Cardiac troponin status of participants

The baseline cardiac biomarker status of the patient serves as an important tool for risk stratification, though the ideal marker and definitions remain unclear and have evolved over time with advances in technology ( creatine kinase‐myocardial band (CK‐MB) versus troponin versus high‐sensitivity troponin). The TACTICS‐TIMI 18 trial had the prespecified intention of testing the 'troponin hypothesis': that is, to test whether benefit from an invasive strategy was limited to troponin‐positive participants. Data for the death or non‐fatal MI endpoint from TACTICS‐TIMI 18 and FRISC‐II suggest that only high‐risk participants with a positive troponin benefited from a routine invasive strategy with respect to this endpoint. However, the CI for this subgroup analysis showed overlap with that of troponin‐negative participants. The Italian Elderly ACS reinforced the importance of baseline troponin status on treatment effect, and identified a significant reduction in the primary endpoint (composite of death, MI, disabling stroke and repeat hospital stay for cardiovascular causes or severe bleeding within one year) amongst participants with an elevated troponin on admission (hazard ratio (HR) 0.43, 95% CI 0.23 to 0.80) but not in those with normal troponin (HR 1.67, 95% CI 0.75 to 3.70). Data from VINO, which only included participants with clinical symptoms, ECG changes and positive cardiac biomarkers, revealed a significant 72% risk ratio reduction in this endpoint at six months. However, the ICTUS trial, which also exclusively enrolled troponin‐positive participants, had an unexpectedly low baseline mortality rate relative to the other included studies (Table 1). This may be partly due to optimal medical therapy in the ICTUS trial versus other included trials wherein, in both trial arms, early use of clopidogrel and intensive lipid‐lowering therapy was recommended to treating clinicians. Alternatively, this may be a statistical outlier given the large CIs for mortality in these studies. Disparate event rates in participants with positive troponin highlights the importance of global risk stratification as opposed to using cardiac biomarkers as a single risk index. Indeed, in a retrospective analysis of the FRISC‐II data (Diderholm 2002), death or non‐fatal MI experienced a significant 40% risk ratio reduction only in participants with both troponin T (TnT) greater than 0.03 ng/mL and ST depression on admission ECG. Hence, although ICTUS participants all had a TnT of greater than 0.03 ng/mL, this sole criterion did not necessarily identify a risk level that might benefit from invasive treatment. The risk associated with troponin elevation has been shown to be a continuous variable and therefore classification as a dichotomous variable may dilute its predictive power.

Though some have argued that the prognostic value of troponin is greater than that of CK‐MB (Montalescot 2009; Saenger 2008; Thompson 1979), troponin may be overly sensitive for the detection of re‐infarction and only elevated CK‐MB has been correlated with evidence of myocardial necrosis (Lim 2011). Retrospective analysis performed by the TACTICS‐TIMI 18 trial authors highlights the limitations of purely using a positive troponin to predict event rates. Analysis of the invasive arm revealed that 6% of the participants with a positive troponin test did not have significant angiographic coronary artery disease (CAD), defined as greater than 50% stenosis of any coronary artery (Dokainish 2005). At six months, these participants had a 3.1% rate of death or re‐infarction, compared to 0% among those with a negative troponin and no angiographic CAD. As would be expected, troponin‐positive participants with angiographic CAD had a high rate of death or re‐infarction (8.6%) at six months. Interestingly, participants with angiographic CAD who had a negative troponin had a 5.8% rate of death or re‐infarction at six months, which is clearly higher than that for troponin‐positive participants without angiographic CAD. Hence, troponin alone cannot be used to risk stratify patients. Moreover, this analysis highlights the limitations of angiography in the assessment of plaque burden. In general in unstable angina studies, positive troponin status has been shown to correlate with complex coronary lesions on angiography and reduced coronary flow (Benamer 1999; Heeschen 1999a; Hochman 1999), but should not be used alone to identify those at high‐risk. However, absolute values of troponin exhibit a linear relationship with subsequent risk of coronary events. Troponin positivity has also been shown to predict benefit from glycoprotein IIb/IIIa receptor antagonists (Hamm 1999; Heeschen 1999b), an early invasive strategy in the elderly (Italian Elderly ACS), and remains a critical element of risk stratification.

