Requirements and sustainability of primary PCI programs in Spain for the management of patients with STEMI. SEC, AEEC, and SEMES consensus document

INTRODUCTION

Coronary and structural heart disease interventions have traditionally relied on fluoroscopy and transesophageal echocardiography as the imaging modalities of choice, especially for intraprocedural monitoring. Imaging-based patient selection has also usually relied on echocardiography. However, the technological and knowledge advancements made in recent years have led to the incorporation of new imaging modalities—particularly computed tomography (CT) and, to a lesser extent, magnetic resonance—into the field of structural heart interventions.

Currently, CT is the imaging modality of choice before structural heart interventions in a wide range of procedures, as well as the screening technique for coronary artery disease, and even for planning coronary interventions.

This review examines the applications and indications of cardiac CT in transcatheter coronary and structural heart disease interventions.

GENERAL FEATURES OF CARDIAC COMPUTED TOMOGRAPHY

Cardiac CT is an optimal technique for evaluating patients prior to a structural heart intervention. This modality offers contrast-enhanced noninvasive imaging with excellent definition of calcium and intravascular space, submillimeter isotropic spatial resolution, and acceptable temporal resolution.

Like invasive coronary angiography, cardiac CT uses an X-ray source to create the image. Modern machines feature an O-shaped gantry ring with the X-ray tube positioned opposite a ring of detectors. The emitted radiation beam is attenuated and absorbed depending on tissue densities, with the captured energy reconstructed to form a medical image.

When acquiring tomographic images of heart structures and coronary arteries, it is important to consider their small-caliber, with each structure moving independently in all 3 spatial axes. Therefore, the equipment must be technically capable of producing conclusive studies. Table 1 outlines key technical parameters of CT generated images.

 

Table 1. Main basic concepts of computed tomography

Concept	Definition
Spatial resolution	The ability to visualize 2 separate points that are very close together. Depends on the size of the detectors; in modern CT scanners, it is < 1 mm.
Isotropism	Image composed of voxels with a similar size in all 3 spatial planes. Allows for image reformatting while minimizing the loss of resolution.
Temporal resolution	The shortest time required by the CT scanner to acquire an image. Depends on the gantry rotation speed and the acquisition method.

 

A cardiac CT scan should employ the ECG-gated technique to compensate for cardiac motion, with the study conducted during breath-holding to minimize respiratory movements. Acquisitions can cover the entire cardiac cycle or a preselected phase. Acquisition of the entire cardiac cycle (called “retrospective” in scanners with < 16 cm z-axis coverage) offers the advantage of allowing reconstruction of all phases, as well as functional assessments (volumes, ejection fraction, leaflet motion) and 4D reconstructions. However, this method requires higher radiation doses. This can be partially mitigated through retrospective acquisitions with dose modulation, acquiring high-quality images in 1 or more predefined phases while capturing the rest at lower quality, thereby reducing radiation exposure.1

Technological advances and the wider availability of CT scanners with cardiac acquisition software have allowed this imaging modality to be established as a standard in various structural interventional procedures. While it is widely acknowledged that the minimum equipment required includes an ECG-gated 64-slice CT scanner, the latest models offer superior image quality, decreased radiation exposure, and reduced contrast use. The latest generation of CT scanners follow various development paths: a) wide-detector CT scanners increase the scanned distance per heartbeat by incorporating more detectors; some scanners have more than 300 detectors, enabling cardiac coverage in a single heartbeat; b) high-pitch dual-source CT scanners use 2 radiation sources at a 90° offset and a high speed table to markedly enhance temporal resolution); c) spectral CT scanners use detectors with differing sensitivities or various energy levels from the emitter to capture images at different energy spectra, allowing a certain degree of tissue characterization; and d) photon-counting CT scanners eliminate the need for intermediate photoluminescent detectors, thus enhancing spatial resolution to 0.2 mm.

In addition to the CT scanner, an at least dual-phase injector is required to allow high flow (4-7 mL/s), a contrast agent with an iodine concentration around 350 mg/mL (ideally iso-osmolar), and a digital processing and image storage system in DICOM format (Digital Imaging and Communication in Medicine).

Preparing patients for a cardiac CT is essential to ensure high-quality diagnostic tests. Prior to the procedure, patients must provide informed consent and undergo an assessment to rule out any contraindications. A peripheral venous line is usually established in the right antecubital fossa (18-20 G). Patients are usually placed in the supine position with their arms raised above their heads. ECG electrodes are applied, ensuring excellent trace quality. It is important to explain and practice the breath-holding technique required during the scan with the patient, as well as to monitor ECG-quality during the breath-hold.

Depending on the indication of the study, if the patient’s heart rate is high or the rhythm is irregular, premedication may be necessary, with the most common choice being IV beta-blockers. In studies that require assessing the coronary lumen, sublingual nitroglycerin is usually also administered. When performing a cardiac CT prior to structural intervention, it is important to remember that severe symptomatic aortic or mitral stenosis is a contraindication for nitroglycerin use. Beta-blockers should be administered with caution, under the supervision of qualified personnel, ensuring that advanced cardiopulmonary resuscitation can be performed if necessary.

APPLICATION TO STRUCTURAL HEART INTERVENTIONS

Coronary computed tomography angiography (CCTA) provides a detailed anatomical assessment of the coronary tree, including its origin and course, detects the presence of atherosclerotic lesions, quantifies affected segments, and determines the severity of stenosis and atherosclerotic burden. CCTA is the standard imaging modality to assess symptomatic patients and can be considered in selected high-risk asymptomatic patients. It has a sensitivity of 97% and a specificity of 78% when taking invasive coronary angiography in a population with a pretest probability of 56% as a reference. While CCTA has the highest sensitivity compared with other invasive imaging modalities, functional imaging techniques such as stress magnetic resonance (80%), stress echocardiography (82%), and positron emission tomography (85%) have superior specificity.2 Despite its lower specificity, the CT-based anatomical strategy has been proven to be noninferior in terms of prognosis compared with the ischemia test-based functional strategy (PROMISE trial).3

Due to its high negative predictive value, CT is recommended by clinical practice guidelines as a first-line imaging modality to rule out obstructive coronary artery disease in low-to-intermediate risk symptomatic patients.4 Table 2 outlines the main indications for CCTA in various clinical scenarios.

 

Table 2. Current indications for computed tomography of coronary arteries and measurement of coronary artery calcium based on the European Society of Cardiology clinical practice guidelines

Acute symptoms	Degree of recommendation	Level of evidence	Year	Ref.
Suspected acute coronary syndrome, normal or uncertain range troponins, normal electrocardiogram, and no recurrence of pain; may be considered as part of the initial diagnostic evaluation	IIA	A	2023	5
Systematic use in patients with suspected acute coronary syndrome	III	B	2023	5
Stable symptoms	Degree of recommendation	Level of evidence	Year	Ref.
Symptomatic patient with suspected coronary artery disease that cannot be clinically ruled out	I	B	2019	4
Risk stratification in patients with suspected or newly diagnosed coronary artery disease	I	B	2019	4
Patients with suspected vasospastic angina to study underlying coronary artery disease	I	C	2019	4
Screening for coronary artery disease in hemodynamically stable patients with aortic vegetations requiring cardiac surgery	I	B	2023	6
Patients with a low-to-intermediate probability of coronary artery disease and a previous equivocal noninvasive stress test	IIA	C	2021	7
Alternative to invasive coronary angiography prior to valvular cardiac surgery in patients with a low probability of coronary artery disease	IIA	C	2021	8
Patients with suspected cardiomyopathy for screening of coronary artery disease, or coronary anomalies that may be causing the cardiomyopathy	IIA	C	2023	9
Intermediate-to-high risk patients with prior nonemergency, noncardiac surgery: a) low-to-intermediate probability of coronary artery disease and suspected chronic or acute coronary syndrome without enzyme mobilization; b) patients ineligible for noninvasive functional tests	IIA	C	2022	10
Coronary computed tomography angiography is not recommended for the routine follow-up of patients with established coronary artery disease	III	C	2019	4
Asymptomatic	Degree of recommendation	Level of evidence	Year	Ref.
Calcium scoring as a risk modifier in asymptomatic patients with moderate cardiovascular risk	IIB	B	2019	4
Selected individuals with no history of coronary artery disease, high cardiovascular risk (SCORE > 10%, strong family history, familial hypercholesterolemia) and desire to start an intensive exercise program	IIB	B	2021	11
High cardiovascular risk (diabetes mellitus, family history, or previous test suggesting coronary artery disease)	IIB	C	2019	4
Asymptomatic adults (> 40 years) with diabetes mellitus	IIB	B	2019	4
Asymptomatic nondiabetic low-risk adults	III	C	2019	4

 

Technological advances and the incorporation of new imaging modalities, such as stress CT perfusion and fractional flow reserve CT (FFR_CT) have increased specificity rates to 85% to 87%.12 This enhances the positive predictive value of the imaging modality and allows meticulous evaluation of intermediate-to-high risk patients.

Landmark studies have been published on the prognosis of patients evaluated using CT. The SCOT-HEART trial13 demonstrated a reduction in cardiovascular deaths and nonfatal myocardial infarctions at the 5-year follow-up with a CT-guided strategy with outcome-based treatment adjustment compared with a conventional management strategy. On the other hand, the DISCHARGE trial14 showed a similar risk of major cardiovascular events during follow-up in patients with intermediate probability and stable chest pain randomized to CT vs invasive coronary angiography, with a lower rate of complications in the noninvasive imaging modality group. These studies support CT as a first-line imaging modality to rule out coronary artery disease, establish preventive treatment in patients with nonobstructive coronary artery disease, stratify patients with obstructive coronary artery disease, and offer an alternative to invasive coronary angiography in a wide range of patients.

In patients with a history of coronary artery disease, CCTA can be used to assess coronary artery bypass graft surgery, verify the patency of coronary stents in specific cases (proximal segments and stents > 3.0 mm), and assess chronic total occlusions prior to percutaneous coronary revascularization. In the BYPASS-CTCA trial,15 which randomized patients with prior surgical coronary revascularization to undergo CT-based anatomical assessment and invasive coronary angiography, or isolated invasive coronary angiography, shorter procedures and fewer episodes of contrast-induced nephropathy were observed in patients with noninvasive assessment of coronary artery bypass grafts.

CCTA should adhere to the recommendations established by the Society of Cardiovascular Computed Tomography.16 There are different image representation formats (axial, multiplanar reformatting, maximum intensity projection, curved multiplanar reformatting, or volumetric reconstruction), each with complementary uses. CCTA reading begins by assessing its quality, identifying potential artifacts, and visualizing the origin, course, and coronary dominance. The following are general principles for interpretation: a) cross-sectional systematic review of each coronary segment from multiple planes; b) vigilance for possible artifacts; c) evaluation of lesion morphology and composition; and d) grading lesion severity using high-resolution images in longitudinal and cross-sectional views of the vessel lumen. Following the modified distribution of the American Heart Association, coronary arteries are divided into 18 coronary segments. Identified lesions are listed based on the affected segment, the nature of the lesion (noncalcified, partially calcified, or calcified), and degree of resulting stenosis: normal (no lesion or stenosis), minimal (< 25% lumen reduction), mild (25%-49%), moderate (50%-69%), severe (70%-99%), or occlusion (> 99%).

Detailed analysis of the CT image enables the selection of a plan for transcatheter intervention and the materials to be used, and potentially reduces procedural length and complexity. This can be particularly useful when optimizing the fluoroscopy angle based on CT analysis in complex or bifurcated coronary artery lesions, as well as when performing complex cardiac catheterizations in patients with percutaneous aortic valve prostheses.17

The overall complexity of coronary artery disease can be represented by indices such as the coronary calcium score, or the number of segments with some degree of coronary artery disease, but several specific scales are available. Among these, the most widely used are the CAD-RADSTM (Coronary Artery Disease Reporting and Data System)18 and its updated version, the CAD-RADSTM 2.0,19 which incorporates parameters of perfusion and plaque complexity. Other more specific scales include the CT-SYNTAX20 scale, which combines CT-based anatomical information with clinical data from the SYNTAX scale, and the Functional CT-SYNTAX21 and Functional FFR_CT22 scales, which add incorporate FFR_CT-based functional information. These scales help refine the decision between surgical and percutaneous revascularization strategies, with promising initial results.23 Their prognostic validation in different scenarios, and their implementation in clinical practice, may represent a paradigm shift in the performance of invasive diagnostic imaging studies in stable patients.

In patients with chronic total coronary occlusions, preprocedural CT analysis allows estimation of the probability of success of percutaneous coronary revascularization; several prognostic scales have been developed for this purpose, such as the J-CTO,24 the CT-RECTOR,25 and the KCCT26 (table 3). The parameters analyzed include the extent of calcification, vascular tortuosity, the morphology of the occlusion stump, the presence of multiple occlusions, and the length of the lesion.

 

Table 3. Prediction scales for the success and complications associated with the revascularization of chronic total occlusions by computed tomography

Score	Variables (points)	Classification
J-CTO	Tapered (0) vs blunt end (1)	Easy (0) Intermediate (1) Difficult (2) Very difficult (≥ 3)
	No calcification (0) vs some calcification (1)
	Occlusion angle ≤ 45° (0) vs > 45° (1)
	Occlusion length < 20 mm (0) vs ≥ 20 mm (1)
	No previous failed revascularization attempts (0) vs with previous attempts (1)
CT-RECTOR	< 2 occlusions (0) vs ≥ 2 complete interruptions (1)	Easy (0) Intermediate (1) Difficult (2) Very difficult (≥ 3)
	Tapered (0) vs blunt end (1)
	< 50% calcification of vessel perimeter on short axis (0) vs ≥ 50% calcification at some point of the occlusion (1)
	Occlusion angle ≤ 45° (0) vs > 45° (1)
	No previous failed revascularization attempts (0) vs with previous attempts (1)
	Duration of chronic total coronary occlusion < 12 months (0) vs ≥ 12 months (1)
KCCT	Tapered (0) vs blunt end (1)	Easy (0) Intermediate (1) Difficult (2) Very difficult (3) Extremely difficult (≥ 4)
	No adjacent collateral branches (0) vs with collateral branches (1)
	Occlusion length < 15 mm (0) vs ≥ 15 mm (1)
	Occlusion angle ≤ 45° (0) vs > 45° (1)
	Vessel calcification on the short axis < 180° of perimeter or < 50% of area (0) vs ≥ 180° of perimeter and ≥ 50% of area (1) vs complete central calcification of 360° of perimeter and 100% of area (2)
	No previous failed revascularization attempts (0) vs with previous attempts (1)
	Duration of chronic total coronary occlusion < 12 months (0) vs ≥ 12 months (1)

 

APPLICATION TO STRUCTURAL HEART INTERVENTIONS

Transcatheter aortic valve implantation

After echocardiographic diagnosis of severe aortic stenosis, CT is the imaging modality of choice for a comprehensive assessment of patients eligible for transcatheter aortic valve implantation (TAVI).27 In a single scan, CT can evaluate vascular access, verify the degree of aortic stenosis and valve morphology, measure the aortic annulus, assess the risk of coronary occlusion, and determine the optimal fluoroscopy angles, among other aspects. In addition, in a high percentage of cases, CT facilitates the screening of proximal obstructive coronary artery disease and assessment of extracardiac findings.28

Preprocedural assessment for TAVI includes: a) an optional noncontrast acquisition to quantify aortic valve calcium; b) ECG-gated acquisition in the systolic phase, at least in the region of the aortic valve complex; and c) depending on the speed and coverage of the equipment used, 1 or more acquisitions for iliofemoral access, without the need for ECG-gated synchronization in this region. The study requires the injection of contrast medium (50-90 mL, with a flow rate of 3-5 mL/s, subject to variations based on the equipment used and the patient’s body surface area).28

The main aspects that should appear in the CT report prior to performing TAVI are listed in table 4.

 

Table 4. Main features that need to be included in the computed tomography report prior to transcatheter aortic valve implantation or percutaneous left atrial appendage occlusion

Transcatheter aortic valve implantation
Aortic annulus	Measurement in systolic phase
	Area and perimeter
	Major and minor diameters,
	Optimal fluoroscopy view
Calcium and valve	Presence, morphology, and extent of calcium
	Valvular morphology
Aorta and accesses	Height of the origin of coronary arteries
	Minimum luminal diameter of each vascular segment
	Description of calcifications and vascular disease
Others	Coronary anatomy
	Extracardiac findings
Percutaneous left atrial appendage occlusion
Thrombus	Screening for arterial/venous filling defect
Morphology and landing zone	Describe the morphology and presence of proximal lobes
	Measure the landing zone, maximum diameter
	Measure the depth and length of the appendage
	Optimal fluoroscopy view
Others	Anatomy of the interatrial septum
	Anatomy of the pulmonary veins
	Describe if there is pericardial effusion

 

Currently, there are 2 general designs of transcatheter aortic valve prostheses: balloon-expandable and self-expanding. Balloon-expandable TAVIs use radial force along with balloon inflation to fit their circular design to the oval shape of the aortic annulus. In contrast, self-expanding TAVIs expand on their own, due to nitinol memory, to fit over the annulus. In addition to technical and design differences, it is important to note that the sizing algorithms for these devices are not interchangeable. Sizing of balloon-expandable prostheses is based on the area of the aortic annulus, while that of self-expandig valves is based on the perimeter.

All the assessments necessary before TAVI are illustrated in Figure 2.

Figure 1. Computed tomography allows the study of coronary arteries to rule out the presence of coronary artery disease (A, normal coronary arteries), or to establish the severity and location of obstructive coronary disease (B, severe lesion in the proximal left anterior descending coronary artery [LAD] and chronic total occlusion in the mid and distal regions of the right coronary artery [RCA]). The functionality of the lesions can be assessed using computer simulation (C, fractional flow reserve computed tomography [FFR_CT], severe lesion in the mid LAD and distal left circumflex artery [LCx]).

Figure 2. Preassessment for transcatheter aortic valve implantation using computed tomography and 3mensio CT analysis software: aortic annulus (A), aortic valvular calcium (B), left ventricular outflow tract (C), diameters of the Valsalva sinuses (D), height of the right coronary artery origin (E), height of the sinotubular junction (F), 3-cusp coplanar view (G), cusp-overlap view (H), and transfemoral accesses (I).

