PART III - LASER THERAPY
TABLE OF CONTENTS
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Released on May 15, 2012
PART III

Laser therapy

Michael Haude, Miltos Papalexandris, Hubertus Degen

Summary

Excimer laser coronary angioplasty (ELCA) was introduced more than two decades ago as an alternative to balloon angioplasty (PTCA) for the treatment of obstructed coronary arteries. This technology is designed to ablate the obstructive atherothrombotic plaque rather than creating plastic deformation to increase vessel lumen dimensions as in PTCA. In addition, beneficial effects on platelet aggregation and thrombus dissolution have been reported. However, despite technical and procedural improvements over time, ELCA has failed to show better angiographic, procedural, or clinical outcome results when compared to PTCA. Moreover, since coronary stents emerged at the same time (as an alternative to PTCA) with superior procedure-related safety results and lower rates of restenosis or reintervention, the coronary ELCA application is now limited to some niche indications. These include: the undilatable lesion, chronic total occlusions with successful wire passage but inability to advance a balloon, long and diffuse atherosclerotic lesions or in-stent restenosis (due to excessive neointimal proliferation), ostial or bifurcation lesions requiring ablative plaque modification, and in primary PCI with large thrombus burden as an adjunct or alternative to conventional thrombectomy devices. Therefore in the current era of drug-eluting stents, the aim of laser therapy is to facilitate an optimal final stent implantation result, Depending on individual operator experience, ELCA has shown its feasibility in all of these niche indications but there is a lack of scientific data supporting a broader application of use. Since it is also a relatively costly technology, coronary ELCA will likely continue to have only a limited use in dedicated centres that can afford the application for at least one of the outlined specific indications.

Introduction

Percutaneous coronary balloon angioplasty (PTCA) was developed by Andreas Grüntzig as an alternative treatment option for patients with coronary artery disease [1]. The mechanism of luminal widening is based on plastic deformation of the obstructive plaque with the creation of intimal tears and dissections (rather than plaque compression), and can impact coronary flow resulting in abrupt vessel closure [2, 3]. Ablation is the removal of material rather than it local redistribution. Therefore, alternative techniques were developed to address plaque ablation in contrast to the purely mechanical effects of balloon angioplasty. These techniques included directional atherectomy, rotational atherectomy and laser catheter ablation [4, 5] View chapter and View chapter .

Basics

THE PRINCIPLE OF LASER ANGIOPLASTY

LASER stands for light amplification by stimulated emission of radiation. Laser energy is produced when an active medium (e.g., XeCl) is excited by electrical energy and emits monochromatic, coherent light. Laser energy can be emitted as a continuous or pulsed wave [6]. The only approved laser system for coronary application is a pulsed excimer (excited dimer) laser system utilising XeCl as the active medium with a wavelength of 308 nm. Excimer laser energy has been shown to ablate inorganic material by photochemical mechanisms that break molecular bonds without generation of excessive heat [7, 8]. In vivo, these photochemical mechanisms, together with localised thermal and mechanical effects, result in an atheroablation which can be documented by intravascular ultrasound studies in humans [9, 10]. ELCA has been shown to have no influence on immediate elastic recoil compared to PTCA [11].

During its technical evolution it was realised that ultraviolet laser energy is avidly absorbed in blood or contrast medium, inducing significant acoustic effects generating fast-expanding and imploding vapour bubbles which produce rapid microsecond dilatation followed by invagination of the adjacent arterial segment.

This can induce tissue disruption with extensive medial necrosis, intramural haemorrhage and subluminal infiltration of leucocytes ( Figure 1), resulting in dissections or even vessel perforations [12]. Therefore, excimer laser coronary angioplasty (ELCA) should only be performed after displacement of blood or contrast medium from the coronary artery by a continuous saline flush during laser activation [13, 14]. Furthermore, pulsed energy delivery is used reduce laser-induced pathological tissue injury [15].

FOCUS BOX 1Mechanisms of ELCA
  • Photochemical mechanisms that ablate inorganic material
  • Breaking of molecular bonds
  • Generation of fast-expanding and imploding vapour bubbles creating dissections or even perforation especially when ELCA is activated in blood or contrast medium
  • The Dotter effect

THE EXCIMER LASER SYSTEM AND CATHETERS

The CVX-300® ELCA system (Spectranetics Inc., Colorado Springs, CO, USA) utilises a XeCl LASER unit and laser catheters for coronary or peripheral application ( Figure 2).

The only currently available ELCA system for coronary application is supplied by the Spectranetics Corporation. Its laser unit uses XeCl as the active medium at a wavelength of 308 nm and it generates a catheter energy output up to 80 mJ/mm2 with a maximum repetition rate of 40 Hz, and a pulse width of 125 - 200 ns. This energy output is described by the term fluence. The system has a warm-up time of 5 minutes and requires calibration.

Laser catheters are available as over-the-wire or rapid exchange devices and consist of different amounts of 50 μm fibres, which are either concentrically or eccentrically ( Figure 3) arranged around a 0.014 inch guidewire (0.018 inch for the 2.0 mm eccentric laser catheter version).

