Bringing It All Together

Integration of Physiology With Anatomy During Cardiac Catheterization

• coronary angiography
• coronary artery disease
• fractional flow reserve
• percutaneous coronary intervention
• risk assessment

Although coronary angiography has been regarded for 4 decades as the “gold standard” for assessing coronary artery disease, anyone who has performed or tried to interpret coronary angiograms becomes aware very quickly that the technique is subject to several critical limitations. Visualization of coronary lesions is often limited by patient morphological features, and is plagued by abundant evidence of poor correlation with pathological findings (1) and considerable interobserver variability with regard to the severity of coronary arterial narrowings (2,3) and their morphology (4). Simple categorization of the extent of coronary artery disease according to the number of diseased vessels was useful for providing a broad prognostic picture when the interventions available were limited to bypass surgery or a small armamentarium of medical therapies, but was of limited utility when a wider variety of treatment options became available. It is also well recognized that angiographic grading of lesion severity is at best an imperfect predictor of the physiological significance (i.e., flow-limiting status) of coronary lesions (5). Technical features related to patient morphology or vessel tortuousity can also limit visualization of specific coronary narrowings.

In preparing a randomized clinical trial of intracoronary stenting with coronary bypass surgery, the SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) investigators devised a scoring system that describes the anatomic complexity of multivessel disease. The score is based on both the amount of myocardium subtended by the coronary artery distal to each narrowing >50% in vessels >1.5 mm in diameter and by the anticipated difficulty of performing percutaneous coronary intervention (PCI) on a given lesion, and can be calculated on a public website (6,7). Within the context of the SYNTAX trial, this system was able to predict the likelihood of serious events after PCI, and was useful to stratify differential outcomes between PCI or coronary bypass graft surgery (8). When stratified into tertiles using the SYNTAX score, patients with higher scores had higher adverse event rates after multivessel stenting, but not after bypass surgery; there were no differences in outcomes between the 2 treatments in the lowest tertile, but there were clear differences favoring surgery in patients in the highest tertile. Although it is clearly an improvement in classification of risk during and after PCI, the SYNTAX score has limitations of its own. Interobserver variability is acceptable, but not outstanding, with weighted kappa values (a measure of correlation between discontinuous variables) reported at approximately 0.45 to 0.65 (9). Even more concerning is that agreement on the number of lesions to be scored (i.e., those >50% narrowed) was suboptimal (weighted kappa = 0.62). Although the calibration (i.e., the relation between observed and predicted outcomes) of the SYNTAX score was excellent within the SYNTAX trial, Capodanno and Tamburino (10) have pointed out that it has been poor in many other studies but may be improved when it is combined with clinical risk scores.

Nearly simultaneously with SYNTAX, in a separate trial, the FAME (Fractional Flow Reserve versus Angiography in Multivessel Evaluation) investigators showed that among patients undergoing multivessel stenting, a strategy of measuring coronary fractional flow reserve (FFR) with a pressure wire and an intravenous infusion of the vasodilator adenosine led to significant improvements in the practice of PCI. When FFR is measured, a value >0.80 is an accurate indicator that a coronary lesion does not result in ischemia (11). In FAME, “deferred” PCI of lesions with FFR >0.80 led to implantation of 30% fewer stents per patient, a 28% reduction in the composite rate of death, myocardial infarction, or revascularization at the end of a year, and similar rates of freedom from angina (12). After 2 years, the risk of death or myocardial infarction was reduced by 35%. Of the 9 myocardial infarctions that occurred in patients assigned to FFR-guided PCI, only 1 could be attributed to a lesion that appeared to be severe on coronary angiography (13).

In this issue of the Journal, Nam et al. (14) for the FAME investigators used FFR measurements to refine the SYNTAX score. Simply, they applied the SYNTAX score based on quantitative coronary angiography to patients enrolled in FAME, stratified the patients into tertiles of risk based on the score, and then reclassified the coronary lesions by including in the score only those lesions with impaired FFR. Therefore, fewer lesions were scored, and the intraobserver variability was improved considerably. More important, patients with angiographically severe but physiologically insignificant (as judged by FFR) lesions were reclassified. As a result, the authors were able to construct a functional SYNTAX score (FSS) in which 32% of patients originally judged to be at high or intermediate risk were moved to lower risk strata. For the year following PCI, the new score (the FSS) proved to be a better discriminator than the SYNTAX score alone of the risk for a composite of death, myocardial infarction, and target vessel revascularization, and of a composite of death and myocardial infarction.

