LITHUANIAN UNIVERSITY OF HEALTH SCIENCES
FACULTY OF MEDICINE
DEPARTMENT OF CARDIOLOGY
THE THERAPEUTIC IMPACT OF STATIN AND ASPIRIN THERAPY IN INDIVIDUALS WITH NON-OBSTRUCTIVE CORONARY ARTERY DISEASE
Final Master Thesis
Author: Jonas Lampsatis
Supervisor: Prof. Rimvydas Šlapikas
TABLE OF CONTENTS
1. SUMMARY ... 3
2. ACKNOWLEDGMENTS ... 5
3. CONFLICT OF INTEREST ... 6
4. ETHICS COMMITTEE APPROVAL ... 7
5. ABBREVIATIONS ... 8
6. INTRODUCTION ... 9
7. AIMS AND OBJECTIVES ... 11
8. LITERATURE REVIEW ... 12
8.1 Non-obstructive coronary artery disease ... 12
8.2 The Impact of Aspirin and Statins ... 24
9. RESEARCH METHODOLOGY AND METHODS ... 36
10. RESULTS AND THEIR DISCUSSION ... 38
11. CONCLUSIONS ... 41
1. SUMMARY
Jonas LampsatisThe therapeutic impact of statin and aspirin therapy in individuals with non-obstructive coronary artery disease
Research aim
The aim of this research is to provide an account of primary literature about non-obstructive coronary artery disease, as well as the therapeutic effect statin and aspirin therapy may have on this pathology.
Objectives
• To describe the significance, incidence, clinical presentation and prognosis of non-obstructive coronary artery disease.
• To investigate the impact of statin therapy on all-cause mortality and coronary revascularization in patients with non-obstructive CAD.
• To investigate the impact of aspirin therapy on all-cause mortality and coronary revascularization in patients with non-obstructive CAD.
Methodology
This literature review involved a primary online search of the following databases: PubMed, Cochrane Library, ScienceDirect and UpToDate. A secondary manual review of the selected publications’ reference lists was also performed. Additionally, Medscape and WHO internet web pages were used to supplement missing information.
Research results and conclusion
The studies investigated in this review showed that non-obstructive CAD is a pathology with significant clinical risks: it is associated with an increased rate of myocardial infarction and mortality and carries a far worse prognosis than no apparent CAD.
ĮŽANGA
Jonas LampsatisTerapinis statinų ir aspirino poveikis pacientams, sergantiems neobstrukcine širdies vainikinių arterijų liga
Darbo tikslas
Atrinkti ir išanalizuoti mokslines publikacijas apie neobstrukcinę širdies vainikinių arterijų ligą, taip pat ištirti kokią įtaką šiai patologijai turi statinų ir aspirino naudojimas.
Darbo uždaviniai
• Apibūdinti neobstrukcinės širdies vainikinių arterijų ligos svarbą, dažnumą, klinikinius požymius ir prognozę.
• Ištirti statinų poveikį mirštamumui nuo visų priežasčių ir vėlyvajai revaskulizacijai pacientams, turintiems neobstrukcinę širdies vainikinių arterijų ligą.
• Ištirti aspirino poveikį mirštamumui nuo visų priežasčių ir vėlyvajai revaskulizacijai pacientams, turintiems neobstrukcinę širdies vainikinių arterijų ligą.
Tyrimo metodai
Atlikta sistematinė literatūros apžvalga, naudojant šias paieškos sistemas: „PubMed“, „Cochrane Library“, „ScienceDirect” ir „UpToDate”. Toliau pakartotinai peržiūrėtos pasirinktų publikacijų bibliografijos. Galiausiai papildant trūkstamą informaciją buvo naudoti „MedScape” ir „PSO” (Pasaulio Sveikatos Organizacija) internetiniai tinklalapiai.
Tyrimo rezultatai ir išvados
Atliktas literatūros šaltinių studijos tyrimas parodė, kad neobstrukcinė širdies vainikinių arterijų liga yra patologija su didele klinikine rizika: susijusi su padidėjusiu miokardo infarktu ir mirtingumu, pacientai turintys šią patologiją turi blogesnes prognozes, nei tie, kurie neturi neobstrukcinės širdies vainikinių arterijų ligos.
2. ACKNOWLEDGMENTS
3. CONFLICT OF INTEREST
4. ETHICS COMMITTEE APPROVAL
5. ABBREVIATIONS
ACCF American College of Cardiology Foundation ACEI angiotensin-converting-enzyme inhibitor
ACS acute coronary syndrome
AMI acute myocardial infarction
ARB angiotensin II receptor blocker
CAG coronary angiography
CACS coronary artery calcium scoring
CAD coronary artery disease
CCTA cardiac computed tomography angiography
CMRI cardiac magnetic resonance imaging
CVD cardiovascular disease
DAPT dual antiplatelet therapy
GFR glomerular filtration rate
HR hazard ratio
ICAD insignificant coronary artery disease
IHD ischemic heart disease
INOCA ischemia with no obstructive coronary artery disease
IVUS intravascular ultrasound
LAD left anterior descending artery
LBBB left bundle branch block
MACE major adverse cardiac event
MI myocardial infarction
MINOCA myocardial infarction with no obstructive coronary arteries NO-CAD non-obstructive coronary artery disease
NSTE-ACS non-ST elevation acute coronary syndrome
PET position emission tomography
SIHD stable ischemic heart disease
TCFA thin-cap fibroatheroma
VIE virtual intravascular endoscopy
6. INTRODUCTION
Non-obstructive coronary artery disease (CAD) is defined as the buildup of atherosclerotic plaque in the coronary arteries with a reduction in luminal diameter by <50%. Since it typically does not obstruct blood flow or result in anginal symptoms, it has historically been considered benign and clinically insignificant, hence the name “insignificant coronary artery disease (ICAD)”. However, recent studies have shown that non-obstructive CAD poses significant risks for major adverse cardiac events and mortality [1][2].
Despite accumulating evidence suggesting otherwise, the concept of “critical” coronary artery stenosis, that is a reduction in luminal diameter >50%, at which point the cardiac flow reserve begins to diminish, has been rooted in clinician’s minds [3]. This idea was first suggested by Gould et al. 40 years ago and presupposes that there is an abrupt change in risk between non-obstructive (<50%) and non-obstructive (>50%) CAD, rather than viewing coronary atherosclerosis as a largely progressive process [3]. It also does not recognize that most acute coronary syndromes are caused by ruptured plaque, rather than occlusive plaque and progressive stenosis [4]. According to recent literature, the majority of this ruptured plaque arises from non-obstructive CAD, which suggests that non-non-obstructive CAD is associated with significant risk for MI and all-cause mortality [1]. It can therefore be said that using the traditional dichotomous differentiation of non-obstructive and obstructive CAD as a means to classify cardiac risk is a misleading oversimplification of the underlying pathophysiology of coronary atherosclerosis. This oversimplified classification has led to individuals with non-obstructive CAD being less likely to be treated with guideline-recommended therapy, compared to individuals with obstructive CAD [5], even though research suggests that preventive therapies may be of use to both groups of patients [6].
