Use of fractional flow reserve in patients with coronary artery disease: The right choice for the right outcome

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Despite advances in therapy, coronary artery disease (CAD) remains the leading cause of morbidity and mortality worldwide. Over the past years, the utilization of revascularization procedures has been refined, and in the best interest of the patient and to reduce the healthcare burden of CAD, it is paramount that patients are appropriately selected for therapies aiming at improving their symptoms and prognosis. Fractional flow reserve (FFR) is the current invasive standard test to identify hemodynamically significant coronary artery stenoses with resultant implications for revascularization and clinical outcomes. In this review, we discuss the current evidence behind the use of FFR as well as new trends in the application of this technique to help guide clinicians in making the best management decisions for patients with CAD.

Section snippets

Introduction: Coronary artery disease and fractional flow reserve

Coronary artery disease (CAD) remains the leading cause of morbidity and mortality worldwide [1], [2], [3]. Accordingly, the goals of care focus on two main objectives—(1) symptom management and (2) prevention of major adverse cardiovascular events and death. Guideline-directed optimal medical therapy is considered the foundation to accomplish these goals, and any additional intervention such as revascularization needs to be sufficiently justified to further increase quality of life and/or life

Limitations of fractional flow reserve: Theoretical assumptions

The two assumptions on which FFR is based upon relate to the proportional linear relationship between coronary perfusion pressure, flow, and coronary (microvascular) resistance (Fig. 2). In reality, the coronary pressure flow relationship is curvilinear and has a nonzero pressure intercept due to venous pressure and collateral blood flow [12]. Thus, when accounting for the right atrial pressure (Pv), the equation amounts to FFR = QS/QN, where QS = (PdPv)/RS and QN = (PaPv)/RN and R defines

Indications for use of fractional flow reserve: Improvement in patient outcomes by patient selection

Despite its theoretical limitations, FFR has been extensively validated based on a multi-testing Bayesian approach to accurately identify coronary stenoses associated with reversible myocardial ischemia by noninvasive stress tests [15]. FFR values of 0.75 and 0.80 have been chosen to discriminate stenoses inducing and not inducing clinically significant ischemia [15], and three prospective randomized studies [16], [17], [18] demonstrated the clinical utility of FFR in guiding revascularization.

Practical aspects of fractional flow reserve 1: Application of FFR to niche situations

As mentioned above, multiple studies have demonstrated the clinical utility of FFR in guiding revascularization in patients with stable ischemic heart disease and multivessel CAD. However, CAD is a complex entity inclusive of diffuse disease, sequential/tandem coronary stenoses, bifurcation lesions, and left main disease coronary artery (LMCA) lesions. Functional assessment of these lesions is different than the traditional assessment of a single coronary artery stenosis. For instance, when

Practical aspects of fractional flow reserve 2: Application of FFR in Acute Coronary Syndromes (ACS)

Given that FFR is directly related to the size and resistance of the perfusion territory one may call to attention the implications of alterations in the maximal vasodilatory capacity of the microcirculation following myocardial infarction. For instance, in addition to the reduction of viable amount of myocardium, there might be variable stunning of the microvasculature of the infarct-related artery with impaired ability to achieve maximal hyperemia, resulting in reduced accuracy of FFR

Practical aspects of fractional flow reserve 3: Application of FFR in coronary artery bypass graft patients

Coronary artery bypass grafting (CABG) has traditionally been used for patients with severe and extensive obstructive CAD based on visual assessment of coronary angiograms. While it is known that bypass grafts occlude over time with differences between venous, arterial, and internal mammary grafts [59], [60], the impact of the severity of native vessel disease on graft patency dynamics, however, has remained largely undefined until recently. In a prospective cohort study, Botman et al. [61]

Practical aspects of fractional flow reserve 4: Application of FFR in other high risk patient groups

It is well known that patients with chronic kidney disease (CKD) and diabetes mellitus are at a higher risk of CAD. In fact, studies have demonstrated the impact of worsening renal function in the form of glomerular filtration rate (GFR) [67], [68] as well as diabetes mellitus [69], [70] on reduced coronary blood flow due to effects on the microcirculation. Several studies have indicated the reliability of FFR measurement in patients with diabetes [71], [72]. A recent study by Liu et al. [73]

Practical aspects of fractional flow reserve 5: Maximal hyperemia and fractional flow reserve

By definition, FFR requires maximum blood flow for which minimal resistance and thus maximum vasodilation of the coronary microcirculation is needed. Without maximal vasodilation, FFR can be overestimated due to the lower flow rate across a stenosis resulting in a lower pressure gradient. To ensure that maximal hyperemia is induced, an appropriate pharmacologic agent must be administrated at an adequate dose.

Classically, vasodilation is achieved via intravenous or intracoronary adenosine [76].

Practical aspects of fractional flow reserve 6: Impact of left ventricular ejection fraction, left ventricular hypertrophy, and right atrial pressure

One assumptions for the equation of FFR = Pd/Pa is that the central venous pressure (Pv) is low or negligible. As such, there is a theoretical concern that FFR may be less accurate in patients with reduced ejection fraction due to the effects of increased left ventricular end diastolic pressure and venous pressure as well as a reduced mass of viable myocardium on maximal flow. However, on analysis of the FAME study data, reduced ejection fraction (defined as either ≤40% or ≤ 50%) had no impact

Overcoming limitations of fractional flow reserve in improving patient selection: Concomitant measurement of pressure and flow

As alluded to on several occasions, in additional to myocardial perfusion mass and territory, the microvasculature holds a key principle for the use of FFR in clinical practice. It is important not only for the technical validity of the data but also the clinical validity of the data [101]. The key clinical measures in this regard are coronary flow reserve (CFR) and IMR (Fig. 2).

CFR assesses the maximum achievable flow relative to baseline flow and is often simplified to coronary flow velocity

Advances in concept of fractional flow reserve 1: Instantaneous wave-free ratio (iFR)

One of the basic prerequisites of assessing the physiological significance of a coronary stenosis is to obtain maximal hyperemia. More recently, the ADVISE study investigators [110] demonstrated a new method to assess the functional significance of a coronary lesion without the use of adenosine, called iFR. This group was able to identify a “wave-free period” during diastole where the intracoronary resistance was naturally constant and minimized, allowing for pressure measurements similar to

Advances in concept of fractional flow reserve 2: Coronary Computed tomography angiography fractional flow reserve (FFRCT)

Coronary computed tomography angiography (CTA) is now increasingly used, primarily to exclude CAD given its high sensitivity and thus high negative predictive value. Recent advances in technology have allowed for the calculation of coronary blood flow and pressure from coronary CTA datasets, permitting a noninvasive calculation of FFR [116]. Three prospective randomized studies [117], [118], [119] demonstrated improvement in diagnostic accuracy and discrimination for FFRCT compared to

Conclusion

Fractional flow reserve is a simple, reproducible, and reliable modality for the functional assessment of epicardial coronary stenoses. Following the results of the FAME trial, its clinical use has increased 16- to 18-fold according to a nationwide inpatient sample, up from around 6% in 2008 [9]. With increased utilization of FFR in clinical practice, it is also important to recognize the inherent pitfalls and limitations of FFR. Although FFR has defined cutoff values for ischemia, it should

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