Author + information
- S0735109716006033-594ec879dbd076de2318a2fcfee8c404Anthony G. Nappi, MDa and
- S0735109716006033-141e48873c809830f9e86682aa11e088William E. Boden, MDa,b,∗ ()
- aDepartment of Medicine, Albany Medical Center, and Albany Medical College, Albany, New York
- bDepartment of Medicine, Samuel S. Stratton VA Medical Center, Albany, New York
- ↵∗Reprint requests and correspondence:
Dr. William E. Boden, Samuel S. Stratton VA Medical Center, 113 Holland Avenue, Albany, New York 12208.
- fractional flow reserve
- multivessel revascularization
- residual SYNTAX score
- SYNTAX revascularization index
The treatment of coronary artery disease (CAD) has been anatomically driven for a half-century, particularly since the advent of percutaneous coronary intervention (PCI) almost 40 years ago (1). Despite technological advances in both coronary revascularization and non-revascularization treatment options, which includes both therapeutic lifestyle intervention and aggressive, multifaceted pharmacological secondary prevention—the combination of which is commonly referred to as optimal medical therapy (OMT)—the overwhelmingly favored clinical approach for CAD management continues to be “fixing all significant coronary stenoses.” Although increasingly more sophisticated noninvasive imaging modalities are widely embraced and incorporated into routine clinical practice, the final common diagnostic pathway seems to inevitably lead to the cardiac catheterization laboratory where the results of coronary angiography very frequently “confirm” the anatomic presence of obstructive CAD—objective findings that most cardiologists have difficulty ignoring—and that frequently result in myocardial revascularization, most often with ad hoc PCI.
Although the limitations of coronary angiography are well known, as is the difficulty of reliably assessing coronary stenosis severity by visual estimation alone, the use of a pressure wire and measurement of fractional flow reserve (FFR) has become the primary invasive method used by angiographers to assess the “functional” (or perhaps more accurately, the “physiological”) significance of an intermediate-grade coronary stenosis (e.g., a 50% to 70% diameter reduction). The FFR, defined as the ratio of maximal blood flow across a coronary arterial stenosis relative to the blood flow in the vessel if the stenosis were not present, has been well validated with noninvasive stress tests to determine whether an angiographic lesion would produce ischemia (2,3). Furthermore, mounting clinical trials data have shown that the performance of a PCI may be safely deferred in coronary lesions that appear angiographically significant, but are not physiologically significant, as assessed by FFR (3–5).
In the original FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) study (5), patients with multivessel CAD were randomized to an anatomically guided PCI strategy based on angiographic criteria (≥50% luminal narrowing) versus an FFR-guided strategy (FFR ≤0.80) (5). This seminal study demonstrated a significant reduction in major adverse cardiac events (MACE) in the patients randomized to FFR-guided PCI and highlighted the importance of revascularization based on the functional significance of coronary lesions. The study also re-emphasized the safety of treating non–flow-limiting coronary stenoses that were not ischemia producing, defined as an FFR >0.8, with OMT, as cited in the preceding text. An additional therapeutic dynamic, however, has evolved in the aftermath of the DEFER (Deferral Versus Performance of PTCA in Patients Without Documented Ischemia) (4), FAME (5), and FAME-2 (6) trials—namely, does the use of a pressure wire to obtain FFR assessments in patients with obstructive CAD provide cardiologists with a more accurate and reliable invasive physiological tool that would potentially provide clinicians with more powerful prognostic information that would derive from such a more selective revascularization approach?
A long-held belief among many practicing cardiologists has been that “angiographically complete” revascularization is associated with improved long-term outcomes after multivessel revascularization for stable CAD as compared with “anatomically incomplete” revascularization, and this would appear to be well validated in recent comparative effectiveness trials that have shown the superiority of coronary artery bypass graft (CABG) surgery versus PCI in patients with extensive multivessel CAD, particularly among diabetic patients and patients with left main stem CAD (7–9). However, might this paradigm of “complete anatomic revascularization” shift if it could be demonstrated that a physiologically directed approach with FFR guidance could better identify which stenotic coronary lesions should be targeted by PCI and which could be safely avoided, particularly if these residual (but functionally insignificant) stenoses did not reflect residual ischemia or predict worse clinical outcomes? In other words, could physiology trump anatomy in our quest to discover the holy grail of which therapeutic approach to “complete revascularization” is both more effective and cost-effective?
In this issue of the Journal, Kobayashi et al. (10) performed a post hoc analysis in which they calculated a residual SYNTAX score (RSS) and SYNTAX revascularization index (SRI) in the FFR-guided PCI cohort of the aforementioned FAME trial. The authors then looked at 1- and 2-year MACE rates in patients subdivided into 4 separate quartiles based on these scores, and the burden of residual angiographic disease. The objective of their analysis was to clarify whether residual angiographic disease, which was ischemia producing, remained of prognostic importance after “functionally” complete revascularization was achieved.
