Article

Review Articles

REC Interv Cardiol. 2022;4:216-227

Calcified coronary artery disease: pathophysiology, intracoronary imaging assessment, and plaque modification techniques

Enfermedad coronaria calcificada: fisiopatología, evaluación por imagen intracoronaria y técnicas de modificación de placa

Angela McInerney, Javier Escaned, and Nieves Gonzalo

Instituto Cardiovascular, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain

Abstract

Calcified coronary artery disease poses a number of challenges to the interventional cardiologist when performing percutaneous coronary interventions, and patients with calcified coronary artery disease continue to have poorer outcomes at both the short and the long-term follow up. Stent underexpansion is the most feared outcome when performing percutaneous coronary interventions in these patients and is a strong predictor of stent failure. Therefore, intracoronary imaging to guide calcium modification is an important step in the treatment of this disease. The following review outlines a stepwise approach using intracoronary imaging in the assessment of coronary calcification, and in the selection of the appropriate calcium modification tool. Additionally, we describe current calcium modification techniques available, the evidence behind their use, their mechanism of action, and the typical results seen on intracoronary imaging.

Keywords: Coronary calcium. Calcium modification. Atherectomy. Lithotripsy. Optical coherence tomography. Intravascular ultrasound.

RESUMEN

Las intervenciones coronarias percutáneas en enfermedad arterial coronaria calcificada representan un desafío para el cardiólogo intervencionista. Además, los pacientes con enfermedad arterial coronaria calcificada tienden a tener peores resultados en el seguimiento a corto y largo plazo. La infraexpansión del stent es el resultado más temido cuando se realiza una intervención coronaria percutánea en estos pacientes y es un gran predictor de falla del stent. Por lo tanto, la modificación del calcio guiada por imágenes intracoronarias, es un paso importante en el tratamiento de esta enfermedad. La siguiente revisión describe el uso «paso a paso» de imágenes intracoronarias en la evaluación de la calcificación coronaria y en la selección de una técnica de modificación de calcio adecuada. Además, se describen las técnicas actuales de modificación de calcio disponibles, la evidencia para su uso, su mecanismo de acción y los resultados típicos que se observan en las imágenes intracoronarias.

Palabras clave: Calcificación coronaria. Modificación de placa calcificada. Aterectomía. Litoplastia. Tomografía coherencia óptica. Ecografía intravascular.

Abbreviations CAD: coronary artery disease. IVI: intravascular imaging. IVL: intravascular lithotripsy. IVUS: intravascular ultrasound. OA: orbital atherectomy. OCT: optical coherence tomography. PCI: percutaneous coronary intervention. RA: rotational atherectomy.

INTRODUCTION

Calcified coronary stenosis is a relatively common finding present in up to 30% of lesions planned for percutaneous coronary intervention (PCI).1 Calcified atherosclerosis presents a number of difficulties when performing PCI especially stent underexpansion, a strong predictor of stent failure (thrombosis and restenosis).2-4 It comes as no surprise, then, that worse clinical outcomes have been found following PCI in moderate-to-severe calcified disease compared to atherosclerotic plaques without calcium.1 A number of plaque modification techniques are available although there is a paucity of head-to-head comparisons among the techniques making device selection difficult. Understanding calcium morphology can contribute to proper device or technique selection, and is best guided by intravascular imaging (IVI). In this review, we outline the assessment of coronary calcium using IVI, propose a simplified calcium modification algorithm we use at our center, and examine the mechanism of action and evidence behind the use of each of these techniques.

Pathophysiology and prognostic implications of coronary calcium

The pathophysiology of atherosclerosis is well documented and starts with injury to the vessel and accumulation of low density lipoprotein which undergoes oxidative changes that result in the release of proinflammatory cytokines. These attract monocytes that migrate towards the intima layer, mature into macrophages, and eventually form foam cells.5 Further recruitment of smooth muscle cells from the media layer produce extracellular matrix that leads to intimal thickening and plaque progression. In time, and in the presence of risk factors including age, male sex, Caucasian race, hypertension, hyperlipidemia, diabetes, and chronic kidney disease, calcification of atherosclerotic plaques can occur and its pathogenesis has much in common with bone formation.1,5-8 Transformation of vascular smooth muscle cells into an osteoblastic phenotype is thought to be the initiation factor prompted by exposure to bone morphogenetic protein-2 (BMP 2) produced by endothelial cells when exposed to stressors like hypoxia, high pressure, turbulent flow, and inflammation.9 The result is the loss of expression of vascular smooth muscle specific markers, and the expression of genes typically found in bone generating cells.10 Other pathways also play a role including apoptosis of vascular smooth muscle cells, and formation of calcifying matrix vesicles by macrophages.6 The early result is the deposition of microcalcifications that eventually coalesce into larger calcium deposits that can be seen as “spotty calcification” on IVI. Further progression ultimately results in calcium sheets or plates which can extend across multiple quadrants of the vessel causing vessel stiffening and altering compliance.11 Nodular calcification, an important morphological subtype which protrudes into the vessel lumen, forms when there is rupture of the calcium sheets.6 Prognostically, the presence of calcified atherosclerosis is associated with poorer cardiovascular outcomes.12,13 Initial spotty calcification represents an unstable period in the evolution of calcified coronary artery disease (CAD), and these lesions are more commonly associated with plaque rupture and acute coronary syndrome.6,14 Conversely, lesions with a higher percentage calcified plaque volume as seen on computed tomography coronary angiography are more stable and present less frequently with acute cardiovascular events, yet more commonly with chronic coronary syndromes and multivessel disease.6,15

