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Guidelines
Authors of the original ESC guidelines document [1]: Gilles Montalescot, Udo Sechtem on
behalf of the Task Force on the management of stable coronary artery disease.
article info
Article history:
Received 19 November 2013
Accepted 6 February 2014
Available online 13 March 2014
Keywords:
Guidelines
Angina pectoris
Myocardial ischaemia
Stable coronary artery disease
Risk factors
Anti-ischaemic drugs
Coronary revascularization
Contents
Preamble. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e260
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e260
Definitions and pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e261
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e261
Natural history and prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e261
Diagnosis and assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e261
Symptoms and signs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e261
Non-invasive cardiac investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e262
Basic testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e262
Three major steps used for decision-making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e262
§
Prepared by the Czech Society of Cardiology.
§§
For permissions: please e-mail: guidelines@escardio.org.
* Corresponding author at: Klinika kardiologie IKEM, Vídeňská 1958/9, 140 21 Praha 4, Czech Republic. Tel.: +420 602 362 748.
E-mail address: michael.zelizko@ikem.cz (M. Želízko).
http://dx.doi.org/10.1016/j.crvasa.2014.02.006
0010-8650/# 2014 The Czech Society of Cardiology. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
e260 cor et vasa 56 (2014) e259–e273
1. Preamble 2. Introduction
Guidelines summarize and evaluate all evidence available, at These guidelines should be applied to patients with stable
the time of the writing process, on a particular issue. known or suspected coronary artery disease (SCAD): (i) those
Guidelines and recommendations should help physicians to having stable angina pectoris or other symptoms felt to be
make decisions in their daily practice. The level of evidence related to coronary artery disease (CAD) such as dyspnoea; (ii)
and the strength of recommendation of particular treatment those previously symptomatic with known obstructive or non-
options were weighed and graded according to predefined obstructive CAD, who have become asymptomatic with
scales, as outlined in Tables 1 and 2. treatment; (iii) those who report symptoms for the first time
Table 2 – Levels of evidence. Table 3 – Main features of stable coronary artery disease.
Level of evidence A Date derived from multiple randomized Pathogenesis
clinical trials or meta-analyses Stable anatomical atherosclerotic and/or functional
Level of evidence B Date derived from a single randomized alterations of epicardial vessels and/or microcirculation
clinical trial or large non-randomized Natural history
studies Stable symptomatic or asymptomatic phases which may be
Level of evidence C Consensus of opinion of the experts interrupted by ACS
and/or small studies, retrospective Mechanisms of myocardial ischaemia
studies, registries Fixed or dynamic stenoses of epicardial coronary arteries;
Microvascular dysfunction;
Focal or diffuse epicardial coronary spasm;
and are judged to already be in a chronic stable condition The above mechanisms may overlap in the same patient and
(for instance because history-taking reveals that similar change over time.
symptoms were already present for several months) [1]. Clinical presentations
Effort induced angina caused by:
epicardial stenoses;
3. Definitions and pathophysiology microvascular dysfunction;
vasoconstriction at the site of dynamic stenosis;
combination of the above.
Stable coronary artery disease is generally characterized by Rest angina caused by:
episodes of reversible myocardial demand/supply mismatch, Vasospasm (focal or diffuse);
epicardial focal;
related to ischaemia or hypoxia, which are usually inducible
epicardial diffuse;
and reproducible by exercise, emotion or other stress, but may
microvascular;
also be occurring spontaneously. Such episodes of ischaemia/ combination of the above.
hypoxia are commonly associated with transient chest Asymptomatic:
discomfort (angina pectoris). SCAD also includes the stabi- because of lack of ischaemia and/or of LV dysfunction;
lized, often asymptomatic, phases that follow an ACS. The despite ischaemia and/or LV dysfunction.
various clinical presentations of SCAD are associated with Ischaemic cardiomyopathy
different underlying mechanisms that mainly include: (i) ACS, acute coronary syndrome; LV, left ventricular; SCAD, stable
plaque-related obstruction of epicardial arteries; (ii) focal or coronary artery disease.
diffuse spasm of normal or plaque-diseased arteries; (iii)
microvascular dysfunction and (iv) left ventricular dysfunction
caused by prior acute myocardial necrosis and/or hibernation cardiac investigations such as stress testing or coronary
(ischaemic cardiomyopathy) (Table 3). imaging. These investigations may be used to confirm the
diagnosis of ischaemia in patients with suspected SCAD, assist
in stratifying risk associated with the disease and to evaluate
4. Epidemiology
the efficacy of treatment.
the threshold at which symptoms occur in relation to physical instability, biochemical markers of myocardial injury—such as
activities (Table 5). troponin T or troponin I—should be measured, preferably
using high sensitivity or ultrasensitive assays. If troponin is
6.1. Non-invasive cardiac investigations elevated, further management should follow the non-ST-
elevation acute coronary syndrome (NSTE-ACS) guidelines.