ST depression on admission

As previously mentioned, ECG changes on admission forebode a worse prognosis in UA/NSTEMI patients. Indeed, data from the TIMI III Registry shows that patients with ST depression on admission ECG have a 2.5‐fold increased risk of death or MI within one year (Cannon 1997). In the ICTUS and TACTICS‐TIMI 18 trials, ST depression was an independent predictor of failure of medical therapy with the conservative strategy (Sabatine 2006; Windhausen 2007b). As discussed above, on post‐hoc analysis of FRISC‐II data, the benefit of a routine invasive strategy on the endpoint of death or non‐fatal MI only achieved statistical significance in participants with ST depression on admission ECG. In FRISC‐II and the TIMI III Registry, the prevalence rates for triple‐vessel and left main artery disease were approximately 50% and 66%, respectively, in participants who had ST depression on admission ECG. Similarly, the TACTICS‐TIMI 18 study identified an odds ratio for three‐vessel disease of 1.79 in participants with ST deviation of 0.05 to 0.09 mV, and an odds ratio of 1.91 in those with a ST deviation greater than 0.10 mV versus those with a ST deviation less than 0.05 mV. Hence, the ECG can be used as a tool to identify patients who are likely to benefit from revascularisation. Analysis of the FRISC‐II data demonstrated that ST depression was still a predictor of benefit from an invasive strategy, even after baseline differences were accounted for (Holmvang 2003). Furthermore, this analysis also suggested that the benefits of a routine invasive strategy were further amplified with increasing amplitude of ST depression in an increasing number of ECG leads.

Data from TACTICS‐TIMI 18 confirms the utility of ST segment changes in identifying a higher‐risk population that may benefit from an invasive strategy. Unfortunately, we could not obtain data for the composite endpoint of death or non‐fatal MI, but the study includes data for the endpoint of death or non‐fatal MI or rehospitalisation for ACS. Using this endpoint, the RR was 0.62 (95% CI 0.53 to 0.74) in participants with baseline ST changes, while no effect was observed in those without such changes. The ICTUS data show a trend towards decreased rates of (spontaneous) MI at one year in those randomised to a routine invasive strategy, with a risk ratio of 0.74 (95% CI 0.40 to 1.38). However, the events were few and CIs were wide. In light of the potential implications of ST‐depression on treatment effect, we have provided the percentages of trial participants with ST depression on index ECG in Table 1, with the highest rates of 62% reported in the LIPSIA‐NSTEMI study. In general the studies eligible for analysis did not provide data for subgroup analysis of ST depression and troponin status. While subgroup analyses may identify populations with increased risk, and hence provide increased power to detect statistical significance, such post‐hoc analyses should be interpreted with caution.

Gender

Disparate outcomes of a routine invasive strategy based on gender has been a source of controversy. The all‐study (Analysis 1) gender subanalysis for intermediate death or non‐fatal MI revealed a benefit of routine invasive strategy confined to males. However, the number of women in the studies was lower than the number of men, and the decreased power to detect any advantage of routine invasive strategy is highlighted by the comparatively wide CIs. TACTICS‐TIMI 18 identified no significant interaction between gender and outcomes based on treatment strategy. Conversely, the FRISC‐II and RITA‐3 trials found significant benefit of a routine invasive strategy for death or MI amongst men, but not women. Supporting this, the OASIS 5 substudy, which randomly assigned 184 women to a routine or selective invasive strategy, identified significantly more deaths after one year (HR 9.01, 95% CI 1.11 to 72.90) and higher rates of major bleeding at 30 days (HR 11.45, 95% CI 1.43 to 91.96) with a routine invasive strategy.

