Risk stratification in non-ST elevation acute coronary syndromes: searching for the right formula

This editorial refers to ‘Risk stratification of patients undergoing medical therapy after coronary angiography’, by N. Bettinger et al., on page 3103. Medicine is the science of uncertainty and the art of probability Enormous progress has been made in the diagnosis and treatment of acute coronary syndromes (ACS) over the past two decades. The emergence of timely reperfusion therapy, in concert with the relatively specific and characteristic ECG calling card of ST elevation, has remarkably improved the outcome of patients with ST elevation myocardial infarction. As Osler opined, however, there remains less certainty about the right formulation for the diagnosis and therapy of the much larger and more heterogeneous cohort of patients with non-ST elevation ACS (NSTE ACS). In part this relates to the development of high sensitivity troponin assays that have shifted the classification of many patients from the unstable angina category to those with small—but apparently prognostically relevant—myocardial infarctions.1 The emergence of other biomarkers, quantitative ECG analysis, and myocardial imaging have also added welcome granularity to the early assessment of outcomes.2,3 Given the wide spectrum of new antithrombotic and antiplatelet therapies, coupled with advances in coronary interventions, physicians must undertake timely management decisions that have potential benefit and risk as well as major resource implications. Hence current guidelines place strong emphasis on early risk stratification to aid in timely triage: those with intermediate to high risk scores are advised to undergo an invasive strategy and revascularization when appropriate.4,5 Not all such patients undergo revascularization once angiography is performed.6 Within this heterogeneous group of medically managed ACS patients are those with non-obstructive coronary artery disease (CAD), others with non-revascularizable lesions, and still others where the decision is based on physician/patient choice often in the milieu of multiple co-morbidities. In this context, in the current issue of the journal, Bettinger et al. report on the prognostic utility of the SYNTAX score (SS) in a subset of 1275 medically managed NSTE ACS patients that represent 9.2% of the overall ACUITY population.7,8 They divided their patients into four groups based on the absence of CAD (SS = 0, comprising two-thirds of the population) or its presence: the CAD patients were then grouped into tertiles (1, SS >0 and ≤5, 13.3%; 2, SS >5 and ≤11, 9.3%; and 3, SS >11, 11.3%). At 1 year, both major adverse cardiac events (MACE; mortality, myocardial infarction, and unplanned revascularization) and all-cause mortality were higher in the upper two SS tertiles when compared with patients in the lower tertile and those with no CAD. A retrospective SS cut-off point of 8 led them to conclude that the SS was ‘a strong predictor of 1 year MACE and mortality.’ Before accepting this assertion, several cautionary notes are germane. Who are the patients in this report? At 1 year they experienced 83 MACE events and 34 deaths (of which only 9 were cardiac, 16 are reported as non-cardiac: it is unclear from table 4 the cause of death in the remainder) and constitute a low risk 28% subset of a previous ACUITY report that studied the much larger medically managed population.9 This probably accounts for the very modest contribution in the current report of the SYNTAX score to the hazard ratios for MACE and mortality, as well as the low sensitivities, specificities, and areas under the receiver operating characteristic curves describing the relationship between SYNTAX score and adverse outcomes. Interestingly, the previous ACUITY report from the overall medically managed group evaluated the venerable jeopardy score, as well as coronary ectasia and number of diseased vessels, and found a more robust relationship to 1 year outcomes than the current report.9 It would be of interest to know how the current study data would unfold if these prior more conventional measures were applied. Perhaps one reason for this disparity is the variation in how the number of diseased vessels is reported: in the original ACUITY study, a somewhat unusual criterion for CAD was employed, i.e. ≥30% narrowing, whereas in the current report using SYNTAX scoring such patients are grouped as either normal or <50% narrowing. Fully one half of such patients had CAD, as evident in table 1. Large plaque burden with thin-cap fibroatheroma in angiographic non-obstructive lesions may pose a future hazard that the conventional 50% coronary narrowing does not take into account.10 Because the conventional SYNTAX score has been shown to be potentially misleading, another prior ACUITY angiographic study evaluated the use of a logistic clinical SYNTAX score acquiring an individualized 1-year mortality prediction comprising the anatomical SYNTAX score, age, creatinine clearance, and left ventricular ejection fraction, and an ‘extended’ model composed of an additional six clinical variables.11 When the Logistic Clinical Syntax Score was applied to patients undergoing percutaneous intervention, it increased the ability to identify death correctly at 1 year over a wide range of thresholds for mortality risk predictions. Although not validated in a medically managed, non-revascularized NSTE ACS population, this would have been useful to report in the current study. The authors adjust the relatively small number of MACE and mortality events for a selected set of clinical covariates. The generally accepted GRACE and GRACE2.0 scores that have been well validated for risk stratification in patients with NSTE ACS would be preferred.4,5 In the Timing of Intervention in Acute Coronary Syndromes (TIMACS) trial,12 their utilization identified the subgroup of patients who appeared to derive benefit from early invasive strategy. Together, these considerations do not provide us with confidence in the predictive value of an SS score >8. An additional musing from the current report ‘in angiographically low risk ACS patients (SS = 0), the use of aggressive optimal medical therapy (OMT) may be debatable and actually, potentially harmful (bleeding risk), difficult to tolerate (hypotension), and potentially less justified.’ deserves additional commentary. Less aggressive OMT based on a coronary luminogram—rather than the ACS patient profile—is potentially problematic, particularly in women (comprising nearly 50% of the current subset). Higher adverse events have been documented in women when compared with men, despite them having less anatomical obstructive CAD.13 Both statins and angiotensin-converting enzyme inhibitors have been suggested to possess potentially beneficial effects on endothelial dysfunction and the microcirculation in these patients with ischaemia and non-obstructive CAD.13 Hence we advise caution about this suggestion of the authors'. Finally, given that ACUITY patients were recruited ∼10 years ago, whether their clinical outcomes apply in 2015 is a moot point. At best, a minority of them received—then contemporary—OMT, thereby probably adversely affecting their outcomes.14 Major advances in current therapies in patients with NSTE ACS—whether revascularized or not—have significantly improved their morbidity and mortality.15,16 Contemporary approach to risk stratification in non-ST elevation acute coronary syndrome (NSTE ACS). CT cor. angiogram, CT coronary angiogram; FFR, fractional flow reserve; GDF-15, growth differentiation factor 15; hs-CRP, high sensitivity C-reactive protein; hs-cTnT, high sensitivity cardiac troponin T; IVUS, intravascular ultrasound; NT-proBNP, N-terminal pro brain natriuretic peptide; OCT, optical coherence tomography; ST2, interleukin-1 receptor. *Functional Syntax Score, Logistic Clinical Syntax Score. Conflict of interest: none declared.

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