Clinical Spectrum and Outcome of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome and No Obstructive Coronary Atherosclerosis

Abstract

Background: Because approximately 10% of patients with no-ST-segment elevation acute coronary syndrome (NSTE-ACS) show no obstructive coronary artery disease (NOCAD) on angiography, we assessed the spectrum of diagnoses and the predictors of outcome of these patients.

Methods and Results: We studied 178 patients admitted to a coronary care unit with an initial diagnosis of NSTE-ACS, based on clinical, ECG and laboratory data, but found to have NOCAD. The final diagnosis in these patients was heterogeneous; true NSTE-ACS (ie, coronary thrombosis on an unstable plaque) was ascertained in 1 patient (0.6%), whereas diagnosis at discharge was microvascular NSTE-ACS in 56.2% of patients, variant angina in 10.1%, myocarditis in 8.9%, takotsubo disease in 7.9%, tachyarrhythmia-related chest pain in 6.7%, and non-cardiac pain in 9.6%. At 24.5-month follow-up, 21 deaths (11.8%) had occurred, 9 (5.1%) from cardiovascular causes, including 2 (1.12%) coronary deaths. By multivariable Cox analysis, age only predicted global (hazard ratio [HR] 1.07 [1.02–1.12]; P=0.006) and cardiovascular (HR 1.08 [1.01–1.16]; P=0.04) mortality; non-coronary vascular disease was the main predictor of cardiovascular death or readmission for cardiovascular disease (HR 3.28 [1.75–6.14]; P<0.001) and coronary death or readmission for angina (HR 3.20 [1.26–8.14]; P=0.014).

Conclusions: Patients with an initial diagnosis of NSTE-ACS constitute a heterogeneous population with different final diagnoses. Patients have a rather high rate of fatal events, most of which, however, are not related to coronary causes. (Circ J 2016; 80: 1600–1606)

Approximately 10% of patients who present with acute chest pain symptoms, associated with ECG and/or biochemical markers of myocardial injury, highly suggestive of acute coronary syndrome (ACS), are found to have normal or near normal coronary arteries (NCAs) on angiography.^1–3 Although these patients show a better prognosis than ACS patients with obstructive coronary artery disease (CAD), a sizeable rate of major clinical events during follow-up has been reported in recent studies.^4–7

Editorial p 1532

Patients with ACS but no obstructive CAD (NOCAD), however, likely constitute a heterogeneous population and the risk of events may depend on the mechanisms responsible for the syndrome.^2,8,9 Yet, previous studies have failed to systematically report the results of in-hospital diagnostic work-up in such patients and the effect of specific diagnoses on clinical outcome. Moreover, no previous studies have identified predictors of long-term clinical events in this population.

In this study we aimed to assess the spectrum of clinical diagnoses, as achieved in clinical practice at a tertiary university hospital, as well as clinical outcomes of NSTE-ACS patients with NOCAD; furthermore, we aimed to identify predictors of clinical events in this population.

Methods

Study Population

We enrolled consecutive patients referred to the coronary care unit, between January 2009 and December 2012, with an admission diagnosis of NSTE-ACS (ie, a clinical picture supposed to be caused by acute atherothrombosis over an unstable coronary plaque), but who were found to have NOCAD on coronary angiography.

Specifically, patients were initially diagnosed as having NSTE-ACS based on their reporting of one or more episodes of chest pain at rest, typical enough to suggest a cardiac ischemic origin, in the previous 24 h, associated with ST-segment and/or T wave abnormalities on the ECG and/or detection of increased serum troponin T levels.

Patients were excluded if they had: (1) ST-segment elevation on the admission ECG during angina pain, or if the ECG showed pacemaker rhythm or left bundle branch block; (2) any history or clinical evidence of other significant heart diseases (cardiomyopathy, valve disease); (3) left ventricular ejection fraction (LVEF) <40%, as assessed by Simpson method¹⁰ on predischarge 2D echocardiography; or (4) died during in-hospital stay.

