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Functional assessment of multivessel coronary artery disease: ischemia-guided percutaneous coronary intervention Jonathan G. Schwartz and William F. Fearon Invasive evaluation and treatment of coronary artery disease (CAD) has traditionally been based upon coronary angiography to determine the need for and the success of revascularization. However, coronary angiography augmented with fractional flow reserve (FFR) creates a paradigm shift, providing a more complete functional assessment of coronary lesions. Measuring FFR to identify ischemic lesions and guide revascularization results in fewer adverse outcomes, including persistent angina, myocardial infarction, and mortality. An ischemic lesion identified by FFR is more likely to lead to adverse events when compared with an angiographically similar lesion with nonischemic FFR when both are treated medically. Although the mechanism explaining this is unclear, it is likely multifactorial, including the impact of mechanical forces, upregulation of inflammatory mediators, and the amount
Introduction Advances in interventional strategies and pharmacologic therapies have revolutionized the modern approach to coronary artery disease (CAD). However, controversy exists with regard to the optimal initial therapy for stable CAD. Until recently, coronary angiography was the reference standard for diagnosing CAD. For many years, therapeutic decision-making in the cardiac catheterization laboratory has been guided solely by angiographic lesion assessment, regardless of functional significance. Angiography assesses anatomy and does not provide functional information. An abundance of data now suggest that identifying ischemia and relieving it can improve outcomes. Unfortunately, noninvasive stress imaging often lacks requisite spatial resolution and accuracy to guide revascularization decisions, especially in multivessel CAD, for which the accuracy of noninvasive stress imaging is notoriously poor. A major current challenge is determining which coronary lesions are responsible for ischemic symptoms and are likely to cause future events in patients with multivessel CAD. A traditional and longstanding belief holds that mild coronary lesions (stenosis < 50%) are more likely to lead to infarction compared with more severe lesions. This concept stems from small retrospective angiographic studies conducted in the late 1980s and early 1990s that suggested that coronary lesions with less than 50% stenosis were most likely to lead to myocardial infarction (MI) through plaque vulnerability and rupture [1–3]. Despite widespread interest in and acceptance of these 0954-6928 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
of distal myocardial tissue at risk. Using both anatomic and ischemia-guided assessments (such as the Functional SYNTAX Score) aids in the therapeutic decision-making process in patients with multivessel CAD. This review focuses on the evidence for FFR-guided management of multivessel CAD. Coron Artery Dis 25:521–528 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Coronary Artery Disease 2014, 25:521–528 Keywords: angioplasty, coronary angiography, coronary artery disease, coronary physiology, fractional flow reserve, functional, ischemia, multivessel Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford University School of Medicine, Stanford, California, USA Correspondence to William F. Fearon, MD, Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford University School of Medicine, Stanford, 300 Pasteur Dr., Rm. H2103, Stanford, CA 94305-5218, USA Tel: + 1 650 723 2621; fax: + 1 650 725 6766; e-mail: [email protected]
findings, these studies were plagued by small and retrospective populations and variable patient follow-up, with extended times between baseline angiography and subsequent MI. Other studies such as the Coronary Artery Surgery Study (CASS) compared baseline stenosis severity with occlusion rates at 5-year angiography and found low rates in non-bypassed vessels with baseline stenosis between 5 and 49% and higher rates in lesions with 81–95% stenosis [4]. Despite this, the term ‘vulnerable’ plaque coined by Muller et al. [5] became an attractive concept, spawning many studies of various adjunctive diagnostic technologies in search of methods for consistent and accurate identification of lesions at risk for rupture and MI. Recent data now suggest that patients with CAD typically have multiple simultaneous plaque ruptures that stabilize and heal to form a more significant stenosis before rupturing again. There are many more mild than severe plaques, and occasionally a mild plaque will rupture and lead to an MI. However, high-grade coronary lesions (although less prevalent) are more likely to lead to MI after rupture [6]. This has been demonstrated in post-mortem studies, which report that most intracoronary thrombi occur in the setting of ruptured plaques with layering, suggesting a cyclical process of multiple plaque rupture events and subsequent healing. Stenosis severity was recently shown to be of greater than 75% cross-sectional area in a majority of these ruptured lesions [7]. The process leading to the development of high-grade stenosis appears to be nonlinear and unpredictable [8,9], arguing that multiple plaque rupture events may be subclinical. In addition, because of a DOI: 10.1097/MCA.0000000000000153
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smaller residual lumen, when severely stenotic lesions develop plaque rupture and thrombosis, infarction is more likely, compared with that of a vessel with milder lumen compromise. The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was designed to further investigate this dilemma – that is, the role mild coronary disease plays in subsequent major adverse cardiovascular events [10]. A total of 697 patients presenting with acute coronary syndromes with subsequent percutaneous coronary intervention (PCI) underwent three-vessel intravascular ultrasonography. This served as a baseline measure of CAD, and patients were then followed for a median of 3.4 years. The most common event in nonculprit vessels was angina progression, with less than 1% presenting with MI in a nonculprit vessel. Notably, the mean diameter of stenosis in patients who suffered events in nonculprit vessels increased from 32 to 65%. These data suggest a low propensity for mild lesions to lead to MI; in fact, there were no major events seen in lesions with less than 40% cross-sectional area at baseline. The two intravascular ultrasound parameters most strongly associated with follow-up events in nonculprit vessels are minimal lumen area and extent of plaque burden. This suggests that angiographically severe lesions are more likely to cause future events.