Percutaneous coronary intervention in calcified atherosclerosis

Calcific stenoses are found in up to 30% of all patients presenting for PCI.1 The subsequent reduction of coronary artery compliance presents a number of procedural difficulties. Inadequate lesion dilation can potentially result in stent underexpansion,16 one of the most important predictors of stent failure.2-4 Other difficulties include a higher risk of dissection and perforation, difficulty passing equipment distally, damage to the stent polymer, altered drug elution kinetics from stents, and potentially stent deformation or loss.1,17,18 Furthermore, patients with coronary artery calcification are less likely to undergo complete revascularization and more frequently experience adverse outcomes following PCI. In a pooled analysis of the HORIZONS-AMI and ACUITY studies, the presence of moderate or severe calcification (as assessed angiographically) was associated with poorer outcomes at 1 year for all endpoints including death, cardiac death, myocardial infarction, and overall major adverse cardiovascular events.1 As a matter of fact, at 1 year, the risk of stent thrombosis increased by 62% and that of ischaemic target lesion revascularization (TLR) increased by 44% in calcified compared to non-calcified lesions. These findings have been replicated across numerous other studies at both short and long-term follow-up.1,7,19-21 In a recent analysis of the SYNTAXES trial, heavily calcified lesions were associated with a higher all-cause mortality rate after 10 years regardless of the type of revascularization used (hazard ratio, 1.79; 95% confidence interval, 1.49-2.16; P < .001).21 Optimizing the results of PCI is, therefore, of paramount importance with plaque preparation with calcium modification is an important step in this process.

Imaging for calcium detection

Detecting the presence of coronary calcium prior to PCI is important for procedural planning and a number of imaging techniques may be used as shown on table 1.14,15,22-28


Table 1. Summary of available imaging techniques for the detection of coronary calcium

Imaging modality Quantification Sensitivity Specificity Advantages Disadvantages

Computed tomography14,15,22,23

• Calcium scoring on non-contrast images

• Percentage calcified plaque

++++

++++

• Non-invasive

• Calcium scoring provides prognostic information

• Highlights the presence of calcium prior to undertaking an invasive procedure

• Provides some information on the plaque morphology and composition (specific software available)

• Percentage calcified plaque is a predictor of future events

• Blooming artifact can overestimate the degree of calcification

• Circumferential arc difficult to assess

• Radiation exposure

• Contrast use

• Does not provide intraprocedural guidance

Coronary angiography23,24,25

• Mild: not visible

• Moderate: radiopacities seen only with cardiac motion

• Severe: radiopacities seen without cardiac motion, before contrast injection affecting both sides of the arterial wall (tram-track appearance)

++

+++ in the presence of severe calcification

+++

• Assessment of anatomical complexity, vessel tortuosity, side branch angulation

• Invasive

• No information on calcium morphology (thickness, circumferential arc)

OCT25,26,27

• Calcium thickness

• Calcium circumferential arc

• Calcium length

++++

++++

• High resolution, 10 µm to 20 µm

• Detailed calcium morphological assessment

Distribution/arc

Depth

Volume

Length

Presence of calcium nodules

• Procedural guidance

Landing zones

Vessel dimensions

Lesion length

Stent length

Guide stent optimization

Assess stent expansion

Identify complications (dissection, under-expansion, malapposition, stent distortion)

• Co-registration with angiography available

• Invasive

• Requires a blood-free environment for image acquisition

• Contrast required for blood clearance

• Limited assessment of ostial lesions

• Difficult to advance the catheter distally in tortuous vessels

IVUS25,27,28

• Calcium arc

• Calcium length

++++

++++

• Moderate-high resolution 100 µm to 150 µm (high-resolution IVUS 20 µm to 30 µm)

• High penetration depth into non-calcific vessel wall ~10 mm

• No specific imaging requirements

• Can assess ostial lesions

• Morphological assessment of calcium

Distribution/arc

Length

Presence of calcium nodules

• Procedural guidance

Landing zones

Vessel dimensions

Lesion length

Stent length

Guide stent optimization

Assess stent expansion

Identify complications (dissection, underexpansion, malapposition, stent distortion)

• Co-registration with angiography available

• Invasive

• Acoustic shadowing in severe calcification

• Difficult to assess calcium thickness

Use of surrogate markers of thickness (reverberations)

IVUS, intravascular ultrasound; OCT, optical computed tomography.


Non-invasive imaging for coronary calcification

Coronary computed tomography angiography is highly sensitive and specific for the detection of calcium and is a non-invasive technique. Coronary computed tomography angiography can determine plaque morphology and percentage of calcified plaque volume, which has prognostic significance.15 Its utility in procedural planning is increasingly seen in the planning of chronic total coronary occlusions, but it is less useful in the specifics of guiding intraprocedural strategy.

