Characteristics and Management of Patients With Acute Coronary Syndrome and Normal or Non-Significant Coronary Artery Disease: Results From Acute Coronary Syndrome Israeli Survey (ACSIS) 2004-2010

Abstract: Background. An important subset of patients presenting with acute coronary syndrome (ACS) are found to have either normal coronaries (NCs) or non-obstructive coronary artery disease (NOCAD; lumen diameter narrowing <50%). Objectives. To explore the characteristics and management strategies in this population in a real-world setting. Methods. The Acute Coronary Syndrome Israeli Survey (ACSIS) database was utilized to compare the characteristics and therapeutic approach for patients who underwent angiography for ACS and had either NC (n = 84; 2%), NOCAD (n = 79; 2%), or obstructive coronary artery disease (OCAD; n = 3523; 96%). Results. Baseline characteristics were comparable, save for a younger age and a higher proportion of females in the NC group (P<.001 for both). Prior to admission, chronic anticoagulant therapy was more frequently used in the NC vs the OCAD group (4.8% vs 1.6%, respectively; P=.02). Recommended ACS evidence-based medications, both in-hospital and at discharge, were less frequently prescribed to patients with NC or NOCAD. Conclusions. In a real-world practice of ACS, underutilization of evidence-based medications in patients with NC or NOCAD was observed. Nonetheless, its prognostic significance is still unknown and must be explored in larger patient cohorts.

J INVASIVE CARDIOL 2014;26(8):389-393

Key words: acute coronary syndrome, normal coronaries, myocardial infarction

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Acute coronary syndrome (ACS) is the leading cause of death in the United States,¹ and translates to 17% of the national health expenditure. Evidence-based guidelines are published to standardize the therapeutic approach for outcome improvement.^2,3 An important subset of ACS patients is reported to have either normal coronaries (NCs) or non-obstructive coronary artery disease (NOCAD, defined as narrowing <50% lumen diameter) on angiography, with a reported prevalence of ~10%.^4,5 This patient subset may be associated with lower mortality when compared to ACS patients with obstructive coronary artery disease (OCAD) when a culprit lesion is documented.⁴ Most studies have included both NOCAD and NC as a single subset compared to OCAD as an entire group. The inclusion of two separate patient subsets makes the differences between OCAD and NC/NOCAD inherently significant. 

We have previously demonstrated that the lack of established prognostic knowledge translates to heterogeneity in the evidence-based pharmacological interventions given to patients with NC/NOCAD compared to those with OCAD.⁶ The present study aims to build upon these data in a larger cohort of ACS patients. Accordingly, the primary aims of the present study are to characterize patients with NC and NOCAD as separate groups and to compare NC/NOCAD patients to those with established OCAD along the full spectrum of ACS in terms of clinical management and outcome.

Methods

The Acute Coronary Syndrome Israeli Survey (ACSIS) is a nationwide survey of all ACS patients admitted to the intensive cardiac care units and cardiology wards of 26 public Israeli hospitals representing most of the percutaneous coronary intervention (PCI)-capable facilities in the country. This survey has been performed biannually over a 2-month period since the year 2000 and has received local ethics committee approval from each hospital. Throughout the survey period, demographic, historical, clinical, and procedural data were recorded on prespecified forms for patients admitted with a diagnosis of ACS. Any patient with suspected ACS at presentation was screened for this registry during the 2-month period. Only patients with ACS as their admission and discharge diagnosis (unstable angina pectoris, non-ST elevation myocardial infarction, or ST-elevation myocardial infarction) were included in the registry. Patients with other etiologies for chest pain or elevation of serum troponin (eg, pulmonary embolism or myocarditis) were excluded. 

Patients were treated at the discretion of each center. All patients were seen either in the clinic or interviewed via telephone at 30 days and at 1 year. The present analysis included all patients with ACS who underwent angiography during the index hospitalization and had a complete angiographic report detailing lesion locations (based upon the Coronary Artery Surgery study⁹) and lesion severity. Patients with prior percutaneous intervention or prior coronary artery bypass grafting surgery were excluded. Patients were grouped according to the final report of the angiography: NC, NOCAD (<50% lumen diameter narrowing), or OCAD. 