 

It is important to understand and analyze the anatomy of the aortic valve complex, which comprises the left ventricular outflow tract (LVOT), the Valsalva sinuses, the fibrous triangles between the aortic leaflets, and the leaflets themselves. A key measurement is the correct assessment of the plane of the aortic annulus, defined as the virtual plane aligned with the lowest insertion point of each aortic cusp or nadir. This involves determining the major and minor diameters, area, and perimeter of the aortic annulus. These measurements guide the selection of TAVI size. The aortic annulus undergoes changes in size and shape throughout the cardiac cycle, with mesosystole (30-35% R-R) often being the optimal time for measurement (larger size and reduced ellipticity).29 Specialized software is available to automate these measurements and simulate the implant procedure, streamlining workflow and reducing inter- and intra-observer variability.

The landing zone for the prosthesis includes the aortic cusps, the aortic annulus, and the LVOT. Severe calcification in the LVOT and aortic valve increases the risk of subsequent periprosthetic regurgitation, while large nodular calcifications may pose a higher risk of aortic annulus rupture, especially with balloon-expandable prostheses.30 It is essential to describe the location and extent of calcification in the aortic valve and the first 5 to 7 mm of the LVOT, as this area serves as the sealing zone for most available TAVIs. The morphology and degree of calcification of the aortic valve should be systematically reported, with particular attention to the presence of bulky calcification or partial fusion of the aortic commissures.28

The perpendicular height from the plane of the aortic annulus to the origin of the coronary arteries must be evaluated. Although absolute cutoff values have not been established, a coronary artery origin height of < 12 mm and sinuses of Valsalva < 30 mm are associated with a higher risk of TAVI-related coronary occlusion.31

The report should also include the optimal CT projections for valve deployment. Identifying these projections reduces radiation dose, contrast, and procedure duration.29 Angulation should be reported to obtain a coplanar projection (3 cusps), aligning the cusps, and the angulation for obtaining an overlapping projection (cusp-overlap), with the left and right cusps overlapped. This plane deploys the LVOT and allows better control of implant depth during valve deployment, especially with self-expanding valves.32

CT allows assessment of vascular access in a single study, providing excellent resolution and detailed delineation of the presence and extent of calcifications. Vascular complications increase the morbidity and mortality associated with TAVI. Factors associated with the occurrence of vascular complications include the sheath-to-femoral artery ratio, the presence of moderate to severe calcification, and vascular tortuosity.33 The report should include details on the minimum luminal diameters, the extent, distribution, and severity of calcification, as well as the presence or absence of vascular disease in all vascular segments between the aortic valve and the left and right common femoral arteries at the level of the femoral head.28 If femoral accesses are deemed unsuitable, alternative accesses can be considered, with the most common being axillary/subclavian, carotid, transcaval, and transapical accesses.

Special attention should be paid to the bicuspid aortic valve, given its lower success rate in procedures and higher rates of periprosthetic regurgitation, albeit with similar clinical outcomes.34 It is essential to determine the type of bicuspid valve (whether sinus fusion, 2 sinuses, or forme fruste),35 presence of a raphe, calcium distribution, annulus size and eccentricity, as well as the origin and height of the coronary arteries. Measuring the aortic annulus can be particularly complex in 2-sinus bicuspid valves, requiring specific methodology.28 The aortic annulus is defined as the virtual plane aligned with the lowest insertion point of the anterior/lateral cusp. Starting from this point, counterclockwise rotation to the lowest insertion point of the posterior/medial cusp is performed. Measurements should be taken at the line perpendicular to these 2 points, centered at the point where the smallest cross-sectional area is reached (as improper angulation can lead to inaccurate size estimation). The major and minor diameters, area, and perimeter of the aortic annulus are then determined. Algorithms have been developed for prosthesis size selection based on aortic annulus size, considering raphe length, calcium volume, and distribution (CASPER, calcium algorithm sizing for bicuspid evaluation with raphe).36 Additionally, a method (LIRA, level of implantation at the raphe) has been proposed by delineating the perimeter of the bicuspid valve opening,37 although its superiority over conventional measurements remains unclear.38

A variant of TAVI is the valve-in-valve implant, in which a percutaneous prosthesis is placed over a dysfunctional bioprosthesis. CT plays a key role in prosthesis size selection, especially when the model or size of the implanted prosthesis is unknown, but also in stratifying the risk of coronary occlusion. Among the main parameters for determining the risk of coronary obstruction are the level reached by the prosthesis cusps relative to the origin of the coronary arteries and the sinotubular junction, risk associated with the proximity of the valve to the sinotubular junction, < 2 mm distance from the virtual TAVI to the sinotubular junction, < 4 mm distance from the virtual TAVI to the origin of the coronary arteries, a prior supra-annular or supracoronary prosthesis, a surgical prosthesis with leaflets implanted outside the annulus (Mitroflow or Trifecta type), a prior implant in a high position, and the presence of moderate or severe commissural misalignment.39,40

After the TAVI procedure, CT allows assessment of the position and geometry of the prosthesis, as well as the thickness and mobility of the prosthetic leaflets. Following TAVI, a CT scan may be performed if prosthetic dysfunction or degeneration is identified by echocardiography, suspected thrombosis, infectious endocarditis, or periprosthetic regurgitation requiring anatomical assessment. The phenomenon of thickening with hypoattenuation and reduced mobility in the prosthetic leaflets has been described, which is associated with subclinical thrombosis and resolves with anticoagulation therapy. This finding has been associated with a higher but nonsignificant tendency for embolic events, and consequently there is no consensus or established indication for systematic performance of CT after TAVI. Its occurrence is more common in valve-in-valve, balloon-expandable prostheses, and larger prostheses, as well as those with eccentric expansion due to bicuspid valves, for example.41

Lastly, there is the option of using CT scans to resolve diagnostic uncertainties regarding the severity of aortic stenosis. Assessing aortic valve calcium can be especially helpful in patients with low-flow, low-gradient aortic stenosis and preserved ejection fraction. Agatston scores ≥ 2000 in men and ≥ 1200 in women indicate severe degenerative aortic stenosis, while scores < 1600 in men and < 800 in women suggest the absence of severe degenerative stenosis.8

Percutaneous left atrial appendage occlusion

Percutaneous closure of the left atrial appendage (LAAO) is an alternative to oral anticoagulation in patients with atrial fibrillation and a contraindication to oral anticoagulation. The traditional technique used for patient selection is transesophageal echocardiography (TEE) to rule out the presence of thrombus in the appendage and to take measurements for device selection. Three-dimensional measurements (3D-TEE, CT) have consistently been shown to be more accurate in selecting device size than 2D-TEE. Therefore, CT is an alternative technique in patient selection, as it allows visualization of the presence of thrombus and evaluation of the anatomy and size of the appendage, as well as the interatrial septum.42

CT evaluation of LAAO should be performed with ECG-gated acquisition, ideally in the telesystolic phase (when the left atrial appendage is maximally expanded), and a second acquisition should be performed in the venous phase, 60 to 90 seconds after contrast administration, to assess the presence or absence of thrombus in the left atrial appendage.43 The main features that should be included in a CT report for LAAO are listed in table 4. If the quality allows, it is advisable to perform an assessment of coronary anatomy.

The morphology of the left atrial appendage is highly variable and complex. Several devices for LAAO have been marketed, with the most commonly used being lobe and disc devices. Measurement of the landing zone is performed using multiplanar reformatting from 2-chamber and coronal planes. In the case of lobe devices, the landing zone extends from the circumflex artery to a point located 10 to 20 mm inside the ligament of Marshall.

The morphology of the left atrial appendage is highly variable and complex. Different devices for LAAO have been commercialized, with the most commonly used being lobe and disc devices. Measurement of the deployment zone is performed using multiplanar reformatting from two-chamber and coronal planes. In the case of lobe devices, the deployment zone extends from the circumflex artery to a point located 10-20 mm inside the ligament of Marshall. The depth is determined from the landing zone to the most distal end of the appendage. With disc devices, the landing zone is located 10 to 12 mm inside the ostium of the appendage, covering the course of the circumflex artery at its lower end. The depth in this type of device is defined from the ostium to the opposite wall of the appendage.43 It is also important to assess the anatomy of adjacent structures, especially the ligament of Marshall, to assess the feasibility of fully covering it with a disc device and to avoid thrombus formation during follow-up,44 as well as the anatomical characteristics of the pulmonary artery in relation to the left atrial appendage.45

Specific software has been designed to automate these measurements and simulate the implantation process (figure 3). Utilizing simulation software through computing enhances device selection and procedural outcomes.46

Figure 3. Planning for percutaneous left atrial appendage occlusion using computed tomography and 3mensio CT analysis software: identification of the left atrial appendage ostium (A and B), left atrial appendage morphology (C), measurement of the landing zone (D, longitudinal and cross-sectional views), simulation of the occluder device (E, longitudinal and cross-sectional views), simulation of the fluoroscopy view and position of the transseptal puncture (F), and simulation of the occluder device in fluoroscopy (G).

 

After LAAO, it is recommended to perform an imaging test 45 to 60 days postimplantation to verify the stability and positioning of the device, to search for residual leaks, and to rule out the presence of device-related thrombus. The most commonly used techniques are TEE and CT. CT allows better visualization of the position and deployment of the device, has equal thrombus detection capability, and has higher sensitivity in detecting residual contrast passage. The latter may be due to device malapposition, the presence of a peridevice leak, or the patency of the covering tissue.47 The clinical relevance of residual leaks, as well as the importance of their size, are not entirely clear.48

Transcatheter mitral valve replacement

Within transcatheter mitral valve intervention, there are options for repair and replacement. Edge-to-edge repair techniques are clinically established, with patient selection and procedural monitoring conducted via TEE. In contrast, for various valve replacement techniques, CT is indispensable. CT with ECG-gated acquisition is required to cover and reconstruct the entire cardiac cycle after contrast administration with adequate opacification of at least the left chambers, and ideally the right chambers, as well as to enhance visualization of the anatomy and its relationships. Detailed recommendations for acquisition and optimization have been published.49 CT allows evaluation of mitral annulus size and shape, selection of prosthesis type and size for implantation, virtual simulation of implantation, assessment of resulting neo-TSVI, selection of optimal fluoroscopy angles, and planning of vascular access (transseptal or transapical).49 (figure 4). Specific measurements for each device are determined by the manufacturer.

Figure 4. Several steps in the planning of transcatheter mitral valve replacement using computed tomography and 3mensio CT analysis software in 2 patients with valve-in-MAC (A-C) and native valve (D-F): delineation and measurement of the mitral annulus (A and D), evaluation of the distance from the virtual valve to the interventricular septum (D and E), and measurement of the neo-left ventricular outflow tract (C and F).

 

Transcatheter mitral valve replacement (TMVR) has been described for native valve, prior surgical annuloplasty (valve-in-ring), dysfunctional bioprosthetic valve (valve-in-valve), and severely calcified native mitral annulus (valve-in-MAC).50 CT is particularly useful to select prosthesis size and assess embolic risk in valve-in-MAC procedures by evaluating the thickness of the mitral annular calcium, its extension around the posterior perimeter or mitral trigones, and the damage to the mitral leaflets.51

The main complication to avoid during TMVR planning is LVOT obstruction after the procedure. The neo-LVOT refers to the distance or area between the lower edge of the virtual implant and the interventricular septum. The main predictors of neo-LVOT obstruction are detailed in table 5.52 The neo-LVOT area should be assessed in meso-telesystole (40%-50% R-R; the smallest area during the cardiac cycle), with obstruction risk increasing as the neo-LVOT area decreases: < 170 mm² indicates very high risk, 170 to 190 mm² indicates high risk, 190 to 220 mm² indicates acceptable risk, and > 220 mm² indicates low risk. In selected high-risk cases, techniques such as laceration of the anterior mitral leaflet (LAMPOON) or interventricular septal ablation (alcohol septal ablation) can be employed to enlarge the neo-LVOT area.53

 

Table 5. Predictors of left ventricular outflow tract obstruction in transcatheter mitral valve replacement

Obstruction predictors	Obstruction risk limit
Area of the neo-LVOT	< 1.9 cm²
Area of the neo-LVOT skirt	< 1.5 cm²
Sizes of the anterior mitral leaflet	> 25 mm
Protruding interventricular septum	Thickness > 15 mm
Distance between the mitral annulus and the interventricular septum	< 17.8 mm
Acute aortomitral angle	< 110°
Small left ventricle	End-diastolic diameter < 48 mm
Left ventricular hypertrophy	Indexed myocardial mass > 105 g/m²
LVOT, left ventricular outflow tract.

 

Transcatheter tricuspid valve replacement

Transcatheter procedures for the tricuspid valve mainly include edge-to-edge repair, annuloplasty, and both orthotopic and heterotopic valve replacement (valve prostheses in the venae cavae).

The acquisition process is similar to that of pre-TMVR CT (ECG-gated covering and reconstructing the entire cardiac cycle following contrast administration). However, it is optimized for contrast in the right heart chambers using triphasic injection protocols (a mixture of contrast and saline at different concentrations). Detailed recommendations for acquisition and optimization have been published.49 CT imaging allows assessment of the tricuspid annulus geometry and size throughout the cardiac cycle, the morphology and mobility of the tricuspid leaflets, the position and relationship of the right coronary artery to the tricuspid annulus, right ventricular volume and ejection fraction, the optimal fluoroscopy angle, and vascular access54 (figure 5).

Figure 5. Evaluation of the tricuspid valve using computed tomography and 3mensio CT analysis software: measurement of the tricuspid annulus (A), simulation of the fluoroscopy view (B), simulation of the percutaneous annuloplasty anchors relative to the right coronary artery (C), distance from the tricuspid annulus to the anterior papillary muscle (D), distance from the tricuspid annulus to the roof of the coronary sinus, the inferior vena cava, and the roof of the right atrium (E), distance from the tricuspid annulus to the right ventricular free wall and apex (F), curved multiplanar reconstruction of the superior (G) and inferior venae cavae, and femoral accesses (H).

 

CT imaging can also aid in assessing the position and relationship of pacing leads with the tricuspid leaflets in selected cases of edge-to-edge repair. However, its main role lies in patient selection and planning of annuloplasty and valve replacement procedures, in which it is the imaging modality of choice. In annuloplasty, CT imaging facilitates device sizing, allows certain possibilities to be ruled out via simulation of the interaction of anchoring systems and the course of the right coronary artery, and evaluates tricuspid leaflet tenting to assess potential residual regurgitation postprocedure.54 In heterotopic replacement, CT enables sizing of the superior and inferior vena cava at different levels, assesses the anatomy and location of the suprahepatic veins, and determines the size of the right atrium, all of which determine the type and size of the device to be implanted.55 Finally, in orthotopic replacement, the selection criteria largely depend on the chosen device; however, it is generally necessary to evaluate the annulus size, distance to the anterior papillary muscle or free wall of the right ventricle, the confluence position of the vena cavae, and the angles between these and the tricuspid annulus, as well as the access route.56

Other procedures

Paravalvular leak closure

CT has shown good diagnostic performance in detecting aortic and mitral paravalvular leaks, allowing definition of the number, location, shape, and size of the defects.57 CT is especially useful in assessing infective endocarditis-related complications,58 as well as for planning and supporting the closure of paravalvular leaks in the aortic position.59 In addition, CT-based simulation prior to procedures can predict the occurrence of paravalvular leaks.60

Congenital heart diseases

Magnetic resonance imaging is the technique of choice in the diagnosis, evaluation, and follow-up of congenital heart diseases due to its ability to acquire any imaging geometry and perform anatomical and functional assessment, tissue characterization, and flow analysis, as well as the absence of radiation in a generally young population. CT is reserved for selected patients and cases.

Either CT or magnetic resonance can be used for patient selection, device choice, and sizing prior to intervention in congenital heart diseases. CT offers higher spatial resolution, enabling more precise delineation of calcification areas and proper sizing of prostheses. The use of CT or magnetic resonance is essential before transcatheter pulmonary valve replacement and percutaneous treatment of aortic coarctation. CT may also prove useful in cases of patent ductus arteriosus and complex fistulas. However, CT has lower added value in the closure of septal defects, such as atrial or ventricular septal defects.61 Nevertheless, in postmyocardial infarction ventricular septal defects, CT can be highly useful for sizing the defect and assessing their morphology, extent, and borders, given the often intricate and complex nature of these defects, which hampers accurate evaluation by echocardiography.62

CT-fluoroscopy image fusion during structural heart interventions

The anatomical information and preprocedural planning can be integrated into procedural monitoring. Using specific software and a workstation, cardiac structures are semiautomatically segmented and coregistered with the patient’s anatomy on the cath lab treatment table from 2 fluoroscopy projections. After coregistration, all CT information can be integrated into the procedure, allowing for expanded visibility, improved understanding of anatomical relationships, placement of markers or trajectories, and planning of optimal fluoroscopy angles.63 However, these are static non-ECG- or respiratory-gated images (figure 6).

Figure 6. Examples of computed tomography and fluoroscopy image fusion in various procedures using Heart Navigator (Philips): transcatheter aortic valve replacement (A), left atrial appendage occlusion (B), transcatheter valve-in-MAC mitral valve replacement (C), valve implantation in the superior (D) and inferior venae cavae (E), and closure of mitral paravalvular leak (F).

 

CT-fluoroscopy image fusion has been shown to reduce procedural length, contrast volume, and radiation exposure in TAVI and LAAO procedures, as well as a decreased need for intraprocedural device size adjustments in LAAO. The application and utility of CT- fluoroscopy image fusion have been reported in various procedures and have been shown to be particularly advantageous in complex interventions such as TMVR, transcatheter tricuspid valve replacement, transcaval TAVI, and paravalvular leak closure.64

CONCLUSIONS

CT is a high spatial resolution noninvasive imaging modality, providing excellent delineation of calcium and intravascular space using contrast media. The technique offers the possibility of performing measurements and virtual simulations for both coronary and structural interventions. CT has been established as the gold standard for patient selection and procedural planning in various scenarios of transcatheter coronary and structural interventions (such as TAVI, LAAO, TMVR, and transcatheter tricuspid valve replacement).

FUNDING

None declared.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence was used in the preparation of this work.

AUTHORS’ CONTRIBUTIONS

The manuscript was drafted by M. Barreiro-Pérez and I. Cruz-González and thoroughly reviewed and approved by all authors. Berenice Caneiro Queija and M. Barreiro-Pérez made corrections and editorial changes, and responded the reviewers.