Invasive imaging for coronary calcification

Invasive coronary angiography has long been known to have low sensitivity but high specificity for the detection of coronary calcium. Compared to intravascular ultrasound (IVUS), its overall sensitivity is ~48%, but it increase up to > 85% in the presence of severe (4 quadrant) calcification.24,25 Nonetheless, an arc > 100° as seen on the IVI is required before calcium can be reliably detected on angiography, thus highlighting the potential for calcium to go undetected when the PCI is guided by angiography alone.25 Calcification on angiography is typically classified as none/mild, moderate or severe (table 1). Although angiography provides valuable information to guide the procedure such as vessel tortuosity, angulation of bifurcations, etc, its limitations are well documented, and studies have consistently shown poorer outcomes when PCI is guided by angiography compared to IVI.29-31

IVI overcomes much of the shortfalls of other imaging modalities. Both optical coherence tomography (OCT) and IVUS are more sensitive for the detection of calcium compared to coronary angiography.25 Furthermore, both imaging modalities provide additional information to guide and optimize the procedure (table 1).27 Co-registration with angiography is available for both modalities, and can reduce the learning curve significantly.32 Although the advantages of IVI over angiography have been shown in a number of studies, no randomized studies have specifically examined its potential benefits regarding calcified CAD. Nonetheless, given the complexity of these lesions, performing IVI-guided PCIs seems reasonable.

Intravascular ultrasound

IVUS has both high sensitivity and specificity (86.7% and 93.3%, respectively compared to histological samples) for the detection of dense calcification, although it is less sensitive for the detection of microcalcifications,33 and in the presence of overlying fibrotic plaque.34 Calcium reflects ultrasound resulting in a bright hyperechoic signal with significant posterior shadowing that often precludes the assessment of calcium thickness (figure 1).35 Surrogate markers for calcium thickness can be used such as the presence of posterior reverberations (correlated with thinner calcium < 0.5 mm) while significant shadowing is suggestive of thicker calcification ( > 1 mm).25 Recently, an IVUS specific scoring system has been found to be useful in predicting stent underexpansion using 4 criteria: calcium arc > 270° for a length of ≥ 5 mm, presence of 360° calcium, presence of calcified nodules, and adjacent vessel diameter of < 3.5 mm. Scores ≥ 2 suggest that calcium modification should be undertaken and therefore operators should aim to measure each of these parameters on IVUS pullbacks.36


Figure 1. Calcium morphology and measurement using intracoronary imaging. A: concentric calcification on optical coherence tomography (OCT); calcium arc of 264°, depth of 0.68 mm, and length of 11 mm - high risk features by OCT for stent underexpansion and plaque preparation is advised. B: concentric calcification; arc 281°, and depth of 0.8 mm. Automatic calcium detection using Ultreon software; degrees of calcium detected outlined by the orange arc surrounding the OCT image. C: eccentric calcium on the OCT; arc < 180 degrees. Note the sharply demarcated borders of calcium that allow the assessment of calcium depth (1.2 mm) D: calcified nodule on the OCT. Significant posterior shadowing is caused by the nodule precluding the assessment of its posterior border. E: concentric calcification on IVUS with an arc of 250° and a length of 9.8 mm. Posterior shadowing and lack of reverberations suggests thick calcium (~1 mm). These features represent a high risk of stent underexpansion. F: concentric calcification on intravascular ultrasound (IVUS) with an arc of 360°. G: eccentric calcification on IVUS with an arc of < 180°. Significant posterior shadowing (blue asterisk). H: calcified nodule on IVUS protruding into the lumen and casting significant posterior acoustic shadowing (blue asterisk). The yellow asterisk (in all OCT images) denotes wire artefact.


Optical coherence tomography

Although significantly more sensitive than angiography OCT is less sensitive compared to the IVUS at detecting coronary calcium. Wang et al. found that ~6% of lesions with IVUS detectable calcium did not show visible calcium on OCT, which was mainly attributed to overlying fibrotic plaque.25 On the OCT, calcium appears as a region of low signal intensity with sharply demarcated borders that facilitate the assessment of calcium depth.26 Fujino et al. demonstrated that calcium arc > 180°, depth > 0.5 mm, and length > 5 mm on the OCT were associated with a higher risk of stent underexpansion and—similar to IVUS—operators should try to analyse each of these parameters.37 Recently, artificial intelligence software has become available (Ultreon OCT system, Abbott, United States), which automatically identifies calcium arc and depth, as well as the external elastic lamina for vessel sizing further simplifying this analysis (figure 1).

In practical terms, therefore, it may be useful to assess the extent of coronary calcification on IVI by considering calcium arc, depth, length, and whether it is superficial or deep as shown on figure 1. Considering the circumferential arc, coronary calcium can be divided into 3 morphological subtypes (figure 1). Eccentric, extending across 2 or less quadrants with an arck < 180°, and concentric, with an arc > 180° and nodular calcification presenting as an eruptive protrusion into the lumen. Calcium can also be divided into superficial (located at < 50% of the depth of the plaque plus media thickness) or deep (located at > 50% of the depth of the plaque plus media thickness).28 Calcium length should be measured on the longitudinal projection on both IVUS and OCT.