Confounding comparison and interpretation of these results, women had less severe CAD across the studies analysed, and were less likely to have an elevated troponin level than men (Clayton 2004; Glaser 2002; Lagerqvist 2001). Moreover, in FRISC‐II and RITA‐3, women in the conservative arm had a better prognosis than men in the conservative arm. A retrospective analysis of TACTICS‐TIMI 18 data suggests that, after adjusting for differences in baseline characteristics, the benefits of an early invasive strategy in women were the same as those seen in men (Glaser 2002). In contrast, similar analyses undertaken by FRISC‐II and RITA‐3 trial authors failed to demonstrate any benefit of an invasive strategy in women, even after they adjusted for baseline characteristics. The RITA‐3 analysis suggested that women had better outcomes than men when managed conservatively and did not benefit from an invasive strategy, even when those with high‐risk features were analysed separately (Clayton 2004). Women in TACTICS‐TIMI 18 and RITA‐3 were less likely than men to undergo CABG, even when trials adjusted for the presence of three‐vessel or left anterior descending artery disease (Clayton 2004; Glaser 2002). Notably in FRISC‐II, where the rates of CABG were similar in both men and women, the one‐year mortality rate in participants undergoing CABG was 9.9% in women versus just 1.2% in men (Lagerqvist 2001). Higher operative CABG mortality has been observed in women enrolled in observational studies and this discrepancy could not be accounted for by age, co‐morbidities or smaller body surface area (Blankstein 2005). These retrospective analyses should be interpreted with appropriate caution. They highlight the importance of further research to determine the optimal treatment strategy in women, and the importance of risk stratification, especially in women who are less likely to have angiographic CAD when compared to their male counterparts, and requisite caution extrapolating results from men to women.

Other subgroups

We have discussed other subgroups of interest that we did not prespecify in our protocol, Hoenig 2004, as a narrative review in this section.

The importance of global risk stratification

As the above discussion highlights, and as subgroup analyses have illustrated, risk stratification is an integral component of managing patients with UA/NSTEMI. The goal of risk stratification is to identify patients with a high likelihood of complicated CAD who are at increased risk of recurrent coronary events or premature death, and to offer such patients the benefits of revascularisation. However, the clinical distinction between UA and NSTEMI does not adequately stratify high‐risk patients (Zaacks 1999). Consequently, the current 2012 ACCF/AHA focused update, Jneid 2012, and the 2011 ESC guidelines, Hamm 2011, recommend using several parameters for risk stratification; as occurs with the application of risk scoring tools, for example the TIMI risk score (Antman 2000). To underscore this point, in a post‐hoc analysis of the FRISC‐II data, participants with troponin T of greater than 0.03 ng/mL and ST depression experienced a statistically‐significant benefit with a routine invasive strategy, whereas participants with only one of these variables did not (Diderholm 2002). Only TACTICS‐TIMI 18 undertook subgroup analyses based on TIMI risk scores, and stratified the participants into three categories based on their TIMI risk score: low‐, intermediate‐ or high‐risk. In this study, only intermediate‐ and high‐risk participants benefited from the invasive strategy, regarding the primary composite endpoint of death or non‐fatal MI or rehospitalisation for ACS. Unfortunately, data for the composite endpoint of death or non‐fatal MI were unavailable and therefore we could not incorporate them into this Cochrane review.