Finally, a sub-study [11] of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial [12] examined patients who underwent clinically driven follow-up coronary angiography to understand which baseline lesions are most likely to cause recurrent symptoms. The investigators identified that the lesions most likely to lead to acute coronary syndrome or MI requiring PCI during follow-up had a baseline severity of greater than 50% stenosis. The average stenosis of the culprit lesions on follow-up was greater than 70%, arguing that severe lesions are most likely to cause subsequent acute coronary syndrome. Although invasive functional CAD assessment was not performed in PROSPECT or COURAGE, these studies suggest that severe lesions are more likely cause ischemia and lead to future events. The interplay of anatomy and ischemia is poorly understood [13]; however data now suggest that ischemia-producing lesions, regardless of angiographic anatomical appearance, are in fact more ‘vulnerable’ to progression. Predicting which lesions will lead to future MI remains a major challenge, with the debate centering on the relative importance of ischemia (function) versus anatomy still continuing [14]. Because functionally significant lesions are more likely to lead to MI, physiologic assessment is vital in understanding the disease process and to optimize therapy.
Fig. 1 max
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Fractional flow reserve (FFR) measurements are derived from a ratio of the driving pressure (Pa) and the distal pressure (Pd) across a lesion. Pd is assumed to be equivalent to the central venous pressure (Pv) when maximum hyperemia is present; in this setting, the relationship between driving pressure and blood flow is linear. Black lines depict flow when no stenosis is present, equivalent to an FFR of 1.0. Gray lines depict a stenosis with a drop in pressure distally to 70 mmHg, which corresponds to 70% of the normal blood flow. The FFR in this setting would be equivalent to 0.70. Under these conditions, driving pressures (Pa, Pd) correspond linearly to flow (QN, QS). Reproduced with permission [21]. Copyright Elsevier (2012).
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FFR-guided PCI Schwartz and Fearon 523
Fig. 4
Fig. 2
20 Deferral of PCI Performance of PCI
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0 FFR ≥ 0.75 Five-year follow-up data from the DEFER trial showing no significant difference in the rate of cardiac death and/or acute MI in nonischemic lesions (FFR ≥ 0.75) when percutaneous coronary intervention is deferred rather than performed. DEFER, FFR to Determine Appropriateness of Angioplasty in Moderate Coronary Stenoses; FFR, fractional flow reserve; MI, myocardial infarction; PCI, percutaneous coronary intervention. Reproduced with permission [23]. Copyright Elsevier (2007).
Fig. 3
Coronary angiography was performed in a 55-year-old male patient with a history of hyperlipidemia and tobacco abuse after presenting with a non-ST elevation myocardial infarction. Multivessel coronary disease was identified, with lesions of varying angiographic severities. A 99% mid-LAD stenosis is identified (arrow); FFR evaluation is not necessary in this lesion given the severity of the stenosis. PCI was performed on this lesion. FFR, fractional flow reserve; LAD, left anterior descending; PCI, percutaneous coronary intervention.
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revascularization [15]. Other limitations of such techniques include the requirement of myocardial perfusion imaging to have at least one nondiseased vessel to detect perfusion defects, which limits accuracy in the setting of multivessel CAD [16] and often leads to underestimation of lesion severity [17]. Multivessel disease can also cause balanced ischemia by perfusion imaging, resulting in falsely normal results.
FFR
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Stenosis classification by angiography Data from the FAME 1 trial are shown in this box-and-whisker plot, showing fractional flow reserve (FFR) values of lesions in the categories of 50–70%, 71–90%, and 91–99% diameter stenosis by angiography. Note the wide range of FFR values in each category. An FFR value of 0.80 or less indicates functional significance corresponding to myocardial ischemia, and is highlighted by the dashed line. Reproduced with permission [38]. Copyright Elsevier (2010).
Although multiple noninvasive techniques can detect ischemia, only a minority of patients presenting to the catheterization laboratory undergo such studies before
For these reasons, real-time invasive assessment of physiology is vital, particularly in multivessel CAD. Coronary pressure wire-derived fractional flow reserve (FFR) is now the reference standard for identifying lesions capable of producing ischemia and more likely to lead to adverse events.
Fractional flow reserve Grüntzig et al. [18] first introduced the principle of measuring resting pressure gradients across stenotic lesions early in interventional cardiology. The concept of measuring the pressure ratio (as opposed to the absolute gradient) during maximal coronary vasodilation using a miniaturized pressure transducer was introduced by Pijls and colleagues [19,20] as FFR. The FFR is defined as the ratio of the maximal blood flow in the presence of a
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stenosis and the maximal flow in the theoretical absence of stenosis (Fig. 1). A pressure-sensing angioplasty guidewire measures the distal mean coronary pressure, which is then divided by the mean aortic proximal coronary pressure during hyperemia. This quotient reflects the functional impact of a lesion on distal myocardial flow. FFR is independent of hemodynamic variation (heart rate, systemic blood pressure, contractility). The spatial resolution of FFR allows interrogation of the ischemic potential of not only the specific vessel, but also the specific lesion, making it ideally suited for multivessel CAD. In the absence of stenosis in a normal vessel, FFR is 1.0; any value less than this indicates a fractional flow reduction (i.e. an FFR of 0.60 indicates a 40% reduction in maximal hyperemic blood flow). FFR less than 0.80 is the accepted cutoff for identification of ischemic lesions, with a ‘gray zone’ between 0.75 and 0.80 [22]. Maximal hyperemia is most often obtained by intravenous or intracoronary adenosine.