Detailed clinical data were acquired in all patients, including cardiovascular risk factors and comorbidities. Troponin T was measured on admission, every 6 h in the first 24 h and every 24 h thereafter until discharge.

Hypertension was defined as blood pressure ≥140/90 mmHg or treatment with any antihypertensive medication; hypercholesterolemia was defined as total blood cholesterol level >200 mg/dl, low-density lipoprotein cholesterol ≥130 mg/dl or treatment with any anticholesterolemic drugs; active smoking was defined as smoking any cigaretted in the past month; diabetes mellitus was defined as fasting plasma glucose >126 mg/dl or treatment with any antidiabetic medication.

Particular attention was paid to the presence of comorbidities, including, in particular, neoplasia, chronic pulmonary diseases, chronic kidney disease and vascular disease in arterial districts other than the coronary arteries.

Coronary angiography was performed within 48 h of admission through femoral or radial access. NOCAD was defined as the presence of either totally NCAs or coronary stenosis >0% but <50% of lumen diameter in one or more major epicardial coronary arteries.

The study was approved by the institutional ethics committee and patients gave their informed consent to participate in the study.

Diagnosic Work-up

Diagnostic work-up during hospital stay after demonstration of NOCAD on angiography was at the total discretion of the attending cardiologists, and could include intracoronary vascular ultrasound study (IVUS) or optical coherence tomography (OCT), cardiovascular magnetic resonance (CMR), and intracoronary or intravenous ergonovine test, as well as any other medical diagnostic test believed helpful to achieve a documented diagnosis. The final diagnosis at discharge was recorded for each patient.

An acute coronary thrombotic mechanism was diagnosed when angiography suggested the presence of a residual thrombus, and this was confirmed by IVUS or OCT; revision of the LV contractile pattern and the outcome of the left ventricle on echocardiography was determinant for a diagnosis of takotsubo disease;¹¹ paroxysmal atrial fibrillation with a high heart rate on the admission ECG allowed identification of a tachyarrhythmia-related cause of acute chest pain; when clinical history suggested coronary artery spasm, Holter ECG monitoring and/or ergonovine test allowed the diagnosis of typical variant angina;^12,13 when clinical history and echocardiographic findings suggested myocarditis, this was confirmed (or excluded) by CMR;¹⁴ a diagnosis of non-cardiac chest pain was mainly based on careful reassessment of the characteristics of chest pain and the results of non-cardiologic (mainly gastroesophageal) tests. Finally, a discharge diagnosis of probable “microvascular NSTE-ACS” was accepted as the likely diagnosis when all other diagnoses had been excluded at the end of diagnostic work-up. No attempts were done to demonstrate coronary microvascular constriction/spasm in these patients, however; accordingly, the diagnosis of microvascular NSTE-ACS was an exclusion diagnosis.

Clinical Endpoints and Follow-up

Clinical outcome was established by clinical visits or, when impossible, by telephone calls. In case of events, accurate information was obtained as to the cause from clinical records or, when unavailable, from the patient’s physician or relatives.

The primary endpoint of the study was all-cause mortality. Cardiovascular deaths, coronary deaths, and the combined endpoints of cardiovascular death or readmission for a cardiovascular cause (combined cardiovascular endpoint) and of coronary death or readmission for recurrent ACS (combined coronary endpoint) were also assessed.

Cardiovascular deaths included coronary deaths and deaths caused by, or consequent to, any acute vascular disease (eg, cerebral ischemia or hemorrhage, pulmonary embolism, etc). Coronary death was defined as death consequent to acute myocardial infarction (AMI) or sudden death, defined as death occurring within 1 h of symptom onset or unwitnessed death in the absence of any apparent critical clinical condition.