The TIMI score was extracted from the unfractionated heparin arm of the TIMI 11B trial (TIMI 11B 1999). It was validated in the enoxaparin arm of TIMI 11B and in both arms of the ESSENCE 1997 trial. The risk score was shown to be a valid predictor of the composite endpoint encompassing all‐cause mortality, MI and urgent revascularisation within 14 days of randomisation. Importantly, the TIMI score also predicted each of the components of this composite endpoint (Antman 2000). The TIMI risk score was subsequently validated in the TIMI III Registryof unselected UA/NSTEMI patients and was shown to predict the endpoint of death, MI or recurrent ischaemia and the components of the composite outcome at both six weeks and one year (Scirica 2002). Further, the TIMI risk score was validated for the death, MI or recurrent ischaemia composite endpoint for up to six months in the PRISM‐PLUS Trial; and it was shown to predict benefit from tirofiban, even in participants with a negative CK‐MB (Morrow 2002). Hence, this versatile risk score is able to identify patients with high event rates who may also benefit from an invasive strategy. Intuitively, one would expect that patients with higher TIMI scores, and therefore a higher risk for mortality and recurrent events, have more extensive CAD on angiography. This has been confirmed in a retrospective analysis of patients with UA/NSTEMI (Garcia 2004). The PRISM‐PLUS Trial authors also confirmed these findings by a retrospective analysis, and found the TIMI score to correlate with impaired epicardial artery blood flow and the presence of visible thrombus on angiography (Mega 2005). Although there are other published risk scores for UA/NSTEMI (de Araújo Gonçalves 2005), the TIMI risk score is perhaps the most widely used. In addition, the low event rates in ICTUS, which exclusively enrolled troponin‐positive participants, highlight the importance of considering multiple variables in risk stratification. Indeed, on five‐year follow‐up by the RITA‐3 trial authors, nine factors other than treatment group emerged as multi‐variate predictors of death or non‐fatal MI (Fox 2005). When the logistic coefficients for the risk factors were added and the study population divided into quartiles based upon risk score, participants in the highest quartile of risk score experienced substantially greater benefit from an invasive strategy. Similarly, the FRISC‐II trial authors developed a FRISC score, ranging from zero to seven, with one point alloted for each of seven factors: age of over 70 years, male sex, diabetes, previous MI, ST depression, increased troponin, and increased interleukin‐6 or C‐reactive protein (Lagerqvist 2005). Having a medium to high‐risk (score of three to seven) predicted benefit from an early invasive strategy, with risk ratios of 0.64 (95% CI 0.51 to 0.80) at two years and 0.75 (95% CI 0.64 to 0.89) at five years for the composite endpoint of death or non‐fatal MI (FRISC‐II). Low‐risk patients (score zero to two) did not benefit and had a trend towards harm for the composite endpoint of death or non‐fatal MI, with a RR of 1.62 (95% CI 0.71 to 3.69) at two years and 1.26 (95% CI 0.66 to 2.40) at five years (FRISC‐II). In contrast, the ICTUS trial authors confirmed the prognostic utility of the FRISC score, but were unable to predict benefit from an early invasive strategy in this trial; even participants with the highest FRISC scores (five to seven) derived no benefit from an early invasive approach (RR 1.30, 95% CI 0.69 to 2.47), in terms of the late death or MI endpoint.

Current 'real world' event rates in patients with UA/NSTEMI compared to rates observed in the included trials

The largest multinational registry, the GRACE registry, which collects data from 30 countries, has reported mortality rates in patients hospitalised with various forms of acute coronary syndrome (ACS). Entry criteria for this registry include a history of chest pain and one of the following: ischaemic ECG changes, increased cardiac biomarkers or a documented history of CAD. The in‐hospital mortality rates for patients recruited between 1999 and 2002 were 5.9% for patients with NSTEMI and 2.7% for patients with unstable angina. Also, the six‐month post‐discharge mortality rates were 6.2% and 3.6% for NSTEMI and unstable angina, respectively (Goldberg 2004). Furthermore, rehospitalisation rates six months post‐discharge were roughly 20%. Another report from the GRACE registry, which included patients recruited between 1999 and 2003, reported the six‐month post‐discharge mortality rates as 11.6% for NSTEMI and 6.8% for unstable angina (Van de Werf 2005). Clearly, the mortality rates from this real‐world registry are higher than those observed in the studies included in our meta‐analysis, as shown in Table 1. However, these patients did not receive optimal medical management in that only approximately 50% of NSTEMI patients received ACE inhibitors, heparin or statins (Goldberg 2004). While over 90% of patients received aspirin and over 80% received beta blockers, it is unlikely that many would have received clopidogrel as the patients studied were entered into the registry prior to publication of the CURE trial (CURE 2001); that is, before use of clopidogrel for UA/NSTEMI became accepted as standard therapy. Similarly, participants enrolled in the UA/NSTEMI trials received higher rates of medical therapy than participants enrolled in the CRUSADE registry (Kandzari 2005). However, the discrepancy in mortality rates between the participants in the included studies of this Cochrane review and registry‐reported mortality rates is arguably too high to be explained by advances in the medical management of UA/NSTEMI alone. Another explanation may be that selection and recruitment protocols may bias trials towards enrolling participants with a risk lower than that seen in unselected participants entered into registries. While analysis of available data suggests that high‐risk patients may benefit from an invasive strategy, this absolute benefit is likely to narrow as early medical therapies and risk stratification procedures for UA/NSTEMI improve, combined with the appropriate use of deferred coronary angiography and revascularisation. Novel medical therapies, such as prasugrel (TRITON‐TIMI 38) and ticagrelor (PLATO) instead of clopidogrel, continue to decrease absolute event rates in patients with UA/NSTEMI. Consequently, future trials of invasive versus conservative management for UA/NSETMI will be required as novel medical therapies are adopted. It is likely that only progressively higher‐risk patients will continue to benefit from routine invasive intervention in the future. A report from the GRACE registry has shown that increasing use of evidence‐based therapies has translated into reduced event rates over time (Fox 2007b). However, the lack of benefit observed for several endpoints in this review may be due to lower‐risk patients having been selected for trial enrolment.