Fig. 5
An angiographically less-severe bifurcation lesion in the LCx is identified (arrow) in the same patient (Fig. 4). FFR was performed on this lesion, found to be not functionally significant with a value of 0.90 (Fig. 6). This lesion was not intervened upon. FFR, fractional flow reserve; LCx, left circumflex.
Multiple trials have shown the benefits of FFR-guided CAD management. The FFR to Determine Appropriateness of Angioplasty in Moderate Coronary Stenoses (DEFER) trial demonstrated the safety of medical management in patients with intermediate
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A screen capture image of the FFR data from the LCx lesion (Fig. 5) in the same patient (Fig. 4). FFR was found to be 0.90, indicating it was not functionally significant. No intervention was performed. FFR, fractional flow reserve; LCx, left circumflex.
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FFR-guided PCI Schwartz and Fearon 525
Fig. 7
ischemia were likely included in previous studies, like COURAGE. However, because the CAD is not responsible for ischemia, these patients have excellent outcomes with medical therapy alone, which would dilute any potential benefit of PCI if they were included in the randomized study. Indeed, in FAME 2, this group, which was followed up in a registry, had very low event rates during follow-up. The randomized portion of FAME 2 was terminated early because of a significantly higher primary endpoint (death, MI, or urgent revascularization) in medically treated patients (4.3 vs. 12.7%, P < 0.001). This difference was driven by higher rates of urgent revascularization, with no significant difference between death and MI. However, a landmark analysis showed that 1 week after enrollment (thereby excluding periprocedural MI), the rate of death or MI was higher in the medically treated patients (1.6 vs. 3.7%, P = 0.05). This is important because other studies have shown that periprocedural MI has little effect on long-term outcome, whereas spontaneous MI is a much stronger predictor of late mortality [28]. FAME 2 data provide further support for the need to identify lesions that are responsible for ischemia and to revascularize these, while treating nonischemic lesions medically.
Continuing with the same patient (Fig. 4), a 50% mid-RCA lesion is identified on coronary angiography (arrow). FFR was again not functionally significant, with a value of 0.82 (Fig. 8). This lesion was also not intervened upon. FFR, fractional flow reserve; RCA, right coronary artery.
single-vessel disease and nonischemic FFR results. Patients with FFR values of 0.75 or higher were randomized to PCI versus deferral. The deferral group had less than 1% risk for cardiac death or MI at the 5-year followup when treated medically, numerically less than half the rate in the PCI arm (Fig. 2) [23]. Subsequently, the Fractional Flow Reserve vs. Angiography in Multivessel Evaluation (FAME) study showed that FFR-guided PCI with drug-eluting stents is superior to angiographyguided decision-making in both stable and unstable patients with multivessel CAD [24]. The primary outcomes of death, MI, and repeat revascularization at 1 year were significantly lower in the FFR-guided PCI group. In addition, there was significantly lower death and MI at the 2-year follow-up, with cost reduction and better resource allocation [25,26]. Most recently, the FAME 2 trial compared PCI guided by FFR with optimal medical therapy in patients with stable single or multivessel CAD [27]. A key difference between FAME 2 and previous studies (e.g. COURAGE) is that FFR was first measured across all lesions considered for PCI. About 25% of patients were not enrolled in the randomized component of the study because FFR across all lesions was greater than 0.80. Patients with CAD that appears significant on angiography but is not responsible for significant
Despite the many benefits of FFR-guided functional assessment of CAD and multiple trials providing compelling data for its use, FFR has a small role in the current guidelines. The ACC/AHA guidelines give a class IIa recommendation (level of evidence A) for FFR assessment for PCI in select patients [29,30], whereas the European PCI guidelines provide a class Ia recommendation (level of evidence A) without objective evidence of ischemia in lesions of uncertain severity [31]. The hesitance for more widespread acceptance and use of FFR may be related to a perceived increased procedure time, pressure from referring physicians and patients for PCI, concern about procedural risk, and reimbursement issues [22]. Concern may also exist about a nonischemic vulnerable plaque being deferred because of a negative FFR and subsequently leading to a coronary event. However, the FAME 1 and FAME 2 trials and numerous other registries rebut this concern by showing very low event rates when nonischemic lesions are treated medically (Fig. 3) [24,25,27].
Reconsidering revascularization: a paradigm shift A major limitation of traditional invasive methods to evaluate and treat CAD is that complete revascularization has been based on angiographic appearance alone, without invasive physiologic assessment. Importantly, no standardized definition of complete revascularization currently exists. Functionally complete revascularization differs from anatomically complete revascularization in that angiographically severe lesions (>70% stenosis) may not be intervened upon if they are non-flow-limiting by
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physiologic assessment. This important concept is controversial and is not always well accepted [32]. Multivessel CAD provides a challenge when attempting to achieve complete revascularization, particularly through a percutaneous approach [33]. Initial data in the bare-metal stent era showed that anatomically complete revascularization has superior long-term outcomes compared with incomplete revascularization, which was associated with increased rates of MI, need for reintervention, angina, mortality, and impaired recovery of left ventricular function [33–35]. However, more recent trials have suggested that anatomically complete revascularization may not improve long-term outcomes and may in fact be harmful [36,37]. Despite these data, current guidelines continue to recommend complete anatomic revascularization in patients with multivessel CAD, driven by angiographic appearance alone [30,31].