CONFLICTS OF INTEREST

M. Barreiro-Pérez has received payments for presentations or educational activities from Abbott Vascular, Edwards Lifesciences, Venus MedTech, Lifetech, and Cardiovalve. I. Cruz-González has received payments for presentations or educational activities from Abbott Vascular and Boston Scientific. R. Estévez Loureiro has received payments for presentations or educational activities from Abbott Vascular, Boston Scientific, Edwards Lifesciences, and Venus MedTech.

REFERENCES

INTRODUCTION

Angina pectoris affects more than 100 million persons worldwide.1-5 According to the OFRECE study, the prevalence of angina in Spain is around 2.6%, indicating that there are more than 270 000 affected individuals.4 A significant number of stable patients referred for coronary angiography due to angina or a positive ischemia test do not have obstructive coronary artery disease.1 Many of these patients have ANOCA (angina with nonobstructive coronary arteries), or INOCA (ischemia with nonobstructive coronary artery disease) of nonobstructive origin. These 2 entities are manifestations of the same disease, which is why the recommendations provided by this document are applicable to both.

Angina pectoris is more prevalent among women (50%-70%) than men (30%-50%), although its true prevalence remains unknown.1-5 In these patients, angina or ischemia is produced by coronary vascular dysfunction due to vasomotor disorders of the epicardial vessels or arterioles, and/or coronary microvascular dysfunction.6-8

An important point is that, currently, angina pectoris is significantly underdiagnosed, and consequently many patients suffer its consequences without receiving potentially effective treatment. The reasons for this lack of diagnosis and treatment are various. First, there is the inertia associated with the paradigm that has dominated the diagnostic approach to patients with angina for decades focused on identifying coronary artery stenosis rather than vasomotor or coronary microvascular disorders. Additionally, patients with angina without coronary artery stenosis have generally been considered low-risk patients with poor response to conventional antianginal medical therapy.9 Second, and partly related to the previous point, many noninvasive techniques are based on identifying the regional ischemia that is characteristic of coronary artery stenosis (dysregulated contraction or isotope uptake during exertion or stress), making them less sensitive and specific for the detection of nonobstructive ischemia. Third, most cardiologists have not had access to the invasive techniques that provide objective evidence of vascular dysfunction in their patients. These intracoronary techniques have been considered the sole domain of interventional cardiologists, who do not usually play a key role in the management and follow-up of patients with INOCA. These barriers prevent the valuable information provided by invasive techniques from being used in the clinical management of these patients. Finally, patients with ANOCA/INOCA often have extracardiac diseases and conditions that require a multidisciplinary approach, complicating follow-up for specialized cardiologists.

In 2019, the European Society of Cardiology guidelines on the diagnosis and management of patients with chronic coronary syndrome represented a significant advance in the recognition of microvascular angina and the value of specific diagnostic techniques. Therefore, in the diagnostic approach in patients with suspected coronary microvascular angina, the guidelines indicate that coronary flow reserve (CFR) and microcirculatory resistance should be measured through pressure-guided techniques in patients with persistent symptoms but angiographically normal coronary arteries, or moderate stenosis and a normal fractional flow reserve (recommendation IIaB). Even the remaining recommendations, such as the administration of intracoronary acetylcholine during coronary angiography, or the use of transthoracic Doppler echocardiography of the anterior descending artery, cardiac magnetic resonance (CMR), or positron emission tomography (PET) for the noninvasive evaluation of CFR, have a lower level of recommendation (IIbB). In patients with suspected vasospastic angina, the guidelines recommend intracoronary provocation testing to identify coronary artery spasm (recommendation IIaB).10

However, over the past few years, numerous studies have been conducted in patients with ANOCA to assess the efficacy profile of new invasive diagnostic tests for their specific diagnosis, as well as randomized clinical trials assessing symptomatic improvement with individualized therapies. These trials consistently suggest that individualized and multidisciplinary approaches to these patients help to relieve symptoms, reduce the number of medical visits and prescribed therapies, and lower the costs associated with this syndrome.11-13

OBJECTIVES OF THIS DOCUMENT

This document is endorsed by the Clinical Cardiology Association, and the Interventional Cardiology Association, Ischemic Heart Disease and Acute Cardiac Care Association, and Cardiovascular Imaging Association of the Spanish Society of Cardiology (SEC) and aims to:

This document was drafted based on the interpretation of the latest scientific evidence, with an eminently practical focus so that the recommendations can be effectively applied in our setting. Each Association of the SEC provided scientific evidence and their view of their respective fields. Afterward, through consensus, they all created a single document including practical recommendations. The selection of the members that would eventually draft the document was left to the presidents of these Associations and was based on their clinical experience and expertise in the field.

IMPORTANCE OF ANOCA IN ROUTINE CLINICAL PRACTICE

While it has been acknowledged for decades that angina without coronary artery lesions could constitute a separate nosological entity (initially called syndrome X), routine clinical practice has paid little attention to affected patients, primarily due to the widespread notion that their prognosis is good.14 However, numerous subsequent studies in which the diagnosis of ANOCA was based on objective evidence of coronary vascular dysfunction, unlike that of syndrome X, consistently showed that nonobstructive ischemia has a significant prognostic impact. The risk of adverse coronary events in these patients is largely determined by factors such as plaque burden, demonstration of myocardial ischemia, microvascular dysfunction, and the presence of vasospasm or coronary endothelial dysfunction. For example, a study of 917 women with signs or symptoms of myocardial ischemia showed that the composite endpoint of myocardial infarction or cardiac death occurred in 6.5% of women without coronary artery disease, 12.8% of those with nonobstructive atherosclerosis, and 25.9% of those with obstructive coronary artery disease at 10 years of follow-up (figure 1).15 A meta-analysis of 54 studies and 35 039 patients confirmed an increased risk of nonfatal myocardial infarction and death, with an incidence rate of 0.98 per 100 person-years in patients with ANOCA at 5 years of follow-up. The risk was higher in individuals with confirmed ischemia (vs those without ischemia) and patients with nonobstructive coronary artery disease (vs those with normal coronary arteries).16

Figure 1. Risk of myocardial infarction or cardiovascular death at 10 years of follow-up in a cohort of women.15 ANOCA/INOCA, angina/ischemia with nonobstructive coronary arteries; CAD, coronary artery disease.

 

Similarly, even in the presence of angiographically normal coronary arteries, microvascular dysfunction demonstrated by a reduced CFR has proven to be a powerful determinant of the risk of death and myocardial infarction in these patients.17 Additionally, more cardiovascular complications, including stroke and heart failure,18 have also been reported in these individuals, along with a higher prevalence of small vessel cerebral disease.19 In conclusion, patients with coronary microvascular dysfunction, identified by an impaired CFR, have a higher risk of major cardiovascular events.20

Intracoronary acetylcholine provocation testing also allows coronary risk stratification. An abnormal response to intracoronary acetylcholine indicates vasomotor disorders due to endothelial dysfunction or smooth muscle cell hyperreactivity. In addition to causing vasospastic angina, coronary vasomotor disorders are associated with a higher long-term risk of cardiovascular events in patients with angina, especially when associated with increased coronary microcirculation.13,21 Even moderate vasoconstrictor responses to acetylcholine can be predictive of a worse prognosis in this context.20

Additionally, patients with ANOCA often show persistent symptoms, partly due to the lack of an early diagnosis, thus leading to treatment delay. This is associated with a higher number of unnecessary diagnostic tests to rule out obstructive coronary artery disease, visits to the emergency room, hospital admissions, anxiety, impaired quality of life, episodes of sick leave, and higher direct and indirect health care costs.16,22,23

Diagnosing INOCA is essential to provide effective therapies to control angina symptoms. The CorMicA trial (Coronary microvascular angina) included 151 patients with ANOCA who underwent cardiac catheterization and invasive functional assessment (CFR determination, index of microcirculatory resistance, and fractional flow reserve) followed by acetylcholine vasoreactivity testing.11 The patients were randomized to reveal their specific endotype, which would guide treatment based on the results (intervention group), vs standard treatment, which would be administered blind to the test results (control group). Targeted therapy was individualized based on the endotypes documented in the invasive study (vasospastic angina: smoking cessation, long-acting calcium channel blockers, long-acting nitrates, and lifestyle changes; microvascular angina: beta-blockers, lifestyle changes, possible angiotensin-converting enzyme inhibitors and statins; noncardiac chest pain: withdrawal of antianginal treatment). Targeted therapy was significantly associated with an improved angina-related quality of life at 6 months (measured using the Seattle Angina Questionnaire), disease perception, and treatment satisfaction, although no differences were reported in the risk of major adverse cardiovascular events. More antianginal drugs were prescribed in the intervention group (87.8% vs 48.7%; P < .001). While these results are very interesting, it is important to note that this was a single study with a limited number of patients.

ENDOTYPES OF PATIENTS WITH ANOCA

The specific causes of ANOCA are not yet fully described, and are likely multifactorial in most patients. Figure 2 illustrates the specific causes discovered so far and the pathophysiological mechanisms involved in their genesis. Of note, specific diagnostic techniques often do not allow us to differentiate among the various pathophysiological mechanisms. In fact, in many patients, these mechanisms overlap. Four pathophysiological mechanisms causing ANOCA have been described to date:

Figure 2. Possible results of an invasive functional study in a patient with ANOCA. Specific causes discovered to date with the pathophysiological mechanisms involved in their genesis. Ach, acetylcholine; ANOCA, angina with nonobstructive coronary arteries; CFR, coronary flow reserve; IMR, index of microcirculatory resistance. (Figure self-developed from Meeder et al.,1 Jansen et al.,3 Kunadian et al.,7 Kunadian et al.,34 and Hokimoto et al.35.)

 

CLINICAL CHARACTERISTICS OF PATIENTS WITH ANOCA

The first step in identifying patients with ANOCA is diagnostic suspicion. Patients with microvascular angina often report angina-like chest pain, typically on exertion, but it can also occur at rest. ANOCA is more common in women, and affected individuals generally show poor response to short-acting nitrates. In some cases, instead of angina, patients may have angina equivalents such as exertional dyspnea or atypical symptoms such as nausea, vomiting, dizziness, or fatigue. In microvascular spasm, which is also more common in women, unstable angina can occur with a variable response to nitrates.1-3

Regarding angina due to coronary vasomotor disorders, the spectrum and clinical signs of these disorders are much more varied than the pattern of Prinzmetal’s angina, which is a highly specific case of vasomotor disorder caused by an occlusive spasm of an epicardial vessel. However, this disorder is not representative of much more common substrates such as nonocclusive diffuse spasm and arteriolar or microvascular spasm. For example, in vasomotor disorders due to endothelial dysfunction, the dominant symptom is exertional angina, whereas in vasomotor disorders triggered by smooth muscle cell hyperreactivity of coronary vessels (such as in Prinzmetal’s angina), angina tends to occur at rest or becomes unstable, especially at night. Nevertheless, it can also be associated with exertional chest pain and be triggered by specific stimuli such as stress, cold, or an increase in vasoconstrictor humoral factors. Angina can also be associated with other conditions such as migraines or Raynaud’s phenomenon. Some anticancer drugs, such as 5-fluorouracil and capecitabine, among others, are known to be associated with vasospastic angina.33 Similarly, the initial clinical manifestation of epicardial spasm can be myocardial infarction with nonobstructive coronary arteries (MINOCA).19 This condition is often associated with smoking, unlike other traditional risk factors such as hypertension, diabetes mellitus, and dyslipidemia.19,32

NONINVASIVE DIAGNOSTIC APPROACH IN PATIENTS WITH ANOCA

The diagnostic approach to patients with ANOCA falls within the diagnostic process of chronic coronary syndrome as recommended by the current clinical practice guidelines and is initially noninvasive.10 However, it is important to note that the available scientific evidence—sometimes scarce—has already been analyzed, and consequently some statements are based not only on clinical trials but also on consensus among the authors of the document.

After angina is suspected, the patient should be referred to the cardiology unit for basic symptom examination, including an electrocardiogram, echocardiogram, a complete blood count, and clinical response to initial antianginal treatment. A noninvasive strategy is advised for most patients with nonlimiting symptoms and a low or intermediate pretest risk of obstructive coronary artery. This strategy involves noninvasive imaging modalities, including functional studies, based on surrogates of myocardial blood flow and CFR, and/or anatomical studies, mainly coronary computed tomography.3 The diagnostic tests performed will depend, among other factors, on the patient’s exercise tolerance and the availability and experience of each center (figure 3).1,3,7,34,35

Figure 3. Diagnostic approach to patients with suspected ANOCA or INOCA. Ach, acetylcholine; ANOCA, angina with nonobstructive coronary arteries; IC, informed consent; CFR, coronary flow reserve; CT, computed tomography; CVRF, cardiovascular risk factors; IMR, index of microcirculatory resistance; INOCA, ischemia with nonobstructive coronary arteries; MPRI, myocardial perfusion reserve index; MRI, magnetic resonance imaging; MVD, microvascular dysfunction; VD, vasodilator. (Figure self-developed from Meeder et al.,1 Perera et al.,2 Jansen et al.,3 Kunadian et al.,7 Ang and Berry,31 Kunadian et al.,34 and Hokimoto et al.35.)

 

Of note, in many patients with ANOCA, noninvasive imaging modalities for detecting ischemia have low sensitivity for the diagnosis of most endotypes, especially those associated with coronary vasomotor disorders. In a registry of patients studied with noninvasive ischemia detection tests and invasive functional tests (considered the reference standard for diagnosis), only 50% of those with a low CFR showed abnormalities in the noninvasive imaging tests.36 In fact, no noninvasive stress test can reliably detect the presence of microvascular spasms or coronary endothelial dysfunction and a negative stress test does not exclude the presence of vasomotor coronary dysfunction, especially in symptomatic patients.7 The reasons for the low sensitivity of these techniques are diverse. However, an important reason is that they rely on visualizing regional differences among myocardial segments (nonuniform tracer uptake in single-photon emission computed tomography, differences in myocardial segment mobility in stress echocardiography). Given the characteristics of microvascular angina, in which ischemia can be widespread, it is difficult to find regional defects in noninvasive tests. Moreover, patients with vasospasms usually test negative in stress tests based on comparison between rest and hyperemia. Therefore, it is important to note that ANOCA should always be suspected in patients with suggestive chest pain and a normal coronary computed tomography scan, or without obstructive coronary artery disease (< 50% reduction in diameter), and in patients who test negative on noninvasive imaging modalities for ischemia detection. Currently, no imaging modality allows the direct anatomical visualization of coronary microcirculation in vivo in humans, which is why its evaluation relies on measuring parameters that reflect functional status, such as myocardial blood flow and myocardial flow reserve.7

However, certain ANOCA endotypes with low CFR and a high suspicion of microvascular angina can be diagnosed noninvasively through various imaging modalities such as PET, transthoracic Doppler echocardiography, contrast-enhanced transthoracic echocardiography, and CMR. CFR is defined as an increased flow between the resting state and maximum hyperemia. CFR values < 2 to 2.5 are considered pathological.1

PET allows determination of myocardial blood flow at rest and during hyperemia in absolute terms, which facilitates the calculation of CFR. Although PET is considered the reference noninvasive imaging modality and correlates well with invasive study (CFR < 2 is associated with a worse prognosis regardless of the severity of coronary artery disease),37 its availability is highly limited in our setting,3,38 due to its high cost and the need for specific cyclotron-produced radiation-emitting radiotracers, such as oxygen-15-labeled water, nitrogen-13-labeled ammonia, or rubidium-82, a potassium analog.

Transthoracic Doppler echocardiography allows for the measurement of baseline and hyperemic blood flow velocity (after adenosine administration) using pulsed-wave Doppler. CFR < 2.5 is considered diagnostic of microvascular dysfunction. However, this imaging modality requires highly trained personnel and can only be used in the left anterior descending coronary artery.3,39 On the other hand, contrast-enhanced transthoracic echocardiography using microbubbles allows estimation of myocardial perfusion flow based on its degree of opacification. The latter imaging modality has shown good correlation with PET, although there may be significant interobserver variability, thus requiring further validation in studies.40

Finally, CMR can determine myocardial perfusion using stress and contrast agents (gadolinium) to calculate the myocardial perfusion reserve index, which is a surrogate parameter of CFR. This imaging modality is more widely available than PET, and has less interobserver variability than echocardiographic studies, making it the most suitable imaging modality for the study microvascular dysfunction in our setting. However, CMR is still pending validation in the remaining ANOCA endotypes.3,41 Hyperemia or coronary vasodilation can be achieved through adenosine infusion, or the administration of a single bolus of regadenoson, and stress vs resting perfusion can be compared quantitatively. The diagnostic ability of stress CMR in microvascular dysfunction was demonstrated 2 decades ago.42 A myocardial perfusion reserve index < 1.84 has shown sensitivity and specificity rates of 73% and 74%, respectively, to predict abnormalities in invasive coronary physiology studies, with an area under the ROC curve of 0.78.41 A quantitative assessment of stress perfusion studies showed an even stronger correlation with invasive studies in a series of 65 patients (50 with stable angina, 46% of whom had no coronary artery lesions, and 15 healthy volunteers) to distinguish multivessel disease from microvascular dysfunction, with an area under the ROC curve of 0.94 (P < .001) for the absolute quantification of myocardial flow during stress < 1.82 mL/g/min.43 In this study, myocardial flow during stress correlated better with invasive measurements than with myocardial flow reserve. Additionally, its prognostic capability has also been demonstrated. In a series of 218 patients with angina and coronary arteries without epicardial lesions,44, a myocardial perfusion reserve index ≤ 1.47 was associated with a 3-fold higher risk of major cardiovascular events compared with patients with values > 1.47 (hazard ratio, 3.14; 95% confidence interval, 1.58-6.25; P = .001). In another series of 395 patients, myocardial perfusion reserve improved the prognostic value vs the baseline model (age, sex, and late enhancement) of the primary endpoint defined as a composite of cardiac death, nonfatal myocardial infarction, aborted sudden death, or late revascularization, at 460 days of follow-up. Moreover, this study confirmed that quantitative perfusion (defined as > 10% ischemic myocardium) was superior to qualitative perfusion (defined as perfusion defects in > 2 segments) in the assessment of ischemia.45 Rahman et al.46 also demonstrated that high-resolution CMR techniques using fully quantitative perfusion were properly accurate and outperformed visual assessment in detecting microvascular dysfunction.