The optimal use of resources is only achieved if pre-test
probabilities based on simple clinical findings are taken into 6.2.2. Three major steps used for decision-making
consideration before selecting non-invasive cardiac investiga- Step I is the determination of the pre-test probability. In patients
tions. Once the diagnosis of SCAD has been made, further with intermediate probability step 2 consists of non-invasive
management decisions largely depend on the severity of testing to establish the diagnosis of SCAD including non-
symptoms, the patient's risk for adverse cardiac events and obstructive atherosclerosis. The latter may also be useful in
on patient preferences. Ideally, decisions about diagnostic and patients with a PTP for SCAD < 15% but intermediate probability
therapeutic management should be made together with the of atherosclerosis e.g. measured by SCORE system. Step 3
patient who needs comprehensible information about risks and consists of stratifying for risk of subsequent events usually on
benefits. the basis of available non-invasive tests in patients at inter-
mediate PTP. Usually, optimal medical therapy will be instituted
6.2.1. Basic testing between steps 2 and 3. In patients with severe symptoms who
This includes standard laboratory biochemical testing, a have a high-intermediate or high pre-test probability of disease,
resting ECG, resting echocardiography (Table 6), possibly early invasive coronary angiography (ICA) with appropriate
ambulatory ECG monitoring (Table 7), and, in selected invasive confirmation of the significance of a stenosis (usually
patients, a chest X-ray. If there is a clinical suspicion of CAD by FFR) and subsequent revascularization may be appropriate
bypassing non-invasive testing in steps 2 and 3.
Table 9 – Clinical pre-test probabilitiesa in patients with Table 10 – Use of exercise or pharmacologic stress testing
stable chest pain symptoms. in combination with imaging.
Age Typical Atypical Non-anginal Recommendations Class a Level b
angina angina pain An imaging stress test is recommended as the initial I B
test for diagnosing SCAD if the PTP is between 66–
Men Women Men Women Men Women 85% or if LVEF is <50% in patients without
typical angina
30–39 59 28 29 10 18 5 An imaging stress test is recommended in patients I B
40–49 69 37 38 14 25 8 with resting ECG abnormalities which prevent
accurate interpretation of ECG changes during stress
50–59 77 47 49 20 34 12
Exercise stress testing is recommended rather than I C
60–69 84 58 59 28 44 17 pharmacologic testing whenever possible.
70–79 89 68 69 37 54 24 An imaging stress test should be considered in IIa B
>80 93 76 78 47 65 32 symptomatic patients with prior revascularization (PCI
or CABG)
ECG = electrocardiogram; PTP = pre-test probability (%); SCAD = An imaging stress test should be considered to assess Iia B
stable coronary artery disease. the functional severity of intermediate lesions on
a coronary arteriography.
Probabilities of obstructive coronary disease shown reflect the
estimates for patients aged 35, 45, 55, 65, 75 and 85 years. CABG = coronary artery bypass graft; ECG = electrocardiogram;
Groups with a PTP < 15% can be managed without further testing. PCI = percutaneous coronary intervention; PTP = pre-test probabil-
Groups with a PTP of 15–65% could have an exercise ECG if feasible ity; SCAD = stable coronary artery disease.
as the initial test. However, if local expertise and availability permit a
Class of recommendation.
a non-invasive imaging based test for ischaemia this would be b
Level of evidence.
preferable given the superior diagnostic capabilities of such tests.
In young patients radiation issues should be considered.
Groups with a PTP between 66 and 85% should have a non-invasive Myocardial perfusion scintigraphy (SPECT/PET): Technetium-
imaging functional test for making a diagnosis of SCAD. 99m (99mTc) radiopharmaceuticals are the most commonly
In groups with a PTP > 85% and one can assume that SCAD is used tracers, employed with single photon emission comput-
present. They need risk stratification only.
ed tomography (SPECT) in association with a symptom-limited
exercise test on either a bicycle ergometer or a treadmill
(Table 15). As with all stress imaging techniques, SPECT
of approximately 85% (Table 8), 15% of all diagnostic results perfusion also provides a more sensitive prediction of the
will be false. Thus, the Task Force recommends no testing in presence of CAD than the exercise ECG. Pharmacological stress
patients with a low PTP < 15% or high PTP > 85% (Table 9). testing with perfusion scintigraphy is indicated in patients
Patients with a reduced left ventricular ejection fraction who are unable to exercise adequately. MPI using positron
(LVEF) of <50% and typical angina are at high risk for emission tomography (PET) is superior to SPECT imaging for
cardiovascular events and they should be offered ICA without the detection of SCAD and may be used if available.
previous testing (Fig. 1). Patients with an intermediate PTP of Stress cardiac magnetic resonance: CMR stress testing, in
15–85% should undergo further non-invasive testing (Fig. 2). conjunction with a dobutamine infusion, can be used to detect
Further testing may, however, be indicated for stratification of wall motion abnormalities induced by ischaemia. The tech-
risk of events, especially if no satisfactory control of symptoms nique has been shown to have a comparable safety profile to
is possible with initial medical therapy. dobutamine stress echocardiography (DSE).