Visual/angiographic–functional mismatch Incorporating FFR into the assessment of multivessel CAD may change treatment strategies when compared with an angiographic assessment alone. Clinical data have shown that such scenarios are often encountered. The FAME data, for example, showed functional significance
in as many as 35% of moderately severe angiographic lesions (50–70% stenosis) and functional insignificance (FFR > 0.80) in up to 20% of angiographically severe lesions (71–90% stenosis) [38]. Of the patients initially deemed as having angiographic three-vessel disease, only 14% had functional three-vessel disease after FFR assessment, and 9% of these patients had no functionally significant lesions. Thus, patients may be subjected to unnecessary CABG surgery, when in fact PCI (or even no intervention at all) may be a better option. Reasons for this mismatch are numerous and complex. Of utmost importance is to consider ischemia as a separate functional entity, different from anatomic/angiographic severity. Angiographically similar stenoses may have different functional significances on the basis of the myocardial mass supplied. Thus, angiographic appearance can be misleading, as angiographically severe lesions may be functionally insignificant if only a small myocardial mass is at risk [39]. Other aspects, such as lesion length, lesion eccentricity, reference vessel size, collateral supply, and microvascular dysfunction can also play a role in discordant findings between the angiogram and the FFR result. Figures 4–8 depict a case of FFRguided management in a patient with multivessel CAD.
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A screen capture image of the FFR data from the RCA lesion (Fig. 7) in the same patient (Fig. 4). Here, FFR was found to be 0.82, indicating it was also not functionally significant. Again, no intervention was performed. FFR, fractional flow reserve; RCA, right coronary artery.
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Functional supplementation of existing riskstratification tools Multiple risk-stratification tools have been developed to aid the decision-making process for practitioners in the setting of multivessel CAD. Most of these tools are based on angiographic lesion severity, and many are now outdated and no longer in use. Others have been updated to incorporate functional assessment, allowing for a more targeted and objective approach to lesions that may otherwise be equivocal based on angiographic data alone. The SYNTAX score is an angiography-based scoring system that stratifies patients on the basis of lesion complexity and severity. However, because it is based on angiography alone, it is inherently limited by the angiographic accuracy for identifying functionally significant disease. The Functional SYNTAX score is based on the calculation of the SYNTAX score, but counts only lesions with significance based on FFR. This tool was tested in the FFR-guided PCI arm of the FAME trial (Fig. 9) [40]. Compared with the SYNTAX score, the functional SYNTAX score reclassified 32% of high and intermediate tertile patients to a lower tertile. After calculating the functional SYNTAX score, 43% of patients with a score greater than 22, in whom CABG is generally recommended, were reclassified to a score less than 22, in which case PCI would be a suitable strategy. The functional SYNTAX score was more reproducible than the classic SYNTAX score, and importantly was a significant independent predictor of subsequent death or MI, whereas the SYNTAX score was not. The functional SYNTAX score is now being tested prospectively in the FAME 3 trial comparing FFR-guided PCI with CABG in patients with three-vessel CAD [41].
Conclusion
The ultimate goal of PCI in CAD is to improve the quality of life and prevent adverse outcomes. Current data strongly suggest that this is best achieved by revascularizing lesions responsible for ischemia and avoiding unnecessary revascularization of nonischemic lesions. FFR is currently the best tool to detect ischemia and to guide PCI decision-making in the catheterization laboratory. The traditional angiographic-only revascularization strategy in most cases is improved with the addition of FFR, which allows a more complete, functional lesion assessment. It is unclear why ischemic lesions with abnormal FFR lead to future adverse events compared with angiographically similar (but nonischemic) lesions with normal FFR. The answers are likely multifactorial and include mechanical forces and changing inflammatory mediators that occur across ischemia-producing lesions. Updated risk-stratification tools, such as the functional SYNTAX score, allow for functionally complete revascularization. As further large prospective and randomized clinical trial data become available, functionally driven ischemiaguided lesion management strategies will likely become the reference standard for multivessel CAD.
Acknowledgements Conflicts of interest
Dr Fearon has received research grants from St. Jude Medical. For the remaining author, there are no conflicts of interest.
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medical therapy in stable coronary disease. N Engl J Med 2012; 367:991–1001. Damman P, Wallentin L, Fox KA, Windhausen F, Hirsch A, Clayton T, et al. Long-term cardiovascular mortality after procedure-related or spontaneous myocardial infarction in patients with non-ST-segment elevation acute coronary syndrome: a collaborative analysis of individual patient data from the FRISC II, ICTUS, and RITA-3 trials (FIR). Circulation 2012; 125:568–576. Kushner FG, Hand M, Smith SC Jr, King SB 3rd, Anderson JL, Antman EM, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009; 54:2205–2241. Patel MR, Dehmer GJ, Hirshfeld JW, Smith PK, Spertus JA. ACCF/SCAI/STS/AATS/AHA/ASNC/HFSA/SCCT 2012 Appropriate use criteria for coronary revascularization focused update: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, American Society of Nuclear Cardiology, and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol 2012; 59:857–881. Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T, et al. Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS); European Association for Percutaneous Cardiovascular Interventions (EAPCI). Guidelines on myocardial revascularization. Eur Heart J 2010; 31:2501–2555. Dauerman HL. Reasonable incomplete revascularization. Circulation 2011; 123:2337–2340. Hannan EL, Wu C, Walford G, Holmes DR, Jones RH, Sharma S, King SB 3rd. Incomplete revascularization in the era of drug-eluting stents: impact on adverse outcomes. JACC Cardiovasc Interv 2009; 2:17–25. Kleisli T, Cheng W, Jacobs MJ, Mirocha J, Derobertis MA, Kass RM, et al. In the current era, complete revascularization improves survival after coronary artery bypass surgery. J Thorac Cardiovasc Surg 2005; 129:1283–1291. Hannan EL, Racz M, Holmes DR, King SB 3rd, Walford G, Ambrose JA, et al. Impact of completeness of percutaneous coronary intervention revascularization on long-term outcomes in the stent era. Circulation 2006; 113:2406–2412. Vander Salm TJ, Kip KE, Jones RH, Schaff HV, Shemin RJ, Aldea GS, Detre KM. What constitutes optimal surgical revascularization? Answers from the Bypass Angioplasty Revascularization Investigation (BARI). J Am Coll Cardiol 2002; 39:565–572. Kim YH, Park DW, Lee JY, Kim WJ, Yun SC, Ahn JM, et al. Impact of angiographic complete revascularization after drug-eluting stent implantation or coronary artery bypass graft surgery for multivessel coronary artery disease. Circulation 2011; 123:2373–2381. Tonino PA, Fearon WF, De Bruyne B, Oldroyd KG, Leesar MA, Ver Lee PN, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. J Am Coll Cardiol 2010; 55:2816–2821. Iqbal MB, Shah N, Khan M, Wallis W. Reduction in myocardial perfusion territory and its effect on the physiological severity of a coronary stenosis. Circ Cardiovasc Interv 2010; 3:89–90. Nam CW, Mangiacapra F, Entjes R, Chung IS, Sels JW, Tonino PA, et al. FAME Study Investigators. Functional SYNTAX score for risk assessment in multivessel coronary artery disease. J Am Coll Cardiol 2011; 58:1211–1218. U.S. National Institutes of Health. A comparison of fractional flow reserveguided percutaneous coronary intervention and coronary artery bypass graft surgery in patients with multivessel coronary artery disease (FAME 3). ClinicalTrials.gov NCT02100722; 2014.
