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Review
Role and relevance of risk stratification models in the modern-day management of non-ST elevation acute coronary syndromes
  1. R Navin Balasubramanian1,
  2. Greg B Mills1,
  3. Chris Wilkinson2,3,
  4. Roxana Mehran4,
  5. Vijay Kunadian1,3
  1. 1 Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK
  2. 2 Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
  3. 3 Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
  4. 4 The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  1. Correspondence to Professor Vijay Kunadian, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne NE2 4HH, UK; vijay.kunadian{at}newcastle.ac.uk

Abstract

We summarise the international guidelines surrounding risk stratification as well as discuss new emerging data for future development of a new risk model in the management of patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS). NSTE-ACS accounts for the bulk of acute coronary syndrome presentations in the UK, but management strategies in this group of patients have remained a subject of debate for decades. Patients with NSTE-ACS represent a heterogeneous population with a wide variation in short-term and long-term clinical outcomes, which makes a uniform, standardised treatment approach ineffective and inappropriate. Studies in the modern era have provided some guidance in treating this subset of patients: the provision of early, more potent therapies has been shown to improve outcomes in patients at a particularly elevated risk of adverse outcomes. International guidelines recommend adopting an individualised treatment approach through the use of validated risk prediction models to identify such patients at high risk of adverse outcomes. The present available evidence, however, is based on dated demographics, different diagnostic thresholds and outdated therapies. In particular, the evidence has limited applicability to female patients and older people with frailty. Moreover, the current risk models do not capture key prognostic variables, leading to an inaccurate estimation of patients’ baseline risk and subsequent mistreatment. Therefore, the current risk models are no longer fit for purpose and there is a need for risk prediction scores that account for different population demographics, higher sensitivity troponin assays and contemporary treatment options.

  • Cardiac Catheterization
  • Acute Coronary Syndrome
  • Atherosclerosis
  • Coronary Stenosis

https://doi.org/10.1136/heartjnl-2022-321470

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    Introduction

    Non-ST segment elevation acute coronary syndrome (NSTE-ACS) is a leading cause of hospitalisation and death worldwide. Patients with NSTE-ACS differ in their individual risks of death and recurrent cardiac events in both the short and longer term, and early and accurate risk stratification of patients plays a central role in treatment. This is because the benefit of more potent and potentially higher risk treatment strategies, such as early invasive coronary angiography and percutaneous coronary intervention (PCI), appears proportional to the baseline risk. However, in recent times, the inverse has been observed: higher risk patients are being treated more modestly.1 In fact, a 2020 report by the Myocardial Ischaemia National Audit Project in the UK revealed that 43.3% of patients who were deemed moderate to high risk did not receive coronary angiography within 72 hours of admission, as recommended by the National Institute for Health and Care Excellence (NICE) guidelines. Although the reasons for this are unclear, it can be partly attributed to a phenomenon known as the risk-treatment paradox.2 This is thought to occur due to subjective risk assessment by physicians, driven by under-recognition of prognostic variables as well as false perceptions of the potential treatment benefits that higher risk cohorts may have.

    To overcome subjectivity and aid clinicians in identifying high-risk patients to guide treatment decisions, several clinical prediction models were designed, with the most used model being the Global Registry of Acute Coronary Events (GRACE). This review discusses the evidence behind risk stratification and risk scores in patients with NSTE-ACS and summarise their role in practice as recommended by international guidelines. We will also consider the GRACE risk score in light of contemporary evidence and whether there is a need for a more individualised risk stratification for patients with NSTE-ACS.