Calcium modification

Although there is a lack of clinical trials comparing modification techniques in varying calcium morphologies, consensus in this regard suggests that balloon-based therapies may be effective in eccentric calcification, which is short in length. Ablative and lithotripsy-based therapies may be more useful in concentric calcification or long calcified lesions with lithotripsy being particularly useful in deeper calcium deposits. Nodular calcification presents the greatest challenge; however many advocate for the use of ablative techniques, and some recently presented data suggests lithotripsy may have a role.38 Uncrossable and undilatable lesions may be treated with rotational atherectomy (RA) or excimer laser coronary angioplasty (ELCA). While acknowledging the paucity of data and the lack of head-to-head trials comparing the different techniques available, we have tried to summarize this practice, and the practice at our center, into a simplified calcium modification algorithm that can provide some guidance (figure 2). table 2 summarizes the mechanism of action and specifications for these techniques. The expected results following calcium modification are shown on figure 3.


Table 2. Calcium modification tools: description, mechanism of action, and specifications

Cutting balloons Scoring balloons High-pressure noncompliant NC balloons Rotational atherectomy Orbital atherectomy Excimer LASER Lithotripsy

Technology description

Balloon platform with a number of microblades

Several nitinol wires wrapped around a semi- or noncompliant balloon

Double layered noncompliant balloon

Diamond coated burr capable of atherectomy in a forward motion

Eccentrically mounted diamond coated crown capable of atherectomy in a forward and a backward motion

Concentric or eccentric array of laser fibers.

Uses a mixture of rare gas and halogen to generate brief pulses of high-frequency, short wavelength UV light

Series of emitters encased within a balloon delivery system

Mechanism of action

Controlled incisions into calcium

Controlled incisions into calcium

Super high-pressure dilation with a rated burst pressure of 35 atm (often dilated at ~50 atm)

High speed burr rotation (140-160 000 rpm) results in differential atherectomy of fibrocalcific tissue Additional effect due to burr vibration (+)

Centrifugal force causes the crown to orbit at high speeds (80 or 120 000 rpm) resulting in calcium sanding

Additional effect due to crown vibration (+++)

Disrupts plaque through 3 mechanisms

Photochemical: by breaking carbon bonds between molecules

Photothermal: by the production of thermal energy and vapour bubbles

Photomechanical: by the expansion of vapour bubbles causing plaque disruption

The light energy (fluence) used ranges between 30 mL/mm2 and 80 mL/mm2

Pulse repetition rate is between 25 Hz and 80 Hz

Emitters generate sparks creating a vapour bubble that expands and propagates an acoustic wave through the vessel wall. Causes compressive and decompressive forces when calcium is found resulting in fracture

Sizes available

A number of brands available in sizes ranging from 2.0 mm to 4.0 mm

A number of brands available in sizes that range from 1.75 mm to 4.0 mm

1.5 mm to 4.5 mm balloons

1.25, 1.5, 1.75, 2.0, 2.15, 2.25, 2.38, 2.5 mm burr

1.25 mm crown

0.9 mm, 1.4 mm, 1.7 mm, and 2.0 mm

2.5 mm, 3.0 mm, 3.5 mm, and 4.0 mm diameters

All sizes are 12 mm in length

Guide catheter compatibility

6-Fr

Some balloon sizes are compatible with 5-Fr and 6-Fr systems

6-Fr

6-Fr; 1.25 & 1.5 mm

7-Fr; 1.75 mm

8-Fr; 2.0, 2.15 mm

9-Fr; 2.25, 2.38 mm

10-Fr; 2.50 mm

6-Fr

6-Fr: 0.9 & 1.4 mm

7-Fr: 1.7 mm

8-Fr: 2.0 mm

6-Fr

Wire compatibility

Conventional 0.014 in guidewires

Conventional 0.014 in guidewires

Conventional 0.014 in guidewires

Specialized 0.009 or 0.014 in wire required

Specialized 0.012 or 0.014 in wire required

Viper wire

Conventional 0.014 in guidewires

Conventional 0.014 in guidewires

Other caveats

1:1 balloon: vessel sizing

Rotating the balloon followed by repeat inflation can increase the number of incisions

1:1 balloon: vessel sizing

1:1 balloon: vessel sizing

Burr-to-artery ratio of 0.5 to 0.6

Lubricant available but not mandatory and contraindicated in egg and olive oil allergies

Specific lubricant required which is contraindicated in egg and soy allergies

Catheter-to-artery ratio of 0.5 to 0.6

Requires continuous infusion of saline through the guide catheter

Contrast infusion increases effectiveness but can also increase the risk of thermal damage

1:1 balloon: vessel sizing

Rigorous balloon preparation to remove all air

May require de-airing while being used

Advantages

Easy to use

Compatible with conventional guidewires

Easy to use

Compatible with conventional guidewires

Easy to use

Compatible with conventional guidewires

Useful in undilatable lesions

May be more useful for nodular calcium than other technologies

Useful in undilatable lesions

May be more useful for nodular calcium than other technologies

Can ablate in both a forward and a backward motion

Produces smaller particles than rotational atherectomy

Easy to use

Compatible with conventional guidewires

Easy to use

Compatible with conventional guidewires

Modifies superficial and deep calcification

No particulate matter created so lower risk of slow flow or no-reflow

Disadvantages

May not be sufficient as monotherapy

Bulky profile

May not be sufficient as monotherapy

Bulky profile

Bulky profile

Specialized wire required

Wire bias may result in differential atherectomy.

Ablation in a forward motion only

Cannot maintain a wire in a side branch during atherectomy.