A comparison was performed among the 3 groups for baseline demographic and clinical characteristics, management strategies during the index event, and outcome at 30 days and at 1 year. Outcome indices included all-cause mortality, recurrent ischemia or myocardial infarction (defined as chest pain >30 minutes followed by reevaluation of cardiac enzymes with/without electrocardiographic changes OR chest pain at rest without electrocardiographic changes or cardiac enzymes elevation), urgent procedure (defined as urgent need for percutaneous coronary intervention or coronary artery bypass grafting surgery). Major adverse cardiovascular event (MACE) rate was defined as the composite of death, recurrent myocardial infarction/ischemia, and urgent procedure. 

Statistical analyses were performed using SAS version 9.1 (SAS Institute, Inc). Continuous variables were compared using Student’s t-test or analysis of variance (ANOVA) and are expressed as mean ± standard deviation for variables with normal distribution. Variables with non-normal distribution were compared using the Kruskal-Wallis one-way ANOVA and are expressed as median and interquartile range (IQR; 25%-75%). Categorical variables were compared using the chi-square or Fisher’s exact test, as appropriate, and are expressed as numbers and percentages. Statistical significance was defined as P-value <.05.

Results 

After analyzing the 2004-2010 ACSIS data, a total of 3687 patients met the inclusion criteria. Of those, 84 patients had angiographic NC (2%), 79 patients had NOCAD (2%), and 3523 patients had OCAD (96%). Baseline clinical and demographic characteristics are shown in Table 1. The 3 groups displayed similar characteristics, with the exception of higher rate of female gender and a younger age in the NC group (P<.001 for both). Myocardial infarction (Q-wave/non-Q wave) was the discharge diagnosis in 60% of NC patients and in 65% of NOCAD patients compared to 89% in the OCAD group (P<.001; Table 1). A discharge diagnosis of unstable angina pectoris was more likely in the NC/NOCAD groups. 

Data regarding chronic medical therapy prior to the index event and medical management following hospitalization and at discharge are presented in Table 2. The three groups were treated with similar medications prior to the index event, with the exception of chronic oral anticoagulation therapy: The highest rate was recorded in the NC group (4.8%), followed by the NOCAD group (2.6%), and the OCAD group (1.6%; P=.02). On admission, when compared to patients with OCAD, patients with both NC and NOCAD were less frequently treated with evidence-based medicine (thienopyridines, β-receptor blockers, angiotensin-converting enzyme inhibitors, and statins). Aspirin and anticoagulant usage was similar among the three groups. This trend continued at discharge, which demonstrated significantly lower rates of evidence-based medical therapy in the NC/NOCAD groups.

In-hospital complications (Table 3), including the incidence of heart failure, renal failure, and sustained ventricular arrhythmias, were comparable among the three groups, except for the transient ischemic attack rate, which was highest (1.3%) in the NOCAD group (P=.02). Complete follow-up was available for the majority of patients (100% of NC and NOCAD, and 99.6% of OCAD completed follow-up at 30 days; at 1 year, 78.6% of the NC group, 79.7% of the NOCAD group, and 74.6% of the OCSD group completed follow-up). At follow-up, patients with NC and NOCAD exhibited a significantly lower MACE rate at 30 days compared to patients from the OCAD group (4.8%, 3.8%, and 13.1%, respectively, P=.02; Figure 1).  

Discussion

The main results of the present study indicate that the rates of NC and NOCAD in a large population of “real-world” ACS patients were lower than previously described. The underutilization of evidence-based medicine in these two populations of ACS patients was further noted.