    Overview of risk scores

    Multiple prognostic models may be used to predict the probability of adverse events in patients with NSTE-ACS, and the two most commonly used are the GRACE and Thrombolysis in Myocardial Infarction (TIMI) scores (figure 1). GRACE was a large prospective observational study that investigated the demographics, clinical characteristics, treatments and outcomes of 11 389 patients with acute coronary syndrome (ACS) across 14 countries.3 The GRACE risk score used multivariable stepwise logistic regression to identify predictors of mortality, which informed a nomogram based on eight variables (figure 1) to derive a score that estimates the risk of in-hospital mortality for the entire spectrum of ACS.4 The model showed excellent discriminatory performance during internal and external validation (c=0.83 and c=0.85, respectively).4 GRACE 2.0 was designed to provide absolute percentage risks instead of calculating a numerical score.5 It also allowed users to substitute Killip class and serum creatinine (which were often not available) with diuretic use and renal failure, respectively. The new model effectively predicted mortality at 1 and 3 years (c=0.83 and c=0.79, respectively)5 and showed good discriminatory capacity in external validation at 1 and 3 years (c=0.83 and c=0.82).5

    Figure 1
    Figure 1

    Comparison of variables used in GRACE and TIMI risk scores. BP, blood pressure; CAD. coronary artery disease; GRACE, Global Registry of Acute Coronary Events; ICA, invasive coronary angiography; MI, myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.

    The TIMI risk score for NSTE-ACS, which has also been extensively validated, was designed to predict a composite of all-cause mortality, new or recurrent myocardial infarction (MI), and severe recurrent ischaemia requiring urgent revascularisation within 14 days of the index event.6 In brief, the TIMI risk score was designed from a retrospective analysis of patients who qualified for enrolment in two phase III trials of treatment for NSTE-ACS: the TIMI-11B trial6 and the ESSENCE trial7 (Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave Coronary Events). The TIMI-11B trial excluded patients who had planned revascularisation within 24 hours. Furthermore, renal dysfunction was an exclusion criterion in the ESSENCE trial8 and naturally this was not captured as a variable in the TIMI risk score.

    The GRACE score tends to have superior discriminative performance compared with TIMI in predicting in-hospital (c=0.81 and c=0.68, respectively) and 1-year (c=0.79 and c=0.69, respectively) mortality.9 10 Aragam et al 11 reported similar results in predicting in-hospital (c=0.85 vs c=0.54) and 6-month (c=0.79 vs c=0.56) mortality. This can be attributed to differences between the two risk scores. GRACE captures a higher number of established prognostic variables and each variable is weighted differently, according to their strength of association with mortality.12

    Role of risk stratification in the modern era

    The management of patients with NSTE-ACS requires a methodical approach, including accurate risk stratification to quantify and evaluate the risk–benefit profile of an individual patient. In NSTE-ACS, risk stratification is particularly useful in guiding the use and timing of invasive therapies. Adopting a routine invasive rather than a conservative or selective invasive approach has been shown to improve outcomes in patients with NSTE-ACS in high-risk subgroups. The FRISC II trial (Fragmin and Fast Revascularization during Instability in Coronary Artery Disease) was among the first trials to demonstrate this effect,13 which was captured in the FRISC score. The score consisted of seven prognostic variables (age ≥70 years, male sex, diabetes, previous MI, ST segment depression, increased serum troponin and interleukin 6 or C reactive protein), with 1 point allotted for each.14 Patients in the high-risk (score of 5–7) and medium-risk (score of 3–4) groups had a decreased risk of death or MI at 1 year when an invasive approach was used compared with a conservative approach, a finding that was not observed in low-risk groups.14

    Using the TIMI risk score, the TACTICS-TIMI-18 trial (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy - Thrombolysis in Myocardial Infarction) found a similar benefit in high-risk patients.6 15 Patients at high risk (score of 5–7) and intermediate risk (score of 3–4) had reduced rates of the primary endpoint (death, non-fatal MI or rehospitalisation for ACS) when treated with an invasive approach compared with a conservative approach. A meta-analysis of seven trials (n=1912) showed that a routine invasive approach was associated with higher short-term mortality than a selectively invasive approach (OR 1.60, 95% CI 1.14 to 2.25).16 This was deemed to be an acceptable risk only in high-risk patients, in whom an invasive approach was associated with a significant reduction in composite of death or MI in the long term (OR 0.82, 95% CI 0.72 to 0.93).16

    Although it is established that a routine invasive strategy is associated with improved outcomes in a high-risk population, the optimum timing for intervention is less clear. Early intervention narrows the window for new ischaemic events, but intervening on an unstable plaque could increase the risk of periprocedural complications and shorten the period of preprocedure plaque stabilisation with antithrombotic therapy.17