Hybrid techniques: Hybrid SPECT/CT, PET/CT and PET/CMR
6.2.4. Stress testing for diagnosing ischaemia imaging are now available at a few selected centres. Hybrid
6.2.4.1. Electrocardiogram exercise testing. The main diagnos- imaging is a novel technique combining functional and
tic ECG abnormality during ECG exercise testing consists of a anatomical aspects.
horizontal or down-sloping ST-segment depression 0.1 mV,
persisting for at least 0.06–0.08 s after the J-point, in one or 6.2.5. Non-invasive techniques to assess coronary anatomy
more ECG leads. The main value of exercise ECG testing is in 6.2.5.1. Computed tomography. Calcium scoring (without con-
patients with normal resting ECGs. Inconclusive exercise ECGs trast injection) has no role in symptomatic patients for
are common and in these patients an alternative non-invasive diagnosing or excluding coronary stenosis. Coronary CT
imaging test often with pharmacological stress should be angiography (CTA) can visualize the coronary artery lumen.
selected. In patients at low intermediate pre-test probability, Since the specificity of coronary CTA decreases with increasing
coronary CTA is another option. amounts of coronary calcium, and the prevalence of coronary
artery stenosis was found to be high in symptomatic
6.2.4.2. Stress imaging. Stress echocardiography is performed individuals with an Agatston score >400, it is reasonable not
with exercise (treadmill or bicycle ergometer) or with to proceed with coronary CTA if the calcium score exceeds 400.
pharmacological agents (Table 10). A pharmacological test is Coronary CTA remains less reliable in patients with coronary
preferred when there is already a significant resting wall stents, due to artefacts caused by metal, the limited spatial
motion abnormality (dobutamine for viability assessment) resolution of CT and overestimation of the degree of stenosis.
and/or if the patient is unable to exercise adequately. Until Registry data confirm an excellent prognosis if coronary CTA
recently, stress echocardiography relied on inducible wall demonstrates the absence of coronary artery stenoses.
thickening abnormalities as a marker of ischaemia (supply–
demand mismatch). The pharmacological agent of choice to 6.2.5.2. Magnetic resonance coronary angiography. This tech-
produce supply–demand mismatch is dobutamine. nique is primarily a research tool.
e264 cor et vasa 56 (2014) e259–e273
Fig. 1 – Initial diagnostic management of patients with suspected SCAD. CAD, coronary artery disease; CTA, computed
tomography angiography; CXR, chest X-ray; ECG, electrocardiogram; ICA, invasive coronary angiography; LVEF, left
ventricular ejection fraction; PTP, pre-test probability; SCAD, stable coronary artery disease.
6.3. Invasive coronary angiography and ICA. An annual mortality >3% is defined as a high event
risk. It is in such patients that revascularization has the
ICA may, however, be indicated following non-invasive risk potential effect of improving prognosis. Low event risk
stratification for determination of options for revasculariza- patients are those with an annual mortality <1% whereas
tion. In patients who have a high PTP and severe symptoms, or the intermediate event risk group has an annual mortality of
a clinical constellation suggesting high event risk, early ICA 1% but 3%/year.
without previous non-invasive risk stratification maybe a good The strongest predictor of long-term survival is LV function
strategy to identify lesions potentially amenable to revascu- and patients with an LVEF <50% are already at high risk for
larization. FFR testing is advised if appropriate (Table 11). events. Especially in patients with tolerable symptoms ICA
and revascularization should be reserved for those patients
6.4. Stratification for risk of events found to be at high risk on the basis of non-invasive stress
testing. Patients with a high pre-test probability who do not
These guidelines provide a uniform definition of risk of need diagnostic testing should nevertheless undergo stress
adverse events based on commonly used non-invasive tests testing for event risk stratification purposes.
cor et vasa 56 (2014) e259–e273 e265
Fig. 2 – Non-invasive testing in patients with suspected SCAD and an intermediate pre-test probability. CAD, coronary artery
disease; CTA, computed tomography angiography; CMR, cardiac magnetic resonance; ECG, electrocardiogram; ICA, invasive
coronary angiography; LVEF, left ventricular ejection fraction; PET, positron emission tomography; PTP, pre-test probability;
SCAD, stable coronary artery disease; SPECT, single photon emission computed tomography.
Assessment of prognosis using ECG stress testing is defects in multiple coronary territories or LV dilatation
performed using the Duke treadmill score (http://www. represent a high risk subset.
cardiology.org/tools/medcalc/duke/). High risk by stress CMR is defined as new wall motion
When stress echocardiography is used, high event risk is abnormalities in 3 segments in the 17 segment model or as
defined by inducible wall motion abnormalities 3 of the 17 >10% (>2 segments) perfusion defect. However, CMR risk
segments. estimates are somewhat limited as only three slices of the LV
Stress-induced large reversible perfusion deficits (SPECT) are currently available for standard CMR tests.