The general paucity of enrolment of participants with cardiogenic shock or an advanced Killip class in the included studies may mean that the results of this systematic review are not applicable to this high‐risk subset. Advanced Killip class has been identified as an independent predictor of mortality in patients with NSTEMI (Khot 2003), while Killip class and congestive heart failure (development of or history of) were shown to predict death and the composite of death or MI in the GRACE registry (Fox 2006). Indeed, the current ACCF/AHA guidelines for UA/NSTEMI recommend using signs of heart failure as markers of increased risk (Jneid 2012). However, most of the included studies did not report Killip class, EF or brain natriuretic peptides among their baseline characteristics; and the event rates in the included studies indicate that participants with cardiogenic shock were excluded. Two exceptions to this are the FRISC‐II trial, in which 13% of participants were reported to have an EF of less than 45% at baseline, and the VINO trial, in which 53% of the sample were reported to be Killip class of II or III at baseline. This high percentage of participants with pulmonary oedema in VINO may explain why this trial had the highest standardised mortality rates of the included studies (Table 1); and, while being a small trial, identified a robust benefit for routine invasive strategy. Observational data have revealed that Killip class II and III patients enjoyed a significant mortality benefit (at 30 days and six months) from an invasive strategy, while Killip class I patients did not benefit (Rott 2001). The SHOCK 1999 trial (302 participants), which recruited STEMI patients with cardiogenic shock, uncovered a significant mortality benefit for a routine invasive versus conservative strategy at six months, with mortality rates of 50.3% and 63.1% (P = 0.027), respectively (SHOCK 1999). These are consistent with observations from the GRACE registry (Dauerman 2002). Similarly, elevated N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) has been shown to predict a poor prognosis in patients with UA/NSTEMI, independently of age, Killip class or left ventricular EF (Jernberg 2004). In a retrospective subgroup analyses from FRISC‐II (2017 participants), NT‐proBNP measured at median of 39 hours after symptom presentation correlated (correlation coefficient, r) with TnT (r = 0.53, P < 0.001), interleukin‐6 (r = 0.29, P < 0.001) and the severity of coronary disease on angiography (Jernberg 2003). A relationship between higher brain natriuretic peptide (BNP) and more severe angiographic coronary disease was also evident in a small retrospective analysis from the TACTICS‐TIMI 18 trial, which also demonstrated higher BNP to be associated with higher TIMI frame counts, consistent with reduced myocardial perfusion (Sadanandan 2004). In FRISC‐II, NT‐proBNP predicted two‐year mortality independently of TnT, interleukin‐6 and left ventricular EF, but failed to predict the incidence of MI. Importantly, this retrospective subgroup analysis from the FRISC‐II trial authors suggested that the early invasive strategy only improved two‐year mortality in participants within the highest tertile for NT‐proBNP (greater than 906 ng/L for men, greater than 1345 ng/L for women) and with an interleukin‐6 concentration greater than 5 ng/mL (absolute risk reduction of 7.3%; RR 0.46, 95% CI 0.21 to 1.00). Such retrospective analyses are hypothesis‐generating and by no means definitive. A similar analysis from TACTICS‐TIMI 18 (1676 participants) measured BNP instead of NT‐proBNP, and dichotomised participants at a BNP of greater than 80 ng/L. The analysis found that participants with an elevated BNP exhibited greater seven‐day and six‐month mortality (2.5% versus 0.7%, P < 0.01; and 8.4% versus 1.8%, P < 0.01 respectively). However, BNP was not shown to predict any benefit from invasive management (Morrow 2003). This may be due to the relatively short follow‐up performed in the TACTICS‐TIMI 18 study, which was only six months (Table 1). The ICTUS trial authors also examined the prognostic influence of NT‐proBNP measured a median of 13 hours after presentation in a 1141‐participant subgroup extracted from the main trial (Windhausen 2007a). In the highest quartile (greater than 1170 ng/L for men, greater than 2150 ng/L for women), one‐year mortality was 7.3%, compared to just 1.1% among participants in the lower three quartiles. However, as with the retrospective analyses from the FRISC‐II and TACTICS‐TIMI 18 trials, NT‐proBNP failed to predict MI and, in contrast to FRISC‐II, elevated NT‐proBNP did not predict any benefit from an early invasive strategy in the ICTUS cohort (Windhausen 2007a). Hence, the role of natriuretic peptides and the assessment of patients for clinical features of congestive heart failure in UA/NSTEMI need to be further elucidated. In the interim, patients with features of congestive heart failure need to be considered at high‐risk for death and managed aggressively.