7. AIMS AND OBJECTIVES
Research aim
The aim of this research is to provide an account of primary literature about non-obstructive coronary artery disease, as well as the effect statin and aspirin therapy may have for individuals with this pathology.
Objectives
1. To describe the significance, incidence, clinical presentation and prognosis of non-obstructive coronary artery disease.
2. To investigate the impact of statin therapy on all-cause mortality and coronary revascularization in patients with non-obstructive coronary artery disease.
8. LITERATURE REVIEW
8.1 Non-obstructive coronary artery disease
Definition of non-obstructive CAD
Since the pathological implications of non-obstructive CAD are not yet fully understood, it is a condition hard to classify, thereby making universally-approved definitions hard to determine. Furthermore, variable methods of coronary angiogram interpretations (visual estimation, differing stenosis quantification methods, differing core labs) amongst medical institutions add another level of uncertainty to the classification.
According to the Women's Ischemia Syndrome Evaluation (WISE) angiographic core lab, any luminal irregularity, considered to be atherosclerotic, must yield a minimum of 20% diameter reduction, compared to the segment of the same part of the coronary artery, which has the most normal appearance [2]. Vessel tapering may result in a 0 to 19% reduction in luminal diameter. This means that any patient with a normal-appearing coronary artery system and no stenoses exceeding 20% is classified as a patient with “no apparent CAD”. Stenoses in one or more coronary arteries ranging from 20 to 50% are classified as non-obstructive CAD, whereas any narrowing exceeding 50% defines obstructive CAD. This can be further classified into single-, double-, or triple vessel CAD.
More recent guidelines described by the American College of Cardiology Foundation (ACCF) have defined non-obstructive CAD as any atherosclerotic stenosis greater that 20% but less than 50% in the left main coronary artery, and greater than 20% but less than 70% in any other major epicardial artery [11]. Normal coronary anatomy was defined as stenosis less than 20% which coincides with the definition brought forth by the WISE.
Incidence of non-obstructive CAD
In fact, prevalence of those with non-obstructive CAD in women is 1.5 times higher than that in men among patients with stable chest pain and twice higher than that in men among those with NSTE-ACS [13]. This significant sex difference has lead a recent study to describe non-obstructive CAD as a “women’s problem” [7]. However, this overrepresentation of women in patients with non-obstructive CAD is only relative to those with obstructive CAD. Men still account for 65% of those with non-obstructive CAD amongst individuals with stable angina and 45% of them amongst patients with NSTE-ACS [13].
Amongst patients undergoing coronary angiography (CAG), non-obstructive CAD is a relatively common finding, occurring in 10 to 25% of patients [1]. Importantly, the development of coronary computed tomography angiography (CCTA) has led to a significant increase of individuals diagnosed with non-obstructive CAD [9]. CCTA is a non-invasive angiographic modality, which provides direct anatomical evidence of coronary atherosclerosis. Being non-invasive and more accurate than CA, the use of CCTA has resulted in an increase of the proportion of obstructive CAD to 15 to 37% [3]. More specifically, patients with non-obstructive CAD occupy 15 to 30% of symptomatic cases and 16% of asymptomatic cases referred to CCTA [9].
Historically, non-obstructive CAD was viewed as a “benign” condition which does not cause ischemia or angina. However, recent research has challenged this idea and while a stenosis of <50% is still thought to produce no ischemia, it has been well documented that patients with non-obstructive CAD may have anginal symptoms, which are clinically relevant and may have detrimental consequences such as MI and even death. According to a paper published by the Mayo Foundation for Medical Education and Research in 2016, individuals with non-obstructive CAD account for 67% of patients with stable angina and 13% of patients with NSTE-ACS [13].
Clinical Presentation of non-obstructive CAD
INOCA
Patients presenting with signs and symptoms suggesting ischemic heart disease, but found to have no obstructed coronary arteries are being increasingly recognized [14]. In recent literature, this syndrome has been described as ischemia and no obstructive coronary artery disease (INOCA) [14]. Typical ischemic signs and symptoms include angina, dyspnea, palpitations, diaphoresis etc. However, atypical symptoms such as stomach pain or simply fatigue may be especially prominent in diabetic patients.
MINOCA
Myocardial infarction with no obstructive coronary arteries or MINOCA is an event where a patient with clinical features of an acute myocardial infarction (AMI), upon early angiography, does not reveal an occluded vessel or possibly any sign of CAD. This occurs is approximately 10% of patients presenting with signs of AMI [15][16].
A systematic review of the literature comparing the clinical characteristics of AMI with and without obstructive CAD revealed that MINOCA patients have no distinguishing clinical presentation. However, these patients tend to be younger, are more frequently female and have significant cardiovascular risk factors [17].
Diagnostic Modalities
Coronary Angiography (CAG)
Fig. 1. Progression of CAD as seen on four CAG images (Yokoya et al. [20])
Fig. 1 visualizes four serial coronary angiograms in a patient with atherosclerotic progression. The stenosis percentages of the left anterior descending coronary artery (arrowhead) are as follows: first CAG 38%, second CAG 45%, third CAG 58% and final CAG 67%. Therefore, the first two angiograms classify as non-obstructive CAD, while the third and fourth angiograms classify as obstructive CAD. Note how the atherosclerotic plaque progresses continuously. The first, second and third CAGs were performed 11, 7 and 4 months prior to the final CAG, respectively. It is important to acknowledge the fact that this 2D representation of the coronary arteries may be insufficient in determining the exact percentage of stenosis. Furthermore, the vulnerability of the plaque cannot be determined using CAG.
Computed Tomography Coronary Angiography (CCTA)
composition, which further strengthens the identification of patients at risk of plaque rupture. However, since there is a large variability of plaque characteristics in relation to plaque vulnerability in CCTA, it may be difficult to precisely identify the culprit lesion [19].
Despite this, recent literature has shown that the diagnostic value of CCTA with regards to non-obstructive CAD is superior to that of CAG. As Leber et al. concluded: CCTA is a “clinically robust modality that allows the identification of proximal coronary lesions with excellent accuracy” [22].