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Functional assessment of multivessel coronary artery disease: ischemia-guided percutaneous coronary intervention Jonathan G. Schwartz and William F. Fearon Invasive evaluation and treatment of coronary artery disease (CAD) has traditionally been based upon coronary angiography to determine the need for and the success of revascularization. However, coronary angiography augmented with fractional flow reserve (FFR) creates a paradigm shift, providing a more complete functional assessment of coronary lesions. Measuring FFR to identify ischemic lesions and guide revascularization results in fewer adverse outcomes, including persistent angina, myocardial infarction, and mortality. An ischemic lesion identified by FFR is more likely to lead to adverse events when compared with an angiographically similar lesion with nonischemic FFR when both are treated medically. Although the mechanism explaining this is unclear, it is likely multifactorial, including the impact of mechanical forces, upregulation of inflammatory mediators, and the amount
Introduction Advances in interventional strategies and pharmacologic therapies have revolutionized the modern approach to coronary artery disease (CAD). However, controversy exists with regard to the optimal initial therapy for stable CAD. Until recently, coronary angiography was the reference standard for diagnosing CAD. For many years, therapeutic decision-making in the cardiac catheterization laboratory has been guided solely by angiographic lesion assessment, regardless of functional significance. Angiography assesses anatomy and does not provide functional information. An abundance of data now suggest that identifying ischemia and relieving it can improve outcomes. Unfortunately, noninvasive stress imaging often lacks requisite spatial resolution and accuracy to guide revascularization decisions, especially in multivessel CAD, for which the accuracy of noninvasive stress imaging is notoriously poor. A major current challenge is determining which coronary lesions are responsible for ischemic symptoms and are likely to cause future events in patients with multivessel CAD. A traditional and longstanding belief holds that mild coronary lesions (stenosis < 50%) are more likely to lead to infarction compared with more severe lesions. This concept stems from small retrospective angiographic studies conducted in the late 1980s and early 1990s that suggested that coronary lesions with less than 50% stenosis were most likely to lead to myocardial infarction (MI) through plaque vulnerability and rupture [1–3]. Despite widespread interest in and acceptance of these 0954-6928 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
of distal myocardial tissue at risk. Using both anatomic and ischemia-guided assessments (such as the Functional SYNTAX Score) aids in the therapeutic decision-making process in patients with multivessel CAD. This review focuses on the evidence for FFR-guided management of multivessel CAD. Coron Artery Dis 25:521–528 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Coronary Artery Disease 2014, 25:521–528 Keywords: angioplasty, coronary angiography, coronary artery disease, coronary physiology, fractional flow reserve, functional, ischemia, multivessel Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford University School of Medicine, Stanford, California, USA Correspondence to William F. Fearon, MD, Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford University School of Medicine, Stanford, 300 Pasteur Dr., Rm. H2103, Stanford, CA 94305-5218, USA Tel: + 1 650 723 2621; fax: + 1 650 725 6766; e-mail: [email protected]
findings, these studies were plagued by small and retrospective populations and variable patient follow-up, with extended times between baseline angiography and subsequent MI. Other studies such as the Coronary Artery Surgery Study (CASS) compared baseline stenosis severity with occlusion rates at 5-year angiography and found low rates in non-bypassed vessels with baseline stenosis between 5 and 49% and higher rates in lesions with 81–95% stenosis [4]. Despite this, the term ‘vulnerable’ plaque coined by Muller et al. [5] became an attractive concept, spawning many studies of various adjunctive diagnostic technologies in search of methods for consistent and accurate identification of lesions at risk for rupture and MI. Recent data now suggest that patients with CAD typically have multiple simultaneous plaque ruptures that stabilize and heal to form a more significant stenosis before rupturing again. There are many more mild than severe plaques, and occasionally a mild plaque will rupture and lead to an MI. However, high-grade coronary lesions (although less prevalent) are more likely to lead to MI after rupture [6]. This has been demonstrated in post-mortem studies, which report that most intracoronary thrombi occur in the setting of ruptured plaques with layering, suggesting a cyclical process of multiple plaque rupture events and subsequent healing. Stenosis severity was recently shown to be of greater than 75% cross-sectional area in a majority of these ruptured lesions [7]. The process leading to the development of high-grade stenosis appears to be nonlinear and unpredictable [8,9], arguing that multiple plaque rupture events may be subclinical. In addition, because of a DOI: 10.1097/MCA.0000000000000153
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smaller residual lumen, when severely stenotic lesions develop plaque rupture and thrombosis, infarction is more likely, compared with that of a vessel with milder lumen compromise. The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was designed to further investigate this dilemma – that is, the role mild coronary disease plays in subsequent major adverse cardiovascular events [10]. A total of 697 patients presenting with acute coronary syndromes with subsequent percutaneous coronary intervention (PCI) underwent three-vessel intravascular ultrasonography. This served as a baseline measure of CAD, and patients were then followed for a median of 3.4 years. The most common event in nonculprit vessels was angina progression, with less than 1% presenting with MI in a nonculprit vessel. Notably, the mean diameter of stenosis in patients who suffered events in nonculprit vessels increased from 32 to 65%. These data suggest a low propensity for mild lesions to lead to MI; in fact, there were no major events seen in lesions with less than 40% cross-sectional area at baseline. The two intravascular ultrasound parameters most strongly associated with follow-up events in nonculprit vessels are minimal lumen area and extent of plaque burden. This suggests that angiographically severe lesions are more likely to cause future events.