Produces larger particles compared to orbital atherectomy

Distal embolization can result in slow flow or no-reflow

Specialized wire required

Specialized lubrication infusion required

Cannot maintain a wire in a side branch during atherectomy.

Distal embolization can result in slow flow or no-reflow

Set up time

Additional UV protection required

Bulky profile for lesion crossing

80 pulses per catheter may require the use of > 1 catheter to treat long lesions

Potential complications

Perforation

Dissection

Slow flow/no reflow

Perforation

Dissection

Slow flow/no reflow

Perforation

Dissection

Slow flow/no reflow

Perforation

Dissection

Burr entrapment

Wire fracture

Slow flow/no reflow

Transient heart block

Perforation

Dissection

Crown entrapment

Slow flow/no reflow

Perforation

Dissection

Thermal injury

Perforation

Dissection

Fr, French; Hz, Hertz; in, inches; NC, noncompliant; rpm, revolutions per minute; UV, ultraviolet.



Figure 2. Calcium modification algorithm. Intravascular imaging (IVI) for lesion assessment is advised prior to undertaking plaque modification. Uncrossable lesions usually require rotational atherectomy or excimer laser coronary angioplasty (ELCA). Crossable lesions with eccentric calcification without high-risk features for stent underexpansion can be treated using noncompliant, cutting or scoring balloons. Concentric calcification or calcium with high-risk features for stent underexpansion can be treated with atherectomy techniques or intravascular lithotripsy (IVL). Nodular calcium can be modified using atherectomy techniques with emerging evidence that IVL may also be effective. Post plaque modification IVI is key for proper plaque modification assessment. Ca, calcium.


Figure 3. Calcium morphologies and results of different modification techniques on intravascular imaging. A: discrete calcium incisions and fracture following cutting balloon (yellow asterisk). B, C: calcium fractures following intravascular lithotripsy on optical coherence tomography and intravascular ultrasound (IVUS) (blue asterisk). Note how reverberations can be seen at fracture points (blue asterisk) on the IVUS due to acoustic waves now being able to pass through the fracture sites. D: results of calcium modification using rotational atherectomy in an uncrossable lesion. A “cored out” appearance can be seen with widening of the lumen and a semilunar appearance in some regions (blue arrow). E: results of calcium modification following orbital atherectomy. The semilunar shape of the orbital atherectomy crown can be seen at the yellow arrows.


Eccentric calcification therapies

Specialized balloon-based technologies

Specialized balloon-based technologies are most commonly used for eccentric calcification although they have some utility in concentric calcification in combination with other techniques. Cutting balloons consist of a number of microblades mounted on a balloon, while scoring balloons consist of a semi-compliant balloon around which several nitinol wires are wrapped. Both aim to make incisions into the calcium to facilitate vessel dilation. The advantage of these technologies is that they anchor to the calcium and are less likely to slip (watermelon seeding phenomenon) thus avoiding dissection of adjacent areas. Although sometimes used interchangeably, a study conducted by Matsukawa et al. using IVI demonstrated better calcium modification and increased luminal gain with cutting balloons vs scoring balloons.39 However, regarding severe calcification, cutting balloons have lower rates of procedural success compared to RA.40 Combining cutting balloons with other technologies may be useful. Observational studies have demonstrated increased luminal gain with cutting balloons following RA compared to conventional balloons or RA alone.41,42

Very high-pressure balloons may be effective to cause calcium fracture in both eccentric and concentric calcification. They are generally not first-line therapies and are most often used in undilatable lesions. They consist of a noncompliant twin-layered balloon with rated burst pressure of ~35 atm. However, in practice they are often dilated at ~50 atm. In a retrospective series of 326 consecutive undilatable lesions, Secco et al. reported angiographic success in > 90% using the OPN high-pressure balloon (OPN NC; SIS Medical AG, Switzerland).43 Calcific lesions with calcium arcs > 270° were more likely to require pressures > 40 atm. More recently, the ISAR-CALC trial randomized lesions with residual stenosis > 30% following standard balloons to receive a scoring balloon or a super high-pressure balloon.44 No differences on OCT defined stent expansion index between groups were found (0.72 vs 0.68; P = .22) nor were there differences in angiographic, procedural, or strategy success. Patients in the super high-pressure balloon group, however, less frequently required further dilation with NC balloons prior to stenting, had larger angiographically assessed minimal lumen diameters, and less residual stenosis compared to those in the scoring balloon cohort. Therefore, super high-pressure balloons play a role in the management of undilatable, but crossable lesions.