The reported incidence of ACS patients without an OCAD is 5%-12%, which is higher than recorded in the present analysis.^4-6,10 This broad reported range most likely reflects the heterogeneity in both the definitions used for “non-obstructive” disease and the inclusion of various subsets of patients in these reports.^4,5,10

Only a few studies have reported on specific angiographic subsets in ACS in specific patient subgroups. Larsen et al reported a 2.8% rate of NCs in a large acute myocardial infarction registry.¹¹ The PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) trial explored the characteristics and outcomes of patients with ACS with either NC or NOCAD on angiography.¹² In the PURSUIT trial, 12% had a non-obstructive disease (6% NC; 6% NOCAD), which is higher than in our report. These differences probably stem from a relatively low number of patients in both groups.

As was previously reported, the subset of patients without obstructive disease, compared to OCAD patients, tends to be younger, with a higher prevalence of women.^6,13,14 In the PURSUIT trial, both age and female gender were strong predictors for NOCAD. This gender disparity is unclear. By measuring the coronary flow velocity reserve, authors of the Women’s Ischemia Evaluation (WISE) study suggested that as opposed to men, women may have higher incidences of microvascular dysfunction leading to angina pectoris in the presence of non-obstructive coronary arteries.¹⁵ This may serve as a plausible explanation for the increased rate of non-obstructive disease in women.

Other baseline characteristics, mainly traditional risk factors for atherosclerosis, were similar among the three groups in this study. This is in contrast to prior studies that demonstrated lower rates of these risk factors in patients with non-obstructive coronary artery disease,^4,11,12 but it is in line with the recent subanalysis report from the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial.¹⁰ Thus, the true understanding of the population characteristics that present with non-obstructive coronary disease is still limited.

The basic pathophysiological paradigm of ACS is that ruptured plaque in a coronary artery initiates a cascade of events leading to a partial or complete occlusion of the artery by a thrombus. The finding of a non-obstructive disease on angiography of patients with ACS may suggest a different process. Microvascular disease can manifest as ACS, which is more frequent in women. Since all groups shared similar risk factors for atherosclerosis, it is possible that plaques and thrombi were generated in vulnerable areas without significant luminal narrowing and were then resolved or dislodged prior to angiography. Other suggested pathophysiological etiologies for non-obstructive ACS are embolization of platelet-fibrin thrombi to the coronary circulation and vasospasm. A combination of the two may lead to this presentation. In the present analysis, a higher prevalence of chronic anticoagulant use was found in patients with NC when compared to the other two groups. This may indicate, at least in part, that the pro-thrombotic state in these patients may lead to thrombosis and embolization.¹⁶

As for medical therapy, significant differences were noted for OCAD patients compared to the NC and NOCAD groups both during hospitalization and more importantly at discharge. These differences in evidence-based medical therapy are intensified in light of the fact that over half of the patients without an obstructive coronary disease were discharged with myocardial infarction as the discharge diagnosis. This is in concordance with both the study by Patel et al⁴ and the HORIZONS-AMI trial,¹⁰ which demonstrated lower rates of evidence-based medical therapy in patients with non-obstructive coronary artery disease. It seems that when the angiography of an ACS patient fails to demonstrate coronary obstruction or thrombus, the therapeutic trend is to withhold evidence-based therapy, all the while disregarding the fact that the major clinical trials demonstrating outcome benefit for medical therapy did not necessarily include coronary obstruction as inclusion criteria (eg, the pivotal PLATO [Platelet Inhibition and Patient Outcomes]and CURE [Clopidogrel in Unstable Angina to Prevent Recurrent Events]trials).^17,18 

The outcome of patients with non-obstructive coronary disease is generally reported as favorable as compared to OCAD patients. Patel et al have reported lower in-hospital death rates for non-obstructive coronary artery disease (including both NC and NOCAD) compared to OCAD,⁴ which was repeated in PURSUIT¹² and HORIZONS-AMI.¹⁰ In the present analysis, no outcome differences were noted among the groups, save for major adverse cardiovascular events driven mainly by recurrent angina pectoris and the need for urgent procedures in the OCAD group (which inherently reflects higher rates of percutaneous interventions in this group). Such differences should be interpreted cautiously due to the low power stemming from the low event rate. Since most of the outcome data for ACS patients presenting with a non-obstructive disease is derived from relatively small cohorts, larger studies are needed to truly appreciate patient outcomes.  