Fig. 2. Grade severity of luminal stenosis, detected by CCTA (Thomas et al. [23])
Fig. 2 demonstrates how CAD severity can be assessed using CCTA. This roughly equates to the diagnostic value of CAG with regards to stenosis quantification. However, the image may be further analyzed. Following stenosis assessment, grading of CCTA-identified plaque features and CAD extent may be assessed.
Further analysis of a CCTA image, as seen on Fig. 3, can reveal features associated with an increased risk of MACE. Image “a” shows extensive non-obstructive calcified plaque in four segments on the coronary artery tree (left main artery, proximal left anterior descending [LAD] artery, proximal left circumflex artery, first obtuse marginal artery). Image “b” shows an atherosclerotic plaque with positive remodeling and low-attenuation plaque in the proximal LAD. Image “c” is a CAG image, demonstrating occlusion of the proximal LAD at the site of high-risk plaque 10 months after the CCTA was performed. This demonstrates that CCTA is a more sensitive diagnostic modality with regards to detecting early atherosclerotic changes, which may result in MACE.
Fig. 4. Virtual intravascular endoscopy (VIE) visualization of mixed plaque (Sun et al.
[19])
Fig. 4 demonstrates a CCTA generated virtual intravascular visualization of mixed plaque in a patient with non-obstructive CAD. This 3D representation may provide aid in evaluating both coronary lesions and lumen changes, which are considered to enhance the diagnostic value of this modality [19].
Diagnostic criteria
MINOCA
The diagnostic criteria for MINOCA include the following [24]: 1. Acute myocardial infarction criteria, including:
a. Positive cardiac biomarker (myoglobin, cardiac troponin I, cardiac troponin T, creatine kinase MB): a rise and/or fall in serial levels, with at least one value above the 99th percentile
b. Clinical evidence of AMI, including any of the following: i. Symptoms of ischemia (chest pain and/or dyspnea)
ii. ECG: new ischemic changes (ST segment, LBBB, pathological Q waves) iii. Myocardial perfusion imaging: new loss of viable myocardium
v. Left ventricular imaging: new regional wall motion abnormality 2. Absence of obstructive CAD: no stenosis ≥50% on angiography
3. No clinically overt cause for AMI presentation
It is important to note that, even though the diagnostic criteria for MINOCA are specific, it should be considered a working diagnosis, rather than a final diagnosis [24]. This concept can be compared to that of heart failure, where the underlying etiology needs further evaluation [15]. After excluding non-cardiac pathologies responsible for elevated troponin levels (pulmonary embolism, renal impairment etc.), cardiac causes should be considered. These disorders may be associated with structural myocardial dysfunction or ischemic myocardial damage and include cardiomyopathy, myocarditis, vasospastic angina, microvascular angina and thrombophilia disorders [15].
Prognosis
Historically, non-obstructive and obstructive CAD were treated as dichotomous entities. NO-CAD was considered insignificant, benign and indicative of a favorable prognosis, while obstructive CAD was the primary focus in CAD management due to its perceived role in cardiac ischemia and accompanying angina symptoms [1]. While it remains true that obstructive CAD has a worse prognosis than its non-obstructive counterpart, the latter has been proven to carry significant risks [1].
Major adverse cardiac event (MACE)
A meta-analysis conducted by Wang et al. [13] for the Mayo Foundation for Medical Education and Research, evaluated the risk of cardiac events (MACE) in patients with non-obstructive CAD referred for CAG or CCTA. It concluded that the risk of hard cardiac events in patients with non-obstructive CAD was 72% lower than that in patients with obstructive CAD but was 85% higher than that in patients with no angiographic atherosclerosis.
Furthermore, Maddox et al. [1] found that the annual event rates in patients with no angiographic CAD, non-obstructive CAD and obstructive CAD were 0,3%, 0,7% and 2,7% respectively amongst patients with stable angina and 1,2%, 4,1% and 17,0% amongst patients with NSTE-ACS. These statistics indicate a gradual increase in MACE risk from no ischemic heart disease, followed by non-obstructive CAD and finally obstructive CAD, rather than abruptly increasing between non-obstructive and obstructive CAD. This trend is visualized on Fig. 5 below.
This finding is supported by Hung et al. [3] who conducted a study, exploring the prognosis of non-obstructive CAD compared to that of normal coronary arteries, determined by invasive CAG or CCTA. 29 studies encompassing a total of 25669 patients (both non-obstructive CAD and normal arteries) reported cases of MACE. Patients with non-obstructive CAD had a significantly higher occurrence of MACE compared to those with normal arteries (622 versus 377).
These findings shed light on the limitations of a dichotomous characterization of CAD into obstructive and non-obstructive to predict MI and highlight the need for preventive pharmacotherapies and lifestyle modifications to mitigate these risks.
All-cause mortality
According to Maddox et al. [1], the risk of all-cause mortality in patients with non-obstructive CAD is 50% lower than that in patients with obstructive CAD and 42% higher than that in patients with no angiographic CAD [13].
A largely progressive relationship with increasing CAD extent, ranging from 1,38% among patients without apparent CAD to 4,30% among patients with obstructive CAD was demonstrated [1]. This progressive relationship is visualized on Fig. 6 below.
Fig. 6. Time-to-event plots for mortality (Maddox et al. [1])
Fig. 7. Survival curves as a function of number of coronary arteries with non-obstructive CAD (Chow et al. [6])
Note that as the number of vessels affected by non-obstructive stenoses increases, the survival rate gradually decreases. This further highlights the importance of atherosclerotic burden: not only the degree of stenosis, but also the plaque distribution determines the overall outcome of non-obstructive CAD.
Prognostic role of plaque morphology
A study conducted by Ahmadi et al. [26] shed light on the prognostic value of morphological features of atherosclerosis. It found that the death rate increased incrementally from calcified plaque (1,4%) to mixed plaque (3,3%) to non-calcified plaque (9,6%). This means that for these patients, calcified plaques carry a better long-term prognosis that non-calcified or mixed plaque, independent of the risk factors or the number of arteries involved (Fig. 8).