Concentric and nodular calcification

Lithotripsy

Intravascular lithotripsy (IVL) (SHOCKWAVE Medical inc, United States) is a recently introduced technique based on the use of acoustic energy. It consists of a balloon-based delivery system containing a number of emitters that generate short electric sparks. The sparks produce a vapour bubble in the fluid inside the balloon that is dilated to 4 atm. The vapour bubble expands creating an acoustic pressure wave that propagates through the vessel wall causing compression and decompression stress when calcium is encountered resulting in fracture.45 Each short-lived pulse delivers an equivalent of ~50 atm of pressure. Nonrandomized studies to date have demonstrated significant fissuring of both superficial and deep calcium on IVI (figure 3). A pooled analysis of the DISRUPT CAD series of studies has demonstrated procedural success (residual angiographic stenosis ≤ 30%) in > 90% of the lesions.46 Although to date, IVL has been predominantly used in concentric calcium, analysis of angiographically defined eccentric vs concentric calcification suggests similar success in these 2 calcium morphologies.47 Also, recently presented data suggests no differences in minimal stent area on OCT when IVL was used to treat eccentric, concentric, and nodular calcium.38 Although still an off-label indication, a number of cases and series have reported on the use of IVL to treat stent underexpansion due to severe calcification, and calcified neoatherosclerosis.48-51 The use of IVL in a newly deployed but underexpanded stent has not been widely reported and there are theoretical concerns regarding damage to the polymer. Our practice to date has been to use IVL predominantly in concentric calcification while further data is awaited. figure 4 shows a case of plaque modification using OCT-guided IVL.


Figure 4. Case example demonstrating calcium modification using intravascular lithotripsy (IVL) guidance with co-registered optical coherence tomography (OCT) imaging using Ultreon software. A: severely calcified left anterior descending coronary artery stenosis with calcium visible on fluoroscopy (inset), B: OCT revealing concentric calcium; arc 258o and depth of 0.95 mm as identified automatically using the Ultreon software with a length of 18 mm. These parameters suggest a high risk of stent underexpansion. C: proximal and distal landing zones and length of stent required. The distal landing zone external elastic lamina to external elastic lamina (dashed white lines automatically detected by Ultreon system) measures 3.16 mm while, proximally, the external elastic lamina cannot be visualized, and lumen diameter is 2.62 mm. The predicted length of the stent required is 45 mm. D: 3.0 mm x 12 mm IVL balloon (1:1 sizing). Sixty pulses delivered along the calcified lesion. E, F: extensive calcium fracture seen on the OCT after IVL (white arrows). A dissection is also noted (white asterisk). G: stent implantation with a 3.0 mm x 48 mm drug-eluting stent according to the sizing by OCT. Optimized with a 3.0 mm x 12 mm noncompliant balloon. F: final OCT; optimal stent expansion (> 90%), no malapposition or complications (eg, dissection) at the proximal and distal landing sites.


Rotational atherectomy

RA (Rotablator, Boston Scientific, United States) uses a diamond-tipped burr that rotates at 140-180 000 rpm Resulting in the differential ablation of calcified tissue while avoiding disruption of healthy elastic tissue. Ablation occurs only in a forward motion. A specialized wire (RotaWire Floppy or RotaWire Extra Support, Boston Scientific, United States) is required and the burr size should not exceed 0.5-0.6 times the size of the vessel. Previously, the infusion of nitroglycerin, verapamil or heparin were advocated to mitigate the effects of debris embolization while temporary pacing wire insertion or aminophylline infusion were used to combat bradycardia particularly when performing RA in the right coronary artery. However, changes to RA techniques have reduced these complications. Aggressive debulking with RA has been replaced by the use of shorter runs (10-15 seconds), a pecking motion of the burr, smaller burr sizes, and resting periods to allow clearance of embolized particles. On IVI, a smoothing out of the calcium can be seen sometimes with a semilunar shape from where the burr has ablated (figure 3).

The ROTAXUS trial randomized 240 patients with calcified CAD to RA or conventional therapy prior to drug-eluting stenting.52 Both procedural success and luminal gain (1.56 mm vs 1.44 mm, P < .01) were higher in the RA group at the index procedure. However, higher late luminal loss in the RA group was seen at 9 months (0.44 mm vs 0.31 mm, P = .04). Furthermore at 2-year follow-up no differences were seen between groups regarding major adverse cardiovascular events, myocardial infarction, target lesion revascularization or target vessel revascularization (P > .05 for all comparisons).53 The PREPARE-CALC study examined RA vs modified balloons (cutting or scoring) in the treatment of severely calcified disease. Similar to the ROTAXUS trial, increased strategy success was seen in the RA arm vs the modified balloon arm (98% vs 81%, P = .0001) mainly attributed to a higher crossover rate in the modified balloon group (10% of modified balloon group).40 However, improved strategy success in the RA arm did not translate into differences in clinical or angiographic outcomes at 9 months.40 This may be partially explained by the fact that final stent expansion as seen on OCT was not different between groups (73.5% vs 73.1% for modified balloons vs RA respectively, P = .85).54

Combinations of complementary calcium modification therapies are increasingly being used. A study of 92 patients conducted by Tang et al. found greater decrease in percent stenosis (54.5% to 36.1% vs 55.7% to 46.9%, P < .001), and greater stent expansion (71.7% vs 54.5%) with RA followed by cutting balloon compared to RA alone.41 Similarly, Amemiya et al. found greater calcium fracture and stent expansion (78.9% vs 66.7%, P < .01) on OCT with cutting balloon vs standard balloon angioplasty after RA.42 Additionally, there have been numerous case reports regarding the use of IVL following RA with good effect.55,56 Larger scale observational and randomized studies are required to determine if improved longer term outcomes can be achieved by these (and other) combinations. In practical terms and in our own clinical practice, RA plays a role in uncrossable and undilatable lesions, and severe concentric calcification (figure 2) often in combination with other techniques.