The appropriate therapeutic approach for ACS patients with non-obstructive disease is unknown. No randomized trial has addressed this question and such a trial is not yet on the horizon. Thus, the knowledge regarding this entity is based on retrospective analyses, which tend to be underpowered to establish an association between therapeutic approach and outcome. The present study adds to the knowledge on this issue mainly due to the inclusion of patients from the full ACS spectrum and the ability to differentiate between two patient subsets within the non-obstructive group. When patients with ACS are grouped according to their coronary anatomy, from NC to NOCAD to OCAD, a continuum is apparently demonstrated. Patients with NOCAD, who actually have some degree of atherosclerosis, seem to represent the lower risk strata of patients with OCAD, while patients with normal coronary arteries probably represent a different population of younger patients with a possible tendency for spontaneous thrombosis and other etiologies leading to ACS (eg, takotsubo cardiomyopathy, variant angina pectoris, microvascular dysfunction, etc).

To date, no formal guidelines include specific recommendations for secondary prevention measures in patients with NC/NOCAD. This report reinforces prior reports that document lower rates of adherence to evidence-based medicine in this patient population, thereby signifying the dilemmas faced by cardiologists. 

By acknowledging the continuum from NC to OCAD in ACS, some general recommendations can be made. First, assuming that the majority of NC/NOCAD patients had a myocardial infarction, evidence-based, secondary prevention therapy should be applied to all patients during hospitalization and more importantly at discharge. This therapy should include statins, β-adrenergic receptor blockers, and angiotensin-converting enzyme inhibitors.² Secondly, although current guidelines dictate 12 months of dual-antiplatelet therapy for ACS patients, clinical judgment should be applied when deciding to withhold this therapy. Since all patients shared similar risk profiles, it seemed plausible to prescribe aspirin to most patients. Regarding a second antiplatelet agent, further diagnostic modalities should be used to elicit the etiology for ACS and guide the therapy accordingly. For example, the use of intravascular ultrasound may demonstrate residual thrombus and disrupted plaques not visualized on angiography, which would support dual-antiplatelet therapy, while magnetic resonance imaging may suggest recent myocarditis, which does not necessitate such therapy.¹⁹

Study limitations. The following limitations should be acknowledged. First, this was a retrospective, observational analysis of a registry and as such is subjected to unknown confounders. Second, two of the three groups were relatively small, which may lead to both type I and type II errors and thus mortality rate comparison was not presented. Third, although patients with obvious etiologies for chest pain were excluded, other etiologies for ACS could not be excluded (ie, takotsubu cardiomyopathy and illicit drug use). Furthermore, due to the small numbers of patients in these groups, the statements regarding actual outcomes should be considered with caution. Despite the relatively small cohort, this report summarizes nationwide data of real-world practice collected over a 6-year period, which reinforces its main conclusions. 

Conclusions. Patients presenting with ACS with normal coronary arteries may represent a group of patients with dissimilar mechanism, other than the ruptured plaque-thrombosis, leading to ACS. These patients were undertreated with evidence-based-medicine therapy in this large, real-world cohort. Evidence-based medicine was also underutilized, especially at discharge, in patients with NOCAD. The exact impact of these discrepancies on patient outcome is still unknown and should be further explored.    