>10% of the total LV myocardium (>2 of the 17 segments), Good prognostic data exist for ICA and patients with left
main disease and proximal triple vessel disease are at high
risk.
Table 11 – Risk stratification by invasive or non-invasive 6.5. Management aspects in the patient with known
coronary arteriography in patients with stable coronary coronary artery disease
artery disease.
Recommendations Class a Level b The clinical course of patients with known SCAD may continue
ICA (with FFR when necessary) is recommended for risk stratification I C to be stable or be complicated by phases of instability, MI and
in patients withj severe stable angina (CCS 3) or with clinical profile
suggesting a high event risk, particularly if the symptoms are heart failure. Re-assessment of the prognosis, following an
inadequately responding to medical treatment
initial evaluation documenting a low event risk status may be
ICA (with FFR when necessary) is recommended in patients with mild I C
or no symptoms with medical treatment in whom non-invasive risk considered after the expiration of the period for which the test
stratification indicates a high event risk and revasculartization is
considered for improvement ofprognosis is valid (Table 12).
ICA (with FFR when necessary)should be considered for event risk IIa C
stratification in patients with an inconclusive diagnosis or non-invasive
testing or conflicting results from different non-invasive studies 6.6. Special diagnostic considerations: angina with
If coronary CTA is available for event risk stratification, possible IIa C 'normal' coronary arteries
oveestimation of stenosis severity should be considered in segments
with severe calcifications. Additional stress imaging may be necessary
CCS = Canadian Cardiovascular Society; CTA = computed tomogra- Patients with microvascular angina have angina with mostly
phy angiography; FFR = fractional flow reserve; ICA = invasive typical features although the duration of symptoms may be
coronary angiography; PTP = pre-test probability; SCAD = stable prolonged and relation to exercise is somewhat inconsistent.
coronary artery disease. Often, these patients have abnormal results of stress tests.
a
Class of recommendation.
b
Patients with vasospastic angina present with typically
Level of evidence.
located anginal pain, which occurs at rest but does not—or
e266 cor et vasa 56 (2014) e259–e273
Table 12 – Re-assessment in patients with stable coronary nitroglycerin as well as isosorbide mononitrate and isosorbide
artery disease. dinitrate, are absolute contra-indications to use of PDES inhibi-
tors, because of the risk of synergistic effects on vasodilatation,
Recommendations Class a Level b
causing hypotension and haemodynamic collapse.
Follow-up visits are recommended every 4–6 therapy for I C
SCAD which may be extended to 1 year afterwards. Visits Hormone replacement therapy is at present not recommended
should be to the general practitioner who may refer to the
cardiologist in case of uncertainty. These visits should include
for primary or secondary prevention of CVD.
a careful history and biochemical testing as clinically
appropriate
An annual resting ECG is recommended and an additional I C 7.2. Pharmacological management of SCAD
ECG if a change in anginal status occurred or symptoms
suggesting an arrhythmia appeared or medication has been
changed which might alter electrical conduction. The two aims of the pharmacological management are to
An exercise ECG or stress imaging if appropriate is I C
recommended in the presence of recurrent or new symptoms
obtain relief of symptoms and to prevent CV events. Table 13
once instability has been ruled out. indicates the main side effects, contraindications and major
Reassessment of the prognosis using stress testing may be IIb C
considered in asymptomatic patients after the expiration of the drug–drug interactions. Table 14 presents the recommenda-
period for which the previous test was felt to be valid tions for drug therapy.
(“warranty period”)
Repetition of an exercise ECG may only be considered after at IIb C
least 2 years following the last test (unless there is a change in
clinical presentation)
7.2.1. Anti-ischaemic drugs
Nitrates offer coronary arteriolar and venous vasodilatation,
ECG = electrocardiogram; SCAD = stable coronary artery disease.
a
Class of recommendation. which are the basis of symptomatic relief of effort angina,
b
Level of evidence. acting by their active component nitric oxide (NO) and by the
reduction of preload. For acute effort angina short-acting
nitrates as sublingual nitroglycerin is the standard initial
occurs only occasionally—with exertion (typically at night and therapy. Nitroglycerin can be used prophylactically when
in the early morning hours). The ECG during vasospasm is angina can be expected, such as activity after a meal,
classically described as showing ST-elevation. Nitrates usually emotional stress, sexual activity and in cold weather. For
relieve the pain within minutes. Angiographically, these angina prophylaxis long-acting nitrates are not continuously
patients may show focal occlusive spasm (Prinzmetal's angina effective. Thus prolonged therapy with isosorbide dinitrate or
or variant angina). isosorbide mononitrate is not evidence-based.