Orbital atherectomy

OA (DIAMONDBACK 360 orbital atherectomy system, Cardiovascular systems Inc., United States) consists of a diamond coated crown that uses centrifugal force to orbit resulting in preferential calcium sanding while flexing away from healthy elastic tissue. It requires a dedicated wire (ViperWire advance), and lubricant infusion (ViperSlide both Cardiovascular systems Inc., United States) during ablation. The 1.25 mm crown orbits at 1 of 2 speed settings (80 or 120 000 rpm), which results in widening or narrowing of the orbital arc. Unlike RA, the OA can ablate both in forward and backward motion, and requires slow smooth movements (~1mm/second). Atherectomy runs should be ≤ 30 seconds with resting periods to allow clearance of debris. IVI following OA demonstrates smoothed out calcium often with a visible arc or semilunar shape where sanding occurred (figure 3). The nonrandomized ORBIT I and II studies examined the safety and effectiveness of OA finding a reduction in percentage diameter stenosis to ≤ 50% in > 98% of the lesions.57,58 Significant dissection occurred in 2.3% of the cases. However, the rate of other complications such as perforation, slow, and no-reflow was low and < 1%.58 The 3-year follow-up of the ORBIT II study demonstrated cumulative rates of major adverse cardiovascular events and target lesion revascularization of 23.5%, and 7.8%, respectively.59 The single arm prospective COAST study examined a modified OA system with a distal microcrown to improve penetration with a reduction in percentage diameter stenosis to ≤ 50% in > 99% of the lesions.60 There are currently no randomized trials comparing OA to other forms of calcium modification. However, a small OCT study suggested deeper calcium modification with OA vs RA,61 and a meta-analysis of observational studies found no difference in procedural complications or 30-day events including death, myocardial infarction, and target vessel revascularization between OA and RA.62 However, although more data is required, our practice is to use OA over RA in larger vessels with concentric or nodular calcium. figure 5 demonstrates an example of OA plaque modification and table 3 summarizes the current data for both OA and RA.


Table 3. Summary of the main prospective studies examining outcomes in RA and OA techniques

Technique Study name Design Number of participants Procedural outcomes Short-to-medium term outcomes Long-term outcomes

Rotational atherectomy

ROTAXUS study52,53

Randomized controlled trial

240

• 120 RA

• 120 Standard therapy (Std Tx)

Strategy success

• RA, 92.5% vs Std Tx, 83.3%, P = .03

Acute luminal gain

• RA, 1.56mm vs Std Tx, 1.44, P < .01

Dissection

• RA, 3.3% vs Std Tx, 3.3%, P = .99

Perforation

• RA, 1.7% vs Std Tx, 0.8%, P = .56

Slow/no flow

• RA, 0% vs Std Tx, 0.8%, P = .32

9-month out comes

In-stent LLL

• RA, 0.44mm vs Std Tx, 0.31, P = .04

Mortality

• RA, 5.0% vs Std Tx, 5.8%, P = .78.

MI

• RA, 6.7% vs Std Tx, 5.8%, P = .79

TVR

• RA, 16.7% vs Std Tx, 18.3%, P = .73

MACE

• RA, 24.2% vs Std Tx, 28.3%, P = .46.

TLR

• RA, 11.7% vs Std Tx, 12.5%, P = .84

2-year outcomes

MACE

• RA, 29.4% vs Std Tx, 34.3%, P = .47

Death

• RA, 8.3% vs Std Tx, 7.4%, P = 1.00)

Myocardial infarction

• RA, 8.3% vs Std Tx, 6.5%, P = .80),

TLR

• RA, 13.8% vs Std Tx, 16.7%, P = .58

TVR

• RA, 19.3% vs Std Tx, 22.2%, P = .62)

PREPARE-CALC40

Randomized controlled trial

200

• 100 RA

• 100 MB

Strategy success

• RA, 98% vs MB, 81%, P = .0001

Dissection

• RA, 3% vs MB, 7%, P = .33

Perforation

• RA, 4% vs MB, 2%, P = .68

Slow/no flow

• RA, 2% vs MB, 0%, P = .49

9 months

In-stent LLL

• RA, 0.22 vs MB, 0.16mm, P = .21

Mortality

• RA, 2% vs MB, 2%, P = 1.00

TVR

• RA, 3% vs MB, 6%, P = .50

TLR

• RA, 2% vs MB, 7%, P = .17

Definite/probable stent thrombosis

• RA, 0% vs MB, 0%, P = 1.00

TVF

• RA, 6% vs MB, 8%, P = .78

Orbital atherectomy

ORBIT I57

Prospective non-randomized

50

• Device success, 98%,

• Procedural success, 94%

• Dissection, 12%

• Perforation, 2%

• In-hospital MACE, 4%

MACE

• 30-days, 6%

• 6 months, 8%

ORBIT II58,59

Prospective multicentre non-randomized

443

• Procedural success, 88.9%

• Angiographic success, 91.4%

• Severe dissection, 2.3%

• Perforation, 0.9%

• Slow/no flow, 0.2%

• In-hospital MACE, 9.8%

MACE

• 30-day, 10.4%

3-years

• MACE, 23.5%

• Cardiac death, 6.7%

• MI, 11.2%

• TVR, 10.2%

• TLR, 7.8%

COAST60

Prospective multicentre single-arm

100

• Procedural success, 85%

• In-hospital MACE, 14%

• Dissection, 2%

• Perforation, 2%

• Slow/no flow, 2%

MACE

• 30-day, 15%

1 year

• MACE, 22.2%

MACE, major adverse cardiovascular events; MB, modified balloons; MI, myocardial infarction; OA, orbital atherectomy; RA, rotational atherectomy; Std Tx, standard therapy, RS, residual stenosis; TIMI, Thrombolysis in Myocardial Infarction; TLR, target lesion revascularization; TVR, target vessel revascularization.