The GRACE investigators identified predictors of a poor prognosis that were derived from and validated in cohorts enrolled in GRACE from 1999 to 2002 and 2002 to 2003, respectively (Eagle 2004). The investigators identified nine variables — older age, history of MI, history of heart failure, increased heart rate, lower systolic blood pressure, elevated serum creatinine, elevated cardiac biomarkers, ST depression and not undergoing PCI — as independent predictors of increased six‐month mortality across the ACS spectrum. Of particular note is that the GRACE risk score incorporates renal function, which is an important, practical risk prognosticator in UA/NSTEMI that was not considered when the TIMI risk score was derived (Antman 2000). In a retrospective subgroup analysis of the FRISC‐II trial, creatinine clearance was estimated from serum creatinine using the Cockcroft‐Gault formula (Johnston 2006). In conservatively‐managed patients, the rates of death or MI for creatinine clearances of less than 69 mL/min, 69 to 90 mL/min and greater than 90 mL/min were 22.4%, 14.6% and 11.6%, respectively. The corresponding event rates in the invasive group were 14.6% (P < 0.01 versus conservative treatment), 9.9% (P = 0.048) and 11.2% (P = not significant), respectively. Indeed, there was a significant interaction between treatment strategy and outcomes in patients with a creatinine clearance of less than 90 mL/min. These data are indeed sobering, since patients with renal dysfunction are often denied aggressive therapy in the real world, possibly because of clinician concerns about bleeding risk and a poor prognosis regardless of therapy. These data are particularly relevant to clinicians practicing in countries where an estimate of glomerular filtration rate is mandatory on adult electrolyte panels, as is standard in the USA and Australia. Hence, risk stratification is an integral part of the management of patients with UA/NSTEMI and needs to be considered carefully in future prospective RCTs on the topic. Moreover, the roles of estimated glomerular filtration rate and NT‐proBNP as risk prognosticators over and above established markers such as the TIMI risk score need to be further evaluated.

Current 'real world' management of patients with UA/NSTEMI, emphasising the relationship between patient risk and subsequent management

Despite the extensive literature that exists on risk stratification, real‐world data from the GRACE registry has shown that high‐risk patients are no more likely to receive enoxaparin or glycoprotein IIb/IIIa receptor antagonists or to undergo catheterisation and PCI than low‐risk patients (Oliveira 2007). In a different analysis from the GRACE registry that only included participants recruited with direct access to a catheterisation laboratory, there was an inverse relationship between the level of patient risk (measured as a GRACE risk score) and the frequency of angiography and PCI (Fox 2007a; Ranasinghe 2011). Indeed, the rates of cardiac catheterisation in low‐, medium‐ and high‐risk patients with UA/NSTEMI were 72%, 68% and 51%, respectively, while the rates of PCI were 40%, 35% and 25%, respectively (Fox 2007a). In addition, thienopyridines and glycoprotein IIb/IIIa receptor antagonists were more commonly used in low‐risk patients than medium‐ or high‐risk patients with similar findings in a Canadian registry (Yan 2007). Likewise, diabetics with UA/NSTEMI, despite their higher risk, are not treated more aggressively than non‐diabetics (Franklin 2004). The reasons for the discrepancy between patient risk and treatment have been unclear, but recent data from a Canadian registry suggest that the most common reason for under‐utilization of an invasive strategy in high‐risk patients is the treating physician's underestimation of patient risk (Lee 2008). In this regard, a focused initiative to educate physicians on risk stratification could enhance quality of care in patients with UA/NSTEMI. It is also important to recognise that access and distance to cardiac catheterisation services are established predictors of treatment strategy.