Unfortunately, some of the tests that could help in the noninvasive functional diagnosis of patients with ANOCA/INOCA are not available in routine clinical practice in many centers in Spain, thus limiting the diagnostic approach in these patients.

 

Table 1 shows the diagnostic criteria for ANOCA, while figure 3 illustrates the complete diagnostic algorithm proposed for patients with ANOCA, specifying the initial strategy, when to schedule invasive studies, and the possible therapies based on the specific endotype.

Table 1. Diagnostic criteria for ANOCA

Endotype	Physiopathology	Criteria	Comments
Microvascular angina	Coronary microvascular dysfunction	Myocardial ischemia symptoms	• Exertional or resting angina • Angina equivalent (exertional dyspnea)
		Evidence of myocardial ischemia	• Positive ischemia detection test
		Absence of obstructive coronary artery disease	• FFR > 0.80 or stenosis < 50% • Confirmed by coronary CT or coronary angiography
		Impaired coronary microvascular function	• Adenosine test: CFR ≤ 2.0 (2.5 according to the method), IMR ≥ 25, HMR ≥ 1.9 • Microvascular spasm (spontaneous or acetylcholine test): angina, EKG changes, without epicardial spasm (lumen reduction < 90%)
Vasospastic angina	Epicardial spasm	Symptoms	• Angina, more at rest, especially nocturnal • Reduced exercise tolerance, especially in the morning • Response to nitrates and calcium antagonists
		EKG changes	• ST-segment changes (elevation/depression) ≥ 1 mV • New negative U waves
		Absence of obstructive coronary artery disease	• FFR > 0.80 or stenosis < 50% • Confirmed by coronary CT or coronary angiography
		Coronary spasm	• Vasoconstriction > 90% with angina and spontaneous EKG changes, or after provocation test (acetylcholine)
		Preserved coronary microvascular function	• Adenosine test: CFR > 2.0 (2.5 according to the method), IMR < 25, HMR < 1.9
Mixed	Microvascular angina and epicardial spasm	Absence of obstructive coronary artery disease	• FFR > 0.80 or stenosis < 50% • Confirmed by coronary CT or coronary angiography
		Microvascular angina	• Microvascular dysfunction • Adenosine test: CFR ≤ 2.0 (2.5 according to the method); IMR ≥ 25, HMR ≥ 1.9
		Coronary spasm	• Angina + EKG changes + epicardial vasoconstriction (> 90%)
Noncardiac chest Pain	None	Absence of obstructive coronary artery disease	• FFR > 0.80 or stenosis < 50% • Confirmed by coronary CT or coronary angiography
		Normal functional tests	• Adenosine test: CFR > 2.0 (2.5 according to the method), IMR < 25, HMR < 1.9 • Negative acetylcholine test
ANOCA, angina with nonobstructive coronary arteries; CFR, coronary flow reserve; CT, coronary computed tomography; EKG, electrocardiogram; FFR, fractional flow reserve; HMR, hyperemic microvascular resistance; IMR, index of microvascular resistance. Table based on data from Meeder et al.,1 Perera et al.,2 Jansen et al.,3 Kunadian et al.,7 Mejia-Renteria et al.,19 Ong et al.,25 Ang and Berry,31 Kunadian et al.,34 and Hokimoto et al.35.

 

INVASIVE DIAGNOSTIC APPROACH IN PATIENTS WITH ANOCA

Although these are very safe procedures, there are risks involved in the invasive assessment of patients with suspected ANOCA. Therefore, it is of paramount importance that the health professionals involved should have specific training in performing and interpreting various tests. Adequate pathways should also be implemented. Currently, the use of 2 functional tests is advised, consisting of a vasospasm provocation test with intracoronary acetylcholine infusion and a microvascular function test using a pressure-temperature sensor-tipped wire at rest and during maximum pharmacological hyperemia.7,11,34,35

Vasospasm provocation testing with intracoronary acetylcholine is advised. Since the technical data sheet of acetylcholine does not include its intracoronary use, the pharmacy department of the medical center must be contacted for prior authorization. In most cases, patients must provide their prior written informed consent for the off-label use of the drug.47 This test has demonstrated high sensitivity and specificity rates (around 90% and 100%, respectively, depending on the patient’s characteristics) for diagnosing micro- and macrovascular vasospastic angina, with very few complications.47,48 Before the test is conducted, the use of long-acting vasodilator drugs should be avoided. A minimum of 18 hours without oral or topical vasodilator agents is advised to avoid false negatives. Although the use of beta-blockers may increase vasoconstriction after acetylcholine infusion, their discontinuation before the test is not advised if these drugs are deemed necessary. In procedures performed via the radial route, the use of calcium antagonists should also be avoided.47 Essentially, the test involves the infusion of increasing acetylcholine doses while simultaneously assessing the reproduction of the patient’s symptoms, changes in the 12-lead electrocardiogram, and the presence of spasms in the epicardial arteries > 90% of their baseline diameter. The Spanish Society of Cardiology Working Group on Cardiac Catheterization and Interventional Cardiology recently published a technical document on the performance and interpretation of this test.47

Microvascular function can be assessed using intracoronary Doppler, or pressure-temperature sensor-tipped wires. However, the only currently available guidewires are pressure-temperature sensor-tipped wires (Pressurewire X, Abbott, United States), which use the thermodilution method. Coronary thermodilution allows coronary flow values to be obtained at rest and during maximum hyperemia after the infusion of any microcirculation vasodilator agent (usually adenosine or its derivatives). These values are obtained after the infusion of 3 mL of physiological saline solution through the guide catheter and by measuring the transit time of this solution between the proximal segment of the artery and the distal segment, where the distal guidewire thermistor is located, both at rest and during maximum hyperemia. By obtaining flow data at rest and during maximum hyperemia, the CFR can be calculated, which under normal conditions should be > 2.5. CFR values ≤ 2.5 are considered diagnostic of microvascular dysfunction. Since the pressure of microcirculation perfusion (measured in the distal segment of the artery where the guidewire is located) can be obtained while performing the test during maximum hyperemia, the minimum microcirculation resistance (IMR) can be estimated. In studies performed in healthy patients, a cutoff value of 25 has been established. IMR values ≥ 25 are also indicative of microvascular dysfunction.7,34,35

There is another promising method in the invasive diagnosis of patients with ANOCA. Using the same pressure guidewire and a dedicated microcatheter (RayFlow, Hexacath, France), absolute coronary flow values (in mL/min) and absolute microcirculation resistances (in Wood units) can be obtained.49 Since these are absolute values, they partly depend on the perfusion territory of the artery and the studied segment. Currently, research is underway to develop an indexed approach using this method.50

THERAPEUTIC APPROACH IN PATIENTS WITH ANOCA

General approach

In patients with ANOCA, treatment should focus on relieving symptoms and improving the risk profile, quality of life, and prognosis. In this regard, early diagnosis, identification of the pathophysiological mechanisms involved, and early initiation of treatment tailored to the INOCA endotype are key to achieving therapeutic success.1,3,7,25,31,34,35,51-54 However, currently available studies of specific medical treatment for this condition are small, with heterogeneous methodologies and variable results, which makes it difficult to establish robust recommendations for the therapeutic management of these patients.

Lifestyle changes and control of cardiovascular risk factors

First, given the impact of cardiovascular risk factors on the development of coronary microvascular dysfunction and epicardial spasm, effective control of these risk factors is essential, including lifestyle changes (weight loss, physical exercise, smoking cessation, stress reduction), and appropriate pharmacological therapies.10 To reduce the risk of coronary vasospasm, it is important to avoid triggering factors such as smoking and the use of certain drugs (cocaine and amphetamine).10

Statins are beneficial not only due to their effect on lipid profile, but also due to their positive effect on endothelial function and in preventing the development of coronary spasms.55,56 Renin-angiotensin-aldosterone system inhibitors are beneficial to reduce blood pressure and improve endothelial function. In fact, these drugs have been reported to have positive effects on both coronary microvascular dysfunction and epicardial coronary vasospasm.55-57 The role of aspirin in patients without known cardiovascular disease is controversial.55,56 In the Japanese guidelines, aspirin is not advised in the absence of angiographically confirmed stenosis in patients with vasospasm (class IIIB indication).35

Antianginal treatment

Antianginal treatment is crucial for symptom relief. Preferential use of drugs that reduce myocardial oxygen consumption is advised in patients with a structural endotype of INOCA (microvascular dysfunction), such as beta-blockers or calcium channel blockers (ivabradine may also be considered in certain cases), along with other drugs such as ranolazine, trimetazidine, and nicorandil. On the other hand, calcium channel blockers, nitrates, nicorandil, or a combination of these, are advised in patients with a vasomotor endotype of INOCA (whether epicardial or microvascular spasm) (table 2).1,3,7,25,31,34,35,51-54

 

Table 2. Therapeutic approach for patients with ANOCA or INOCA

General treatment
Lifestyle changes	• Mediterranean diet • Physical exercise • Weight control • Stress reduction
Cardiovascular risk factor control	• Hypertension • Dyslipidemia • Diabetes • Smoking cessation
Aspirin	• With previous CVD • Without previous CVD, its use is controversial
ACEI or ARA II	• Blood pressure reduction • Improvement in endothelial function: possible benefit in microvascular coronary dysfunction and coronary vasospasm
Statins	• Reduction in total cholesterol and LDL • Improvement in endothelial function • Possible benefit in vasospastic angina
Anti-anginal drugs	Microvascular angina	Beta-blockers	• Decreased myocardial oxygen consumption*
		Calcium antagonists	• Decreased myocardial oxygen consumption • Vascular smooth muscle relaxation
		Ranolazine	• Improvement in microvascular perfusion reserve
		Trimetazidine	• Increased cellular tolerance to ischemia
	Vasospastic angina	Calcium antagonists	• Decreased myocardial oxygen consumption • Decreased coronary spasm via relaxation of vascular smooth muscle
		Nitrates	• Decreased myocardial oxygen consumption • Decreased coronary spasm via relaxation of vascular smooth muscle
		Nicorandil	• Coronary vasodilator effect
	Microvascular angina + vasospastic angina	Calcium antagonists, nitrates, ranolazine, trimetazidine, nicorandil
* Consider the use of nebivolol due to its antioxidant properties through nitric oxide. ACEI, angiotensin-converting enzyme inhibitors; ANOCA, angina with nonobstructive coronary arteries; ARA II, angiotensin II receptor antagonists; CVD, cardiovascular disease; INOCA, ischemia with nonobstructive coronary arteries; LDL, low-density lipoproteins. Table based on data from Meeder et al.,1 Jansen et al.,3 Kunadian et al.,7 Kobayashi et al.,26 Ang and Berry,31 Kunadian et al.,34 Hokimoto et al.,35 Beltrame et al.,51 Mehta et al.,52 Seitz et al.,53 and Abouelnour et al.54.

 

There is some evidence on nebivolol compared with other beta-blockers, due to its potential vasodilatory effect that targets the production of nitric oxide.58 A beneficial effect of carvedilol has also been suggested by improving endothelium-dependent dilation.59 A randomized clinical trial of 81 patients demonstrated the benefit of ranolazine treatment in relieving symptoms in patients with CFR values < 2.5.60 Diltiazem treatment shows no benefits in improving symptoms, quality of life, or coronary microvascular function in the randomized EDIT-CMD trial of 73 patients with ANOCA in a 6-week course of treatment, although there was a reduction in induced epicardial vasospasms.12 Finally, there are promising potential benefits associated with drugs that have new therapeutic targets, such as cilostazol, a phosphodiesterase 3 inhibitor that targets coronary vasospasm,61 or zibotentan, a selective endothelin A antagonist with benefits on microcirculation and endothelial dysfunction,62 or fasudil, a rho-kinase enzyme inhibitor capable of reducing the IMR in patients with a positive vasospasm provocation test and elevated IMR.13

Treatment for resistant angina

The use of drugs such as low-dose tricyclic antidepressants (which modulate norepinephrine uptake and have anticholinergic effects, which can induce analgesia), or neurostimulators that block the transfer of pain at the spinal cord has been proposed in patients with resistant angina, and even coronary interventions in the case of vasospastic angina refractory to medical therapy.51

Patient follow-up

The follow-up of these patients should be coordinated between primary care physicians and cardiologists, and once symptoms are under control, follow-up should preferably be conducted in primary care units, with referrals to cardiology if there is decompensation. In addition, given the particularities of ANOCA, it is essential to inform patients about their disease and its implications. A multidisciplinary approach is necessary since other health professionals, such as psychologists, internists, and pain clinics, may sometimes be required.

Future lines of research

Finally, ongoing clinical trials are currently exploring whether intensive treatment of coronary atherosclerosis with high-intensity statins, renin-angiotensin-aldosterone system inhibitors, and low doses of aspirin improves angina and ischemia. The WARRIOR trial (NCT03417388) is studying whether such treatment improves outcomes, and the MINOCA-BAT trial (NCT03686696) is investigating whether the combined use of beta-blockers and renin-angiotensin-aldosterone system inhibitors reduces major cardiovascular clinical events.

CONCLUSIONS

Patients with suspected ANOCA exhibit a wide array of presentations that can currently be diagnosed and treated with effective individualized therapies. It is important for clinical cardiologists to become familiar with the various abnormalities in patients with ANOCA, and the currently available diagnostic and therapeutic tools. Invasive diagnostic tests constitute a new option requiring specific training for their correct performance and interpretation, as well as CMR with adenosine or regadenoson for myocardial perfusion calculation. In conclusion, specific actions need to be taken by all health centers to create diagnostic and therapeutic protocols for the management of these patients.

FUNDING

None declared.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

Artificial intelligence has not been used in the preparation of this document.

AUTHORS’ CONTRIBUTIONS

All authors contributed equally to the conception, literature search, development, drafting, reading, and final approval of the manuscript. C. Escobar served as the consensus coordinator.

CONFLICTS OF INTEREST

J. Escaned, a recipient of the Intensification of Research Activity Project INT22/00088 from Instituto de Salud Carlos III, declared speaker’s fees for his involvement in educational activities for Abbott and Philips. C. Escobar, J.M. Gámez, and V. Barrios declared lecture fees from Menarini. The remaining authors declared no conflicts of interest whatsoever.

REFERENCES

IMPLICATIONS OF CALCIFICATION IN PERCUTANEOUS CORONARY INTERVENTIONS

Vascular calcification is a process closely associated with atherosclerosis. It can occur in the media (in peripheral arteries mainly) or intima layers (in coronary arteries). In the context of coronary atherosclerosis it debuts in intermediate or advanced stages in plaque evolution due to conversion of smooth muscle cells into osteoblastic phenotypes and infiltration of atheromatous plaque due to macrophages that clear out apoptotic smooth muscle cells and contain calcified vesicles.1 Atheromatous plaque calcification can take different shapes that probably correspond to different stages of the same disease like microcalcifications (< 15 μm), punctiform calcifications (circumferential arc < 90º), leaves or thin calcium layers (circumferential arc > 90º or > 3 mm in length), and calcium nodules.1

The main risk factors associated with coronary artery calcification are age, Caucasian race, diabetes mellitus, and chronic kidney disease.1

The prevalence of coronary artery calcification if variable based on the population studied and the diagnostic method used.2 The traditional angiographic definition of moderate calcification described radiopacities seen during cardiac motion while severe calcification is described as radiopacities seen without cardiac motion, usually on both sides of the arterial lumen. The prevalence of moderate or severe calcification is between 18% and 60%.3,4

Calcification complicates percutaneous coronary interventions (PCI) for various reasons: a) resistance to the advance of different devices especially in the presence of tortuosity (eventually, “non-crossable” lesions); b) reduced plaque compliance that will eventually require higher pressure in dilatation balloons or plaque modification devices (“non-dilatable” lesions); and c) difficulties advancing the stent and expanding it.5 Other issues would be malapposition and polymer damage that can lead to a non-homogeneous release of antiproliferative drugs. Everything combined makes calcification one of the major determinants of the SYNTAX score,6 and associated with worse PCI outcomes and higher rates of adverse events at follow-up including mortality in patients with extremely calcified coronary artery lesions.7 In addition, it increases the rate of procedural complications associated with calcification per se and with the tools necessary for treatment: coronary artery dissection, loss of side branches, PCI material entrapment, stent distortion or even stent loss, and the dreaded coronary artery perforation that is particularly severe since it is very difficult to advance any kind of sealing materials.8

To stop these issues and their prognostic implications from happening numerous plaque modification devices have been developed. The appropriate use of these devices is essential to perform safe and effective PCIs on calcified coronary artery lesions.

This position paper has been promoted by the Interventional Cardiology Association of the Spanish Society of Cardiology (ACI-SEC) with contributions from different expert professionals in this setting. It describes the plaque modification techniques currently available in our field and proposes an algorithm for the management of calcified coronary artery lesions.

INTRACORONARY IMAGING MODALITIES FOR CALCIFIED LESION ASSESSMENT

Intracoronary imaging modalities play a key role in the assessment of calcified coronary artery lesions. The use of optical coherence tomography (OCT) or intravascular ultrasound (IVUS) can be very useful to improve the detection and assesment of coronary artery calcium, select the plaque modification technique, and optimize results especially in association with stent expansion.

Calcification detection and assessment

Angiography is a limited sensitivity tool to detect coronary artery calcium. Unlike angiography both the IVUS and the OCT have higher sensitivity and specificity to assess the characteristics and degree of calcification, which are basic aspects to determine the therapeutic options.2,9 Table 1 shows the differences of these 2 intracoronary imaging modalities regarding calcium detection. The main difference between the 2 is that, since calcium creates posterior acoustic shadowing on the IVUS, calcium thickness cannot be properly assessed. As alternative marker, the presence of reverberations on the IVUS has been associated with the presence of thinner calcium layers (< 0.5 mm). On the OCT, parietal calcium does not create posterior acoustic shadowing and, therefore, its thickness can be assessed accurately. Nodular calcium, however, creates a shadow in both the IVUS and the OCT (figure 1).