The current expert consensus states that morphology, composition and degree of inflammation of a coronary atherosclerotic plaque is more important than the degree of luminal stenosis [27], as it predicts its vulnerability and likelihood to rupture, thereby causing coronary thrombosis. This, in turn, may result in potentially devastating events, such as heart attack and stroke. Studies have shown that approximately 76% of all fatal coronary thrombi are precipitated by plaque rupture [28]. The prototype of rupture-prone plaque is primarily composed of a large lipid-rich necrotic core containing macrophages and smooth muscle cells, covered by a thin and inflamed fibrous cap, conjointly known as thin-cap fibroatheroma (TCFA) [29]. It is characterized by angiogenesis, adventitial inflammation and remodeling. In a major prospective follow-up study, conducted by Stone et al. [30], the TCFA phenotype was associated with an increased risk of recurrent MACE after ACS. Most of the events not related to the previous culprit lesion occurred at sites with TCFA, whereas the degree on stenosis was a poor predictor of plaque rupture as the average stenosis of a culprit lesion was only 30% [30].
This finding gives further importance to the use of CCTA as a diagnostic modality, as it is capable of identifying high-risk plaques before they cause significant stenosis and accompanying symptoms.
Role of Angina
Jespersen et al. [31] investigated the prognostic implications of stable angina pectoris in individuals with normal or non-obstructive coronary arteries, compared to patients with no known ischemic heart disease. The authors were able to demonstrate that, if stable angina is present, individuals with normal coronary arteries were associated with a 52% increased risk of MACE and those with diffuse non-obstructive CAD were associated with an 85% risk increase. MACE was defined as cardiovascular mortality, hospitalization for MI, heart failure or stroke. In addition to this, all-cause mortality risk increased 29% and 52%, respectively, for these two groups. In conclusion, a graded increase in future MACE risk and all-cause mortality with increasing atherosclerotic burden was demonstrated.
Prognosis of MINOCA
from single- or double-vessel CAD. In addition to MACE outcome, Grodzinsky et al. [33] reported that 25% of MINOCA patients continued to experience angina symptoms 12 months after the AMI occurrence. This is comparable to the rate in individuals with AMI with obstructive CAD.
Abdelmonem et al. [34] demonstrated that patients with non-obstructive CAD admitted with ACS carried a better outcome than those with obstructive CAD. Non-obstructive CAD patients showed a lower cardiovascular risk profile, as they were less likely to be old, male, diabetic, hypertensive or dyslipidemic. Furthermore, the likelihood of being diagnosed with ST-elevated ACS was drastically lower in patients with MINOCA than it was for those with MI with obstruction.
Table 1. In-hospital outcome for patients admitted for ACS with non-obstructive (group I) and obstructive CAD (group II) (Abdelmonem et al. [34])
Amongst patients admitted with symptoms of ACS, in-hospital clinical outcome was better in those with non-obstructive CAD (group I) than it was for those with obstructive CAD (group II): they had lower rates of recurrent angina and cardiogenic shock (Table 1).
Table 2. Outcome after 3 months for patients admitted for ACS with non-obstructive (group I) and obstructive CAD (group II) (Abdelmonem et al. [34])
8.2 The Impact of Aspirin and Statins
When looking at the prognostic implications of non-obstructive CAD, and the detrimental consequences associated with it, it is easy to deduce that preventive measures are needed to improve survival and quality of life, by reducing risk of future MIs and decreasing the need for interventional procedures. Numerous guideline-recommended strategies target prevention and regression of atherosclerosis in obstructive CAD and promising innovative therapies, targeting this group of patients are being developed [7]. Though most patients with non-obstructive CAD likely have coronary atherosclerosis, no guideline-recommended therapy (except for CVD risk factor management and symptomatic relief) is available. This group of patients should receive the same clinical attention as those with obstructive CAD, yet they are often dismissed as having an insignificant clinical condition.
A retrospective cohort study conducted by Maddox et al. [5] focused on 1489745 patients undergoing coronary angiography, aiming to evaluate medication prescription at hospital discharge among eligible patients. Specifically, the rates of aspirin, statins, beta-blockers, and ACEI/ARB prescription at hospital discharge between patients with non-obstructive CAD and obstructive CAD were compared.
The study concluded that “the presence of non-obstructive CAD was significantly and strongly associated with lower rates of secondary prevention medication prescription at hospital discharge compared to patients with obstructive CAD”.
Fig. 9. Rates of secondary prevention medication prescription at hospital discharge amongst patients with mild non-obstructive, moderate non-obstructive, and obstructive
As can be seen on Fig. 9, prescription rates exhibited a dose-response relationship with CAD severity, with mild non-obstructive CAD patients receiving the lowest rates of prescription, followed by moderate non-obstructive CAD, and finally obstructive CAD.
Fig. 10. Secondary prevention medication prescription at hospital discharge among patients with obstructive CAD, mildly obstructive CAD, and moderately
non-obstructive CAD all in comparison to non-obstructive CAD (Maddox et al. [5])
Fig. 10, also taken from the Maddox et al. study [5], visualizes the discrepancies of preventive medication prescription upon hospital discharge between patients with mildly non-obstructive CAD, moderately obstructive CAD and obstructive CAD. Note that patients with non-obstructive CAD (especially those with mild non-non-obstructive CAD), who have undergone coronary angiography, persistently have a lower rate of prescription when being discharged. De Ferrari et al. [35] reported similar findings when exploring whether the detection of non-obstructive CAD at coronary angiography was an independent predictor of lower prescription of guideline recommended discharge medications. The main finding was that patients with ACS and non-obstructive CAD were significantly less likely to be treated with guideline- recommended therapy.
Statins
General Information
Statins reduce cholesterol synthesis in the liver by competitively inhibiting the enzyme HMG-CoA reductase and its activity. The reduction of intracellular cholesterol concentration results in LDL receptor expression on the hepatocyte cell surface, thereby increasing extraction of LDL from the blood and reducing its circulation concentration [36]. Besides lowering LDL-cholesterol, statins have pleiotropic effects such as reducing inflammation, reducing thrombus formation, and improving endothelial function [37].
A number of large-scale clinical trials have demonstrated that statins significantly reduce cardiovascular morbidity and mortality in both primary and secondary prevention [38]. Statins have also been shown to halt progression and even promote regression of coronary atherosclerosis [10]. They should therefore be used as the drugs of first choice in patients with hypercholesterolemia or combined hyperlipidemia. For these patients the treatment target of LDL cholesterol is 1.8 mmol/l (70 mg/dl) and/or a 50% reduction if the target level cannot be reached [36].
The Impact of Statins on non-obstructive CAD
The role of statin therapy in improving lipid profiles extends to patients with non-obstructive CAD. However, the effect of statins on “hard” endpoints (MACE, death) continues to be subject to debate.
for composite endpoints which occurred 1.17% of statin users and 1.67% of non-statin users. The composite endpoint for this study was defined as mortality and late coronary revascularization (>90 days after CCTA).