    Of six recent trials (table 1), only one study (n=2147, 34% female, mean age 64 years) showed that an immediate invasive strategy was associated with a lower risk of death or MI across the cohort.18 This benefit was observed predominantly due to reduced rates of new MI in the precatheterisation period.18 In two trials, TIMACS (Timing of Intervention in Acute Coronary Syndromes; n=3031, 35% female, mean age 65 years) and VERDICT (Very Early vs Deferred Invasive Evaluation using Computerized Tomography; n=2147, 34% female, mean age 64 years), the benefit associated with an early strategy was limited to the high-risk population (GRACE risk score >140).19 20 The authors of VERDICT speculated that a high GRACE score was associated with high-risk angiographic features (such as left main disease, >70% stenosis of the proximal left anterior descending artery and/or two-vessel to three-vessel disease involving the left anterior descending artery). The findings of TIMACS and VERDICT form the basis of international guideline recommendations to offer early invasive therapy to high-risk patients.

    View this table:
    Table 1

    Main findings of recent RCTs comparing early invasive versus delayed invasive approaches in patients with NSTE-ACS

    Importantly, the patient demographics of the trial participants differ from our contemporary patient population. For example, in four of the studies, the mean age was 65 years or younger, yet in current UK practice the median age at presentation with NSTE-ACS is 71 years overall (75 years among women).21 Furthermore, men accounted for over two-thirds of the trial population (table 1), yet there is evidence of differences between men and women in the magnitude of benefits associated with early invasive therapy.22 The advent of high-sensitivity cardiac troponin assays means that smaller troponin rises are now being detected, which has an impact on the risk–benefit decisions regarding invasive therapy. Furthermore, an elevated troponin result has decreasing specificity for type 1 NSTE-ACS with increasing age.23

    The inclusion criteria were inconsistent between trials: two trials included patients presenting with non-ST elevation myocardial infarction (NSTEMI), whereas the other four trials also included those with unstable angina. They also tended to be underpowered to detect differences in hard clinical endpoints between groups due to challenges with recruitment. Two studies used biochemical markers as primary endpoints which do not necessarily correlate with clinical events. In both studies that revealed a benefit of the early strategy in high-risk subgroups,19 20 there was no significant difference between groups in the primary outcome analysis, which should be considered in the interpretation of subsequent subgroup analyses.

    Katritsis et al 24 (n=4013) found that the benefit of early invasive therapy was limited to fewer episodes of refractory ischaemia (relative risk (RR) 0.57, 95% CI 0.44 to 0.74) and a shorter hospital stay (reduction by 28%, 95% CI 22% to 35%). Milasinovic et al 25 (n=6089) reported a similar finding of reduced refractory ischaemia. The authors also highlighted discrepancies in the definition of new/periprocedural MI among studies and its possible impact on the results: studies used a definition solely using biomarkers and these tended to report higher rates of new MI compared with studies where the definition included ECG changes and clinical signs of ischaemia along with biomarker values.25 The authors of the study that defined MI using creatine kinase-MB levels only speculated that this could be explained by revascularisation causing a brief increase in biomarkers, potentially diminishing the observed benefit of early invasive therapy.26

    A meta-analysis of eight randomised controlled trials (RCTs) including ABOARD (Angioplasty to blunt the rise of troponin in Acute coronary syndromes Randomized for an Immediate or Delayed Intervention)27 and ELISA-3 (Early or Late Intervention in high-risk non-ST elevation Acute Coronary Syndromes),28 which involved a total of 5324 patients,29 showed no statistically significant difference in all-cause mortality or non-fatal MIs between early and delayed strategies. In a subgroup analysis, patients with a GRACE score of >140 had lower mortality rates when an early invasive strategy was used (HR 0.70, 95% CI 0.52 to 0.95). A more recent meta-analysis evaluated 17 RCTs involving a total of 10 209 patients.30 The authors demonstrated that, although early invasive strategy did not confer benefits in mortality or MI, it did lead to a reduction in length of stay (median reduction of 22 hours, 95% CI 8 to 37 hours, p=0.003) as well as recurrent ischaemia (RR 0.57, 95% CI 0.40 to 0.81).