 

Table 1. Intracoronary imaging modalities for calcified coronary artery lesion calcification

Imaging modality	Sensitivity	Specificity	Calcium pattern	Calcium arc	Calcium length	Calcium thickness	Disadvantages
OCT	++++	++++	Parietal calcium: low reflectivity structure with demarcated borders and without posterior shadowing (figure 1A) Calcium nodule: Protruding structure into the lumen with posterior shadowing (figure 1C)	Allows quantification	Allows quantification	Can be measured	Requires clearing the blood from the vessel lumen for image acquisition. This can increase the contrast volume compared to IVUS Does not acquire proper images of ostial lesions
IVUS	+++++	++++	Parietal calcium: hyperechogenic structure with posterior shadowing (figure 1B) Calcium nodule: Structure protruding into the lumen with posterior shadowing (figure 1D)	Allows quantification	Allows quantification	Cannot be measured due to posterior shadowing Reverberations are a marker of thin calcium (< 0.5 mm)	Posterior shadowing complicates calcium thickness assessment In the 20 MHz IVUS the limited resolution and near-field clutter artifact can complicate the definition of calcium depth with respect to lumen in severe lesions
IVUS, intravascular ultrasound; OCT, optical coherence tomography.

Figure 1. Coronary artery calcium assessment with IVUS and OCT. A: Parietal calcium on the OCT, low reflectivity structure with demarcated borders (asterisk). B: Parietal calcium on the IVUS, hyperechogenic structure with posterior shadowing. C: Calcium nodule on the OCT, structure protruding into the lumen with posterior shadowing. D: Calcium nodule on the IVUS, structure protruding into the lumen with posterior shadowing.

 

Different scoring systems have been developed for both intracoronary imaging modalities (table 2) including the characteristics of calcification that have been associated with stent underexpansion. The first OCT suitable scale ever developed includes 3 different parameters: calcium arc > 180º (score = 2), length > 5 mm (score = 1), and thickness > 0.5 mm (score = 1). Lesions with scores > 2 have a higher risk of stent underexpansion if proper plaque preparation is lacking.5 A similar scale has been developed for IVUS using 4 different criteria: calcium arc > 270º with > 5 mm in length (score = 1), calcium arc > 360º (score = 1), presence of calcified nodule (score = 1) and adjacent vessel < 3.5 mm (score = 1). Scores ≥ 2 are indicative of the need for plaque modification prior to stenting.10

 

Table 2. Intracoronary calcium scores based on optical coherence tomography and intravascular ultrasound

	OCT		IVUS
		Scores		Scores
Máximo arco de calcio	≤ 180°	0	≤ 270º	0
	> 180° (> 50%* of arc circumference)	2	270º and > 5 mm in length	1
			360º	1
Máximo grosor de calcio	≤ 0.5 mm	0
	> 0.5* mm	1
Longitud de calcio	≤ 5 mm	0
	> 5* mm	1
Type of calcium			Non-nodular	0
			Nodule	1
Vessel diameter			≥ 3.5 mm	0
			< 3.5 mm	1
IVUS, intravascular ultrasound; OCT, optical coherence tomography. Scores ≥ 2 on the IVUS and > 2 on the OCT are suggestive when using calcium modification techniques due to the risk of stent underexpansion. * Rule of 5: Lesions where calcium occupies > 50% of the arc circumference extend longitudinally > 5 mm and have > 0.5 mm of thickness require advanced calcium modification techniques.

 

Selection of plaque modification techniques under intracoronary imaging modality guidance

The characteristics of calcium as seen on the intracoronary imaging modalities can contribute to the selection of the most adequate plaque modification technique. There is in depth information on this aspect in the last section of the document but, overall, lesions where calcium does not have underexpansion risk criteria can be treated with high-pressure or modified balloons (scoring, cutting). However, if these criteria exist it will be necessary to use more advanced plaque modification techniques. Added to these criteria, we should also mention calcium depth since some imaging modalities only act on the superficial—not deep—layer of the plaque.

Optimization of stenting under intracoronary imaging modality guidance

Both the IVUS and the OCT allow us to determine whether proper stent expansion has been achieved. This is especially relevant in calcified coronary artery lesions that happen to be the ones that are most associated with stent underexpansion, the parameter most strongly associated with stent failure.11 Proper apposition and lack of dissection or significant border hematoma, as well as proper lesion coverage are other optimization parameters under intracoronary imaging modality guidance that should also be assessed after stenting.12

BALLOON-FREE TECHNIQUES

Rotational atherectomy

The rotational atherectomy (RA) technique uses a metal olive-shaped burr covered with diamond crystals in its distal third that rotates at high speed and performs a differential cut when advancing through the vessel (figure 2A) while pulverizing calcified tissue and preserving the adjacent elastic tissue.13

Figure 2. Plaque modification devices. A: Rotational atherectomy device. B: Orbital atherectomy device. C: Coronary laser device with the 2 existing console models. D: Intracoronary lithotripsy device. Modified with permission from Cubero-Gallego et al.13

 

It appeared over 30 years ago to facilitate the management of coronary artery lesions by reducing plaque burden. Early enthusiasm turned into an elevated use of RA in different settings without the proper scientific back-up. This triggered suboptimal results14 that reduced its use to highly selected cases only. Through all these years, RA has evolved with technological improvements, and also of the technique itself, as well as the selection of patients.

Currently, the ROTAPRO system (Boston Scientific, United States) is available. It has made the technique easier because it has replaed the pedal of the early version for a button placed on top of the olive-shaped burr advancer. There is another button on the side of the advancer to change to the Dynaglide mode (rotation at low revolutions is advised to introduce and remove the burr). Console is smaller and comes with a digital screen. Size of the burrs is between 1.25 mm and 2.5 mm, and they are compatible with 6-Fr-to-8-Fr catheters based on the size of the olive-shaped burr that advances on a 0.009 in specific guidewire (0.014 in the radiopaque side) of which 2 different versions exist (RotaWire Floppy and RotaWire Extra-Support) that should be used depending on the characteristics of the plaque and support needed.13

The main indication is to treat extremely calcified non-crossable or non-dilatable coronary artery lesions with balloon. Probably, the optimal scenario is a concentric calcified lesion with a smaller luminal area compared to the olive-shaped burr. Eccentric angulated lesions are less favorable since they are associated with a higher risk of complications.13,15 It can be used as a primary or a bailout strategy after “balloon failure”. The primary strategy has been associated with shorter procedures, less radiation and contrast, and probably lower cost regarding the material used.15

The target of RA has also changed from the old idea of removing as much plaque as possible (debulking) to the modern approach of modifying plaque to “facilitate” the PCI. Technical recommendations to perform RA have evolved too. Current recommendations are shown on table 3.16

 

Table 3. Recommendations for a safe use of rotational atherectomy

Arterial access	It depends on the maximum size of the olive-shaped burr. Currently, the most widely used is radial access because it allows the use of burrs of up to 1.75 mm (when using a 6-Fr catheter) or 2.15 mm (when using a 7-Fr catheter)
Guide catheter	High-support catheters with a simple curve are advised
Guidewire	Direct guidewire placement is often feasible, although a conventional guidewire can be used, and exchange performed using a microcatheter or a coaxial balloon Based on the lesion characteristics, the RotaWire Floppy or Extrasupport can be used
Size of olive-shaped burr	The use of small burrs is advised to keep the burr/artery ratio ≤ 0.5. The size of the most widely used burr is 1.5 mm. In some cases, the gradual increase of the size of the burr is advised
Rotablation speed	Selection of rotablation speeds < 180 000 rpm—ideally between 135 000 rpm and 150 000 rpm—is advised. High speeds should be spared for cases where the burr cannot cross despite using the optimal technique available. Special attention should be paid to avoid drops > 5000 rpm during rotablation
Ablation time	Shorter ablation times (ideally ≤ 15 seconds) reduce the risk of complications (atrioventricular block, flow slowing down)
Ablation motion	Gradual, and continuous pecking motion
Cleansing serum	Heparinized saline solution should be used with vasodilators/spasmolytics (verapamil, nitrates)
Pacemaker	The use of olive-shaped burrs of smaller diameter, lower speeds, and the position of the burr with the Dynaglide mode have proven to reduce the number of transient atrioventricular blocks during rotablation substantially In selected cases, above all, in dominant right coronary or left circumflex arteries the preventive use of IV atropine or transient pacemaker implantation can be considered

 

The most common complication is slow/no-flow although its rate has dropped down to 2.6%.17 It is due to debris embolization towards microcirculation and there is higher risk in long lesions where multiple and prolonged passes with large olive-shaped burrs are performed without proper pauses among them and in the presence of a poor distal vessel. The management of dominant right coronary or left circumflex coronary arteries can be associated with transient conduction disorders. Severe complications like burr entrapment, perforation, and coronary dissection are rare.13 Factors predisposing burr entrapment are lesion severity, steep angulations, and the use of very small burrs. Tortuosity and the lack of guide catheter coaxiality in the management of ostial lesions can trigger dissections and coronary perforations.

Although RA has demonstrated that it facilitates PCI with higher rates of success compared to balloon angioplasty, No clinical benefit has been yet confirmed.18-21

To analyze its results we should mention that RA has been used in patients of higher clinical risk with more complex coronary artery lesions.22 Another aspect we should take into consideration is the high percentage of cases where this technique was used as a bailout strategy (12% to 50%)20,21,23 meaning that without RA these cases would not have been performed or had had worse results. Although ongoing trials are studying the advantages of elective or bailout RA, proper patient and lesion assessment should lean towards increasing its elective or earlier use with a potential beneficial impact on clinical outcomes.24

In conclusion, when performed under the current recommendations RA is a safe and effective procedure. It should become part of our therapeutic arsenal in our cath labs with trained personnel for proper use.

Orbital atherectomy

The Diamonback-360 (OAS) device (Cardiovascular Systems, United States) is a diamond-coated bidirectional orbital crown that uses a combination of centrifugal force (by creating elliptical orbits) and friction to the surface to modify the calcified plaque and increase compliance (figure 2B). Also, with the pulsatile impact of the crown after speeding up, microfractures can occur that eventually modify deep calcium layers (figure 2B and figure 3). That is why a single 1.25 mm crown can treat vessels from 2.5 mm up to 4 mm.

Figure 3. Characteristics of orbital atherectomy catheter and its effects. (Modified with permission from Cardiovascular Systems.25)

 

Compared to the remaining plaque modification techniques, this orbital atherectomy (OA) has arrived late to our country and our experience is still scarce.

Its main indication is to treat no-dilatable calcified coronary artery lesions.26

Preparation is very similar to RA, but here a specific guidewire is needed, the Viper-Wire. Crown advances with the Glide-Assist system (rotation at low revolutions) until coming close to the lesion. Another distinctive feature of this device is its antegrade and retrograde ablation functionalities. Unlike RA, the speed at which the device moves forward needs to be very slow (between 1 mm and 3 mm per second) to guarantee good procedural results and reduce complications.17,26 The mechanism of action of OA consists of the crown elliptical rotation that achieves a gradual increase of orbital diameter as rotation speed increases from 80 000 rpm up to 120 000 rpm. Cycles ≤ 30 seconds are advised (it comes with a sound warning signal to end the cycle) with pauses between 20 and 30 seconds among them that can duplicate in cases of poor hemodynamic tolerance.26 The continuous infusion of a lubricant solution is necessary to minimize thermal lesions during OA. Also, 18 mL/min are administered to cool the device down and get rid of debris, thus reducing the chances of ischemia and distal embolization.13,26,27

Complications are similar to those of RA. However, the possibility of retrograde application reduces the chances of crown entrapment and the risk of dissection or perforation in angulated or ostial lesions. The rate of perforation is between 0.7% and 2%.28,29 Theoretically speaking, the debris created by OA is smaller compared to the debris created by RA. This added to the fact that the crown does not stop coronary flow during atherectomy reduces the risk of slow/no-reflow and endothelial thermal lesion.27 However, transient conduction disorders are not rare when dominant right coronary or left circumflex arteries are treated.

Current evidence available is based on the ORBIT I30 and ORBIT II28 clinical trials where OA obtained good results regarding procedural success (94% and 89%, respectively) with higher rates of major adverse cardiovascular events (MACE), and target lesion failure of 23.5% and 7.8%, respectively, at 3 years.31 Afterwards, the COAST trial29 was conducted where the new MicroCrown system was used. A total of 100 patients were included with rates of procedural success and MACE of 85% and 22.2%, respectively, at 1-year follow-up. We are waiting to see the results from the ECLIPSE trial that will randomize a total of 2000 patients with severe calcifications to receive OA or balloon predilatation prior to by drug-eluting stent implantation.

In conclusion, OA is another calcium plaque modification technique with potential technical advantages like having only 1 size of crown compatible with 6-Fr to treat all lesions and with pull-back capabilities. Although there are insufficient data from comparative studies, choosing this technique will depend on the profile of the patient and the lesion to be treated, the intracoronary being an essential aspect.

Excimer laser

Excimer laser coronary angioplasty (ELCA) is based on a xenon chloride laser that generates short ultraviolet pulses of 308 mm that only penetrate 50 µm in depth, which makes it safer compared to old continuous-wave-near-infrared lasers. It modifies the plaque through a triple mechanism: photochemical (by breaking molecular binds), photothermal (through tissue vaporization), and photokinetic (through the expansion and collapse of the bubble of the catheter tip as it moves forward). Fragments released are < 10 μm, which minimizes microvascular damage after being absorbed by the reticuloendothelial system.

The system currently used is the CVX-300 Laser System (Philips) although there is already a new generation one, the LAS-100 Laser System (Philips) that will be replacing it shortly (figure 2C). There are different sizes of catheters available (0.9 mm, 1.4 mm, 1.7 mm, and 2.0 mm) (table 4). The selection of the catheter depends on the type of lesion and size of the vessel (catheter to vessel diameter ratio, 0.5-0.6) being the 0.9 mm catheter the most widely used for its lower profile and because it can reach higher fluency (80 mJ/mm²), pulse repetition rate (80 Hz), and longer application durations (10 seconds with 5-second rests), which increases the chances of success in fibrous calcific plaques.32,33

 

Table 4. Characteristics of Excimer laser coronary angioplasty catheters

	0,9 mm-X 80	1,4 mm	1,7 mm	2 mm
Compatible guide catheter	6-Fr	6-Fr/7-Fr	7-Fr	8-Fr
Minimum vessel diameter (mm)	2	2.2	2.5	3
Energy (mJ/mm2)	30-80	30-60	30-60	30-60
Frequency (Hz)	25-80	25-40	25-40	25-40
Application/pause time (seconds)	10/5	5/10	5/10	5/10

 

Before being used, it is necessary to calibrate the console and then the catheter. In both cases, health professionals and patients should use protective glasses to prevent eye damage. Afterwards, a 0.014 in intracoronary guidewire is inserted until it reaches the lesion. There is a monorail system to facilitate moving forward. Energy is released through the catheter distal border as it slowly advances (0.5 mm/second) to modify the plaque. Catheter withdrawing can also be applied. It is important to optimize support to ensure that the catheter advances. There is no limit in the number of pulses that can be administered since the more it is used, the stronger the effect. However, there is also a higher risk of complications involved. Some authors suggest a maximum of 12 applications.33 The state of the vessel should be assessed after each application. Regarding the selection of parameters, traditionally it started at 45 mJ/mm², and 25 Hz. However, more and more operators prefer higher energies and initial frequencies especially to treat resistant or calcified lesions.33

Before and during the applications, the blood vessel should be washed, and contrast administered through the infusion of a physiological saline solution (1 mL/s to 3 mL/s). In resistant lesions with severe calcification or underexpanded stents, more energy may be needed. This can be reached by not washing the blood with the physiological saline solution or even administering contrast during applications (the so-called “explosion technique”). This technique reaches maximum power although it increases the chances of complications. Some authors33 recommend it as the first option to treat non-thrombotic lesions, although it seems reasonable to spare it for ELCA-resistant lesions with saline infusion.

Traditionally, the indications for ELCA have been categorized into 2 different groups: “thrombotic” (not discussed in this document) and “calcified” lesions (non-thrombotic like in-stent restenosis, chronic total coronary occlusions, calcified lesions, etc.). The latter can be categorized into non-crossable or non-dilatable lesions:

Non-crossable lesions

The laser main advantage is that it is compatible with all intracoronary guidewires. Therefore, non-crossable lesions with balloon/microcatheter are its main indication.17 In a multicenter registry of non-crossable lesions, the rate of procedural success was 87.3% with 0.8% of dissections showing an impaired flow and no perforations.34 Severe calcification has been associated with a higher probability of technique failure34 since ablation is primarily performed in the tissues between calcium.35 However, the use of ELCA with contrast can increase its chances of success in these lesions.33

Non-dilatable lesions

Although the success of ELCA in non-dilatable lesions is high,36 it has never been the first-line therapy. Among these lesions, an interesting scenario is in-stent lesions (restenosis or underexpansion). In acute underexpansion, ELCA could be the treatment of choice. It allows the modification of resistant tissue located behind the stent without changing its architecture. Its use with contrast can be safer thanks to the stent “protective” effect. Isolated cases and small case series with success rates > 95% and few complications have been published.37

It is a safe technique when the recommendations given are observed. Coronary artery dissection is the most common complication (5), although it is rarely flow-limiting (1%). The rate of coronary artery perforation is < 1%,38 and distal embolizations and ventricular arrhythmias are exceptional.39

In conclusion, ELCA is especially useful to treat non-crossable lesions thanks to its compatibility with all kinds of angioplasty guidewires. It has also proven effective to treat non-dilatable lesions including in-stent lesions. However, there is still scarce information on its efficacy in calcified coronary artery lesions.

BALLOON-BASED TECHNIQUES

Cutting and scoring balloons

Cutting balloons (CB) are plaque modification devices that appeared as an alternative to old coronary angioplasty balloons.40 Their objective is to achieve controlled ruptures of the plqeu (through incisions in fibrocalcific tissue) (figure 4), thus facilitating balloon expansion, minimizing damage to the intima layer, and reducing stenosis.18,41

Figure 4. Rotacutting technique. Rotational atherectomy (RA) effect and cutting balloon (Rotacutting) with greater plaque modification and minimum lumen area.

 

There are 2 different types: CB and scoring balloon (BS). Their use has been described in different settings like in-stent restenosis, aorto-ostial lesions, bifurcations, and small vessels associated with the use of drug-eluting stents.42

The main limitations of CBs are their worst navigability and crossing profile compared to conventional balloons. However, over the past few years, both aspects have improved. SBs are associated with better navigability compared to old CBs.