Risk factors, such as age, sex, presence of diabetes or hypertension were more frequent in statin users, however, risk adjusted survival curves demonstrated that statin therapy was associated with a significant reduction in study endpoints (adjusted HR all-cause mortality 0.397, for composite endpoint 0.430).
Fig. 11. All-cause mortality free survival for statin users versus non-users amongst patients with non-obstructive CAD (Hwang et al. [8])
Fig. 11 shows a risk adjusted survival curve of statin users versus non-users amongst patients with non-obstructive CAD. Note that statin users have a better prognosis in terms of all-cause mortality-free survival than statin non-users.
Fig. 12, taken from the same study [8], compares the all-cause composite end point-free survival of statin users and non-users amongst patients with non-obstructive CAD. Patients undergoing statin therapy are significantly less likely to experience a composite end point than those not being treated with statins.
These results show that, despite having more risk factors, statin users showed better survival, regardless of age, presence of diabetes, hypertension or aspirin use. This study clearly demonstrated that the use of statins was associated with lower risk of all-cause mortality and coronary revascularization in patients with non-obstructive CAD.
Chow et al. [6] acquired similar results in their study, which examined “the impact of baseline statin on mortality in individuals with non-obstructive CAD”, as well as those without coronary plaque. The study comprised 3465 statin users, of which 29 (0.76%) died, and 6953 non-statin users, of which 91 (1.31%) died. Amongst the patients with non-obstructive CAD, death occurred in 9 patients (0.6%) in statin users and 32 patients (0.8%) in non-statin users. Looking at the population with no atherosclerotic coronary plaque, death occurred in 20 patients undergoing statin therapy (1.0%) and 59 non-statin users (2.2%). These results can be seen on the Table 3 below.
Table 3. Mortality rates for statin users and non-users in patients with non-obstructive coronary artery disease
It was concluded that baseline statin therapy was associated with lower mortality (0.76% for users, 1.31% for users) and a lower annual death rate (0.33% for users, 0.59% for non-users) in patients with non-obstructive CAD. In multivariable risk adjusted models, statin use was associated with a significant survival benefit (HR 0.52), as can be seen on Fig. 13.
All patients (n = 10418) No plaque (n = 5712) Non-obstructive CAD (n = 4706)
Total Deaths Total Deaths Total Deaths
Statin users 3465 29 (0.76%) 1432 20 (1.0%) 2033 9 (0.6%) Non-statin
users
Fig. 13. Survival curves for statin users and users amongst patients with non-obstructive CAD (Chow et al. [6])
For patients with normal coronary arteries, however, baseline statin therapy was not associated with lower mortality (0.6% versus 0.8%) or annual death rate (see Fig. 14). Subgroup analysis showed that the effect of statin use was only observed for patients with non-obstructive CAD (HR 0.39 [0.23 - 0.65]), but not in those with normal coronary arteries (HR 0.64 [0.30 - 1.37]).
Fig. 14. Survival curves for statin users and non-users amongst patients without CAD
(Chow et al. [6])
Currently, there are no randomized trials addressing recommended therapies for patients with MINOCA. However, a recent study by Lindahl et al. [16] provides the first insight into potential long-term medical therapy in the management of MINOCA. 9136 MINOCA patients admitted to a cardiac unit in Sweden were studied between 2003 and 2013 for a mean of 4.1 years. 19% of these patients were treated with statins and experienced a significant 23% lower (HR 0.77 [0.68–0.87]) risk of a MACE compared to those without statin therapy. This statistic is visualized on the graph below (Fig. 15).
Fig. 15. Survival curves for statin users and non-users amongst MINOCA patients
(Lindahl et al. [16])
Aspirin
General Information
Aspirin remains the cornerstone of pharmacological prevention of arterial thrombosis [10]. It inhibits thromboxane production by irreversibly binding platelet cyclooxygenase-1 (COX-1). To achieve this effect, a minimal dosage of 75 mg/day is required. Unlike the antiplatelet effects, gastrointestinal side-effects occur more frequently at higher dosages. According to ECS guidelines, the ideal risk-benefit ratio appears to be achieved with a daily dosage of 75 to 150 mg [39].
The 2012 ACCF guidelines for the diagnosis and management of patients with stable ischemic heart disease (SIHD) recommends a treatment with aspirin (75 to 162 mg daily) to patients with SIHD in the absence of contraindications [40]. As previously discussed, patients with non-obstructive CAD may very well have ischemic signs and symptoms (INOCA) and therefore fall into this category of individuals. However, non-obstructive CAD is never specifically mentioned in recent ACCF guidelines for SIHD, which focuses on obstructive CAD as the pathophysiology of ischemia. Though ischemia resulting from non-obstructive CAD has been acknowledged in the most recent ESC guidelines on the management of stable coronary artery disease [39], thrombosis prevention guidelines for this group of patients are not present.
The Impact of Aspirin on non-obstructive CAD
Aspirin’s established role as a thrombosis prevention medication in patients with obstructive CAD, at risk of MACE, has led to speculation about its use in non-obstructive CAD patients. Recent studies have shown that even without obstructive lesions which may cause myocardial ischemia, prescription of preventive medications such as aspirin, was significantly increased and/or intensified after CCTA in patients with non-obstructive CAD [41]. However, the effect of aspirin in these patients has not yet been established.
of the population was 61.4 years and the majority were male (70.3%). 3751 (44.8%) patients started using aspirin after CCTA. Compared to aspirin non-users, aspirin users were older, suffered from comorbidities more frequently and had more medication prescriptions. The proportion of patients with a history of cerebrovascular disease was higher in the branch of aspirin users (29.9%) than it was in the branch of aspirin non-users (13.8%). The use of clopidogrel was also more prevalent in aspirin users (20.8% versus 6.7%). Baseline serum glucose, HbA1c and CACS were higher and GFR was lower in aspirin users.
During 828 days of follow-up, a total of 221 (2.6%) cases of all-cause mortality and 295 (3.5%) cases of the composite end point (all-cause mortality and late coronary vascularization) were observed. Annualized mortality rate was 0.97% amongst aspirin users and 1.28% amongst non-users. Proportional hazard regression models showed that the initiation of aspirin therapy after CCTA was significantly associated with a lower risk of all-cause mortality (HR 0.649). This can be seen on the graph below (Fig. 16).
Fig. 16. All-cause mortality free survival curves for aspirin users versus non-users amongst patients with non-obstructive CAD (Hwang et al. [9])
Fig. 17. Composite endpoint (mortality or late coronary revascularization)-free survival for aspirin users versus non-users amongst patients with non-obstructive CAD (Hwang et al.