In post-MI patient b-blockers achieved a 30% risk reduction
for CV death and MI. b-blockers may be the first line anti-
7. Lifestyle and pharmacological management anginal therapy in stable CAD patients without contraindica-
tions. Nevibolol and bisoprolol are partly secreted by the
7.1. Lifestyle modification kidney, whereas carvedilol and metoprolol are metabolized by
the liver, hence being safer in patients with renal compromise.
The aim of the management of SCAD is to reduce symptoms Calcium channel blockers reduce the peripheral vascular
and improve prognosis. The management of CAD patients resistance. Group of non-dihydropyridine (heart rate-lowering
encompasses lifestyle modification, control of CAD risk calcium channel blockers)—verapamil has a large range of
factors, evidence-based pharmacological therapy and patient approved indications, including all varieties of angina (effort,
education. Lifestyle recommendations include smoking ces- vasospastic, unstable), supraventricular tachycardias and
sation a healthy diet, regular physical activity, weight and lipid hypertension. Indirect evidence suggests good safety but with
management, BP and glucose control. risks of heart block, bradycardia and heart failure. Dihydro-
Smoking is a strong and independent risk factor for CVD and pyridines are powerful arterial vasodilators with a few serious
all smoking, including environmental smoking exposure, side-effects. However, the CCB and b-blocker combination is
must be avoided. Quitting smoking is complex because in often underused.
general, when smoking is both pharmacologically and Ivabradine is a heart rate-lowering agent selectively inhibits
psychologically highly addictive. the sinus node I(f) pacemaking current, thereby decreases the
A healthy diet reduces CVD risk. Healthy weight—is myocardial oxygen demand without effect on inotropism.
BMI < 25 kg/m2. Following the rules for a healthy diet, no Ivabradine is thus an effective anti-anginal agent, alone or in
dietary supplements are needed. combination with b-blockers.
Regular physical activity is associated with a decrease in CV Nicorandil is a nitrate derivative of nicotinamide may be
morbidity and mortality in patients with CAD. Cardiac added after b-blockers and CCBs. Long-term use of oral
rehabilitation is commonly offered after MI or recent coronary nicorandil may stabilize coronary plaques. Occasional side-
intervention, but should be considered in all patients with effects include oral, intestinal and perianal ulceration.
CAD, including those with chronic angina. Exercise training Trimetazidine is an anti-ischaemic metabolic modulator.
should be advocated to improve exercise capacity and reduce Trimetazidine added to beta-blockade improved effort-in-
myocardial oxygen consumption. duced myocardial ischaemia.
Sexual activity is associated with an exercise workload of up Ranolazine is a selective inhibitor of late sodium channel
to 6 METS. Pharmacological therapy with phosphodiesterase current with anti-ischaemic and metabolic properties. Rano-
type 5 (PDES) inhibitors (sildenafil, tadalafil and vardenafil) are lazine prolongs QTc.
effective, safe and well tolerated in men with stable CAD. Allopurinol, an inhibitor of xanthine oxidase reduces
However, use of nitric oxide donors, i.e. all of the preparations of vascular oxidative stress.
cor et vasa 56 (2014) e259–e273 e267
Table 13 – Major side-effects, contra-indications, drug–drug interactions (DDI) and precautions of anti-ischaemic drugs.
Drug class Side effectsa Contraindications DDI Precautions
Short-acting and Headache Hypertrophic obstructive PDE 5 inhibitors –
long-acting nitrates Flushing cardiomyopathy (sildenafil or similar
Hypotension agents)
Syncope and postural a-Adrenergic blockers
hypotension CCBs
Reflex tachycardia
Methaemoglobinaemia
b-Blockersb Fatigue, depression Low heart rate or heart Heart-rate lowering CCB Diabetics
Bradycardia conduction disorder Sinus-node or AV COPD
Heart block Cardiogenic shock Conduction depressors
Bronchospasm Asthma
Peripheral vasoconstriction COPD caution; may use
Postural hypotension cardioselective b-blockers if
Impotence fully treated by inhaled
Hypoglycaemia/mask steroids and long-acting
hypoglycaemia signs b-agonists
Severe PVD
Decompensated heart failure
Vasospastic angina
CCBs: heart-rate Bradycardia Low heart rate or heart rhythm Cardiodepressant –
lowering Heart conduction defect disorder (b-blockers, flecainid)
Low ejection fraction Sick sinus syndrome CYP3A4 substrates
Constipation Congestive heart failure
Gingival hyperplasia Low BP
CCBs: Headache Severe aortic stenosis CYP3A4 substrates –
dihydropyridines Ankle swelling Obstructive cardiomyopathy
Fatigue Cardiogenic shock
Flushing
Reflex tachycardia
Ivabradine Visual disturbances Low heart rate or heart rhythm QTc prolonging drugs Age >75 years
Headache, dizziness disorder Macrolide antibiotics Severe renal
Bradycardia Allergy Anti-HIV failure
Atrial fibrillation Severe hepatic disease Anti-fungal
Heart block
Nicorandil Headache Cardiogenic shock PDE5 inhibitors –
Flushing Heart failure (sildenafil or similar
Dizziness, weakness Low blood pressure agents)
Nausea
Hypotension
Oral, anal, gastrointestinal
ulceration
Trimetazidine Gastric discomfort Allergy None reported Moderate renal
Nausea Parkinson disease impairment
Headache Tremors and movement Elderly
Movement disorders disorders
Severe renal impairment
Ranolazine Dizziness Liver cirrhosis CYP450 substrates –
Constipation (digoxin, simvastatin,
Nausea cyclosporine)
QT prolongation QTc prolonging drugs
Allopurinol Rash Hypersensitivity Mercaptopurine/azathioprine Severe renal failure
Gastric discomfort
AV = atrioventricular; CCBs = calcium channel blockers; CHF = congestive heart failure; PVD = peripheral vascular disease, COPD = chronic
obstructive pulmonary disease; DDI = drug–drug interactions; HIV = Human Immunodeficiency virus; PDE5 = phosphodiesterase type 5.