Statistical Analysis

Data are reported as mean and standard deviation (continuous variables) or number and proportions (discrete variables), unless otherwise indicated. Cox regression survival analysis was applied to identify univariate predictors of clinical endpoints. Multivariable Cox regression was applied to identify independent predictors of events. To this aim only variables showing significant or borderline association with the event (P≤0.1) were included in the multivariable models and data were also corrected for pharmacological therapy at discharge. Results are shown as hazard risk ratio with 95% confidence interval. A survival curve was constructed by Kaplan-Meier method. Data were analyzed with the SPSS 21.0 statistical software (Chicago, IL, USA). P<0.05 was always required for statistical significance.

Results

Clinical Findings

In total, 194 patients were enrolled in the study, 16 of whom (8.2%) were lost to follow-up. Thus, the final population of the study included 178 patients (118 females, 60 males, age 66.5±15 years).

The main clinical data of the patients eventually included in the study are summarized in Table 1 : 70 patients (39.3%) had NCAs, and 108 patients (60.7%) showed the presence of 1 or more non-significant stenosis on angiography. Serum troponin T levels showed an increase-decrease curve compatible with an AMI in 84% of patients.

Table 1. Main Clinical Characteristics of Patients Diagnosed With Non-ST-Segment Elevation ACS on Admission

Age (years)	66.5±15
M/F	60/118 (33.7/66.3%)
CV risk factors
Diabetes	32 (18.0%)
Hypertension	125 (70.2%)
Hypercholesterolemia	90 (50.8%)
Smoking	38 (21.5%)
Comorbidities
Vascular disease	33 (18.5%)
Neoplasia	25 (14.0%)
Chronic pulmonary disease	20 (11.3%)
Renal failure	6 (3.4%)
Coronary angiography
Non-significant CAD	108 (60.7%)
Normal coronary arteries	70 (39.3%)
Peak troponin T (ng/ml)*	0.09 (0.02–0.27)
LVEF <50%	34 (19.1%)
Diagnosis at discharge
Microvascular NSTE-ACS	100 (56.2%)
Thrombotic NSTE-ACS	1 (0.6%)
Variant angina	18 (10.1%)
Myocarditis	16 (8.9%)
Takotsubo disease	14 (7.9%)
Paroxysmal AF	12 (6.7%)
Non-cardiac chest pain	17 (9.6%)
Therapy at discharge
Aspirin	128 (71.9%)
β-blocker	118 (66.3%)
Statin	113 (63.5%)
ACEI/AT-II antagonists	120 (67.4%)
Calcium antagonist	52 (29.2%)

*Median (interquartile range). ACEI, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; AF, atrial fibrillation; AT-II, angiotensin II; CAD, coronary artery disease; CV, cardiovascular; LVEF, left ventricular ejection fraction; NSTE, non-ST elevation.

Comorbidities were quite frequent; a history of neoplasia, in particular, was present in 25 patients (14%) and vascular diseases other than CAD in 33 (18.5%).

Advanced diagnostic evaluation included IVUS or OCT in 11 patients (6.2%; 3 and 8 patients, respectively), CMR in 33 patients (18.5%) and ergonovine test in 34 (19.1%).

Clinical Diagnosis

A flowchart of the clinical diagnoses achieved in this patient population is shown in Figure 1. True NSTE-ACS (ie, acute chest pain related to transient thrombosis over an unstable coronary lesion) was the diagnosis at discharge in 1 patient only (0.56%), in whom a residual thrombus at the level of a ruptured non-obstructive plaque was suggested on angiography and confirmed by OCT.

Figure 1.

Flow chart of clinical diagnoses and work-up in a population of patients diagnosed with no-ST-segment elevation acute coronary syndrome (NSTE-ACS) on admission. AF, atrial fibrillation; CP, chest pain; IVUS, intravascular ultrasound; LVD, left ventricular dysfunction; MR, magnetic resonance; OCT, optical coherence tomography.