References

1. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123(8):933-944.
2. Steg PG, James SK, Atar D, et al. Task force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33(20):2569-2619.
3. Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32(23):2999-3054.
4. Patel MR, Chen AY, Peterson ED, et al. Prevalence, predictors, and outcomes of patients with non-ST segment elevation myocardial infarction and insignificant coronary artery disease: results from the can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the ACC/AHA guidelines (CRUSADE) initiative. Am Heart J. 2006;152(4):641-647.
5. Gehrie ER, Reynolds HR, Chen AY, et al. Characterization and outcomes of women and men with non-ST segment elevation myocardial infarction and non-obstructive coronary artery disease: results from the can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the ACC/AHA guidelines (CRUSADE) quality improvement initiative. Am Heart J. 2009;158(4):688-694.
6. Minha S, Behar S, Krakover R, Boyko V, Vered Z, Blatt A. Characteristics and outcome of patients with acute coronary syndrome and normal or near-normal coronary angiography. Coron Artery Dis. 2010;21(4):212-216.
7. Lopes NH, Paulitsch FS, Gois AF, et al. Impact of number of vessels disease on outcome of patients with stable coronary artery disease: 5-year follow-up of the medical, angioplasty, and bypass surgery study (MASS). Eur J Cardiothorac Surg. 2008;33(3):349-354.
8. Jaski BE, Cohen JD, Trausch J, et al. Outcome of urgent percutaneous transluminal coronary angioplasty in acute myocardial infarction: comparison of single-vessel versus multivessel coronary artery disease. Am Heart J. 1992;124(6):1427-1433.
9. National Heart, Lung, and Blood Institute coronary artery surgery study. A multicenter comparison of the effects of randomized medical and surgical treatment of mildly symptomatic patients with coronary artery disease, and a registry of consecutive patients undergoing coronary angiography. Circulation. 1981;63(6 Pt 2):I1-I81.
10. Larsen AI, Nilsen DW, Yu J, et al. Long-term prognosis of patients presenting with ST-segment elevation myocardial infarction with no significant coronary artery disease (from the HORIZONS-AMI trial). Am J Cardiol. 2013;111(5):643-648.
11. Larsen AI, Galbraith PD, Ghali WA, et al. Characteristics and outcomes of patients with acute myocardial infarction and angiographically normal coronary arteries. Am J Cardiol. 2005;95(2):261-263.
12. Roe MT, Harrington RA, Prosper DM, et al. Clinical and therapeutic profile of patients presenting with acute coronary syndromes who do not have significant coronary artery disease. The platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial investigators. Circulation. 2000;102(10):1101-1106.
13. Hochman JS, Tamis JE, Thompson TD, et al. Sex, clinical presentation, and outcome in patients with acute coronary syndromes. Global use of strategies to open occluded coronary arteries in acute coronary syndromes IIb investigators. N Engl J Med. 1999;341(4):226-232.
14. Glaser R, Herrmann HC, Murphy SA, et al. Benefit of an early invasive management strategy in women with acute coronary syndromes. JAMA. 2002;288(24):3124-3129.
15. Reis SE, Holubkov R, Conrad Smith AJ, et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J. 2001;141(5):735-741.
16. Kardasz I, De Caterina R. Myocardial infarction with normal coronary arteries: a conundrum with multiple aetiologies and variable prognosis: an update. J Intern Med. 2007;261(4):330-348.
17. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.
18. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Clopidogrel in unstable Angina to Prevent Recurrent Events trial I. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
19. Collste O, Sorensson P, Frick M, et al Myocardial infarction with normal coronary arteries is common and associated with normal findings on cardiovascular magnetic resonance imaging: results from the Stockholm myocardial infarction with normal coronaries study. J Intern Med. 2013;273(2):189-196.

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From the ¹Department of Cardiology, Assaf-Harofeh Medical Center, Zerifin, Israel; ²Heart Institute, Bikur Cholim Campus, Shaare Zedek Medical Center, Jerusalem, Israel; ³Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Hashomer, Israel; ⁴Cardiac Rehabilitation Institute, Leviev Heart Center, Sheba Medical Center, Tel-Hashomer, Israel; ⁵Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel; ⁶Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted September 18, 2013, provisional acceptance given November 7, 2013, final version accepted January 30, 2014.

Address for correspondence: Sa’ar Minha, MD, MedStar Washington Hospital Center, 110 Irving St, NW, Suite 4B, Washington, DC 20010. Email: minha.saar@gmail.com