a
Very frequent or frequent; may vary according to specific drugs within the therapeutic class.
b
Atenolol, metoprolol CR, bisoprolol, carvedilol.
Table 14 – Pharmacological treatments in stable coronary ACS, including after the acute phase, when the patients are
artery disease patients. stabilized, but cannot be recommended systematically in SCAD
Indication Class a Level b patients. Platelet function testing in SCAD patients undergoing
General considerations PCI is not recommended as a routine.
Optimal medical treatment indicates at least one drug for I C
angina/ischaemia relief plus drugs for event prevention
SCAD patients should be treated with statin with a target of
It is recommended to educate patients about the disease, risk factors and I C LDL-C < 1.8 mmol/l and/or >50% reduction if the target level
treatment strategy
cannot be reached.
It is indicated to review the patient’s response soon after starting therapy. I C
Angina/ischaemiac relief ACE inhibitors reduce total mortality, MI stroke and heart
Short-acting nitrates are recommended I B failure in patients with co-existing hypertension, LVEF 40%,
First-line treatment is indicated with ß-blockers and/or calcium channel I A
blockers to control heart rate and symptoms diabetes or CKD. ARB treatment may be an alternative when
For second-line treatment it is recommended to add long-acting nitrates IIa B ACE is not tolerated.
or ivabradine or nicorandil or ranolazine, according to heart rate, blood
pressure and tolerance Aldosterone blockade with spironolactone or eplerenone is
For second-line treatment, trimetazidine may be considered IIb B recommended in post-MI patients without significant renal
According to comorbidities/tolerance it is indicated to use second-line I C
therapiesas first line treatment in selected patients
dysfunction or hyperkalaemia, who are already receiving
In asymptomatic patients with large areas of ischaemia (>10%) ß- IIa C therapeutic doses of an ACE inhibitor and a b-blocker, have an
blockers should be considered
LVEF 40% and have either diabetes or heart failure.
In patients with vasospastic angina, calcium channel blockers and nitrates IIa B
should be considered and beta-blockers avoided Fig. 3 summarizes the medical management of SCAD
Event prevention patients. It is recommended in the first line a b-blocker or a
Low-dose aspirin daily is recommended in all SCAD patients I A
Clopidogrel is indicated as an alternative in case of aspirin intolerance I B CCB to a short-acting nitrate.
Statins are recommended in all SCAD patients I A
It is recommended to use ACE inhibitors (or ARBs) if presence of other I A
conditions (e.g. heart failure, hypertension or diabetes) 7.3. Treatment of particular forms of SCAD
ACE = angiotensin converting enzyme; SCAD = stable coronary
artery disease. All patients with microvascular angina should achieve optimal
a
Class of recommendation. coronary risk factor control. Short-acting nitrates can be used
b
Level of evidence. to treat anginal attacks, but often they are only partially
c
No demonstration of benefit on prognosis. effective. b-blockers are recommended as first line treatment,
calcium antagonists as second line. ACE inhibitors (ARBs) may
improve microvascular function. Xanthine derivatives (ami-
low-dose aspirin (75–150 mg/day). P2Y12 inhibitors, including nophylline, bamiphylline) reduce angina by adenosine recep-
thienopyridines act as antagonists of the platelet adenosine tor blockade.
diphosphate (ADP) receptor P2Y, thereby inhibiting platelet All patients with vasospastic angina should achieve optimal
aggregation. Clopidogrel is a second-line treatment for aspirin- coronary risk factor control. A drug-related cause (e.g. cocaine or
intolerant CVD patients. Prasugrel and ticagrelor are new P2Y12 amphetamines) should be systemically researched and man-
antagonists that achieve greater platelet inhibition, compared aged if detected. Chronic preventive treatment of vasospastic
with clopidogrel. Dual antiplatelet therapy combining aspirin angina is mainly based on the use of CCBs, usually prevent
and a thienopyridine is the standard of care for patients with spasm in about 90% of patients In about 10% of cases, coronary
Fig. 3 – Medical management of patients with stable coronary artery disease. ACEI, angiotensin converting enzyme inhibitor;
CABG, coronary artery bypass graft; CCB, calcium channel blockers; CCS, Canadian Cardiovascular Society; DHP,
dihydropyridine; PCI, percutaneous coronary intervention.