The most dreaded complication is the rupture of coronary artery, although it has significantly increase following its use.

The main difference among the different devices lays in their different external atherotomy elements as described herein (figure 5).

Figure 5. Characteristics of modified balloons. A: Cutting balloon (Boston Scientific, United States). B: WOLVERINE (Boston Scientific, United States). C: AngioSculpt (Spectranetics, United States). D: Scoreflex (OrbusNeich, Hong Kong). E: Grip (Acrostak, Switzerland). F: NSE-Alpha (B.Braun, Germany). G: Naviscore (iVascular, Spain).

 

Cutting Balloon Flextome

Cutting Balloon Flextome (Boston Scientific, United States) consists of a noncompliant (NC) balloon with 3 microrazors longitudinally mounted on the surface. Its superiority over conventional balloons in A/B lesions has not been confirmed yet, which is why, so far, its use is limited to complex17 and calcified lesions only.43

WOLVERINE

Wolverine (Boston Scientific, United States) is an evolution of the former one with a better crossing profile, greater flexibility, and a more visible tip.

AngioSculpt

AngioSculpt (Spectranetics, United States) is a semicompliant balloon with low crossing profile surrounded by 3 nitinol filaments arranged in a helical cage to secure balloon anchorage. There is a lower risk of dissection or perforation associated with this device.17 It provides more flexibility and better navigability compared to old CBs,44 as well as good results compared to dilatation with semicompliant balloons.45

Scoreflex

Scoreflex (OrbusNeich, Hong Kong) is a NC consisting of a NC balloon with a nitinol dual-wire system to facilitate the controlled modification of the plaque at low pressures. It has a low profile and a combination of hydrophilic and hydrophobic coating that minimizes friction during lesion crossing.

Grip

Grip (Acrostak, Switzerland) is a high-pressure balloon with 4 rows of 3 or 4 knobs in each row. It allows dilatations of up to 22 atm. It comes with a cone-shaped tip in 2 different versions: Grip with a short 2 mm tip, and Grip TT with a long 4 mm tip for greater navigability in tortuous anatomies. It comes with a hydrolubricated coating on its tip and the catheter (not on the balloon), which facilitates both its anchorage to the lesion and navigability across lesions.

NSE Alpha

NSE Alpha (B. Braun, Germany) is a SB with 3 nylon scoring elements and 1 triangular cutting section connected in both borders of the balloon and arranged in a 120º disposition. We should mention its flexibility and navigability with good results in de novo lesions and in-stent restenosis.18

NaviscoreTM (iVascular, Spain)

NaviscoreTM (iVascular, Spain) is a SB with a design that combines the benefits of SB plus CB. It consists of a high-pressure balloon with 125 μm nitinol filaments. These have an axial orientation for greater crossing abilities and flexibility, and plaque modification in a 90º angle, which is associated with lower chances of perforation. The catheter hydrophilic coating improves its navigability.

In conclusion CBs and SBs are useful plaque modification devices to treat non-dilatable lesions when calcification is not very severe. Their main advantage is how easy they are to use since it is a balloon-based technique compatible with conventional angioplasty guidewires.

Very high-pressure balloons

The NC very high-pressure balloon (VHPB) OPN (SIS medical, Switzerland) is a double-layer balloon for homogeneous expansion at extremely high pressures without increasing its diameter (from 2 mm to 4 mm) with a rated burst pressure of 35 atm, although the manufacturer’s testing rated burst pressure limit is 45 atm (table 5).46

 

Table 5. Compliance of the NC very high-pressure OPN balloon

Pressure (atm)	NC OPN 2.0 (mm)	NC OPN 2.5 (mm)	NC OPN 3.0 (mm)	NC OPN 3.5 (mm)	NC OPN 4.0 (mm)
10	2.0	2.5	3.0	3.5	4.0
20	2.1	2.6	3.14	3.67	4.19
30	2.18	2.7	3.29	3.85	4.37
35	2.2	2.77	3.36	3.91	4.41
NC, noncompliant.

 

The VHPB has been used for over 10 years now and it has proven safe and effective in up to 40 atm in extremely calcified coronary artery lesions where other devices have failed or in stent underexpansion. Success rates are as high as 75% to 100% without evidence of dissection, perforation or balloon bursts in small case series.47 Compared to conventional NC balloon, it can achieve minimum luminal diameters and major acute gains with less residual stenosis in non-dilatable lesions.48

The largest registry ever conducted to this date included 326 patients with non-dilatable lesions treated with VHPB after failed NC balloon. Patients were categorized into 2 groups: those who responded to pressures between 30 atm and 40 atm, and those who responded with pressures > 40 atm. Procedural success was reached in up to 96.6% of the patients. A total of 53% of the patients responded to pressures between 30 atm and 40 atm while the remaining 47% did so to pressures > 40 atm. A total of 180 patients were treated with intracoronary imaging modalities and 106 of these showed calcifications > 270º. In this subgroup of patients, the pressured needed for optimal expansion was > 40 atm in 78.3% of the cases. Three patients (0.9%) showed coronary artery ruptures that resolved with prolonged inflation or covered stent implantation. In the 3 cases, the ruptures occurred during predilatation and were associated with balloon bursts with pressures between 30 atm and 40 atm. This is suggestive that perforations don’t seem to be associated with inflation pressure but with the characteristics of the plaque or the vessel size estimate that was angiographic in the 3 cases reported.49

The ISAR-CAL trial50 was published back in 2021. It randomized 70 patients with extremely calcified coronary artery lesions and failed predilatation with NC balloon to receive a SB or a VHPB. The study primary endpoint was to compare stent expansion on the OCT. No differences were reported in the percentage of stent expansion. However, differences were seen in angiographic secondary endpoints like improved minimum luminal diameters and residual stenoses favorable to VHPB.50

Finally, chronic total coronary occlusions are the pinnacle of calcified complex lesions. In the PLACCTON trial the use of the VHPB both alone and with other plaque modification techniques was safe and effective in selected cases with chronic total coronary occlusions.51

In conclusion, the VHPB is a safe and effective alternative to treat non-dilatable calcified coronary artery lesions. Randomized clinical trials better defining this device strategy of use and the remaining plaque modification techniques are lacking.

Intracoronary lithotripsy

Intracoronary lithotripsy (ICL) system consists of a specific balloon catheter (Shockwave Medical, United States) connected to a rechargeable portable generator (figure 2D). The generator produces energy pulses that are transmitted to emitters placed inside the balloon. Pulses are emitted at a frequency of 1 per second up to a maximum of 10 pulses per application. Each balloon catheter can administer a maximum of 80 pulses. The catheter consists of a rapid-exchange semicompliant balloon with a 0.042 in crossing profile compatible with any 0.014 guidewires and 6-Fr guide catheters.

Its main indication is to treat calcified non-dilatable coronary artery lesions.

A 1:1: ratio between the vessel and balloon diameters is advised. Once it has been placed inside the lesion, the balloon inflates at 4 atm to secure proper contact between the balloon surface and the vascular wall to allow energy transfer. The balloon includes 2 emitters that receive an electric discharge from the generator that vaporizes the fluid inside generating sound waves that have a local effect. Each pulse releases the equivalent of 50 atm.

These waves run across soft tissues causing selective calcium microfractures at intima and media layer level. After pulse emission and the corresponding modification of calcium, the balloon inflates up to 6 atm to maximize luminal gain. Balloon catheter is only available at a length of 12 mm and comes in diameters of 2.5 mm, 30 mm, 3.5 mm, and 4.0 mm.52

The greatest evidence available comes from the Disrupt-CAD III trial, a prospective registry that assessed the efficacy and safety profile of ICL in 431 patients with calcified lesions. The 30-day rate of MACE (death, infarction or target lesion revascularization) was 7.8% while the rate of effectiveness (procedural success with in-stent stenosis < 50%) was 92.4%. No patients with acute myocardial infarction or complex lesions were included in this study.53 Recently, 12-month follow-up results have been published confirming rates of MACE and stent thrombosis of 13.8% and 1.1%, respectively.54

Controlled break down of coronary calcium is the basis of treatment of ICL balloons. In a OCT substudy of the Disrupt-CAD II trial after ICL calcium fractures were seen in 79% of the lesions55 compared to 67% of the lesions of the Disrupt-CAD III trial.53

Although the use of ICL balloons has become very popular worldwide, information on its safety and efficacy profile regarding its use in complex settings is still scarce (acute coronary syndrome, chronic total coronary occlusions, bifurcations or aorto-ostial lesions). As a matter of fact, its use is often limited to isolated cases or short series.52 The main limitations of this system are its reduced crossing profile in extremely calcified or tortuous stenoses and difficult use in diffuse or multivessel lesions (due to the limited number of pulses per catheter and the different caliber of target vessels).

A recent trial assessed the use of underexpanded stents due to severe coronary artery calcification and confirmed angiographic success rates of up to 73%, which is lower compared to the 75% seen in native lesions56 probably because it is more difficult to expand a calcified lesion when the stent has already been deployed. Therefore, regardless of the technique used, stenting is ill-advised until the lesion has been properly prepared. Also, the application of lithotripsy in this context, especially on freshly implanted stents, can cause structural damage to the polymer.57 Another multicenter registry proved the device was successful 92.3% of the times in this type of lesions.58 Mid- and short-term data on the safety profile of this technique are still lacking.

The combined use of ICL balloon and other plaque modification devices like RA,59 OA60 or ELCA61 has been described, and it seems like a very attractive strategy in cases where the ICL balloon cannot reach the target lesion.

In conclusion, ICL has grown exponentially in the management of non-dilatable calcified coronary artery lesions thanks to its safety and efficacy profile, and short learning curve. However, information on its use in complex scenarios and comparative results with other plaque modification techniques are still lacking.

COMBINED TECHNIQUES

There is not much evidence on the combination of devices or plaque modification techniques in extremely calcified coronary artery lesions.

The use of RA followed by CB (RotaCutting) (figure 4) or lithotripsy (RotaTripsy) (figure 6) has been described as an additional, safe, and effective technique.62-64 In both cases the concept is similar. Primarily, RA damages superficial calcium, but not the deepest calcium layers, and there are times when it is not enough for proper plaque preparation. On the other hand, CB or lithotripsy can complement the plaque modification provided by RA. However, when calcified lesions progress into very severe aortic stenosis, the target lesion can be difficult to reach with these balloons. In a combined use, RA modifies superficial calcium by creating a tunnel that the CB or lithotripsy balloon can use to move forward and, when in position, complete plaque modification. One of the differences between both techniques is that CB can contribute to breaking down the calcium layer in the absence of very severe calcification. The RotaTripsy technique59,63 can be more effective to treat extremely calcified coronary artery lesions with thick calcium layers. However, its cost is also higher. Based on a similar concept, the combination of OA plus lithotripsy has been recently described with good results.60

Figure 6. Rotatripsy technique. A: Extremely calcified stenosis in left anterior descending coronary artery. Intravascular ultrasound (IVUS) with 360º calcification. B: Rotational atherectomy (RA) (1.5 mm olive-shaped burr). C: 3 mm noncompliant balloon underexpansion after RA. D: Intracoronary lithotripsy with 3 mm balloon and proper expansion at 6 atm after 50 pulses. E-G: IVUS and optical coherence tomography showing the combined effect of RA plus lithotripsy with multiple zones of intimal “sanding/dissection” caused by the RA (asterisks), and deep and intimal fractures caused by lithotripsy. H: Final outcomes after stenting.

 

RA has also teamed up with ELCA (the RASER technique).65 Laser can be the only option in truly non-crossable lesions to facilitate the advancement of a microcatheter, perform the RotaWire exchange, and complete the PCI. This can also be used similarly by combining laser plus OA.

The combination of ELCA plus lithotripsy (the ELCATripsy technique) has been described for cases where RA or OA are ill-advised like nearby lesions or at freshly implanted stent level. In these cases, laser can create a tunnel through which the lithotripsy balloon can advance without the risk or damaging the freshly implanted stent.61

ALGORITHM FOR THE OPTIMAL MANAGEMENT OF CALCIFIED CORONARY ARTERY LESIONS

To select the most suitable plaque modification technique we need to become familiar with the characteristics of the different techniques available, their indications, and risks (table 6). Also, the patient’s clinical profile should be taken into consideration, as well as the characteristics of the lesion, the resources available, and the operator’s skills. In some complex cases, it can be reasonable to perform an ad hoc PCI for proper planning and even an angioplasty between 2 expert operators.

 

Table 6. Comparison of the different plaque modification techniques available

 

Current evidence available from comparative or clinical trials allowing us to select among the different plaque modification techniques available is very limited66,67 (table 7). Therefore, although several algorithms have been proposed on the type of calcium and the plaque modification technique that should be used,67 there are no clear indications in the routine clinical practice guidelines. Currently ongoing studies may bring us more in-depth information in the future.

 

Table 7. Main clinical trials on plaque modification techniques

Trial (year)	Design and sample size	Type of lesion	Main results
Rotational atherectomy
ROTAXUS20,24 (2013)	RCA of 240 p. (120 RA: 120 ST)	Moderate to severe calcification	– Successful strategy: RA, 92.5% vs ST, 83.3%; P = .03 – Acute luminal gain: RA, 1.56 mm vs ST, 1.44 mm; P < .01 – No significant differences regarding dissections, perforations or slow/no-reflow – Stent luminal loss at 9 months: RA, 0.44 mm vs ST, 0.31 mm; P = .04 – MACE at 9 months: RA, 24.2% vs ST, 28.3%; P = .46 – MACE at 2 years: RA, 29.4% vs ST, 34.3%; P = .47
PREPARE CALC21 (2018)	RCA of 200 p. AR vs MB (cutting or scoring)	Severe calcification	– Successful strategy: RA, 98% vs MB, 81%; P = .0001 – No significant differences regarding dissections, perforations or slow/no-reflow – Luminal loss at 9 months: RA, 0.22 mm vs MB, 0.16 mm; P = .21 – TLR at 9 months: RA, 2% vs MB, 7%; P = .17 – No significant differences at 9 months regarding mortality or stent thrombosis
Orbital atherectomy
ORBIT I30 (2013)	NRPT of 50 p	Calcification (mild to severe)	– Procedural success (residual stenosis <20% after stenting): 94% – Rate of MACE at 6 months: 8% – Dissection: 12% – Perforation: 2%
ORBIT II28,31 (2014)	NRPT of 443 p	Severe calcification	– Procedural success (stenosis < 50% after stenting without in-hospital MACE): 98.6% – Severe dissection: 2.3% – Perforation: 0.9% – Slow/no-reflow: 0.2%M – MACE at 30 days and 3 years: 10.4% and 23.5%, respectively
COAST29 (2020)	NRPT of 100 p	Severe calcification	– Procedural success (stenosis < 50% after stenting without in-hospital MACE): 85% – Dissection: 2% – Perforation: 2% – Slow/no-reflow: 2% – MACE at 30 days and 1 year: 15% and 22.2%, respectively
ELCA
Fernandez et al.36 (2013)	Observational trial of 58 p	– Balloon failure (non-crossable or non-dilatable lesions) treated with ELCA ± RA – Calcification > moderate: 82.1%	– Procedural success (stenosis < 20% after stenting without flow-limiting dissection or type II or III perforations): 91% – ELCA success isolated in 76.1%; ELCA after failed RA, 6.8% and ELCA + RA, 8.6% – Only 1 successful case of RA when ELCA failed – 4 procedural complications reported (1 transient slow flow, 1 side branch occlusion, and 2 perforations)
ELLEMENT37 (2014)	Observational trial of 28 p	– Stent underexpansion treated with high-energy ELCA with contrast after NC balloon failure – Calcification: 89.3%	– Laser success (increase ≥ 1 mm2 in SMA with IVUS or ≥ 20% MLD on the quantitative coronary angioggraphy after predilatation with the NC balloon that failed before ELCA): 96.4% – Perioperative infarction: 7.1% – Transient slow flow: 3.6%
LEONARDO68 (2015)	Observational trial of 100 p	– Balloon failure in complex lesions – Calcification: 57%.	– Procedural success (stenosis <50% after stenting): 91.7% – No perforations, dissections, significant side branch occlusions, spasms or lack of flow
LAVA69 (2018)	Observational trial of 130 lesions	– Non-crossable lesions with balloon: 43.8% – Non-dilatable lesions with balloon: 40.8% – Moderate or severe calcification: 62% – ISR: 37%	– Procedural success: 88.8% (93.8% in non-dilatable lesions and 83.7% in non-crossable lesions) – Perforation: 1.78% – Perioperative infarction: 0.86%
Ojeda et al.34 (2020)	Observational trial of 126 lesions	– Non-crossable lesions with balloon – Calcification ≥ moderate: 62.7% – Chronic total coronary occlusion: 46%	– Technical success (residual stenosis < 30% and TIMI grade-3 flow): 90.5% – Procedural success (technical success without in-hospital adverse events): 87.3% – Severe calcification associated with failed ELCA
Modified balloons (cutting or scoring balloons), and VHPB
ISAR-CALC50	RCA of 74 p (VHPB vs SB)	– Extremely calcified non-dilatable lesions with balloon	– Stent expansion on the CTO similar compared to VHPB and SB (0.72 ± 0.12 vs 0.68 ± 0.13; P = .22) – VHPB: higher increase of MLD (2.83 mm ± 0.34 mm vs 2.65 mm ± 0.36 mm; P = .03) and less stenosis (11.6% ± 4.8% vs 14.4% ± 5.6%; P = .02) – No differences associated with procedural success
Intracoronary lithotripsy
DISRUPT CAD III53,54	NRPT of 431 p	Severe calcification	– Procedural success (residual stenosis < 50% without in-hospital MACE): 92.4% – Perioperative infarction 6.8% – Severe dissection: 0.3% – Perforation: 0.3% – Slow or no-reflow 0% – TLR at 30 days: 1.3% – Stent thrombosis: 0.8% – MACE at 1 year 13.8%
ELCA, Excimer laser coronary angioplasty; ISR, in-stent restenosis; IVUS, intravascular ultrasound; MACE, major adverse cardiovascular events; MB, modified balloon; MLD, minimum luminal diameter; NC, noncompliant; NRPT, non-randomized prospective trial; OCT, optimal coherence tomography, p, patients; QCA, quantitative coronary angiography; RA, rotational atherectomy; RCA, randomized clinical trial; SB, scoring balloon; SMA, stent minimal area; ST, standard therapy; TIMI, Thrombolysis in Myocardial Infarction; TLR, target lesion revascularization; VHPB, very high-pressure balloon.