    Given the limitations of the trials that were discussed earlier, there is uncertainty around the magnitude of any association between early invasive therapy and mortality reduction in the high-risk population and whether the benefits are generalisable to a contemporary population. There is a need for pragmatic large-scale trials that mirror the contemporary population, are adequately powered for hard clinical endpoints and use the fourth universal definition of MI.

    Prospective evaluation of the GRACE risk score

    Two prospective RCTs studied the impact of the use of GRACE risk score on the management and clinical outcomes of patients with NSTE-ACS: AGRIS (Australian GRACE Risk Score Intervention Study)31 and UKGRIS (UK GRACE Risk Score Intervention Study).32 Both studies showed no benefit from the use of GRACE risk score on adherence to the guideline recommendations for management of NSTE-ACS or on major adverse cardiovascular events at 12 months when compared with standard care. Table 2 summarises the strengths and limitations of using prognostic risk scores in guiding treatment decisions in NSTE-ACS.

    View this table:
    Table 2

    Strengths and limitations of prognostic risk scores

    Clinical practice guidelines

    NICE recommends assessing a patient’s prognosis using established risk scoring systems that predict 6-month mortality and explicitly mentions GRACE as an example.33 In addition, NICE recommends consideration of factors including clinical features, levels of cardiac enzymes and ECG changes to estimate mortality.33 NICE recommends a conservative approach for low-risk patients (predicted 6-month mortality of ≤3%) and coronary angiography (with follow-on PCI if needed) within 72 hours of admission for intermediate-risk to high-risk patients (predicted 6-month mortality of >3%). These guidelines do not apply to clinically unstable patients, who should be offered immediate coronary angiography. They note that younger patients who are classed as low risk may still be at high risk of adverse cardiovascular events and may benefit from early angiography.33

    The European Society of Cardiology (ESC) recommends using established risk scores as part of prognostic stratification, explicitly mentioning the GRACE risk score.34 This recommendation, currently listed under class IIa based on level B evidence, was previously listed under class I in the 2015 edition of the ESC guidelines.35 The downgrade implies the need for further research on the use of risk scores in guiding management decisions, beyond simply estimating prognosis. Under recommendations for coronary revascularisation, a GRACE risk score of >140 is listed as one of the criteria for being considered high risk and therefore qualifies for invasive coronary angiography within 24 hours.34 As discussed previously, the two trials that this recommendation is based on have a considerably different demographic profile than the contemporary population. This could potentially necessitate the revisiting of the class of this particular recommendation.

    The American College of Cardiology/American Heart Association (ACC/AHA) recommend the use of TIMI or GRACE risk scores as one of the criteria to identify high-risk patients for early invasive therapy (class I recommendation).36 High-risk patients (GRACE risk score >140) are recommended for early invasive treatment within 24 hours, whereas low-risk patients (GRACE risk score <109, TIMI 0–1) are recommended for conservative management.36 Patients classed as intermediate to low risk (GRACE risk score 109–140) qualify for invasive therapy within 25–72 hours (figure 2). However, the guidelines refer to different versions of the GRACE score in their recommendations. The NICE guidance recommendation is based on 6-month predicted mortality, whereas the ESC and AHA/ACC use an in-hospital prediction. One needs to be careful when applying these recommendations to clinical practice as the weighting of the variables differs between the risk scores.5

    Figure 2
    Figure 2

    Use of risk scores in clinical practice guidelines in management decisions. ACC/AHA, American College of Cardiology/American Heart Association; ESC, European Society of Cardiology; GRACE, Global Registry of Acute Coronary Events; MACE, major adverse cardiovascular events; NICE, National Institute for Health and Care Excellence; NSTEACS, non-ST segment elevation acute coronary syndrome; TIMI, Thrombolysis in Myocardial Infarction.