[9])
Although aspirin therapy was associated with a lower risk of all-cause mortality, the effects were not consistent amongst all subgroups. Patients older than 65 years, with hypertension, hsCRP >2mg/l, GFR <60 ml/min/1.73m2 and those with diabetes showed a significant
association between aspirin use and decreased all-cause mortality, though the remaining subgroups did not. Equally, the benefits of aspirin were not significant for the composite endpoint.
These results clearly demonstrate that there are benefits of aspirin use for patients with non-obstructive CAD and higher risk: the patients with age >65 years, diabetes, hypertension, decreased renal function, or higher CACS, LDL-C or hsCRP. However, it is always important to weigh the preventive cardiovascular effect of aspirin against its unavoidable major bleeding risk, especially in patients who only have some of these risk factors. It can be concluded that for lower risk patients, the use of aspirin therapy is not justifiable. For these patients, the absolute benefit which aspirin therapy carries is far less than those with higher risk, while the risk of bleeding outweighs the benefits.
>100 but not in those with 0 CAC. The study emphasized that aspirin preventive therapy was more beneficial in those with high cardiovascular risk and endorsed the clinical application of CAC as a means of guiding aspirin treatment.
Fig. 18. Risk-benefit ratio of aspirin in primary prevention, estimated by CAC score
(Miedema et al. [42])
Fig. 18 demonstrates that, for the primary prevention of CVD, patients with a CAC score ≥100 are estimated to have a net treatment benefit of aspirin while those with a CAC score of zero have unfavorable risk/benefit profiles while undergoing aspirin therapy. Both of these findings are independent of CVD risk based on traditional risk factors. For patients with CAC between 1 and 99, aspirin has a net benefit only for those with a CHD (Framingham) risk score of >10%. Chow et al. [6] investigated “the effects of aspirin use on mortality in individuals with non-obstructive CAD”. According to their cohort study, aspirin therapy was not associated with a mortality benefit, irrespective of the status of plaque. A mortality reduction was not observed in those with non-obstructive CAD (HR 0.72 [0.46–1.14]) or normal coronary arteries (HR 0.84 [0.40–1.76]). The authors stated that this finding may be clinically important but not statistically significant, due to a low number of observed events (n = 120) resulting in statistical underpowering.
(33%) was also non-significant (HR 1.33 [0.73–2.42]). These results can be seen on the graph below (Fig. 19).
Fig. 19. Survival curves for dual antiplatelet therapy (DAPT) users and non-users amongst MINOCA patients (Lindahl et al. [16])
9. RESEARCH METHODOLOGY AND METHODS
This literature review involved an extensive primary online search of the following databases: PubMed, Cochrane Library, ScienceDirect and UpToDate. The key terms used while searching these databases were ‘non-obstructive coronary artery disease’ with or without ‘statins’ or ‘aspirin’. Publications from 2008 until 2018 were considered, though more recent studies were preferred. A total of 1398 publication which matched these criteria were found.
All titles were independently reviewed for inclusion. If considered relevant to the topic, the full text was acquired. 88 such publications were obtained. Thereafter, the abstracts and conclusions of the selected publications were reviewed as to further evaluate relevance. A total of 29 publications were found to meet all desired criteria. The primary search process used to identify relevant publications is visualized below (Fig. 20).
This primary search was supplemented by a secondary manual review of the selected publications’ reference lists. A further 13 publications were selected for this literature review, bringing the total number of studies used to 42.
Additionally, Medscape and WHO internet web pages were used to supplement missing information.
Selection Criteria
After searching the previously mentioned databases using the topic-related key words, only the results meeting the following criteria were considered: published in the last 10 years, full text available, English or Lithuanian language, focused on non-obstructive CAD. All population groups were included.
Fig. 20. Primary search process used to select relevant publications
1398 potentially relevant publications identified using medical databases
88 publications obtained for further review
29 relevant publications identified through primary search
1310 articles excluded after title review and duplicate removal
10. RESULTS AND THEIR DISCUSSION
When looking at literature regarding non-obstructive CAD taken from the last ten years, it becomes evident that it is a pathology with significant clinical implications, yet is often misunderstood, undertreated and insufficiently studied. The realization that coronary atherosclerosis and its associated risk is a progressive continuum, rather than abruptly increasing between non-obstructive and obstructive CAD, has undoubtedly underscored the limitations of the traditional dichotomy between “significant” and “insignificant” coronary stenosis. While obstructive CAD has long been the primary focus of CAD management due to its role in causing ischemia and angina pectoris, we now know that the majority of plaque ruptures and resultant myocardial infarctions result from non-obstructive plaque lesions [1]. Furthermore, non-obstructive CAD is a relatively common finding, occurring in up to 25% of patients undergoing elective coronary angiography. With the increased use of the more sensitive CCTA, these numbers have risen even further. In fact, a recent European consecutive-case registry has stated that the prevalence of non-obstructive CAD was 65% among women and 32% among men [31]. Similarly the American College of Cardiology – National Cardiovascular Data Registry found the prevalence to be at 51% in women and 32% in men [14]. This further illustrates that non-obstructive CAD is not only clinically relevant but also prevalent and should therefore be given the appropriate attention.
Clinicians must be aware of the heterogeneous nature of non-obstructive CAD to identify and treat it early enough as to prevent MACE. CCTA has proven to be a very useful diagnostic modality for early detection, as it can assess stenosis severity, plaque morphology and risk of rupture, as well provide a virtual 3D intravascular visualization [19]. Furthermore, it has proven to be a reliable prognosticator and a gatekeeper for further management. If all of these aspects are taken advantage of, CCTA is far superior to conventional invasive CAG in identifying early atherosclerotic lesions which may have devastating consequences.
These consequences have been thoroughly studied in recent literature and further highlight the fact that non-obstructive CAD is far from “insignificant”. It has been demonstrated that patients with non-obstructive CAD have an associated risk of MI which is 2 to 4.5 – fold greater than among those with no apparent CAD. Similar observations were noted with 1-year mortality rates, ranging from 1.38% among patients without apparent CAD to 2.72% among patients with 3-vessel non-obstructive CAD [1]. At 10 years, CVD death or MI occurred in 6.7% of those with no evident angiographic CAD, and in 12.8% among those with non-obstructive CAD [2]. Despite these risks, it has been found that patients with non-obstructive CAD, compared to those with obstructive CAD, receive significantly fewer secondary medication prescriptions at hospital discharge [5]. This highlights both substantial gaps and potential opportunities to improve the treatment regimens and clinical outcomes for these individuals.
be younger and have fewer comorbidities. Overall, it can be said that all studies investigated in this review concluded that individuals with non-obstructive CAD benefit from statin therapy.