Quality of life endpoints

Although not an initial outcome of this systematic review, this section provides a narrative discussion of health‐related quality of life (HRQOL) outcomes. Four studies (Eisenberg 2005; RITA‐3; FRISC‐II; TACTICS‐TIMI 18) specifically compared HRQOL and functional status following invasive versus non‐invasive management for NSTEMI. One trial (Eisenberg 2005) selected change in QOL as a primary endpoint, and the other three (RITA‐3; FRISC‐II; TACTICS‐TIMI 18) had HRQOL measures as secondary endpoints. In the primary endpoint trial, which included only 88 participants (Eisenberg 2005), there was no difference between the two groups at 12 months in terms of the level of peak exercise reached on an endurance exercise treadmill (7.8 versus 6.7 metabolic equivalents). Functional status was improved in the invasive group (Duke Activity Status Index scores 4.3 versus −3.5, P = 0.04), as was angina‐specific quality of life, assessed using the Seattle Angina Questionnaire measure of anginal stability (21.6 versus −5.3, P = 0.020), anginal frequency (22.9 versus 2.3, P = 0.02) and treatment satisfaction (11.2 versus −10.3, P = 0.02).

In the RITA‐3 trial, Kim 2005 assessed HRQOL was assessed with the Short Form‐36 (SF‐36), Seattle Angina Questionnaire (SAQ), EuroQOL Visual Analogue Scale (EQ‐VAS) and EuroQOL 5‐Dimensional Classification (EQ‐5D) scale at baseline, four months and one year follow‐up. Mean changes from baseline EQ‐VAS scores were better for the invasive versus non‐invasive strategy at four months (treatment difference of 3.0, P < 0.001) and one year (2.3, P < 0.01). The EQ‐5D utility scores were also higher in the invasive group at four months (treatment difference 0.036, P < 0.01) but not at one year (0.016, P = 0.20). For the SF‐36, the invasive strategy group scored significantly better at four months for physical function, physical role function, emotional role function, social function, vitality and general health. The SAQ scores for exertional capacity, anginal stability and frequency, treatment satisfaction and disease perception were significantly better for the invasive strategy group at both four months and one year, though attenuated at the last follow‐up. The study authors concluded that improvements in HRQOL associated with the invasive strategy were most likely due to improved in anginal symptoms.

In theFRISC‐II trial, Janzon 2004 measured HRQOL was measured using the generic Medical Outcomes Study SF‐36 and the disease‐specific Angina Pectoris Quality of Life Questionnaire (APQLQ) at baseline and three, six and 12 months follow‐up. The invasively‐treated group reported a significantly better quality of life in all eight scales and both component scores (physical and mental) of the SF‐36 at three and six months of follow‐up (P < 0.01) relative to the non‐invasively treated group. These differences remained at 12 months follow‐up, with significance in seven of the scales and in the physical component score. The invasive group scored significantly higher on all five subscales of the APQLQ scores at three months (P < 0.01), and on four subscales at six months (P < 0.05), but only on one subscale at one year.

Regarding the TACTICS‐TIMI 18 trial, Weintraub 1999 planned to assess health status using some measure of utility in order to perform cost‐effectiveness evaluations of invasive versus non‐invasive strategy, but subsequent publications failed to disclose HRQOL data (Mahoney 2002). From the available evidence, it would appear that improvements in HRQOL as a result of an invasive strategy are modest and last on average no more than 12 months, with anginal relief likely the key determinant of improved HRQOL.