Finally, a sub-study [11] of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial [12] examined patients who underwent clinically driven follow-up coronary angiography to understand which baseline lesions are most likely to cause recurrent symptoms. The investigators identified that the lesions most likely to lead to acute coronary syndrome or MI requiring PCI during follow-up had a baseline severity of greater than 50% stenosis. The average stenosis of the culprit lesions on follow-up was greater than 70%, arguing that severe lesions are most likely to cause subsequent acute coronary syndrome. Although invasive functional CAD assessment was not performed in PROSPECT or COURAGE, these studies suggest that severe lesions are more likely cause ischemia and lead to future events. The interplay of anatomy and ischemia is poorly understood [13]; however data now suggest that ischemia-producing lesions, regardless of angiographic anatomical appearance, are in fact more ‘vulnerable’ to progression. Predicting which lesions will lead to future MI remains a major challenge, with the debate centering on the relative importance of ischemia (function) versus anatomy still continuing [14]. Because functionally significant lesions are more likely to lead to MI, physiologic assessment is vital in understanding the disease process and to optimize therapy.
Fig. 1 max
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Fractional flow reserve (FFR) measurements are derived from a ratio of the driving pressure (Pa) and the distal pressure (Pd) across a lesion. Pd is assumed to be equivalent to the central venous pressure (Pv) when maximum hyperemia is present; in this setting, the relationship between driving pressure and blood flow is linear. Black lines depict flow when no stenosis is present, equivalent to an FFR of 1.0. Gray lines depict a stenosis with a drop in pressure distally to 70 mmHg, which corresponds to 70% of the normal blood flow. The FFR in this setting would be equivalent to 0.70. Under these conditions, driving pressures (Pa, Pd) correspond linearly to flow (QN, QS). Reproduced with permission [21]. Copyright Elsevier (2012).
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FFR-guided PCI Schwartz and Fearon 523
Fig. 4
Fig. 2
20 Deferral of PCI Performance of PCI
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0 FFR ≥ 0.75 Five-year follow-up data from the DEFER trial showing no significant difference in the rate of cardiac death and/or acute MI in nonischemic lesions (FFR ≥ 0.75) when percutaneous coronary intervention is deferred rather than performed. DEFER, FFR to Determine Appropriateness of Angioplasty in Moderate Coronary Stenoses; FFR, fractional flow reserve; MI, myocardial infarction; PCI, percutaneous coronary intervention. Reproduced with permission [23]. Copyright Elsevier (2007).
Fig. 3
Coronary angiography was performed in a 55-year-old male patient with a history of hyperlipidemia and tobacco abuse after presenting with a non-ST elevation myocardial infarction. Multivessel coronary disease was identified, with lesions of varying angiographic severities. A 99% mid-LAD stenosis is identified (arrow); FFR evaluation is not necessary in this lesion given the severity of the stenosis. PCI was performed on this lesion. FFR, fractional flow reserve; LAD, left anterior descending; PCI, percutaneous coronary intervention.
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revascularization [15]. Other limitations of such techniques include the requirement of myocardial perfusion imaging to have at least one nondiseased vessel to detect perfusion defects, which limits accuracy in the setting of multivessel CAD [16] and often leads to underestimation of lesion severity [17]. Multivessel disease can also cause balanced ischemia by perfusion imaging, resulting in falsely normal results.
FFR
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Stenosis classification by angiography Data from the FAME 1 trial are shown in this box-and-whisker plot, showing fractional flow reserve (FFR) values of lesions in the categories of 50–70%, 71–90%, and 91–99% diameter stenosis by angiography. Note the wide range of FFR values in each category. An FFR value of 0.80 or less indicates functional significance corresponding to myocardial ischemia, and is highlighted by the dashed line. Reproduced with permission [38]. Copyright Elsevier (2010).
Although multiple noninvasive techniques can detect ischemia, only a minority of patients presenting to the catheterization laboratory undergo such studies before
For these reasons, real-time invasive assessment of physiology is vital, particularly in multivessel CAD. Coronary pressure wire-derived fractional flow reserve (FFR) is now the reference standard for identifying lesions capable of producing ischemia and more likely to lead to adverse events.