Definitions

• Strategy success: Successful stent delivery, < 20% in-stent RS, TIMI grade-3 flow without crossover or stent failure

• Device success: < 50% RS following OA without device malfunction

• Angiographic success: stent delivery with RS < 50%

ROTAXUS

• MACE: MI, TVR, and cardiac death

ORBIT I

• Procedural success: < 20% in-stent RS

• MACE: cardiac death, MI or TLR

ORBIT II

• Procedural success: stent delivery with a < 50% RS without in-hospital MACE.

• MACE: MI, TVR, and cardiac death

COAST

• MACE: cardiac death, MI or TVR



Figure 5. Calcium modification using orbital atherectomy guided by co-registered optical coherence tomography (OCT) imaging. A: severely calcified mid-left anterior descending coronary artery stenosis B: OCT showing severe circumferential calcification; arc of ~270°, depth of 0.7 mm, and length > 5 mm suggesting a high risk of stent underexpansion according to OCT criteria. Distal and proximal reference luminal diameters of 2.5 mm, and 3.25 mm, respectively, with a predicted stent length of 33 mm. C: orbital atherectomy (yellow arrow) using the DIAMONDBACK 360 orbital atherectomy system, and a 1.25 mm crown advanced at 1 mm/s. Sanding/atherectomy was performed in a forward and a backward motion. Dynamic road mapping was also used to guide the procedure (bottom left). D: smoothed out appearance after orbital atherectomy. Image shows that calcium ‘cap’ has been greatly reduced by the sanding effect of orbital atherectomy (OA). A semilunar shape can be seen as an effect of the orbiting crown (white arrows). E: post-OA angiography demonstrating significantly reduced percent stenosis. F: implantation of a 2.5 mm x 36 mm drug-eluting stent with proximal optimization using a 3.5 mm x 10 mm noncompliant balloon (inset). G: final co-registered OCT post-OA, and stenting demonstrating adequate stent expansion and apposition without complications.


Excimer laser coronary angioplasty

Excimer laser coronary angioplasty (ELCA) uses a mixture of rare gas and halogen to generate brief pulses of high-frequency ultraviolet light which disrupts atherosclerotic plaque through 3 mechanisms: photochemical by breaking down the carbon bonds between the molecules, photothermal due to the production of heat and vapour bubbles causing cell rupture, and photomechanical by the expansion of vapour bubbles causing the disruption of the plaque. Fluence (energy measured in mJ/mm2), and pulse frequency can be altered to increase its effectiveness. Constant saline infusion is advised to avoid thermal injury. Also, the short wavelength (~308 nm) of ultraviolet light used reduces the depth of penetration, thus avoiding damage to healthy tissues. Evidence on the use of ELCA in calcified CAD is limited. A prospective multicentre study of 100 uncrossable/undilatable lesions demonstrated technical success in 92% of lesions63 while a more recent prospective multicentre study of 126 uncrossable lesions demonstrated success in ~82% of cases.64 However, severe calcification was significantly associated with ELCA failure. In the setting of in-stent restenosis, more calcium fracture on OCT was seen in the ELCA vs conventional treatment group.65 Given the paucity of large-scale studies and considering the data available to date, ELCA has a relatively niche role predominantly for the management of uncrossable lesions although we prefer to use RA as the first-line ablative therapy in this circumstance.

CONCLUSIONS

Calcified CAD continues to present a barrier for successful PCI. Furthermore, our ageing population suggests that the proportion of patients with calcified CAD who will present for PCI is likely to increase. Its presence is associated not just with poorer acute outcomes, but also with more adverse events at long-term follow-up. Stent underexpansion is one of the most powerful predictors of stent failure, and often occurs in the presence of significant coronary calcification. Identifying the presence of coronary calcium is key in planning a PCI, and is more accurately done using IVI. A number of technologies with different mechanisms of action are now available to modify coronary calcium although head-to-head comparisons between these techniques are lacking. Nonetheless, we propose a simplified calcium modification algorithm based on IVI findings that is currently used at our center. Future studies should aim to compare techniques and elucidate the best technique combinations to ensure improved outcomes in these complex patients.

FUNDING

None whatsoever.

AUTHORS’ CONTRIBUTIONS

A. McInerney: concept, design, and drafting of the manuscript. J. Escaned: contributed clinical images, and was involved in the critical review of the manuscript. N. Gonzalo: concept, design, drafting, and critical review of the manuscript. Contributed clinical images.

CONFLICTS OF INTEREST

N. Gonzalo reports consultancy and speaker fees from Abbott and Boston Scientific. The remaining authors reported no conflicts of interest pertaining to the current publication.

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* Corresponding author:

E-mail address: nieves_gonzalo@yahoo.es (N. Gonzalo).

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