 

In cases of mild angiographic calcification and proper balloon expansion, further plaque preparation prior to stenting may not be required. However, when angiographic calcification is moderate or severe, the use of intracoronary imaging modalities is advised for their great utility to plan the procedure and optimize results (figure 7).

Figure 7. Central figure. Calcified plaque modification algorithm. ELCA, Excimer laser coronary angioplasty; NC, noncompliant; OA, orbital atherectomy; RA, rotational atherectomy; SC, semicompliant; VHPB, very high-pressure balloon.
0 Predilatation with low-profile balloons can be attempted. At times, this allows early assessment with intravascular imaging tools.
1 Of choice if microcatheter is unable to cross.
2 If lithotripsy balloon is unable to cross, predilatation can be attempted with balloon or combination of other techniques (Rotatripsy, Elcatripsy, Orbital-tripsy).
3 Currently, lithotripsy is preferred in the presence of acute stent underexpansion.
4 In addition to NC balloon final angiographic expansion, intracoronary imaging are useful to confirm the effect of the techniques used on plaque modification.

 

Overall, it is useful to apply the “rule of 5”: lesions where calcium occupies < 50% of arc circumference (180º), does not extend longitudinally > 5 mm, and thickness is not > 0.5 mm can be properly treated with high-pressure or modified balloons (CB or SB).

If these criteria are met or calcium nodules are spotted further advanced plaque modification techniques should be used. In addition to circumferential and longitudinal spread, and thickness, calcium depth is important as well since some techniques like RA act basically on the superficial—and not on the deep—portion of calcium plaque.

Lesions with extremely severe calcifications so stenotic that cannot be crossed with the IVUS or OCT probe probably need RA/OA or laser (that can be of choice if the lesion is non-crossable not even with a microcatheter to allow specific RA/OA guidewire exchange). Another alternative is to try predilatation with low-profile balloons that often allow early assessments with intravascular coronary imaging to guide the decision-making process as already described.

Balloon expansion after using these techniques will guide us on proper plaque preparation. Also, intracoronary images are very useful to confirm proper calcium modification to allow stent expansion. The effects of different techniques like the presence of fractures (with balloon or lithotripsy), superficial calcium sanding (with RA) or both effects (with OA)70 can be visible when intracoronary imaging modalities are used (figure 6). After the use of ELCA, superficial and deep fractures have been described. However, effects may not be visible on the OCT and, same as it happens with ICL, that does not mean that the plaque has not been modified.

Based on the type of lesion and effects caused by these techniques, the combination of 1 or more of these techniques can be necessary to secure optimal stenting and favorable clinical outcomes.

CONCLUSIONS

Coronary artery calcification is probably the greatest determinant of poor PCI outcomes and incomplete percutaneous revascularizations, and is associated with higher rates of adverse events. Intracoronary imaging modalities play a key role in the understanding of calcified coronary artery lesions, help us select the plaque modification technique we’ll eventually use, and optimize the PCI results. Knowing the different plaque modification techniques available is essential for the optimal management of calcified coronary artery lesions. Until comparative trials among techniques are conducted, it seems reasonable to combine them depending on the type of lesion. In addition, there are situations in which techniques should be combined to secure optimal stenting and the most favorable clinical outcomes.

FUNDING

None whatsoever.

AUTHORS’ CONTRIBUTIONS

Manuscript drafting: A. Jurado-Román, A. Gómez-Menchero, N. Gonzalo, J. Martín-Moreiras, R. Ocaranza, Soledad Ojeda, J. Palazuelos, O. Rodríguez-Leor, P. Salinas, B. Vaquerizo, X. Freixa, and A.B. Cid-Álvarez. Design, coordination, review process of the final version, and manuscript submission: A. Jurado-Román.

CONFLICTS OF INTEREST

S. Ojeda is an associate editor of REC: Interventional Cardiology; the journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. A. Jurado-Román, X. Freixa, and A. B. Cid-Álvarez are members of the ACI-SEC board of directors.

REFERENCES

INTRODUCTION: MATHETMATICS, PROBABILITY, AND STATISTICS

In the words of world famous astrophysicist Stephen Hawking, the goal of science is «nothing less than a complete description of the universe we live in».1 Male and female scientists alike pursue this objective by building theories and assessing their predictions. It is the very essence of the scientific method.

Statistics is a scientific discipline that designs experiments and learns from data. It formalizes the process of learning through observations and guides the use the knowledge accumulated in decision-making processes. Concepts like chance, uncertainty, and luck are almost as old as mankind, and reducing uncertainty has always been a common goal for most human civilizations. Probability is the mathematical language used to quantify uncertainty and is at the core of statistical learning that represents—in probabilistic terms—both the study populations and the random samples that come from such populations.

There is not such a thing as a single statistical methodology. The most widely known and used ones are, by far, frequentist statistics, and Bayesian statistics. Both share common goals and use probability as the language of statistical learning. However, both understand the concept probability different. As a matter of fact, it is the element on which they largely disagree. According to the frequentist concept, it is only legitimate to assign probabilities to random phenomena that can be defined through experiments that can be repeated multiple times, and only under identical and independent conditions.

The Bayesian concept of probability is a much wider idea because it allows us to assign probabilities to all elements with uncertainty regardless of their nature. Bayesian probability applies to the occurrence of random events, both those that can be repeated under the conditions required by frequentist probability and those that don’t (chances that Arnau, a 60-year-old male who lives alone will recover from a heart attack). The differences between both methodologies grow even larger because Bayesian probability assigns probabilities to different parameters (like the prevalence of people between the ages of 45 and 65 who have suffered a heart attack), statistical hypotheses (the efficacy of a new treatment for diabetic patients with heart failure is greater compared to conventional treatment), probabilistic models or even to missing data generated by non-randomized losses to follow-up (eg, ignoring the information of patients with losses to follow-up in a survival study on a given end-stage process would introduce biased information to the study).

The second distinctive element between both statistical methodologies is the use of Bayes’ theorem. For Bayesian statistics it is an essential tool to sequentially update the relevant information that comes from a study. Therefore, after an initial analytical phase, the knowledge generated will be used to start a new process of learning that will be providing new information on the problem at stake.

Both the frequentist and Bayesian concepts of probability share the same axiomatic system, and the same probabilistic properties. This common niche makes them share a common mathematical language too.

The map of basic Bayesian concepts and their different associations is not easy to explain without falling into a plethora of technicalities. And this is even more evident in real-world studies in the cardiovascular research setting. Therefore, in this article we will be working on very clear cases we believe are powerful examples regarding conceptual terms that are, nonetheless, simple, and devoid of technical complexities.

This article includes 6 different sections. The first one, this introduction, refers to the general wisdom regarding Bayesian statistics and its association with mathematics, probability, and statistics. The second section includes brief historical references on Bayesian methodology. The next section is about Bayes’ theorem in its most innocent version regarding the occurrence of random events. Afterwards, we’ll be dealing with the concepts and basic protocol of Bayesian statistics: previous distribution, function of verisimilitude, posterior distribution, and predictive distribution to predict experimental results. Also, we’ll include a brief explanation on the computational problems associated with the practical application of Bayesian methods and their power to generate inferences on relevant derived quantities. Hypothesis testing—the P value in particular—will also be dealt with later on as well as the Bayesian hypothesis testing proposal. The article will end with a small comment on the use of prior distributions.

IT ALL STARTED WITH BAYES, PRICE, AND LAPLACE

Knowing a little bit of Bayesian history is important because it allows us to put it into a temporal and social perspective that illuminates and boosts its learning. We’ll give a few relevant hints on this history now. McGrayne2 gives us an easy-to-understand and rigorous big picture on Bayesian history.

The very first time anybody heard of Bayes’ theorem was in Great Britain halfway into the 18^th century through Reverend Thomas Bayes while trying to prove the existence of God through mathematics. He would never dare to publish his findings. Prior to his death, he bequeathed all his savings to his friend Richard Price who—if okay with it—was supposed to spend this money to publish the findings, which is something he eventually did. However, these results went totally unnoticed.

We’re still in the 18^th century, but now we’ll have to travel to France to meet Pierre-Simon Laplace, one of the most prominent mathematicians in history. He discovered, independently of Bayes and Price, Bayes’ theorem in the format that we know today. Also, he developed the Bayesian concept of probability. After his death, his work fell into oblivion, under attack too because it was not in tune with the ruling idea of objectivity so embedded in the scientific world at the time.

Back to Great Britain now. Bletchley Park was a 19^th century mansion in Northern London turned into a working center to break the secret messages of the German army during the Second World War (1939-1945). Here Alan Turing and his team—that included the Bayesian statistician Jack Godd—played a key role in the history of Bayesian statistics: Bayes’ theorem was tremendously useful to decipher the code of the Enigma machines the Germans were using to code and decode messages. After the war, the British government classified all the information that had anything to do with Turing, mathematics, statistics, and decoding as top secret. Bayes’ theorem became a useful tool for just a handful of scientists, and an anathema (or worse) for most of them. As a truly revealing anecdote, McGrayne2 tells the story when Good presented the details of the method that Turing and his team had used to decipher the Nazi codes to members of Britain’s Royal Statistical Society. This is what the next speaker had to say about the whole thing: «After that nonsense […]».

During the second half of the 20^th century, the future of Bayesian statistics looked grim: support from the English-speaking academic world grew thin, and the rest of the scientific community knew very little about Bayesian statistics. Also, there were many computational difficulties to implement it to real-world studies with data. But what seemed to be destined to happened never did. We’re now back to the Second World War to Los Alamos National Laboratory in the state of New Mexico, United States. This center was created with absolute secrecy during Second World War to investigate the construction of nuclear weapons under the umbrella of the so-called Manhattan Project, led by the United States with the participation of Great Britain and Canada. It is in this context where the early Monte Carlo simulation methods were discovered back in 1946 by Polish mathematician Stanislaw Ulam while playing solitaire. Also, at that time, Metropolis et al.3 publish the first Markov chain Monte Carlo (MCMC) simulation algorithm while conducting his investigations on the H-bomb.

Several years go by without any direct links whatsoever between Bayesian statistics and MCMC methods. However, some studies are published—especially on image recognition—combining both elements.4 Encouraged by the technological advances made, especially in computing, Alan Gelfand, an American, and Adrian Smith, a British, collect former studies on MCMC methods and make a direct connection with Bayesian statistics.5 This will mark the beginning of the great Bayesian revolution that starts in the field of applications to, little by little, move on to the academic world. Bayesian inference is now recognized, accepted, and validated by the scientific community as a useful statistical methodology for scientific and social development.

BAYES’ THEOREM

The most widely known format of Bayes’ theorem is presented for the occurrence of random events. If A and B are random events, then

being p(A) the probability of event A, p(A|B) the associated probability A conditioned by the information that B occurred, and comparably p(B)> 0 and p(B|A). It is important to distinguish between probabilities p(A) and p(A|B). Both quantify the occurrence of A, but p(A) does so in absolute terms while p(B|A) does so in relative terms and conditioned by the information picked up in B. For example, nobody would question that the chances that a person may suffer from angina pectoris are higher if this person is hypertensive as opposed to not having that information available, p (Angina pectoris|Hypertension) > p (Angina pectoris).

Example I: Infections and tests

The prevalence that a certain infection affects any given population is .004. There is a test to detect its presence with a 94% sensitivity and a 97% specificity. We want to assess the chances that a person from such population is really infected if he tested positive for an infection.

We will use V and V^c to define a success that describes whether a person is infected or not, respectively. Therefore, p(V) = .004 and p(V^c) = .996. We’ll use (+) and (–) to describe a positive and negative test result for infection, respectively. In probabilistic terms, if a person is infected, he will test positive with a .94 probability, and negative with a .06 probability, p(+|V) = .94 and p(–|V) = .06 (false negative). If not infected, the person will test negative with a .97 probability and positive with a .03 probability, p(–|V^c) = .97 and p(+|V^c) = .03 (false positive).

According to Bayes’ theorem, the chances that a person is infected with a positive test result are

being p(+) = p(+|V) p(V) + p(+|V^c) p(V^c) = .0336 after implementing the total probability theorem (figure 1).

Figure 1. Posterior probability of infection with a positive test result p(V|+) (upper chart) and a negative test result p(V|–) (upper chart) in relation to the prior probability, p(V), of infection.

 

In principle, it is disconcerting that such a reliable test and with a positive test result for infection generates a small posterior probability, .112 favorable to the infection. However, if we take into consideration that the initial probability of being infected is p(V) = .004 and that, after the positive test result, probability is p(V|+) = .112, we’ll see that it has gone up from 4 to 112 by a thousand—has multiplied by a factor of 28—and we believe that the influence of the test result in such posterior probability is more relevant. Anyways, we would, at least, need a second test to increase the evidence for or against the infection.

Figure 2 shows 2 charts. The upper curve is the posterior probability of infection when the test is positive, p(V|+). The lower curve is the probability of infection too, but with a negative test result, p(V|–). In both cases, such posterior probabilities are represented in terms of prior probability, p(V), of being infected. When p(V) is close to 0, as it is the case with this example, the probability p(V|+) goes up a lot although, in absolute terms, it remains very low. On the contrary, when p(V) is close to 1, the probability p(V|–) will still be high despite evidence against a very reliable negative test result. The main element to understand this situation is that posterior probability, p(V|+) = .112, combines a very small probability of having an infection with a very high probability of testing positive when infected.

Figure 2. Approximate number of people infected, not infected, true positives, true negatives, false positives, and false negatives in a population of 100 000 inhabitants with an early prevalence for infection of .004 and a 94% sensitivity test and a 97% specificity test.

 

We’ll move on now to assess our results. The prevalence of infection, p(V) = .004 indicates that in a population of 100 000 people we should be expecting around 400 people infected and, approximately, 99 600 people not infected (figure 2). If the entire population were tested, we would expect to see that around 376 of the 400 people infected would test positive (true positives), as opposed to 24 (false negatives). In the group of healthy people, around 96 612 people would test negative (true negatives), but nearly 2988 people would test positive (false positives). If we looked at the number of people who tested positive, we’d have around 376 true positives, and 2988 false positives. Therefore, most people with a positive test (nearly 89%) would not actually be infected.

A second test with a positive result too would provide further evidence favorable to the infection. Its probability should be updated including the positive result of the second test as new information. If now (+1) and (+2) represent a positive test result for the first and second tests, the relevant probability would be p(V|+1,+2). The sequential use of Bayes’ theorem allows us to estimate such probability considering p(V|+1) = .112 as prior probability. The result obtained, p(V|+1,+2) = .798, is meaningful evidence favorable to an infection after 2 positive test results.

PARAMETER ESTIMATE

The true protagonists of basic Bayesian studies are probabilistic models governed by unknown parameters. These are at the core of Bayesian inferential machinery. We should mention that a parameter is a characteristic of a statistical population under study. Examples of parameters are the percentage of effectiveness of any given drug, the 5-year survival rate of soft tissue sarcoma, the basic reproduction factor R₀ of an infection, etc. Parameters are estimated using partial information of the study population from data samples obtained through random procedures that guarantee their representativity and small population condition.

The most widely known probabilistic model is normal distribution with a dome-shaped symmetrical density function and defined by 2 different parameters, mean, µ, and standard deviation (σ). Mean is the center of gravity of distribution and corresponds to the peak of the dome. Standard deviation is a dispersion measurement that determines the width of the dome: in all normal distributions, the interval (µ − 3σ, µ + 3σ) includes 99.7% of the values of distribution. Therefore, the interval-related probability (−3, 3) in a normal distribution with mean = 0 and standard deviation = 1 would be the same as the one associated with the interval (−6, +6) of a normal distribution with mean = 0 and standard deviation = 2 (figure 3).

Figure 3. Chart of normal density with mean of 0, and standard deviation of 1 (green color), and normal density with mean of 0, and standard deviation of 2 (gray color).

 

Mean and standard deviation are unknown parameters in most studies based on normal data. In our case, and to avoid any technical complications, we’ll assume that the standard deviation is known. Therefore, the statistical process will only have eyes from the mean µ. Bayes’ theorem adapts itself to the territory of probability distributions with focus on the population mean symbol µ as parameter of interest according to the following formula

being p(μ) the previous distribution (or prior distribution) of μ that quantifies, in probabilistic terms, the initial information available on μ and p(μ | data), the posterior distribution of µ that contains the information on µ available when the initial information is added to data. The term p(data | μ) is the verisimilitude function of μ, a measurement that assesses the compatibility of data with the possible μ values. The element p(data) is the previous predictive distribution (also evidence in the automatic and machine learning setting), and assesses the plausibility of the data obtained.

Example II: the heart of boys and girls with spinal muscular atrophy

Falsaperla et al.6 present the results of an observational study on the heart electrical conduction system disorder that causes bradycardia or electrocardiographic abnormalities in boys and girls with spinal muscular atrophy type 1 and 2 (SMA1, and SMA2, respectively). We gained our inspiration from this study to build a simulated database. Therefore, the results from this example do not come from Falsaperla et al.6 and should not be compared to those from the original study.

We simulated the data on the PR interval length that extends from the origin of atrial depolarization until the origin of ventricular depolarization from 14 children with SMA2. We assumed a normal model with unknown measurement and known standard deviation. Out statistical goal was to estimate the mean.

We’ll go on now with the Bayesian protocol. First, we need a previous distribution p(μ) to express our information of such parameter. Afterwards, we consider a scenario without new information on μ except for the information provided by data and use Jeffreys Prior to treat all possible μ values the same way.7 The posterior distribution of μ, p(μ | data), is a normal distribution with a mean of .13, and a standard deviation of .03/√∙14 seconds that we can graphically see on figure 4. We estimate that μ is .13 seconds, and directly assess the accuracy of such estimate through a credibility interval that tells us that the posterior probability of μ will be taking values between .114 and .146 seconds is .95. We give it a very low probability of .05 that μ will be > .146 or < .114.

Figure 4. Posterior distribution of the PR interval mean length in children with spinal muscular atrophy type 2.

