The generalization of percutaneous coronary intervention has led to a gradual decrease in mortality due to acute coronary syndrome (ACS) in recent years, particularly in relation to ST-segment elevation myocardial infarction (STEMI).1 The clinical practice guides (CPGs) recommend an early invasive strategy (EIS) in the first 24 h in patients with high-risk non-ST-segment elevation acute coronary syndrome (NSTEACS (NSTEACS), and in the first few hours in very high risk cases.2,3 The establishment of coordinated care poses an organizational challenge with a significant consumption of healthcare resources.4 Although adherence to the recommendations referred to ACS has increased in recent years,5,6 few data are available on the application of risk-adjusted EIS (RAEIS) in patients with NSTEACS in our setting.

The objectives of the present study were to: (a) analyze the application of RAEIS; (b) describe the factors associated to this management strategy; and (c) analyze its prognostic impact in a series of non-selected patients with NSTEACS admitted to Intensive Cardiac Care Units (ICCUs).

A total of 629 patients with NSTEACS were admitted during the study period. Their mean age was 66.6 years, and the majority were males (76.8%, n = 483). Overall, the series presented a high risk profile, with a considerable percentage of conditions such as diabetes (37.8%, n = 238), previous stroke (8.9%, n = 56) or peripheral vascular disease (16.9%, n = 106). In turn, 18.9% of the patients (n = 119) presented signs of heart failure upon admission, and 91.3% (n = 574) showed serum troponin elevation. The mean GRACE score in the series was 141 (SD 36). A little over one-third of the patients (35.9%, n = 225) had very high risk criteria upon admission, while 62.6% (n = 392) presented high risk criteria.

The adoption of EIS during admission was the predominant practice (96.2%, n = 605). The information on the interval to coronary angiography was available in 603/605 patients (99.7%). The median time elapsed from ICCU admission to the performance of coronary angiography was 20 h (IQR 3–46 hours). Overall, RAEIS was applied in 45.6% of the cases (n = 284). This proportion was 54.6% in the patients at high risk, and lower in the patients with very high risk criteria (31.3%).

Impact of RAEIS upon patient prognosis at 6 months

The patients subjected to RAEIS showed better clinical outcomes after discharge (Table 3), with a lesser incidence of new ACS, a lesser need for new coronary revascularization, and a tendency towards lower in-hospital mortality. These patients likewise had a clearly lower incidence of the combination death or readmission at 6 months (relative risk [RR]: 0.53; 95% confidence interval [95%CI] 0.38–0.76; p = 0.001) (Table 4). After adjusting for potential confounders, the association between the application of RAEIS and the incidence of death or readmission remained statistically significant (RR: 0.66; 95%CI 0.45–0.97; p = 0.035) (Table 4). Fig. 1 shows the cumulative incidence of death or readmission at 6 months according to the application of RAEIS.

Table 3.

Management at discharge and posterior evolution according to adherence to the recommendations regarding the invasive strategy.

	RAEIS (n = 284)	No RAEIS (n = 341)	P-Value
Drug treatment at hospital discharge
Aspirin, n (%)	260 (92.5)	312 (93.1)	0.771
Clopidogrel, n (%)	112 (39.9)	150 (44.8)	0.219
Prasugrel, n (%)	15 (5.3)	12 (3.6)	0.289
Ticagrelor, n (%)	93 (33.1)	85 (25.4)	0.035
Rivaroxaban, n (%)	0	3 (0.9)	0.161
Dabigatran, n (%)	5 (1.8)	5 (1.5)	0.512
Apixaban, n (%)	3 (1.1)	5 (1.3)	0.462
Warfarin, n (%)	7 (2.5)	6 (1.8)	0.547
Acenocoumarol, n (%)	15 (5.4)	39 (11.7)	0.006
Beta-blockers, n (%)	214 (76.2)	246 (73.7)	0.476
Diuretics, n (%)	70 (24.9)	122 (36.4)	0.002
ACEIs, n (%)	158 (56.2)	183 (54.6)	0.691
Statins, n (%)	263 (93.6)	311 (92.8)	0.710
Proton pump inhibitors, n (%)	233 (82.9)	283 (84.5)	0.601
Clinical outcome at 6 months
Reinfarction, n (%)	8 (2.9)	25 (7.9)	0.009
New revascularizations, n (%)	13 (4.7)	29 (9.1)	0.038
Global mortality (%)	10 (3.7)	23 (7.1)	0.070
Mortality or readmission, n (%)	47 (17.3)	102 (31.2)	0.001

RAEIS: risk-adjusted early invasive strategy; ACEIs: angiotensin-converting enzyme inhibitors.

Table 4.

Predictors of patient death or readmission at 6 months.