Such results ought not to be surprising. If distinguishing patients according to the presence or absence of flow-limiting lesions leads to implantation of fewer stents, then the up-front “cost” of the procedure (i.e., periprocedural myocardial infarction or stent thrombosis) can be avoided without impairing the patient's short-term risk. In light of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial (15) and of the absence of evidence that prophylactic stenting reduces a patient's risk of death or myocardial infarction, most physicians are likely to accept this finding. The broader question is whether the FFS will be adopted. Currently, about 6% of patients undergoing PCI in the United States have FFR measured before undergoing PCI (16). Although technically easy to perform, FFR measurement is relatively cumbersome and is modestly time consuming—the nursing staff must mix an adenosine infusion, and procure and load an infusion pump; the flow wire must be connected to a console and patient demographic data entered; and the infusion must be run for 2 min before FFR is measured for each lesion. Although usually easy to use, the pressure wire does not share all of the favorable handling characteristics of the guidewires currently favored by PCI operators. After performing angiography and measuring FFR, an operator would then have to log into the SYNTAX score website and enter the appropriate values into the calculator. Although this series of steps is clearly appropriate in many patients in whom the coronary anatomy and decision making are complex, it would prove fairly time consuming in the patient in whom the decision would seem to be easy to make, or in whom ad hoc PCI is planned. In addition, although physicians are reimbursed for measuring FFR on a per vessel basis, hospitals are not. Finally, in many patients who are referred for PCI, the flow-limiting capacities of many arterial lesions may have already been assessed using nuclear scintigraphy or stress echocardiography.

What is likely to provide incentive to use this technology more broadly? If the FSS were found useful for deciding which patients were best served by coronary bypass surgery and which by PCI, there might be strong motivation to increase the use of FFR measurement. Although it is very tempting to apply the findings of Nam et al. (14) to situations in which decisions must be made between surgery and PCI, it is important to remember that the current findings refer only to clinical events at 1 year. Second, and most important, the populations studied in SYNTAX and FAME differed, so the risk incurred by patients in the new tertiles may be different, and their event rates after bypass surgery may differ as well. Patients enrolled in FAME were selected for multivessel PCI, so one assumes that coronary bypass surgery was already excluded from consideration, whereas those in SYNTAX were subject to equipoise on the part of the investigators. Thus, the mean number of angiographic lesions per patient within SYNTAX was 4.3, whereas in FAME it was 2.8, and the number of total occlusions in the former study was 23% compared with 9% in the latter. Nonetheless, the concept of more precise selection of patients for PCI or bypass surgery is attractive. In fact, assessing lesions for physiological significance may turn out to be attractive for surgeons as well, since avoiding the placement of vein grafts to bypass nonobstructive lesions might prevent many early graft closures and have a salutary effect on the outcome after surgery that parallels the benefit of the FFR-guided strategy seen in FAME.

Reconciling these findings with the 2 decades of knowledge concerning the need to revascularize all lesions in patients with multivessel disease may at first seem difficult. Originally made in patients undergoing bypass surgery, these observations have been extended to patients undergoing PCI. Two years ago, Rastan et al. (17) suggested the term “reasonable incomplete revascularization,” pointing out that revascularization of small vessels, or vessels subtending nonviable territory made little sense. The findings of Nam et al. (13) lend credence to the concept that selective incomplete revascularization may have advantages, at least in the intermediate term. It is important to emphasize the term “selective.” Unlike previous reports, the lesions for which revascularization was “deferred” were not those that were inaccessible to PCI or bypass grafting, or for which there was disagreement about visual interpretations, but rather were judged objectively to be anatomically but not physiologically suitable for stent placement. In nearly all the retrospective reports, event rates among patients with incomplete revascularization were notably worse during the first year after the procedure, whereas in FAME, there was no suggestion of “catch-up” among patients assigned to receive stents only if the FFR were <0.80.

Where does this leave us? Development of the SYNTAX score has provided the beginning of a rational system to assess coronary anatomy. It is being tested prospectively in the EXCEL (Evaluation of Xience Prime versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial, which will compare stenting versus surgery among patients with left main disease with SYNTAX scores <26. No doubt, EXCEL will provide considerable guidance in managing this group of patients, but will also lead to new questions about the treatment strategies. Nam et al. (14) make a compelling case for integrating physiology into this type of assessment. Is the FSS ready for clinical adoption? Probably not. Although measuring FFR is currently viewed as an established standard for interventional cardiologists deciding whether or not to implant a stent in a particular vessel, applying this technique to distinguish which patients should undergo bypass surgery and to decide how the surgery should be performed is not. Integrating the concept of “watchful waiting” espoused by FAME into a surgical strategy is intriguing but challenging. Would such a strategy be broadly applicable, or should it be restricted only to vessels that could subsequently be approached percutaneously if they were to progress or become symptom producing? Pursuing this course might be more palatable if we were confident that the likelihood of progression (or disruption) of anatomically severe but physiologically mild lesions could be prevented with modern medical therapy. Gaining such confidence would require several important steps. Duration of observation of the cohorts defined in the current study should be extended, and the approach should be validated in a second database. The next step toward its adoption would be prospective inclusion into the next generation of clinical trials comparing physiologic based stenting with physiologic based bypass surgery. We would then be ready to apply a more refined standard to selecting the appropriate revascularization approach for individual patients.

• American College of Cardiology Foundation