The authors found that the patients with MACE had higher SYNTAX scores (SS) than patients without MACE (17.3 ± 7.3 vs. 13.9 ± 7.1, p = 0.001), whereas they had similar RSS and SRI indices after PCI (RSS: 7.2 ± 6.6 vs. 6.4 ± 5.6, p = 0.51 and SRI: 60.8 ± 29.8% vs. 54.3 ± 32.9%, p = 0.24), respectively (10). The Kaplan-Meier analysis also showed a similar incidence of MACE at 1 year with the RSS/SRI stratifications (log-rank p = 0.55 and p = 0.54, respectively). From these findings, the authors concluded that after functionally complete revascularization with FFR guidance, the residual angiographic lesions, which were not functionally significant, did not appear to correlate with residual ischemia or predict a worse long-term clinical outcome (10). In short, this analysis supported the physiological appropriateness of functionally complete revascularization rather than anatomically complete revascularization.
The authors cite some obvious limitations of their study: exclusion of recent (within 5 days) ST-segment elevation myocardial infarction patients, absence of a control arm, inclusion of a small portion of patients with functionally significant lesions that were left untreated, and the caveat that such a post hoc analysis should only be considered hypothesis generating. Additionally, the study participants in FAME would generally be considered a low- to intermediate-risk group on the basis of the degree of angiographic disease at baseline (average baseline SS of 14.4), and thus it remains unclear to what degree these findings can be generalized to higher-risk angiographic subsets with more extensive or complex CAD. Nevertheless, the authors could not demonstrate that clinical outcomes at 1 and 2 years differed among the RSS and SRI subgroups, irrespective of the baseline SS stratification, which would suggest the applicability of these results to the broader population of patients with more complex CAD.
What are the clinical implications of these study findings? Although RSS and SRI may not be routinely used in clinical practice, the results of this post hoc analysis does further support the concept of a more judicious approach to revascularization that is physiologically directed and selectively targeted to only those coronary stenoses that are functionally significant and ischemia producing, rather than a purely anatomic approach that seeks to revascularize all stenotic coronary segments, regardless of whether they are ischemia producing or not. Subjecting patients with functionally insignificant coronary lesions to anatomically directed PCI alone where there is not compelling evidence that revascularization of such stenoses correlates prognostically with future events could conceivably tilt the balance of PCI risk versus benefit toward the former.
How might these data inform clinical decision making for revascularization? A common dilemma facing clinicians is to identify which mode of revascularization is best suited for a patient with multivessel CAD. For example, in the diabetic patient with extensive, multivessel CAD, the superiority of surgical revascularization over multivessel PCI with drug-eluting stents in patients considered appropriate for both forms of revascularization is believed to be due to the more complete revascularization afforded by surgery in subjects with diffuse angiographic disease, based on the results of several recent trials (7–9). The cardioprotective benefit of CABG is postulated to result from bypass grafts to the mid-coronary vessels that not only treat culprit lesions (even anatomically complex ones), but also afford prophylaxis against new proximal disease, whereas stents treat only suitable stenotic segments with little or no benefit against native coronary disease progression (11). Yet, in these 3 trials, revascularization by PCI was entirely anatomically directed. There are likely subsets of diabetic patients with 3-vessel CAD in whom only 2 of the 3 coronaries display physiological flow limitation that may be appropriate for an FFR-guided 2-vessel PCI rather than CABG, as would be traditionally recommended. Such a targeted, physiologically directed revascularization approach would, therefore, better inform individual clinical decisions regarding CABG or PCI. It would also potentially enable the clinician to feel more comfortable treating the residual stenotic (albeit functionally insignificant) CAD with OMT alone.
Finally, do these findings provide insight into the design and conduct of current trials? Whether revascularization plus OMT of ischemia-producing disease is superior to OMT alone in a large population of stable CAD patients remains unproven. The ongoing ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) (NCT01471522) (12) will hopefully provide some clarity because this study is designed and powered to evaluate the long-term superiority of revascularization of choice (FFR-guided PCI or CABG surgery) plus OMT versus a strategy of OMT alone for the composite endpoint of cardiovascular death or myocardial infarction in subjects with moderate-to-severe ischemia as assessed by stress imaging studies. Additionally, the FAME-3 trial seeks to address a similar question in patients with 3-vessel CAD who are randomized to an FFR-guided PCI approach with new-generation drug-eluting stents versus CABG surgery (13), which will directly test physiologically directed versus anatomically directed revascularization strategies, respectively. Until these ongoing studies conclude, clinicians will need to make individual revascularization decisions based on currently available trials data. Thus, the present analysis adds importantly to our scientific evidence base that a physiologically directed PCI approach to identifying and treating only functionally significant coronary stenoses can lead to better clinical outcomes, and defines for us a path forward to utilize PCI in a more selective, safe, and cost-effective manner.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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