	Univariate analysis		Multivariate analysis
Variable	Hazard ratio (95%CI)	P-Value	Hazard ratio (95%CI)	P-Value
RAEIS	0.53 (0.38–0.76)	0.001	0.66 (0.45–0.97)	0.035
Age (years)	1.03 (1.02–1.05)	0.001
Male gender	0.67 (0.44–1.02)	0.063
Arterial hypertension	1.94 (1.26–2.98)	0.002
Diabetes mellitus	1.91 (1.39–2.64)	0.001
Active smoker	0.88 (0.72-1.08)	0.229
Previous stroke	2.76 (1.89–4.02)	0.001	1.84 (1.20–2.82)	0.006
Peripheral arterial disease	2.36 (1.66–3.37)	0.001	1.66 (1.12–2.47)	0.012
Previous myocardial infarction	2.08 (1.49–2.89)	0.001	1.42 (0.96–2.09)	0.080
Previous heart failure	2.53 (1.64–3.89)	0.001	1.93 (1.20–3.11)	0.007
Previous atrial fibrillation	2.15 (1.43–3.25)	0.001
Previous neoplastic disease	1.66 (1.10–2.51)	0.016
Charlson Index score	1.22 (1.12–1.32)	0.001
Number of habitual prescription drugs	1.12 (1.08–1.16)	0.001
Heart rate	1.02 (1.01–1.02)	0.001	1.01 (1.00–1.02)	0.009
Killip class upon admission ≥ ii	1.89 (1.55–2.29)	0.001
Positive troponin	1.83 (0.90–3.74)	0.096
LVEF	0.97 (0.96–0.98)	0.001
Multivessel disease	1.39 (0.99–1.96)	0.058
Hemoglobin upon admission	0.81 (0.75–0.87)	0.001
Basal creatinine clearance	0.99 (0.98–0.99)	0.001	0.99(0.99–1.00)	0.048
GRACE score	1.01 (1.00–1.01)	0.001	1.00 (1.00–1.01)	0.095
Revascularization	0.80 (0.57–1.13)	0.212

RAEIS: risk-adjusted early invasive strategy; LVEF: left ventricular ejection fraction; CI: confidence interval.

Figure 1.

Cumulative incidence of death or readmission according to the application of a risk-adjusted early invasive strategy (RAEIS).

(0.1MB).

On the other hand, the propensity score matching analysis showed an independent association between the application of RAEIS and a lesser incidence of death or readmission at 6 months (HR 0.57; 95%CI 0.36–0.89; p = 0.022).

The main findings of the present study are: (a) RAEIS was applied in a minority (45.6%) of the patients with NSTEACS admitted to the ICCU; (b) application of the strategy was more common in younger patients with a lower comorbidity burden and a lesser global risk profile; and (c) the application of RAEIS was associated to a lower incidence of events during follow-up.

The EIS approach in patients with NSTEACS has been shown to offer prognostic benefits.12,13 Accordingly, the CPGs recommend an invasive approach in the great majority of these patients, with adaptation of the earliness of EIS to the patient risk profile.2 The available data on the application of RAEIS in clinical practice in our setting are very limited.

The results of our study show that less than half of the patients admitted to the ICCU due to NSTEACS undergo invasive coronary angiography within the recommended timeframes. Interestingly, the patients subjected to RAEIS were comparatively younger, with fewer comorbidities and lower GRACE scores. This apparent paradox has been widely described before, though fundamentally in patients admitted to conventional hospital wards.5,6 The information available on patients admitted to critical care units is much more limited.14–16 The location of patients with NSTEACS in care units other than the ICCU is often conditioned by a certain age profile and by comorbidities. Furthermore a cardiological high risk profile (high GRACE scores, acute heart failure, positive troponin) often coexists with an “untreatable” risk component (advanced age, comorbidities, frailty).17,18 In this regard, mention must be made of the relatively young age of the included patients and the low percentage of women compared with other series.19 In our opinion, one of the main strengths of the present study is that it exclusively refers to consecutive patients admitted to an ICCU, and who in theory are fully amenable to high complexity invasive measures.

The application of EIS was highly prevalent in our series (96.2%), confirming the rising trend in this respect observed in different Spanish registries in recent years.5,6 Other factors such as the level of hospital complexity and the availability of cardiological resources can also condition the percentage of patients subjected to EIS.20 All the centers participating in our study are third-level institutions with the availability of a hemodynamics laboratory – a fact that undoubtedly contributed to the high EIS rate recorded in our series. Likewise, the percentage of patients subjected to percutaneous revascularization in this study was significantly higher than reported elsewhere.5,6

The mentioned recommendations in patients with NSTEACS are based on a series of clinical trials involving a high degree of patient selection and the enrolment of individuals with a relatively low risk profile.21–23 The extrapolation of their findings therefore may prove questionable. In our opinion, another strong point of the present study is that it included consecutive patients admitted to this clinical setting from all over the region of Catalonia (Spain) during a period of 6 months, thereby offering a reliable representation (in our opinion) of routine clinical practice in our setting.