cor et vasa 56 (2014) e259–e273 e269
artery spasm is refractory to standard vasodilator therapy. PCI than immediate revascularization (low-risk population). The
with stent implantation at the site of spasm (even in the absence recent fractional flow reserve vs. angiography for multivessel
of significant stenosis), as well as chemical or surgical sympath- evaluation (FAME-2) study confirmed that SCAD patients with
ectomy have been reported but are not recommended. Because stenoses having FFR 0.80 gain a benefit from PCI revasculari-
of the high prevalence of silent ischaemic episodes and possible zation in addition to OMT. FFR measurement may change the
arrhythmias 24-h ambulatory ECG monitoring can be used. strategy and the extent of revascularization in multivessel
disease (PCI vs. CABG) and noncritical LM stenosis.
IVUS is far superior to FFR to provide an anatomical
8. Revascularization characterization of the lesion in terms of vessel size and
plaque composition and can control stent expansion and strut
8.1. Percutaneous coronary intervention apposition. Previously accepted cut-off limits of minimal
luminal area of 3.5 or 4.0 mm2 for major epicardial artery
8.1.1. Type of stent and dual antiplatelet therapy stenosis and 6.0 mm2 for left main stenosis have been shown
Bare metal stents (BMS) are associated with a 20–30% rate of to be poorly correlated with FFR.
angiographic stenosis within 6–9 months after implantation. More recently, optical coherence tomography (OCT) has
Drug-eluting stents (DES) reduce the incidence of restenosis and been developed as a new intracoronary imaging tool with
ischaemia-driven repeat revascularization. The most recent superior resolution (<10 mm) able to offer detailed assessment
DES (with thinner struts and biodegradable or more biocompat- of superficial components (presence of thrombus, stent
ible polymers) showed superior clinical outcomes for both expansion and apposition, healing, fibrous cap measurement).
efficacy and safety and are therefore the recommended option
in SCAD patients with no contra-indication to DAPT (Table 15). 8.2. Coronary artery bypass surgery
Clopidogrel pretreatment in stable patients undergoing
elective PCI does not reduce mortality or major adverse cardiac When technically feasible, with an acceptable level of risk and
events (MACE), but after stenting, premature discontinuation a good life expectancy, revascularization is indicated in
of antiplatelet therapy is a major risk factor for stent chronic angina refractory to OMT
thrombosis. Current guidelines recommended 6–12 months
of DAPT after first-generation DES and shorter duration of 8.2.1. Arterial vs. venous grafts
DAPT with a latest-generation DES might be sufficient in stable For the last 25 years the principle technique has been the use of
coronary patients. Patients on concomitant anticoagulant an internal mammary artery (IMA) to the LAD coronary artery
treatment the use of clopidogrel only has shown significant with supplemental vein grafts as required. Angiographic
advantages in a single small-scale trial (WOEST). studies have confirmed the superior patency of both IMA
grafts in comparison to vein grafts, this translate into a
8.1.2. Intracoronary assessment of stenosis severity survival benefit and reduced incidence of MI, recurrent angina
(fractional flow reserve, intravascular ultrasound and optical and the need for repeat revascularization. Bilateral IMA
coherence tomography) grafting reported a significant survival benefit with (OR 0.81)
In patients with FFR > 0.80, studies in the BMS era have especially in patients with diabetes. The radial artery has also
demonstrated that medical treatment provides better outcomes been proposed as a second arterial graft.
Fig. 4 – Global strategy of intervention in stable coronary artery disease (SCAD) patients with demonstrated ischaemia. CABG,
coronary artery bypass graft; CAD, coronary artery disease; LAD, left anterior descending; LV, left ventricular; OMT, optimal
medical treatment; PCI, percutaneous coronary intervention.
in STEMI has demonstrated a significant reduction of death or bypass surgery or PCI vs. medical therapy are likely to be
MI. undertaken in patients with LM CAD.
8.3.4. Left main coronary artery disease 8.5. Limitations of the randomized studies
LM CAD (stenosis 50% or greater) continues to be a Class I
indication for revascularization due to the survival advantages Typically, populations of these studies were selected after an
(VACS, CASS). No further randomized, controlled trials of angiogram, had demonstrated at least one significant stenosis
cor et vasa 56 (2014) e259–e273 e271
Table 16 – Indications for revascularization of stable with typical or suspected angina—with or without documen-
coronary artery disease patients on optimal medical ted myocardial ischaemia—with, in general, good LV function,
therapy (adapted from ESC/EACTS 2010 Guidelines). no comorbidities and excluding patients at high angiographic
Indicationa To To risk, patients with LM coronary disease, CABG, multivessel
improve improve disease, or lesions deemed to be treated with revascularization
prognosis symptoms
persistent without further discussion for OMT only. Crossover rates from
on OMT to revascularization were much higher than initially
OMT
Class d Level e Class d Level e
expected (33–42%).