Findings from studies in the pre‐stent era and other reviews on this topic

We excluded two large trials that were undertaken during the pre‐stent era (TIMI‐3b; VANQWISH 1998). The early invasive arm of TIMI‐3b involved cardiac catheterisation an average of 36 hours after randomisation and coronary revascularisation by coronary angioplasty or CABG. The early invasive strategy had no effect on the hard clinical endpoints of death, MI, stroke or the composite of death or MI. As is consistent with more recent clinical trials, the early invasive strategy reduced recurrent hospitalisation at both six weeks and one year, with RRs of 0.54 (95% CI 0.40 to 0.74) and 0.79 (95% CI 0.68 to 0.93), respectively (TIMI‐3b). In TIMI‐3b, a routine invasive strategy did not reduce the need for anti‐angina medications at one year. In contrast, the VANQWISH 1998 study demonstrated increased risk associated with the early invasive strategy, which involved cardiac catheterisation an average of 48 hours after randomisation. In fact, the early invasive strategy was associated with an increased risk ratio of mortality prior to hospital discharge, and at one month and one year (RR 3.47 (95% CI 1.41 to 8.52); RR 2.53, 95% CI 1.19 to 5.42; and RR 1.60, 95% CI 1.08 to 2.37, respectively) (VANQWISH 1998). Similarly, increased risk was associated with the early invasive strategy for the composite endpoint of death or non‐fatal MI. The hazard of an early invasive strategy on these endpoints ceased to be significant by the end of the study (average 23 months). Forty‐four percent of participants in the invasive arm of this trial underwent a revascularisation procedure, of which 47% involved CABG. The mortality associated with CABG in the invasive arm was 11.6%, compared to 3.4% in the conservative arm. Braunwald 2003 has cited this discrepancy as an explanation for the increased mortality in the early invasive arm of the VANQWISH 1998 trial. Unsurprisingly, rates of background medical therapy were low by contemporary standards.

Two older meta‐analyses on this topic that included the aforementioned pre‐stent era trials, plus trials that we excluded for reasons other than low stent use, reached different conclusions than the ones presented here (Choudhry 2005; Mehta 2005). These reviews did not include the most recent trials, including the OASIS 5 substudy, LIPSIA‐NSTEMI, Italian Elderly ACS and ICTUS studies. A subsequent meta‐analysis included the early trials and the one‐year results from ICTUS (Bavry 2006). The review by Mehta 2005 associated an invasive strategy with an increased risk of mortality during the period from randomisation to hospital discharge (RR 1.61, 95% CI 1.14 to 2.27). When Mehta 2005 analysed the outcomes from hospital discharge to end of follow‐up, the early invasive strategy was associated with reductions in death and non‐fatal MI (RR 0.78, 95% CI 0.64 to 0.94; and RR 0.56, 95% CI 0.47 to 0.68, respectively). When they analysed trial data from randomisation to the end of follow‐up, the invasive strategy exhibited no effect on mortality, but induced a reduction in non‐fatal MI (RR 0.77, 95% CI 0.67 to 0.89). This Cochrane review analysed the endpoints at certain time points, since we felt that combining outcomes collected from studies of short duration (six months) with those of longer duration (five years) would not provide a meaningful point estimate (see the 'Characteristics of included studies' table). All reviews consistently found a significant reduction in recurrent angina and rehospitalisation with an invasive strategy (Bavry 2006; Choudhry 2005; Mehta 2005). More recently, a meta‐regression analysis that included the earlier studies but excluded VANQWISH 1998 revealed the benefit of an invasive strategy — with respect to the endpoint of death or the composite of death or MI — to be related to the comparator odds ratio for events in the conservative group (Tarantini 2007). This implies that the benefit of an invasive strategy relates to the level of baseline risk in the comparator group. One meta‐analysis has been published since the publication of late follow‐up data from the ICTUS trial. This report, which included the older studies, identified no benefit of an invasive strategy on the endpoints of death, MI, or the composite of death or MI (Qayyum 2008). The findings from our analysis differ, because we excluded older studies and utilised the reported 'spontaneous' MI endpoint for our analysis, in light of the controversy surrounding the routine peri‐procedural biomarker assessment undertaken by the ICTUS trial authors.

Relevant international guidelines for management of UA/NSTEMI

Both the current AHA (Anderson 2007; Jneid 2012) and ESC (Hamm 2011) guidelines make class 1 recommendations for an invasive strategy in patients who are symptomatic or are considered (Level A evidence). The AHA guidelines also endorse the option of treating stabilised but high‐risk (for example troponin‐positive) patients conservatively, however with only Class IIb recommendation.