agency has no role study, analysis and interpretation of results.