 

A frequentist analysis of this data would never allow direct probabilistic assessments of μ. A frequentist 95% confidence interval for μ would provide the same numerical results compared to the Bayesian interval. However, it should be interpreted in a completely different way. The frequentist 95% confidence interval is on the capacity of the interval to include μ true value, and not on the possible μ values. The interval built, (.114, .146), has a .95 probability of capturing μ true value, but also a .05 probability of not doing so. We should remember that the frequentist concept of probability prevents allocating probabilities to parameters and establishing direct probabilistic assessments of μ.

PREDICTING NEW OBSERVATIONS

Prediction and estimation are fundamental statistical concepts. We estimate parameters, but we predict data and experimental results always through distributions of probability.

The posterior predictive distribution of the results of a future experiment is built by combining the probabilistic model that correlates future data and parameters with posterior distribution. A significant aspect of predictive process regarding estimation is its greater uncertainty. Overall, the precision of estimations improves with larger samples, which means that in the hypothetical case of having all the data available, our estimation would be accurate. The process of prediction does not have such a feature. Although the precision of predictions increases parallel to the size of the sample, in the hypothetical case of having access to all the information from a population, error-free predictions would still be impossible.

Example II: the heart of boys and girls with muscular atrophy (continues)

In the estimation stage we studied the PR interval mean length in girls and boys with SMA2, learning based on a sample of 14 simulated data. Now we’ll be dealing with totally different situation. We have a kid with SMA2 who did not participate in the study. Our objective is to predict his PR interval length. The goal now is not to estimate population means with SMA2, but to predict the value of the PR interval length in a particular kid.

Figure 5 shows the posterior predictive distribution of the PR interval length of a new boy with SMA2. Although this prediction is based on information from 14 children from the sample, it is about a new boy with SMA2. The anticipated value of this new child’s PR interval length is .13 seconds. The accuracy of prediction is quantified through prediction intervals. In this case with a .95 probability, the anticipated value will be between .069 and .191 seconds.

Figure 5. Posterior predictive distribution of the PR interval length of a new child with spinal muscular atrophy type 2.

 

SIMULATION AND GROUP COMPARISON

The Bayesian protocol with the 3 basic elements, previous distribution, verisimilitude function, and posterior distribution is common to almost all kinds of settings, both the basic ones including some parameters, as well as the complex ones with many sources of uncertainty with complex hierarchical structures. It is a robust and easy-to-use protocol, and a powerful and appealing idea.

Difficulties appear if we want to extrapolate this protocol to real studies of certain complexity. It is in just a couple of these cases that an analytical expression for the posterior distribution of parameters can be achieved. Impossible, nonetheless, for posterior distributions associated with derived quantities of interest. In most studies, mathematics becomes complicated, and posterior distributions are difficult to obtain. In these cases, the MCMC methods come to the rescue of Bayesian analysis. They can simulate our estimates of the relevant posterior distribution and from them generate the inferences or predictions required by the study.

In the following example we’ll be showing the most basic situation we have discussed: starting with a target posterior (analytical) distribution we’ll be simulating posterior distributions of relevant, non-analytical quantities of interest.

Example III: acute myocardial infarction and stents

The following example has been inspired by Iglesias et al.8. This is a study of 1300 patients with acute myocardial infarction treated with percutaneous coronary intervention. Each patient was randomized to sirolimus-eluting stent implantation with degradable polymer (group S) or everolimus-eluting stent implantation with durable polymer (group E).

We compared both treatments in relation to the rate of deaths 12 months after treatment. A total of 35 out of the 649 patients from group S stopped treatment or were lost within first year of follow-up, and 24 died. In group E, initially with 651 patients, 25 were lost or stopped treatment, and 22 died. The presence of missing data due to losses to follow-up is an important issue that should be dealt with carefully. In this case we’ll omit it because our goal is to illustrate Bayesian procedures using the least possible technicalities.

We’ll start by analyzing the risk of death θ_s and θ_E in groups S and E, respectively 1 year into treatment. Since anybody from either one of the 2 groups can die, or not, within the first year of treatment, in each group, the probabilistic model is binomial distribution that will be describing the number of deaths reported. The risk of death from each group is a rate with values that range between 0 and 1. For each rate we’ll be selecting beta distribution because it’s the proper probabilistic model to use with rates and doesn’t pose any estimate difficulties. β distribution (that we’ll representi as Be(α, β)) has 2 different parameters, α > 0 and β > 0, that determine the way of the distribution as well as its mean and variance. It is a flexible distribution that can be symmetrical or asymmetrical, positive or negative (figure 6).

Figure 6. Chart of β densities: Be(.5, .5) in green color, Be(2, 2) in gray color, Be(3, 22) in maroon color, Be(12, 2) in blue color, and Be(12, 12) in pumpkin color.

 

The prior β distribution that best describes the lack of information is Be(.5, .5). Its justification only responds to theoretical criteria. In each group, the posterior distribution of the risk of death will also be β whose updated parameters can be obtained by adding the number of deaths and the number of people alive in the study to the 2 values 0.5 and 0.5 of the prior beta distribution:

p(θ_s) = Be(.5, .5); p(θ_s | data) = Be(24.5, 590.5),

p(θ_E) = Be(.5, .5); p(θ_E | data) = Be(22.5, 604.5).

The estimation of the risk of death in patients from groups S and E is the mean of its posterior distribution, .040 and .036, respectively. Also, with a .95 probability the risk of death of group S is between .026 and .057, and between .023 and .052 in group E. These results indicate that the rate of death from both groups is small, although slightly higher in group S. The 95% credibility interval—both of θ_s and θ_Eis very informative (figure 7).

Figure 7. Posterior distribution of the mortality rate reported in patients from group S (green color) and group E (gray color).

 

We assume that our goal is to compare the 1-year mortality risk in both groups. Although the tool we could think of first is hypothesis testing (that we’ll introduce later on), the epidemiological and statistical literature on this regard is abundant, and 2 groups are often compared through relative risk (RR) or absolute risk (AR).9 The 1-year RR of mortality in patients with type S stents vs patients with type E stents is RR = θ_s/θ_E, a ratio between 2 rates. RR values < 1 are indicative that the mortality rate from group S is lower compared to group E while values > 1 are indicative of precisely the opposite. Since RR is defined through θ_s and θ_E, the information from both rates, expressed through its posterior distribution, can propagate to RR as a posterior probability distribution, p(RR | data) (figure 8). This distribution is not analytical, but it can come close to it through a Monte Carlo simulation from the 2 posterior distributions p(θ_s | data) and p(θ_E | data). Using this approximation, the posterior RR mean is 1.160, its standard deviation, .346, and the posterior probability of RR being >1 is .641. An analogue frequentist analysis would be more complicated from the mathematical standpoint and would not provide a direct probabilistic assessment of RR.

Figure 8. Posterior distribution of the relative risk of mortality at 1 year in patients with S-type stents vs patients with E-type stents. The shadow region is the probability, .641, that the mortality rate of group S is higher compared to group E.

 

If we compare both groups through the AR of mortality at 1 year, our goal would be AR = θ_s-θ_E. This is a difference between 2 rates that could take values between −1 and 1. Negative values will be indicative that the mortality rate of group E is higher compared to groups S while positive values will indicate just the opposite. figure 9 shows the AR posterior distribution.

Figure 9. Posterior distribution of the absolute risk of mortality at 1 year in patients with S-type stents vs patients with E-type stents. The shadow region is the probability, .641, that the mortality rate of group S is higher compared to group E.

 

The posterior AR mean is .004, its standard deviation, .011, and with a .641 probability, the AR will be > 0.

HYPOTHESIS TESTING: FREQUENTIST P VALUES

Hypothesis testing is the topic that generates the most irreconcilable differences between the Bayesian and the frequentist scientific communities because it is here where the consequences of their different concepts of probability become more evident. Testing hypothesis means testing new theories. Most of the latest theories have a quiet appearance among the scientific community, but little by little they start accumulating evidence in their favor until the sitting evidence is debunked.

The most widely known and used concept in frequentist statistics is the P value, as well as its .05 value that in some studies appears as the magical number used to reject or accept hypotheses or scientific theories. P value is another tool in the frequentist inference armamentarium that simply does not exist in the Bayesian one regarding the testing of 2 different hypotheses: the null hypothesis H₀ (that often represents the sitting scientific theory), and the alternative hypothesis H₁ (the new theory). P values are always associated with data because without the latter there are no P values. Under these conditions, P value is the probability that a certain theoretical summary of data will be equal to the one observed or more incompatible with the null hypothesis supposing that such hypothesis holds true. Such compatibility is often represented by the P = .05 threshold. P values ≥ .05 keep confidence in the null hypothesis; P values < .05, however, are favorable to the alternative one.

The excessive, and sometimes, inappropriate use of P values in scientific studies is still under discussion in the statistical community. It started in small scientific circles, but the use of the P value soon became a somehow «magical» element rather than a scientific tool. Back in 2014, the American Statistical Association, one of the world’s leading statistical societies, approached this issue and drafted a document that has become the go-to guideline on this topic.10 The following ones are some of the conclusions on significant P values for the management of biometrical data:

1. They are a probabilistic measurement of the compatibility of data with the null hypothesis. Smaller P values are associated with more data incompatibility with such hypothesis.
2. Do not assess the probability that a hypothesis will hold true or not.
3. The conclusions of a study should not only be based on whether a given P value exceeds this or that threshold. The use of the expression «statistically significant» (P < .05) to establish conclusions distorts all scientific procedures.
4. Do not measure the size of an effect or the significance of a given result. All small effects can produce small P values when the size of the sample or the accuracy of measurements is big, and all big effects can generate big P values with small samples or imprecise observations.

The P value has been given an unfair treatment because it has been attributed fantastical and surreal properties that have turned against it. Controversy has shattered the scientific debate and encouraged criticism in scientific disciplines that use data to generate knowledge. The huge interest in today’s scientific reproducibility topics owes volumes to this debate.11^-15

ACCUMULATING EVIDENCE FOR THE PROBABILISTIC ASSESSMENT OF NEW THEORIES

The Bayesian concept of probability is the key element to put hypotheses and theories to the test because it allows us to assign direct probabilities to both hypotheses and theories, both prior, p(theory holds true) and posterior, p(theory holds true|data ).16

Frequentist statistics is based on hypothesis testing using p-type probabilities (data|theory holds true) while Bayesian statistics is based on p-type probabilities (theory holds true|data). The p-type(data|theory holds true) frequentist probability assumes that the theory tested holds true, and based on that assumption assesses the concordance of data with such hypothesis. The p-type(theory holds true|data) Bayesian probability probabilistically assesses the certainty of the theory being tested in association with the data obtained.

The fundamental tool of Bayesian statistics to choose between hypotheses

H₀: theory #1 holds true,

H₁: theory #2 holds true,

based on a dataset is Bayes factor,17 the ratio between the probabilities associated with data according to both theories. It can also be expressed as the ratio between posterior odds (p(theory #1 holds true|data )/p(theory #2 holds true|data)) favorable to the certainty of theory #1 compared to theory #2 and the corresponding prior odds (p(theory #1 holds true)/p(theory #2 holds true). Like this:

Bayes factor (B) holds evidence favorable to the certainty of theory #1 (compared to theory #2) provided by data: it turns prior probabilities into posterior probabilities. In logarithmic scale, log (B), the Bayes factor is also known as «weight of evidence», a term coined by Turing back in Bletchley Park during Second World War. Small Bayes factor values give little support to H₀ vs H₁; however, big Bayes factor values provide extensive support to H₀.

Example I: Infections and tests (continues)

Let’s go back to the data from example I: Vallivana needs to be diagnosed on an infection with 2 positive test results. This problem can be faced as 2 hypotheses being tested:

H₀: Vallibana has an infection

H₁: Vallibana doesn’t have an infection

We assume that Vallibana does not have any particular characteristics that give her a probability of infection different from the remainder of the population. Therefore, we know that p(Vallibana has an infection) = .004, and p(Vallibana doesn’t have an infection) = .996. Vallibana’s prior odds favorrable to the infection compared to non-infection are:

Vallibana takes the test, and it turns out positive (+₁). She decides to retake it and tests positive again (+₂.). Vallibana’s posterior odds favorable to the infection compared to non-infection are:

The Bayes factor in favor of Vallibana being infected, that is, the ratio between the posterior odds and the prior odds is 987.75. Indeed, this value provides strong evidence in favor of Vallibana being infected (+).

Example II: the heart of boys and girls with spinal muscular atrophy (continues)

Now let’s go back to the study conducted by Falsaperla et al.6 from example II that aimed to compare the PR interval mean length in girls and boys with SMA1 and SMA2—that we’ll refer to as μ₁ and μ₂, respectively—through hypothesis testing:

H₀: μ₂ ≤ μ₁

H₁: μ₂ > μ₁

where the null hypothesis, H₀, claims that the PR interval mean length in girls and boys with SMA2 is shorter or equal to that reported in children with SMA1. The alternative hypothesis H₁ says otherwise. Here we’ll be working with simulated normal data in both groups: n₁ = 14 observations in the SMA1 group with sample mean and standard deviation values of .10 and .02 seconds, respectively, and n₂ = 14 observations in the SMA2 group with sample mean and standard deviation values of.13 and .03 seconds, respectively.

What we´ll do is build an inferential process for the mean of each group separately. In both cases, we’ll be considering a neutral previous distribution that gives all prominence to data. figure 10 shows the posterior distribution of the mean of each group. Both distributions are rather separate from one another, which means that the posterior probabilities associated with each hypothesis will be very different as well: .002 for H₀, and .998 for H₁.

Figure 10. Posterior distribution of the PR interval mean length in girls and boys with spinal muscular atrophy type 1 (green color), and type 2 (gray color).

 

p(H₀|data) = p(μ₂ ≤ μ₁|data) = .002

p(H₁|data) = p(μ₂ > μ₁|data) = .998

On a roughly basis, it is 500 times more likely that H₁ will hold true than not. In light of such an overwhelming piece of evidence the wise decision would be to choose H₁. The frequentist treatment of this testing is based on the P value. In our case, we’d obtain a P value of .002, which would imply rejecting the null hypothesis in favor of the alternative one. Both methodologies propose the same decision and provide the same numerical results: probabilities of .002. However, both probabilities are conceptually different. Bayesian probability tests the null hypothesis based on the data reported. Frequentist probability assesses the data observed with the assumption that the null hypothesis will hold true.

Still following in the footsteps of Falsaperla et al.6 we wish to mention that our examples are not based on original cases. They are merely illustrative of Bayesian procedures. We’ll now be working with the P-wave on the electrocardiogram. We wish to compare the P-wave mean length in children with SMA1 and SMA2. We’ll be simulating 14 observations of the P-wave length in the group of children with SMA1 and compared it to children with SMAs. The sample mean and standard deviation is .09 and .05 seconds in group SMA1, respectively, and .07 and .03 seconds in group SMA2. We’ll be comparing the means of both groups through hypothesis testing:

H₀: mean P-wave in SMA1 = mean P-wave in SMA2

H₁: mean P-wave in SMA1 > mean P-wave in SMA2

based on Bayesian inferential process like the one from the previous example. figure 11 shows the posterior distribution of the P-wave mean length in both groups. There are fewer data from the group of girls and boys with SMA2 compared to the group with SMA1. The posterior probability associated with each hypothesis is:

p(H₀ | data) = p(mean P-wave in SMA1 ≤ mean P-wave in SMA2 | data)

p(H₁ | data) = p(mean P-wave in SMA1 > mean P-wave in SMA2 | data)

These results provide a significant piece of evidence favorable to the alternative hypothesis that is almost 8 times more likely than H₀. From the frequentist standpoint, the P value associated with data would be .107 (>.05), which is why we would conclude that data does not provide enough evidence to reject H₀. Bayesian decision could perfectly be the same. However, the Bayesian analysis provides a direct assessment on the certainty of both hypotheses. The findings from the Bayesian analysis could be used as previous information in future studies with more data. Therefore, the posterior distributions obtained (figure 11) would be prior distributions in this new study. Bayes’ theorem allows us to generate knowledge sequentially searching for evidence for or against different hypothesis.

Figure 11. Posterior distribution of the P-wave mean length in girls and boys with spinal muscular atrophy type 1 (green color), and type 2 (gray color).

 

CARDIOLOGY POSES SOME OF DOUBTS ON THE IMPLEMENTATION OF METHODOLOGY IN CLINICAL TRIALS

One of the most controversial topics in Bayesian methodology is the selection of previous distributions. A Bayesian analysis will always allow us to avoid using any information on the amount of interest not provided by data. In this case, it works with previous distributions that play a neutral role in the learning process and that are useful only as the starting point of the Bayesian inferential protocol.

Previous informative distributions contain information that adds to the one provided by data like expert knowledge18^-20 or results from previous studies.21^,22 It is a highly valuable Bayesian characteristic in studies on which data is scarce like studies on rare diseases and orphan drugs. We should mention that inferential processes based on previous informative distributions should include sensitivity analyses of the results obtained regarding previously used distribution or distributions. Similarly, it has become popular to consider communities of previous distributions with diverse previous distributions—and a certain degree of skepticism or enthusiasm—with the effect under test because they provide a scientific framework of reference.

On many occasions, in clinical trials, the use of previous informative distributions reduces the sizes of frequentist samples based on preassigned values of the test power, and previous parameter estimates.22 An example of this situation is the BIOSTEMI trial.8 The 1300 patient-sample was estimated using Bayesian methods through a previous robust distribution as a mixture that included—in equal proportion—historical information of 407 patients from the BIOSCIENCE trial,23 and a practically non-informative distribution. The flexibility of Bayesian sequential learning is a key element of the so-called adaptative Bayesian designs24 that allow us to include additional information in different phases of the trial without damaging the consistency and reliability of results.

FUNDING

This study was partially funded by Biotronik Spain S. A, and by project PID2019-106341GB-I00 from the Spanish Ministry of Science and Innovation, and Universities of the Spanish Government.

AUTHORS’ CONTRIBUTIONS

C. Armero was involved in the structure, content, and drafting of this manuscript; P. Rodríguez, and J.M. de la Torre Hernández were actively involved in the review process of the manuscript final version.

CONFLICTS OF INTEREST

C. Armero, P. Rodríguez, and José M. de la Torre Hernández declared no conflicts of interest regarding the content, authorship, and publication of this manuscript. J.M. de la Torre Hernández is the editor-in-chief of REC: Interventional Cardiology. The journal’s editorial procedure to ensure impartial handling of the manuscript has been followed.

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