    The need for contemporary risk scores

    It is imperative that the risk scores used in clinical practice are robust and accurate in distinguishing patients who are at high risk from those who are not reflecting contemporary practice. In this section, we will discuss the shortcomings of traditional risk scores that may lead to misclassification of the risk level of patients. Therefore, there is a need for contemporary risk scores that reflect current practice, with inclusion of patient cohorts who have previously been excluded from clinical research.

    Sex specificity

    In the last 40 years, age-adjusted cardiovascular disease mortality has declined in the West.37 38 However, the mortality rate has decreased to a lesser extent in women than in men. This can in part be attributed to differences in baseline demographics and comorbidity profile, and in coronary anatomy including smaller height-adjusted coronary artery size and lower elasticity than men. Women also have an increased tendency to develop endothelial and smooth muscle dysfunction than men. A previous study showed that women are doubly at risk of cardiovascular disease following a pregnancy complicated by pre-eclampsia.39 40 These added risks are not captured by the GRACE risk score, which does not take sex into account. Furthermore, women are under-represented in studies of treatment strategies. Including sex and sex-specific risk factors into a future iteration of the GRACE score would provide a more accurate representation of the risk level of women and guide management strategies.

    Reducing emphasis on age

    The GRACE score is heavily age-weighted. Older patients with NSTE-ACS are more likely to be classed as intermediate-risk or high-risk patients and therefore invasive therapy is recommended according to the NICE guidelines.33 However, this is not well supported by the current evidence base for older people.41 RCTs42–46 investigating invasive and conservative approaches in older patients with NSTE-ACS have not shown definitive answers on the optimal treatment strategies (table 3), although in the context of recruitment problems and small sample sizes. The BHF SENIOR-RITA trial (British Heart Foundation older patients with non-ST Segment Elevation myocardial infarction Randomized Interventional Treatment) is a large, multicentre RCT (target n=1668) designed to determine whether a routine invasive approach is superior to conservative management in patients aged ≥75 years, which will hopefully shed light on the efficacy of treatment strategies in this group.

    View this table:
    Table 3

    Main findings of RCTs comparing invasive versus conservative approaches in older patients with NSTE-ACS

    The prognostic utility of frailty

    Frailty is a condition characterised by a decline in function in multiple physiological mechanisms that is associated with an increased risk of adverse outcomes. In a recent meta-analysis of 15 studies, frailty in patients with NSTEMI (n=5835) was associated with a 2.6 times increased risk of mortality (adjusted HR 2.63, 95% CI 1.51 to 4.60).47 However, there is no specific recommendation on the formal evaluation of frailty across the guidelines.33 34 48 A point-based scoring system, FRAIL-HEART (table 4), was developed as part of the ICON-1 study (Improve Cardiovascular Outcomes in high-risk older patients).49 This includes the Fried frailty criteria, hypertension, extracoronary arterial disease, age, raised Killip class and trouble dressing self. The FRAIL-HEART score was superior to GRACE score in predicting 1-year primary composite endpoint of MI, stroke, significant bleeding, urgent repeat revascularisation and all-cause mortality.50 This score will be externally validated in the BHF SENIOR-RITA trial, and if it proves to be accurate it can be used to discriminate higher risk patients within the older age group instead of using GRACE.

    View this table:
    Table 4

    The FRAIL-HEART score

    Conclusion

    Patients with NSTE-ACS are a heterogeneous population who are at risk of adverse outcomes that in a selected population may be reduced with the provision of invasive interventions. The optimal management strategy requires an individualised approach, which in turn requires a scoring system to accurately estimate the risk profile and likely prognosis of an individual to inform shared decision-making and provision of evidence-based treatments. Such a scoring system should achieve good balance between complexity and utility. Yet current risk models are no longer fit for purpose and there is a need for risk prediction scores that account for different population demographics, higher sensitivity troponin assays and contemporary treatment options.

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    Footnotes

    • Twitter @rbnavn, @wilkinsoncg, @VijayKunadian

    • Contributors VK conceived the idea and undertook multiple revisions. RNB wrote multiple drafts. GBM, CW and RM performed critical review and revisions.

    • Funding VK has received research funding from the British Heart Foundation (CS/15/7/31679). CW is funded by the NIHR as an Academic Clinical Lecturer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.