Aspirin therapy for patients with non-obstructive CAD continues to be subject to debate. It has been suggested that there is an association between aspirin use and lower mortality risk for patients with >65 years, diabetes, hypertension, CAC score >100, LDL cholesterol >130 mg/dl, hsCRP >2 mg/l or GFR <60 ml/min/1.73m2 [9]. Furthermore, the benefits of aspirin were not
significant to the risk of coronary revascularization. These findings indicate that aspirin therapy in individuals with non-obstructive CAD is only beneficial to those with higher cardiovascular risk. This is contradicted by a study conducted by Chow et al. [6], which demonstrated that aspirin therapy is of no benefit to non-obstructive CAD patients, regardless of their risk factors. The authors also state, however, that this finding may be because of statistical underpowering, as the number of observed events was relatively small (n = 120). MINOCA patients don’t seem to benefit from a dual antiplatelet therapy, as it was shown that the risk of a future MACE was not significantly reduced [16].
11. CONCLUSIONS
The following conclusions can be drawn from this literature review:
1. Non-obstructive CAD is relatively prevalent (25% of patients undergoing CAG) and carries a great clinical risk and should therefore be treated accordingly.
2. Affected patients have a significantly greater 1-year MI risk, all-cause mortality risk and future MACE risk, compared to patients with no apparent CAD.
3. Non-obstructive CAD is a clinically heterogenous pathology, with presentations ranging from asymptomatic to MINOCA.
4. Baseline statin therapy is associated with a significant reduction in all-cause mortality and coronary revascularization risk for patients with non-obstructive CAD and for those with MINOCA.
5. Aspirin therapy was associated with lower all-cause mortality risk only in patients with >65 years, diabetes, hypertension, CAC score >100, LDL cholesterol >130 mg/dl, hsCRP >2 mg/l or GFR <60 ml/min/1.73m2. The benefits of aspirin were not significant
12. REFERENCES
[1] Maddox TM, Stanislawski MA, Grunwald GK, Bradley SM, Ho PM, Tsai TT, et al. Nonobstructive coronary artery disease and risk of myocardial infarction. JAMA 2014;312:1754–63. doi:10.1001/jama.2014.14681.
[2] Sharaf B, Wood T, Shaw L, Johnson BD, Kelsey S, Anderson RD, et al. Adverse outcomes among women presenting with signs and symptoms of ischemia and no obstructive coronary artery disease: findings from the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) angiographic core laboratory. Am Heart J 2013;166:134–41. doi:10.1016/j.ahj.2013.04.002. [3] Huang F-Y, Huang B-T, Lv W-Y, Liu W, Peng Y, Xia T-L, et al. The Prognosis of
Patients With Nonobstructive Coronary Artery Disease Versus Normal Arteries Determined by Invasive Coronary Angiography or Computed Tomography Coronary Angiography. Medicine (Baltimore) 2016;95:e3117.
doi:10.1097/MD.0000000000003117.
[4] Ahmadi A, Leipsic J, Blankstein R, Taylor C, Hecht H, Stone GW, et al. Do Plaques Rapidly Progress Prior to Myocardial Infarction?: The Interplay Between Plaque Vulnerability and Progression. Circ Res 2015;117:99–104.
doi:10.1161/CIRCRESAHA.117.305637.
[5] Maddox TM, Ho PM, Roe M, Dai D, Tsai TT, Rumsfeld JS. Utilization of Secondary Prevention Therapies in Patients With Nonobstructive Coronary Artery Disease Identified During Cardiac Catheterization Cath-PCI Registry 2010.
doi:10.1161/CIRCOUTCOMES.109.906214.
[6] Chow BJW, Small G, Yam Y, Chen L, McPherson R, Achenbach S, et al. Prognostic and Therapeutic Implications of Statin and Aspirin Therapy in Individuals With Nonobstructive Coronary Artery DiseaseSignificance. Arterioscler Thromb Vasc Biol 2015;35:981–9. doi:10.1161/ATVBAHA.114.304351.
[7] Pepine CJ, Ferdinand KC, Shaw LJ, Light-McGroary KA, Shah RU, Gulati M, et al. Emergence of Nonobstructive Coronary Artery Disease. J Am Coll Cardiol
[8] Hwang I-C, Jeon J-Y, Kim Y, Kim HM, Yoon YE, Lee S-P, et al. Statin therapy is associated with lower all-cause mortality in patients with non-obstructive coronary artery disease. Atherosclerosis 2015;239:335–42.
doi:10.1016/j.atherosclerosis.2015.01.036.
[9] Hwang I-C, Jeon J-Y, Kim Y, Kim HM, Yoon YE, Lee S-P, et al. Association between Aspirin Therapy and Clinical Outcomes in Patients with Non-Obstructive Coronary Artery Disease: A Cohort Study. PLoS One 2015;10:e0129584.
doi:10.1371/journal.pone.0129584.
[10] Nicholls SJ, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, et al. Effect of Very High-Intensity Statin Therapy. Change 2006;295:1556–65.
doi:10.1001/jama.295.13.jpc60002.
[11] Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. J Am Coll Cardiol 2011;58. doi:10.1016/j.jacc.2011.08.007.
[12] The top 10 causes of death. World Heal Organ 2017.
http://www.who.int/mediacentre/factsheets/fs310/en/ (accessed March 11, 2018). [13] Wang ZJ, Zhang LL, Elmariah S, Han HY, Zhou YJ. Prevalence and Prognosis of
Nonobstructive Coronary Artery Disease in Patients Undergoing Coronary Angiography or Coronary Computed Tomography Angiography. Mayo Clin Proc 2017;92:329–46. doi:10.1016/j.mayocp.2016.11.016.
[14] Bairey Merz CN, Pepine CJ, Walsh MN, Fleg JL. Ischemia and No Obstructive Coronary Artery Disease (INOCA): Developing Evidence-Based Therapies and Research Agenda for the Next Decade. Circulation 2017;135:1075–92.
doi:10.1161/CIRCULATIONAHA.116.024534.
[15] Pasupathy S, Tavella R, McRae S, Beltrame JF. Myocardial Infarction With Non-obstructive Coronary Arteries — Diagnosis and Management. Eur Cardiol Rev 2015;10:79. doi:10.15420/ecr.2015.10.2.79.
Perspective. Circulation 2017;135:1481–9. doi:10.1161/CIRCULATIONAHA.116.026336.