Fractional flow reserve Grüntzig et al. [18] first introduced the principle of measuring resting pressure gradients across stenotic lesions early in interventional cardiology. The concept of measuring the pressure ratio (as opposed to the absolute gradient) during maximal coronary vasodilation using a miniaturized pressure transducer was introduced by Pijls and colleagues [19,20] as FFR. The FFR is defined as the ratio of the maximal blood flow in the presence of a
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stenosis and the maximal flow in the theoretical absence of stenosis (Fig. 1). A pressure-sensing angioplasty guidewire measures the distal mean coronary pressure, which is then divided by the mean aortic proximal coronary pressure during hyperemia. This quotient reflects the functional impact of a lesion on distal myocardial flow. FFR is independent of hemodynamic variation (heart rate, systemic blood pressure, contractility). The spatial resolution of FFR allows interrogation of the ischemic potential of not only the specific vessel, but also the specific lesion, making it ideally suited for multivessel CAD. In the absence of stenosis in a normal vessel, FFR is 1.0; any value less than this indicates a fractional flow reduction (i.e. an FFR of 0.60 indicates a 40% reduction in maximal hyperemic blood flow). FFR less than 0.80 is the accepted cutoff for identification of ischemic lesions, with a ‘gray zone’ between 0.75 and 0.80 [22]. Maximal hyperemia is most often obtained by intravenous or intracoronary adenosine.
Fig. 5
An angiographically less-severe bifurcation lesion in the LCx is identified (arrow) in the same patient (Fig. 4). FFR was performed on this lesion, found to be not functionally significant with a value of 0.90 (Fig. 6). This lesion was not intervened upon. FFR, fractional flow reserve; LCx, left circumflex.
Multiple trials have shown the benefits of FFR-guided CAD management. The FFR to Determine Appropriateness of Angioplasty in Moderate Coronary Stenoses (DEFER) trial demonstrated the safety of medical management in patients with intermediate
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A screen capture image of the FFR data from the LCx lesion (Fig. 5) in the same patient (Fig. 4). FFR was found to be 0.90, indicating it was not functionally significant. No intervention was performed. FFR, fractional flow reserve; LCx, left circumflex.
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FFR-guided PCI Schwartz and Fearon 525
Fig. 7
ischemia were likely included in previous studies, like COURAGE. However, because the CAD is not responsible for ischemia, these patients have excellent outcomes with medical therapy alone, which would dilute any potential benefit of PCI if they were included in the randomized study. Indeed, in FAME 2, this group, which was followed up in a registry, had very low event rates during follow-up. The randomized portion of FAME 2 was terminated early because of a significantly higher primary endpoint (death, MI, or urgent revascularization) in medically treated patients (4.3 vs. 12.7%, P < 0.001). This difference was driven by higher rates of urgent revascularization, with no significant difference between death and MI. However, a landmark analysis showed that 1 week after enrollment (thereby excluding periprocedural MI), the rate of death or MI was higher in the medically treated patients (1.6 vs. 3.7%, P = 0.05). This is important because other studies have shown that periprocedural MI has little effect on long-term outcome, whereas spontaneous MI is a much stronger predictor of late mortality [28]. FAME 2 data provide further support for the need to identify lesions that are responsible for ischemia and to revascularize these, while treating nonischemic lesions medically.
Continuing with the same patient (Fig. 4), a 50% mid-RCA lesion is identified on coronary angiography (arrow). FFR was again not functionally significant, with a value of 0.82 (Fig. 8). This lesion was also not intervened upon. FFR, fractional flow reserve; RCA, right coronary artery.
single-vessel disease and nonischemic FFR results. Patients with FFR values of 0.75 or higher were randomized to PCI versus deferral. The deferral group had less than 1% risk for cardiac death or MI at the 5-year followup when treated medically, numerically less than half the rate in the PCI arm (Fig. 2) [23]. Subsequently, the Fractional Flow Reserve vs. Angiography in Multivessel Evaluation (FAME) study showed that FFR-guided PCI with drug-eluting stents is superior to angiographyguided decision-making in both stable and unstable patients with multivessel CAD [24]. The primary outcomes of death, MI, and repeat revascularization at 1 year were significantly lower in the FFR-guided PCI group. In addition, there was significantly lower death and MI at the 2-year follow-up, with cost reduction and better resource allocation [25,26]. Most recently, the FAME 2 trial compared PCI guided by FFR with optimal medical therapy in patients with stable single or multivessel CAD [27]. A key difference between FAME 2 and previous studies (e.g. COURAGE) is that FFR was first measured across all lesions considered for PCI. About 25% of patients were not enrolled in the randomized component of the study because FFR across all lesions was greater than 0.80. Patients with CAD that appears significant on angiography but is not responsible for significant
Despite the many benefits of FFR-guided functional assessment of CAD and multiple trials providing compelling data for its use, FFR has a small role in the current guidelines. The ACC/AHA guidelines give a class IIa recommendation (level of evidence A) for FFR assessment for PCI in select patients [29,30], whereas the European PCI guidelines provide a class Ia recommendation (level of evidence A) without objective evidence of ischemia in lesions of uncertain severity [31]. The hesitance for more widespread acceptance and use of FFR may be related to a perceived increased procedure time, pressure from referring physicians and patients for PCI, concern about procedural risk, and reimbursement issues [22]. Concern may also exist about a nonischemic vulnerable plaque being deferred because of a negative FFR and subsequently leading to a coronary event. However, the FAME 1 and FAME 2 trials and numerous other registries rebut this concern by showing very low event rates when nonischemic lesions are treated medically (Fig. 3) [24,25,27].