The diagnostic work-up during hospital stay excluded typical NSTE-ACS in the other patients, but led to heterogeneous final diagnoses at discharge, which included variant angina in 18 patients (10.1%), myocarditis in 16 (8.9%), takotsubo disease in 14 (7.9%), and chest pain related to paroxysmal atrial fibrillation with a high ventricular rate in 12 patients (6.7%), Importantly, NSTE-ACS likely related to coronary microvascular constriction/spasm was diagnosed in the other 100 patients (56.2%), after excluding all possible identifiable cardiac and non-cardiac causes of acute chest pain.

Clinical Outcome

Patients were followed-up for a period of 24.5±12 months (range 8–51). Clinical events that occurred during follow-up are shown in Table 2. Overall, there were 21 deaths (11.8%) and the causes are summarized in Table 3. The survival curve of this population is shown in Figure 2. Overall, there were 12 deaths (6.7%) from non-cardiovascular causes and 9 deaths (5.1%) from cardiovascular causes, including 2 (1.12%) coronary deaths, 1 resulting from ST-segment elevation AMI and 1 from sudden death. Cardiovascular deaths occurred in 6 patients with non-significant coronary stenosis (5.6%) and in 3 with NCAs (4.3%; P=0.50); both coronary deaths occurred in patients with non-significant coronary stenosis on angiography.

Table 2. Clinical Events in a Population of Patients Diagnosed With Non-ST-Segment Elevation ACS on Admission

Deaths
Total deaths	21 (11.8)
CV deaths	9 (5.1)
Coronary deaths	2 (1.12)
Admission for CV disease	36 (20.2)
Admission for angina recurrence	22 (12.4)
Coronary revascularization	2 (1.12)
Admission for CV disease+CV death	45 (25.3)
Admission for angina+coronary death	24 (13.5)
Coronary angiography	16 (9.0)

ACS, acute coronary syndrome; CV, cardiovascular.

Table 3. Causes of Death in a Population of Patients Diagnosed With Non-ST-Segment Elevation ACS on Admission

Cause of death	n
CV death
Acute myocardial infarction	1
Sudden death	1
Heart failure	3
Ischemic stroke	1
Hemorrhagic stroke	1
Death after inferior limb amputation	1
Intestinal infarct	1
Non-CV death
Chronic pulmonary disease	2
Neoplasia	6
Sepsis	3
Acute pancreatitis	1

ACS, acute coronary syndrome; CV, cardiovascular.

Figure 2.

Kaplan-Meier survival curve of total mortality in in a population of patients diagnosed with no-ST-segment elevation acute coronary syndrome on admission.

Readmission for non-fatal acute cardiovascular disease occurred in 36 patients, 25 with non-significant coronary stenosis (25.0%) and in 9 with NCAs (13.8%; P=0.01). Readmission for recurrent angina occurred in 16 (16.0%) and 6 (9.2%) patients with non-significant coronary stenosis and with NCAs, respectively (P=0.038). Only 2 patients (1.12%), both with non-significant stenosis, underwent coronary revascularization during follow-up.

Predictors of Outcome

Univariate survival Cox regression results of the relationship of clinical and laboratory variables with fatal and combined endpoints are summarized in Table 4 and Table 5, respectively.

Table 4. Univariate Association of Variables With Clinical Endpoints in a Population of Patients Diagnosed With Non-ST-Segment Elevation ACS on Admission

	Total deaths (n=21)	CV deaths (n=9)
Age	1.07 (1.03–1.12)*	1.07 (1.00–1.13)*
Male sex	0.89 (0.34–2.31)	0.67 (0.14–3.29)
Diabetes	0.44 (0.10–1.91)	1.18 (0.24–5.71)
Hypertension	1.65 (0.60–4.53)	4.54 (0.54–36.9)
Hypercholesterolemia	2.62 (1.01–6.82)**	3.34 (0.67–16.6)
Smoking	0.54 (0.12–2.34)	0.69 (0.08–5.72)
Microvascular NSTE-ACS	1.27 (0.51–3.15)	1.30 (0.32–5.20)
Comorbidity	1.12 (0.46–2.71)	0.23 (0.03–1.84)
Non-coronary CV disease	1.09 (0.36–3.24)	2.32 (0.58–9.31)
Non-significant CAD	1.23 (0.51–3.03)	1.56 (0.39–6.25)
LVEF <50%	1.63 (0.59–4.58)	1.58 (0.33–7.71)
Peak troponin T	1.41 (0.52–3.85)	1.19 (0.19–7.48)

*P<0.01; **P<0.05. Abbreviations as in Table 1.