[17] Pasupathy S, Air T, Dreyer RP, Tavella R, Beltrame JF. Systematic Review of Patients Presenting With Suspected Myocardial Infarction and Nonobstructive Coronary
Arteries. Circulation 2015;131:861–70.
doi:10.1161/CIRCULATIONAHA.114.011201.
[18] Brian Boudi F. Coronary Artery Atherosclerosis Workup. Medscape 2016. https://emedicine.medscape.com/article/153647-workup#c19 (accessed April 21, 2018).
[19] Sun Z, Xu L. Coronary CT angiography in the quantitative assessment of coronary plaques. Biomed Res Int 2014;2014. doi:10.1155/2014/346380.
[20] Yokoya K, Takatsu H, Suzuki T, Hosokawa H, Ojio S, Matsubara T, et al. Process of progression of coronary artery lesions from mild or moderate stenosis to moderate or severe stenosis: A study based on four serial coronary arteriograms per year.
Circulation 1999;100:903–9. doi:10.1161/01.CIR.100.9.903. [21] Lin EC. Coronary CT Angiography. Medscape 2017.
https://emedicine.medscape.com/article/1603072-overview#a3 (accessed April 21, 2018).
[22] Leber AW, Knez A, Von Ziegler F, Becker A, Nikolaou K, Paul S, et al. Quantification of obstructive and nonobstructive coronary lesions by 64-slice computed tomography: A comparative study with quantitative coronary angiography and intravascular
ultrasound. J Am Coll Cardiol 2005;46:147–54. doi:10.1016/j.jacc.2005.03.071. [23] Thomas DM, Divakaran S, Villines TC, Nasir K, Shah NR, Slim AM, et al.
Management of Coronary Artery Calcium and Coronary CTA Findings. Curr Cardiovasc Imaging Rep 2015;8. doi:10.1007/s12410-015-9334-0.
[24] Pasupathy S, Tavella R, Beltrame JF. The What, When, Who, Why, How and Where of Myocardial Infarction With Non-Obstructive Coronary Arteries (MINOCA). Circ J 2016;80:11–6. doi:10.1253/circj.CJ-15-1096.
ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J 2016;38:ehw149. doi:10.1093/eurheartj/ehw149. [26] Ahmadi N, Nabavi V, Hajsadeghi F, Flores F, French WJ, Mao SS, et al. Mortality
Incidence of Patients With Non-Obstructive Coronary Artery Disease Diagnosed by Computed Tomography Angiography. Am J Cardiol 2011;107:10–6.
doi:10.1016/j.amjcard.2010.08.034.
[27] Gössl M, Versari D, Hildebrandt H, Mannheim D, Olson ML, Lerman LO, et al. Vulnerable Plaque: Detection and Management. Med Clin North Am 2007;91:573– 601. doi:10.1016/j.mcna.2007.03.004.
[28] Falk E. Pathogenesis of Atherosclerosis. J Am Coll Cardiol 2006;47:0–5. doi:10.1016/j.jacc.2005.09.068.
[29] Saraste A, Knuuti J. Prognosis of non-obstructive coronary plaques with high-risk CT morphology. Eur Heart J Cardiovasc Imaging 2014;15:255–6.
doi:10.1093/ehjci/jet272.
[30] Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, et al. A Prospective Natural-History Study of Coronary Atherosclerosis. N Engl J Med 2011;364:226–35. doi:10.1056/NEJMoa1002358.
[31] Jespersen L, Hvelplund A, Abildstrøm SZ, Pedersen F, Galatius S, Madsen JK, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J 2012;33:734–44. doi:10.1093/eurheartj/ehr331.
[32] Kang WY, Jeong MH, Ahn YK, Kim JH, Chae SC, Kim YJ, et al. Are patients with angiographically near-normal coronary arteries who present as acute myocardial infarction actually safe? Int J Cardiol 2011;146:207–12.
doi:10.1016/j.ijcard.2009.07.001.
[33] Grodzinsky A, Arnold S V., Gosch K, Spertus JA, Foody JM, Beltrame J, et al. Angina frequency after acute myocardial infarction in patients without obstructive coronary artery disease. Eur Hear J - Qual Care Clin Outcomes 2015;1:92–9.
[34] Abdelmonem YY, Bakr AA, El-Hossary HG, Ghany MMA. Patients with non-obstructive coronary artery disease admitted with acute myocardial infarction carry a better outcome compared to those with obstructive coronary artery disease. Egypt Hear J 2017;69:191–9. doi:10.1016/j.ehj.2017.03.001.
[35] De Ferrari GM, Leonardi S, Baduena L, Chieffo E, Lesce A, Repetto A, et al. Patients with acute coronary syndrome and nonobstructive coronary artery disease in the real world are markedly undertreated. J Cardiovasc Med 2011;12:700–8.
doi:10.2459/JCM.0b013e328348e575.
[36] Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J
2016;37:2999–3058l. doi:10.1093/eurheartj/ehw272.
[37] Lim SY. Role of Statins in Coronary Artery Disease. Chonnam Med J 2013;49:1. doi:10.4068/cmj.2013.49.1.1.
[38] Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009;338:1–8. doi:10.1136/bmj.b2376.
[39] Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, et al. 2013 ESC guidelines on the management of stable coronary artery disease. Eur Heart J 2013;34:2949–3003. doi:10.1093/eurheartj/eht296.
[40] Fihn SD, Julius Gardin CM, Chair V, Abrams J, Berra K, Blankenship JC, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and
Management of Patients With Stable Ischemic Heart Disease: Executive Summary. J Am Coll Cardiol J Am Coll Cardiol Immed Past Chair 2012;60:44–164.
doi:10.1016/j.jacc.2012.07.012.
[41] Cheezum MK, Hulten EA, Smith RM, Taylor AJ, Kircher J, Surry L, et al. Changes in Preventive Medical Therapies and CV Risk Factors After CT Angiography. JACC Cardiovasc Imaging 2013;6:574–81. doi:10.1016/J.JCMG.2012.11.016.
Estimates from the multi-ethnic study of atherosclerosis. Circ Cardiovasc Qual Outcomes 2014;7:453–60. doi:10.1161/CIRCOUTCOMES.113.000690.
[43] Pasupathy S, Tavella R, Beltrame JF. Myocardial Infarction with Nonobstructive Coronary Arteries (MINOCA): The Past, Present, and Future Management. Circulation 2017;135:1490–3. doi:10.1161/CIRCULATIONAHA.117.027666.
[44] Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients
presenting with ST-segment elevation. Eur Heart J 2018;39:119–77. doi:10.1093/eurheartj/ehx393.
[45] Antithrombotic Trialists’ (ATT) Collaboration AT (ATT), Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet (London, England) 2009;373:1849–60.