Data on the ideal timing of EIS according to risk are more limited. Specifically, the recommendation to adopt an early strategy in patients at high risk is based on the results of the TIMACS study.24 This trial randomized 3031 patients with NSTEACS to either an early invasive strategy (<12 h) or a later invasive strategy (>36 h) - the primary study endpoint being the combination of death, myocardial infarction or stroke at 6 months. Coronary angiography was performed after an average of 14 h in the early invasive strategy group. Although no decrease was observed in the incidence of the primary endpoint between the two groups, there was a reduction of the secondary endpoint combining death, infarction or refractory ischemia at 6 months. Likewise, the analysis by subgroups revealed a decrease in the primary endpoint in those patients at greater risk (GRACE score >140).

More recently, the VERDICT study25 randomized 2147 patients with NSTEACS to an early invasive strategy (<12 h) versus a more delayed invasive strategy (48–72 h) - the primary endpoint being the combination of death, myocardial infarction, hospitalization due to recurrent ischemia, or hospital admission due to heart failure. Coronary angiography was performed after an average of 4.7 h in the early invasive strategy group. This study likewise observed no significant differences in the incidence of the primary endpoint between the two groups, though the differences were greater in the subgroup of patients at higher risk (GRACE score >140) (p-value for the interaction = 0.023).

Lastly, Jobs et al.26 performed a meta-analysis including 5324 patients with NSTEACS belonging to 8 clinical trials. Here again, the benefits in terms of mortality associated to EIS were limited to decreased mortality only in the patients with a GRACE score >140, diabetes mellitus, age >75 years and the elevation of myocardial damage markers.

The results of our study also reflect an improved clinical course in the patients subjected to RAEIS. In addition to the fact that this is an observational study, the main difference between our series and the other mentioned publications is that it includes risk stratification in line with the recommendations of the guides (i.e., earlier EIS in the patients at higher risk) within the group of subjects in which RAEIS was applied. It should be noted that the patients included in our registry had a high risk profile, since 35.9% met very high risk criteria and 62.6% had high risk criteria.3

The GRACE score is associated to the probability of presenting more severe and complex coronary disease (involvement of the common trunk, proximal anterior descending artery or multivessel disease),27 which could explain improvement of the patient prognosis when early intervention is carried out. In the present study, the mean GRACE score was 141, which is very similar to the score of the patients included in the VERDICT trial.25 The fact that the patients subjected to RAEIS had a higher revascularization rate despite the absence of differences in the proportion of multivessel coronary disease could indicate a lesser complexity of coronary disease in this subgroup – a notion that would be consistent with the lower GRACE score recorded in these patients. Furthermore, the patients subjected to RAEIS showed a lesser incidence of new ACS and of new revascularizations, and a clearly lower incidence of death or readmission at 6 months. This could be related to the high risk profile of the patients of our study. Although the groups were scantly comparable in terms of their global risk profile, the exhaustive adjusted analysis performed revealed an association between the application of RAEIS and the incidence of events at 6 months.

The application of RAEIS in our setting poses some difficulties, due in part to the great time dedicated by the hemodynamics laboratories to activities such as the dissemination of primary percutaneous coronary intervention practices in Spain in patients with ST-segment elevation myocardial infarction (STEMI)28 or the growing indication of other types of procedures (percutaneous aortic prosthesis implantation, revascularization of chronic coronary occlusions).29 In view of the above, the full application of RAEIS in patients with NSTEACS requires an important organizational and logistic effort, with a notorious investment of healthcare resources (between-hospital transfer systems, material and staff provisions of hemodynamics laboratories). In our opinion, the results of the present study underscore the need to advance in this direction with a view to optimizing the management and prognosis of these patients.

This study has some limitations, such as the size of the subgroups or the moderate number of events. Furthermore, the fact that this is an observational study does not allow us to rule out the presence of a certain selection bias or a potential effect of non-analyzed confounders (particularly taking into account the considerable differences between the patients subjected and not subjected to RAEIS). On the other hand, in relation to RAEIS in the very high risk patients, the considered time interval to coronary angiography was less strict than the two hours stipulated by the current recommendations. The data corresponding to some potentially relevant variables of medical treatment (earliness of treatment with angiotensin converting enzyme inhibitors or beta-blockers, duration of anticoagulation) were not fully available. Lastly, the duration of follow-up of 6 months could have been insufficient to detect a stronger impact of RAEIS upon the patient prognosis.

Despite the above, in our opinion this study offers relevant and novel information on the application of RAEIS in patients with NSTEACS admitted to the ICCU in our setting, it’s determining factors, and its possible impact upon the clinical outcomes. The optimization of management of patients with this high risk profile could have notorious medical, economic and social consequences.

In conclusion, RAEIS was applied in a minority of patients with NSTEACS admitted to the ICCU. The patients subjected to this strategy were younger, with fewer comorbidities and presented a lesser global risk profile. The patients subjected to RAEIS had a lower incidence of events during the follow-up.

MG, SM, CT, GB, DV, TO, JSR, JC, IH, MPR: data collection and critical review of the article.

IL, AA: data collection and analysis; drafting of the manuscript.

JAGH, JA, AS, CG, JO, RA, AC: critical review and intellectual contribution to the article.

None.

None.