Table 5. Univariate Association of Variables With Clinical Endpoints in a Population of Patients Diagnosed With Non-ST-Segment Elevation ACS on Admission

	CV death or admission for CV disease (n=45)	CAD death or admission for angina (n=24)
Age	1.02 (0.99–1.04)	1.01 (0.98–1.04)
Male sex	1.13 (0.59–2.16)	1.09 (0.44–2.70)
Diabetes	0.83 (0.37–1.86)	0.91 (0.31–2.70)
Hypertension	1.39 (0.71–2.71)	1.12 (0.45–2.76)
Hypercholesterolemia	1.32 (0.72–2.44)	1.50 (0.64–3.51)
Smoking	1.67 (0.81–3.45)	2.29 (0.87–5.99)*
Microvascular NSTE-ACS	0.76 (0.41–1.38)	0.71 (0.30–1.65)
Comorbidity	1.08 (0.59–1.99)	1.07 (0.47–2.48)
Non-coronary CV disease	3.39 (1.82–6.33)*	3.06 (1.26–7.41)*
Non-significant CAD	2.44 (1.20–5.00)*	3.03 (1.01–9.09)**
LVEF <50%	1.35 (0.62–2.93)	0.93 (0.27–3.18)
Peak troponin T	1.26 (0.58–2.74)	0.58 (0.14–2.43)

*P<0.01; **P<0.05. Abbreviations as in Table 1.

Age and hypercholesterolemia were the only variables significantly associated with total mortality, while age was the only variable associated with cardiovascular mortality. Furthermore, non-coronary vascular disease and non-significant coronary stenosis on angiography were the only variables associated with both the combined cardiovascular and combined coronary endpoints. Of note, a final diagnosis of microvascular NSTE-ACS vs. any other specific diagnosis did not predict any cardiovascular outcomes.

The results of multivariable Cox survival analysis are summarized in Table 6. Although multivariate analysis was not performed for cardiovascular mortality, as only age showed a significant univariate association with this endpoint, age also emerged as the only significant independent predictor of total mortality. The presence of non-coronary vascular disease and non-significant CAD were independent predictors of the combined endpoint of cardiovascular death or admission for cardiovascular disease, whereas only non-coronary vascular disease predicted the combined endpoint of coronary death or readmission for angina recurrence.

Table 6. Multivariate Cox Regression Survival Analysis in a Population of Patients Diagnosed With Non-ST-Segment Elevation ACS on Admission

	Total deaths	P value	CV death or admission for CV disease	P value	CAD death or admission for angina	P value
Age	1.07 (1.02–1.12)	0.003	–	–	–	–
Hypercholesterolemia	2.42 (0.92–6.34)	0.072	–	–	–	–
Smoking	–	–	–	–	2.28 (0.86–6.04)	0.098
Non-coronary vascular disease	–	–	3.11 (1.65–5.85)	0.001	2.94 (1.19–7.29)	0.02
Non-significant CAD	–	–	2.17 (1.06–4.54)	0.034	2.63 (0.86–7.69)	0.089

Data are shown as hazard risk ratio with 95% confidence interval. Only variables with P≤0.1 on univariate analysis were included in the multivariable model of each clinical endpoint. Abbreviations as in Table 1.