Reconsidering revascularization: a paradigm shift A major limitation of traditional invasive methods to evaluate and treat CAD is that complete revascularization has been based on angiographic appearance alone, without invasive physiologic assessment. Importantly, no standardized definition of complete revascularization currently exists. Functionally complete revascularization differs from anatomically complete revascularization in that angiographically severe lesions (>70% stenosis) may not be intervened upon if they are non-flow-limiting by
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physiologic assessment. This important concept is controversial and is not always well accepted [32]. Multivessel CAD provides a challenge when attempting to achieve complete revascularization, particularly through a percutaneous approach [33]. Initial data in the bare-metal stent era showed that anatomically complete revascularization has superior long-term outcomes compared with incomplete revascularization, which was associated with increased rates of MI, need for reintervention, angina, mortality, and impaired recovery of left ventricular function [33–35]. However, more recent trials have suggested that anatomically complete revascularization may not improve long-term outcomes and may in fact be harmful [36,37]. Despite these data, current guidelines continue to recommend complete anatomic revascularization in patients with multivessel CAD, driven by angiographic appearance alone [30,31].
Visual/angiographic–functional mismatch Incorporating FFR into the assessment of multivessel CAD may change treatment strategies when compared with an angiographic assessment alone. Clinical data have shown that such scenarios are often encountered. The FAME data, for example, showed functional significance
in as many as 35% of moderately severe angiographic lesions (50–70% stenosis) and functional insignificance (FFR > 0.80) in up to 20% of angiographically severe lesions (71–90% stenosis) [38]. Of the patients initially deemed as having angiographic three-vessel disease, only 14% had functional three-vessel disease after FFR assessment, and 9% of these patients had no functionally significant lesions. Thus, patients may be subjected to unnecessary CABG surgery, when in fact PCI (or even no intervention at all) may be a better option. Reasons for this mismatch are numerous and complex. Of utmost importance is to consider ischemia as a separate functional entity, different from anatomic/angiographic severity. Angiographically similar stenoses may have different functional significances on the basis of the myocardial mass supplied. Thus, angiographic appearance can be misleading, as angiographically severe lesions may be functionally insignificant if only a small myocardial mass is at risk [39]. Other aspects, such as lesion length, lesion eccentricity, reference vessel size, collateral supply, and microvascular dysfunction can also play a role in discordant findings between the angiogram and the FFR result. Figures 4–8 depict a case of FFRguided management in a patient with multivessel CAD.
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A screen capture image of the FFR data from the RCA lesion (Fig. 7) in the same patient (Fig. 4). Here, FFR was found to be 0.82, indicating it was also not functionally significant. Again, no intervention was performed. FFR, fractional flow reserve; RCA, right coronary artery.
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FFR-guided PCI Schwartz and Fearon 527
Functional supplementation of existing riskstratification tools Multiple risk-stratification tools have been developed to aid the decision-making process for practitioners in the setting of multivessel CAD. Most of these tools are based on angiographic lesion severity, and many are now outdated and no longer in use. Others have been updated to incorporate functional assessment, allowing for a more targeted and objective approach to lesions that may otherwise be equivocal based on angiographic data alone. The SYNTAX score is an angiography-based scoring system that stratifies patients on the basis of lesion complexity and severity. However, because it is based on angiography alone, it is inherently limited by the angiographic accuracy for identifying functionally significant disease. The Functional SYNTAX score is based on the calculation of the SYNTAX score, but counts only lesions with significance based on FFR. This tool was tested in the FFR-guided PCI arm of the FAME trial (Fig. 9) [40]. Compared with the SYNTAX score, the functional SYNTAX score reclassified 32% of high and intermediate tertile patients to a lower tertile. After calculating the functional SYNTAX score, 43% of patients with a score greater than 22, in whom CABG is generally recommended, were reclassified to a score less than 22, in which case PCI would be a suitable strategy. The functional SYNTAX score was more reproducible than the classic SYNTAX score, and importantly was a significant independent predictor of subsequent death or MI, whereas the SYNTAX score was not. The functional SYNTAX score is now being tested prospectively in the FAME 3 trial comparing FFR-guided PCI with CABG in patients with three-vessel CAD [41].
Conclusion
The ultimate goal of PCI in CAD is to improve the quality of life and prevent adverse outcomes. Current data strongly suggest that this is best achieved by revascularizing lesions responsible for ischemia and avoiding unnecessary revascularization of nonischemic lesions. FFR is currently the best tool to detect ischemia and to guide PCI decision-making in the catheterization laboratory. The traditional angiographic-only revascularization strategy in most cases is improved with the addition of FFR, which allows a more complete, functional lesion assessment. It is unclear why ischemic lesions with abnormal FFR lead to future adverse events compared with angiographically similar (but nonischemic) lesions with normal FFR. The answers are likely multifactorial and include mechanical forces and changing inflammatory mediators that occur across ischemia-producing lesions. Updated risk-stratification tools, such as the functional SYNTAX score, allow for functionally complete revascularization. As further large prospective and randomized clinical trial data become available, functionally driven ischemiaguided lesion management strategies will likely become the reference standard for multivessel CAD.
Acknowledgements Conflicts of interest
Dr Fearon has received research grants from St. Jude Medical. For the remaining author, there are no conflicts of interest.
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2 Fig. 9
Cumulative death or MI rate (%)
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