The Functional SYNTAX Score — A Huge Step Forward or Research in Motion?

Abstract: In a recent manuscript in the Journal of the American College of Cardiology, the newly introduced “functional SYNTAX score” (FSS) was found to be a better tool to assess the extent and severity of coronary artery disease than the SYNTAX score (SS) and has reclassified 1/3 of the studied cohort into lower-risk categories.

Besides being more invasive, costly, and time consuming, FSS still suffers from inherent deficiencies of its own. Like SS, FSS does not incorporate clinical risk predictors and consequently is a suboptimal tool for predicting PCI risk. FSS is not supported by a wealth of contemporary outcome data in a wide range of patient and lesions subsets. 

Key unanswered questions are whether PCI of hemodynamically significant lesions (FFR <0.80) is superior to optimal medical therapy (OMT) and whether complete revascularization yields considerably better outcomes than partial revascularization.

Since partial revascularization is still an option, operational FSS (taking into account only the FSS of lesions subject to PCI) combined with a clinical risk score will probably better predict the procedural risk of the planned PCI.

J INVASIVE CARDIOL 2012;24(6):304-305

Key words: fractional flow reserve, functional SYNTAX score

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Dr Nam and the Fractional Flow Reserve versus Angiography for Multi-vessel Evaluation (FAME) Investigators have published the correlation between SYNTAX  score (SS) and Functional SYNTAX score (FSS) and their ability to predict post-percutaneous coronary intervention (PCI) major adverse cardiac events (MACE) in a cohort of 497 patients enrolled in the FAME study.¹ These authors concluded that substituting the angiography-based visual assessment (SS) with FFR-based hemodynamic assessment (FSS) results in a significant reduction in the patients with higher-risk class in favor of lower-risk class (32% of the patients were reallocated to a lower-risk class) and better discriminate risk for MACE in patients with multi-vessel coronary artery disease (CAD) undergoing PCI.

The FSS addresses the 2 major shortcomings of the SS: (1) a 50%-90% stenosis based on visual assessment of an angiogram does not accurately predict whether these lesions will be hemodynamically significant or ischemic2 and is not reproducible (subject to considerable inter and intra-observer variability); (2) SS assigns similar risk to all lesions ranging between 51%-99% stenosis even though this dichotomy is probably not justified based on either ischemia or adverse outcomes.

The FSS, however, harbors some of the same limitations that affect the SS:

1. Neither score takes into account myocardial viability downstream from the stenosed or occluded coronary. The presence of a totally occluded proximal left anterior descending (LAD) or right coronary artery (RCA) leading to non-viable myocardium will dramatically increase the SS or FSS but will not have meaningful operational consequences. Similarly, vessels that are viewed as inappropriate or unsuitable targets for revascularization by both surgery and PCI (diffuse calcific small diameter vessels) should not be incorporated into the risk assessment since these non-target vessels will not undergo revascularization.
2. Certain angiographic parameters are inadequately accounted for in SS and FSS; for instance, small vessel diameter or previous diffuse in-stent restenosis do not receive incremental scoring, but add considerably to target vessel failure.
3. Any attempt to provide an estimate of procedural risk based merely on angiographic or even ischemic or hemodynamic assessment of the coronary tree while ignoring the patient’s clinical and demographic characteristics, co-morbidity, functional or symptomatic status, and clinical presentation is likely to be inaccurate. Analysis of NCDR registry data that included over 580,000 patients demonstrated that clinical parameters are much more powerful than angiographic markers in predicting the incidence of 30-day mortality post PCI. Hence, it is concerning that any PCI risk scoring system can totally ignore clinical predictors (like ST-elevation myocardial infarction, acute coronary syndrome, advanced age, heart failure, renal failure, and diabetes) that are clearly associated with excessive cardiovascular mortality and MACE. A recent study comparing SS to clinical SYNTAX score (CSS, which incorporates clinical predictors of MACE into the score), suggested that the latter has superior risk stratification (especially for harder endpoints like cardiovascular or total mortality) and far better discriminatory power and calibration. Similar data emerged from other clinical scores like the New Risk Stratification Score (NERS) and the Global Risk Classification (GRC). 

Sadly, FSS has its own inherent limitations:

1. The FSS requires extensive triple-vessel FFR assessment. In the case of sequential lesions or diffuse disease, it requires continuous pullback of the FFR wire documenting the percent pressure drop (delta) across each and every lesion. This mission is time-consuming, costly, invasive, and can potentially result in adverse events or wire-induced injury, spasm, or pseudolesions.
2. FSS is especially limited in cases of diffuse multi-vessel coronary disease. The presence of multiple sequential or parallel lesions may result in under- and overestimation of the FFR, respectfully. Consequently, after initial PCI of the most critical lesion(s) and redistribution of both flow and demand, a second set of FFR measurements is required to confirm that the modification of the flow and demand map (due to the initial PCI) did not yield a drop or rise in the measured FFR of parallel and sequential lesions, respectively. Similarly, PCI of an occluded vessel can result in reduced flow through the artery feeding the collateral flow and consequently an increase in FFR. 
3. While FAME has suggested that the outcome of lesions bearing FFR >0.80 is better if treated with optimal medical therapy (OMT) than PCI, this conclusion needs to be further substantiated by large-scale randomized trials with a heterogeneous patient population including those excluded from FAME (for instance, patients with left main stenosis, tortuous calcific vessels, post bypass surgery, and immediate acute coronary syndrome) undergoing contemporary revascularization. Moreover, the efficacy and safety of PCI, bypass surgery, or medical therapy may shift with time and can make the conclusions of former studies irrelevant and non-applicable. Improvements in revascularization efficacy and safety are especially notable in the field of PCI, where second-generation drug-eluting stents and more effective platelet inhibitors have resulted in significant MACE and stent thrombosis reduction, while the radial approach has reduced the burden of bleeding complications.
4. There are no compelling data to suggest that lesions with FFR <0.80 do poorly on current OMT. The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) trial suggested that lesions with minimal luminal area of <4 mm² were associated with low event rates composed mostly from worsening angina (5.4% over 3.4 years; OR, 2.77; 95% CI, 1.32-5.81; P=.007, but still with a negative predictive value of 94.6%). Moreover, at this moment we do not have any randomized clinical trials that support the notion that partial revascularization results in excessive MACE when compared with complete revascularization. The efficacy of OMT versus contemporary PCI in FFR-based hemodynamically significant lesions will be studied in FAME 2. Until the detailed results of that study (which was discontinued by the independent data safety monitoring board due to excess events in the OMT arm) are available, these lesions should be considered for revascularization based on the presence of ischemic symptoms and the likelihood that the revascularization procedure could be done safely and provide sustained beneficial effects on symptoms, morbidity, and mortality. 

Conclusion

In summary, although both the SS and FSS are sufficient tools to assess the extent and severity of CAD, these scores do not incorporate clinical risk predictors and consequently are suboptimal tools for predicting PCI risk, and especially PCI mortality. Moreover, their discriminatory power and calibration are not satisfactory. 

Key unanswered questions include whether PCI of hemodynamically significant lesions (FFR <0.80) is superior to OMT and whether complete revascularization yields considerably better outcomes than partial revascularization.

Since partial revascularization is still an option, operational FSS (taking into account only the FSS of lesions subject to PCI) will probably be more appropriate to predict the procedural risk of the planned PCI, while FSS will probably better reflect the extent of CAD.  

References

1. Nam CW, Mangiacapra F, Entjes R, et al; FAME Study Investigators. Functional SYNTAX score for risk assessment in multivessel coronary artery disease. J Am Coll Cardiol. 2011;58(12):1211-1218.
2. Tonino PA, De Bruyne B, Pijls NH, et al; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-224. 
3. Serruys PW, Onuma Y, Garg S, et al. Assessment of the SYNTAX score in the Syntax study. Eurolntervention. 2009;5(1):50-56
4. Wykrzykowska JJ, Serruys PW, Onuma Y, et al. Impact of vessel size on angiographic and clinical outcomes of revascularization with biolimus-eluting stent with biodegradable polymer and sirolimus-eluting stent with durable polymer the LEADERS trialsubstudy. JACC Cardiovasc Interv. 2009;2(9):861-870. 
5. Peterson ED, Dai D, DeLong ER, et al; NCDR Registry Participants. Contemporary mortality risk prediction for percutaneous coronary intervention: results from 588,398 procedures in the National Cardiovascular Data Registry. J Am Call Cardiol. 2010;55(18):1923-1932.
6. Matheny ME, Ohno-Machado L, Resnic FS. Discrimination and calibration of mortality risk prediction models in interventional cardiology. J Biomed Inform. 2005;38(5):367-375.
7. Girasis C, Garg S, Räber L, et al. SYNTAX score and clinical SYNTAX score as predictors of  very long-term clinical outcomes in patients undergoing percutaneous coronary interventions: a substudy of SIRolimus-eluting stent compared with pacliTAXel-eluting stent for coronary revascularization (SIRTAX) trial. Eur Heart J. 2011;32(24):3115-3127.
8. Chen SL, Chen JP, Mintz G, et al. Comparison between the NERS (New Risk Stratification) score and the SYNTAX (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score in outcome prediction for unprotected left main stenting. JACC Cardiovasc Interv. 2010;3(6):632-641.
9. Capodanno D, Miano M, Cincotta G, et al. EuroSCORE refines the predictive ability of SYNTAX score in patients undergoing left main percutaneous coronary intervention. Am Heart J. 2010;159(1):103-109.
10. Capodanno D, Caggegi A, Miano M, et al. Global risk classification and clinical SYNTAX (synergy between percutaneous coronary intervention with TAXUS and cardiac surgery) score in patients undergoing percutaneous or surgical left main revascularization. JACC Cardiovasc Interv. 2011;4(3):287-297.
11. Sachdeva R, Uretsky BF. The effect of CTO recanalization on FFR of the donor artery. Catheter Cardiovasc Interv. 2011;77(3):367-369.
12. Stone GW, Maehara A, Lansky AJ, et al; PROSPECT Investigators. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364(3):226-235.

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From the Division of Cardiology, University Hospital and New Jersey Medical School (UMDNJ), Newark, New Jersey.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted January 18, 2012, provisional acceptance given February 20, 2012, final version accepted February 28, 2012.
Address for correspondence: Edo Kaluski, MD, Professor of Medicine UMDNJ, 185 South Orange Ave, MSB, Room I-538, Newark, NJ 07103. Email: ekaluski@gmail.com