Discussion

This is the first study to show that patients admitted with a diagnosis of NSTE-ACS, but found to have NOCAD on angiography, constitute a heterogeneous population with a wide spectrum of final clinical diagnoses. Of note, our data reflect a real-world, clinically-guided, approach to these patients as observed at a tertiary university hospital with a large experience in the field of coronary syndromes with NOCAD,¹⁵ rather than being the result of systematic search for specific causes in all patients, which can hardly be applied to clinical practice.

The second important finding was that, in these patients, the rate of fatal events at follow-up was considerably high, but most deaths were not related to coronary events. Finally, our study is the first to assess the predictors of clinical outcome in NSTE-ACS patients with NOCAD, showing that age was the only variable independently associated with mortality, whereas non-coronary vascular disease was the most relevant predictor of non-fatal cardiovascular events.

Clinical Diagnosis

The syndrome of stable, usually exercise-related, angina with NCAs or near NCAs on angiography has been known for many years¹⁶ and has been extensively studied in the past decades, with the consensus now being that coronary microvascular dysfunction plays a pivotal role in its pathogenesis.¹⁵ Instead, only recently has there been growing interest in patients with an ACS presentation who show NOCAD on angiography, mainly after consistent evidence that they constitute a sizeable proportion of patients, approximately 10% of NSTE-ACS patients.^1,2,4,7–9

Previous studies, however, have failed to report whether the initial diagnosis of NSTE-ACS was in fact confirmed in the patients by diagnostic work-up after coronary angiography had shown the absence of obstructive CAD. Yet this is a crucial point, as different final diagnoses may portend different future risk of events and suggest different clinical management.^8,9

Some studies showed a varying rate of specific cardiac diagnoses among these patients, in particular, myocarditis^17–19 and vasospasm,^20,21 but none aimed to systematically clarify the spectrum of possible diagnoses in an unselected population of patients. Our study confirmed that these patients constitute a heterogeneous group, with very different final clinical diagnoses. In this population, indeed, a specific diagnosis, other than NSTE-ACS, was achieved in approximately 45% of patients, and included variant angina, myocarditis, takotsubo disease and atrial fibrillation-related chest pain, most of which have indeed been previously reported to simulate NSTE-ACSs;^17–24 furthermore, in 9.6% of patients a non-cardiac cause was eventually identified. Of note, a diagnosis of takotsubo disease was achieved in 7.9% of these patients, a proportion similar to that reported in a recent study.²⁵ On the other hand, among 34 patients with suspect variant angina, ergonovine test confirmed this diagnosis in 18 (53%), and CMR confirmed a diagnosis of myocarditis in 16 of 33 (48%) with the clinical suspicion. Finally, intracoronary imaging confirmed a thrombotic origin of NSTE-ACS in 1 of 11 (9%) patients with only a suspicion of plaque rupture on angiography. A likely diagnosis of microvascular NSTE-ACS²⁶ was eventually done in 100 (56.2%) patients following an “exclusion-based” diagnosis.¹⁵

Clinical Outcome

Recent evidence suggests that patients with NSTE-ACS and NOCAD may not be at low risk of events, although the studies show quite discordant data. In a retrospective analysis of pharmacological clinical trials, the 1-year rate of major adverse events in patients with NOCAD was 2.1%, with death and AMI occurring in approximately 1% and 1.2% of patients, respectively; the rate of adverse events reached 10%, however, when coronary revascularization and angina recurrence were included.⁶ In the TACTICS-TIMI 18 trial, mortality at 6 months of NOCAD patients was 0.9%, but no cases of AMI occurred.⁷

In the angiographic substudy of the ACUITY trial, however, the 1-year total and cardiovascular death rate was 4.7% and 2.6%, respectively, with recurrent MI being 1.5%.²⁵ In a recent Italian study, mortality in patients with MI and NOCAD was 4.4% at 26-month follow-up, but the rate of major coronary events was only 0.3% in those with non-significant CAD and 0% in those with NCAs.²⁷ Finally, in a very recent systematic review of 8 studies, a global annual mortality of 4.7% was found in MI patients with NOCAD, but no data were provided about major coronary events.²⁸

In our study we found the highest mortality hitherto reported in this population of patients; global mortality was 6.0% per year, with a 2.5% rate of cardiovascular deaths. Coronary death, however, was relatively low, occurring in approximately 0.5% of patients per year, whereas 57% of deaths were of non-cardiovascular origin, in agreement with some previous data.^25,27 Finally, readmission for non-fatal cardiovascular diseases was 15%, with most of these admissions being related to ACS recurrence.