A Heart Team approach to revascularization is I C I C
recommended in patients with unprotected left 8.6. Percutaneous coronary intervention vs. coronary
main, 2–3 vessel disease, diabetes or comorbidities
Left main >50% diameter stenosisb I A I A
artery bypass graft
Any proximal LAD >50% diameter stenosisb I A I A
2–3 vessel disease with impaired LV function / I B IIa B In SYNTAX trial patients with three-vessel or left main
CHF
Single remaining vessel (>50% diameter stenosisb ) I C I A coronary artery disease were randomized to undergo CABG
Proven large area of ischaemia (>10% LV c) I B I B or PCI. At 12 months higher rate of major adverse cardiac or
Any significant stenosis with limiting symptoms or NA NA IIa B
symptoms not responsive/tolerant to OMT cerebrovascular events was in the PCI group, in large part
Dyspnoea/cardiac heart failure with >10% IIb B IIa B because of an increased rate of repeat revascularization. At 5
ischaemia/viability c supplied by stenosis >50%.
No limiting symptoms with OMT in vessel other III A III C
years, all-cause death was 13.9% with PCI, against 11.4% with
than left main or proximal LAD or single remaining CABG (P = 0.10). This benefit was driven only by the upper two
vessel or vessel subtending area of ischaemia <10%
of myocardium or with FFR ≥0.80
tertiles of the SYNTAX score; although PCI and CABG
performed as well on all endpoints for SYNTAX scores of 22
CCS = Canadian Cardiovascular Society; CHF = congestive heart
or less. The FREEDOM trial demonstrated a significant
failure; FFR = fractional flow reserve; LAD = left anterior descend-
ing; LV = left ventricle; NA = not available; OMT = optimal medical reduction on the primary ischaemic outcome at 5 years in
treatment; SCAD = stable coronary artery disease. diabetic patients with multivessel disease treated with CABG
a
In asymptomatic patients, the decision will be guided by the vs. PCI.
extent of ischaemia on stress testing. For patients with three-vessel disease when they present
b
With documented ischaemia or FFR, 0.80 for angiographic with a syntax score 22 or when complete revascularization is
diameter stenoses 50–90%.
c not achievable by PCI or when they have diabetes CABG should
As assessed by non-invasive test (SPECT, MRI, stress echocardio-
graphy).
be the preferred option in patients that are eligible for surgery
d
Class of recommendation. (Fig. 5).
e
Level of evidence. In SYNTAX, the results patients with LMS disease showed
no overall difference between CABG and PCI in terms of death
Fig. 5 – Percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) in stable coronary artery
disease without left main coronary artery involvement. CABG, coronary artery bypass graft; LAD, left anterior descending;
PCI, percutaneous coronary intervention.
e272 cor et vasa 56 (2014) e259–e273
Fig. 6 – Percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) in stable coronary artery disease
with left main coronary artery involvement. CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.
or MI, but a higher incidence of stroke with CABG Repeat patients with multivessel disease after discussion in a Heart
revascularization was higher with stents (P = 0.004). Another Team meeting.
study (PRECOMBAT) reported a composite endpoint of death,
cerebrovascular accident and MI as 4.7% for CABG and 4.4% for 9.3. Patients with chronic kidney disease
PCI. Meanwhile, angiographic characteristics of the LM disease
are key in selection between PCI and CABG (calcifications, Chronic kidney disease is a risk factor for CAD and has a major
ostial/mid/distal, LM size, distal lesions, etc.) and, for lower impact on outcomes and therapeutic decisions. The use of drugs
severity of LMS disease, PCI produces at least equivalent—if and iodinated contrast agents is exposes patients to more
not superior—outcomes to CABG (Fig. 6). complications. This is also a group of patients poorly explored in
clinical trials, with limited strong evidence based medicine.
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Gersh, Anselm K. Gitt, Jean-Sebastien Hulot, Nikolaus Marx,
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Ruschitzka, Manel Sabaté, Roxy Senior, David Paul Taggart,
[1] 2013 ESC guidelines on the management of stable coronary
Ernst E. van derWall, Christiaan J.M. Vrints. The original text
artery disease. The Task Force on the management of stable is available free on the ESC website: http://www.escardio.
coronary artery disease of the European Society of org/guidelines-surveys/esc-guidelines/Pages/stable-angina-
Cardiology Task Force Members: Gilles Montalescot*, Udo
pectoris.aspx and was originally published in European
Sechtem*, Stephan Achenbach, Felicita Andreotti, Chris
Heart Journal (2013) 34, 2949–3003.
Arden, Andrzej Budaj, Raffaele Bugiardini, Filippo Crea,
All references supporting the recommendations in this docu-
ment can be found in the original full text.