The reasons for the differences in case fatalities among published studies are not entirely clear, but they are likely to be found in differences in inclusion and exclusion criteria for patient enrolment, as well as differences in patient referral to different types of hospitals.

Predictors of Outcome

Despite the increasing interest in patients with ACSs and NOCAD, no data are available on the clinical predictors of outcome. In our patient group only older age was an independent predictor of fatal events, which was in keeping with the evidence of multifactorial serious conditions in this population. Age is indeed an obvious common predictor of death in all diseases, including vascular diseases.³

In contrast, no independent prognostic value was shown for troponin T level or LVEF, 2 variables usually correlated with prognosis in patients with obstructive CAD.^28–31 The number of patients included in the present study, however, was small, and the study might not have been sufficiently powered to detect a significant association of these variables with outcome. Furthermore, patients with significant impairment of myocardial function (LVEF <40%) were excluded. Thus larger studies are needed to better assess the prognostic role of these 2 variables in these patients.

A relevant point of our study is that the presence of non-coronary vascular disease was the only independent predictor of recurrent vascular events, mainly readmission for vascular causes, including readmission for recurrent angina, which suggests that patients with ACS and NOCAD should be carefully assessed for the presence of diseases in other vascular districts.

Finally, it is important to underscore that deaths occurred in a similar proportion of patients with non-significant CAD and in those with NCAs, probably reflecting the very low prevalence of coronary death. However, non-fatal vascular events in these patients more frequently occurred in those with non-obstructive stenosis, as compared with those with NCAs, and the only 2 coronary deaths occurred in patients with evidence of non-significant coronary stenosis on angiography. Thus, taken together, our data suggest that, among patients with NSTE-ACS but NOCAD, those with non-significant stenosis have a worse clinical outcome than those with NCAs.

Clinical Implications

The main clinical implication of our findings is that identification of a specific mechansism responsible for the clinical presentation among patients with NOCAD initially admitted with a diagnosis of NSTE-ACS may lead to a focused therapeutic approach. Thus, identification of a thrombotic mechanism, for example, will recommend antithrombotic therapy, whereas spasm documentation will primarily recommend calcium-antagonist therapy, and the latter might also be recommended in those with a diagnosis of microvascular NSTE-ACS,³² although the optimal treatment of the latter group of patients remains to be established.

Study Limitations

Some limitations of our study should be highlighted. The number of patients was relatively small; thus, larger studies are needed to confirm our data.

The discharge diagnosis of microvascular NSTE-ACS in approximately one-half of the present patients was based on an “exclusion criterion” only; thus it is possible that other mechanisms were responsible for the syndrome in at least some patients; this would not significantly change the main messages emerging from our data.

Finally, it is possible that our patients were in some way selected. For example, while, in agreement with previous studies, female sex predominated,^1–7 the patients were instead older, compared with most (although not all)²⁶ previous reports and seem also to have high rates of comorbidities, which may explain, at least in part, the quite high mortality rate recorded at follow-up.

Conclusions

Our study showed that patients with an initial diagnosis of NSTE-ACS constitute a heterogeneous population, with different final clinical diagnoses. These patients, on the whole, had a rather high rate of fatal events at follow-up, mostly, however, from non-coronary causes. Age was the only independent predictor of events in this population of patients with NSTE-ACS and NOCAD. The challenge for clinicians is to identify the various possible diagnoses responsible for NSTE-ACS in individual patients. Risk prediction and clinical management of individual patients will indeed depend on the correct diagnosis.

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