The 0.9 mm catheter has a maximum tip outer diameter of 0.038 inch and is compatible with 5 French (Fr) guide catheters, while the 1.4 mm catheter has a maximum tip outer diameter of 0.057 inch and requires a 7 Fr guide catheter. The 1.7 mm catheter has a maximum tip outer diameter of 0.069 inch and is still 7 Fr compatible whilst the 2.0 mm catheter with a maximum tip outer diameter of 0.079 to 0.080 requires an 8 Fr guide catheter. The recommended laser catheter size should not exceed 0.5 to 0.6 times the reference vessel diameter. Since ELCA catheters are contact lasers, the maximum tip outer diameter defines the maximum achievable lumen with a single passage. The eccentric versions of the ELCA catheters were developed to increase the size of ablation and to address eccentric coronary lesions. By fluoroscopically guided rotation of this eccentric version the operator can target the lasing part of the catheter tip towards the target plaque burden ( Figure 4). Despite being bulky in comparison to other coronary catheters the versions of ELCA catheter which are available provide a contemporaneous pushability and trackability. Table 1 summarises the data relating to ELCA catheters which are available for coronary application.

Further developments have included improvements in laser catheter design allowing a more homogenous distribution of light to reduce vessel wall trauma during ELCA [16]. This achievement has been made possible by thicker laser fibres, as well as the exclusion of dead space around multiple fibres in the ELCA catheter. As a result, energy density can be reduced by 70% without losing efficacy in tissue crossing or penetration.

EXCIMER LASER ANGIOPLASTY PROTOCOL

Once there is an indication to use ELCA, the laser unit should be set up and the warm-up time started. Following the initial set-up,, the laser catheter with the intended size needs to be calibrated. During this calibration process laser eye protection glasses must be worn by the patient and all personnel in the catheter laboratory. This is not necessary during laser activation within the patient´s body.

After a guide catheter with appropriate dimensions to accommodate the laser catheter size is positioned in the ostium of the target coronary artery, a 0.014 inch (or smaller) guidewire should be passed across the target lesion under fluoroscopic control in the conventional way. The laser catheter is then advanced over the wire to come into contact with the target lesion. Before laser activation, the guide catheter is flushed with at least 10 to 20 mls of saline to wash-out blood or contrast medium. The first passes should be performed with a fluence of 45 mJ/mm2 and a repetition rate of 25 Hz. If resistance occurs, fluence and repetition rates can be increased to a maximum fluence of 80 mJ/mm2 and a repetition rate of 80 Hz depending on the laser catheter used. The system automatically defines the maximum lasing period of 5 or 10 seconds followed by a 5 or 10 second regeneration period during which the system cannot be activated. During each lasing pass continuous saline infusion via the guide catheter at 1 to 2 ml per second is mandatory. When over-the-wire laser catheters are used, saline injection can be performed manually, or via an indeflator through the wire lumen if the guidewire size does not exceed 0.014 inch ( Figure 5). During laser activation the catheter is advanced gently, and slowly, at less than 0.5 to 1 mm per second, through the target lesion under fluoroscopic guidance. This slow advancement is necessary to allow for optimised tissue ablation, whilst if the catheter is advanced too fast there is almost a pure ‘’Dotter effect’’ (mechanical displacement of tissue). The operator should start and prematurely terminate the laser pass if necessary while allowing another person to activate fluoroscopy. Larger laser catheters, including the eccentric versions, can be used to increase the post-ablation lumen, while some push or pull on the guidewire with subsequent passes of the same catheter size can also result in a modest increase in lumen.
When ELCA is finished the intervention can be completed, typically by additional balloon angioplasties or stent implantation if indicated.

FOCUS BOX 2Essentials of the ELCA procedure
  • Obtain good guide catheter support
  • Choose guide catheter sizes according to the planned ELCA catheter size
  • Secure correct guidewire positioning in the vessel lumen
  • Allow a laser unit warm-up time of five minutes
  • Choose ELCA catheter diameter to vessel diameter ratio of 0.5 to 0.6
  • Flush guide catheter with at least 10 to 20 mls saline before laser activation
  • Start with low fluence of 45 mJ/mm2 at a repetition rate of 25 Hz and increase if necessary
  • During laser activation flush guide catheter with 1 to 2 ml per second
  • During laser activation advance ELCA catheter slowly (0.5 to 1 mm per second)

ADJUNCTIVE PHARMACOTHERAPY

Patients undergoing ELCA should be pre-treated with dual antiplatelet therapy as per ESC guidance, including aspirin (100 to 500 mg) and clopidogrel (300 or 600 mg loading dose, 75 mg maintenance dose), at least 6 hours (in elective patients) before the procedure. In primary PCI, including ELCA for the treatment of ST elevation or non-ST elevation myocardial infarction, ESC guideline recommended dual antiplatelet loading applies. Newer and more potent antiplatelet therapies, including glycoprotein IIb/IIIa inhibitors and prasugrel or ticagrelor, can be administered as indicated although no particular data are available for these drugs in the context of ELCA. At the time of the procedure, unfractionated heparin is administered to achieve a target activated clotting time (ACT) of 300 sec. A liberal use of intracoronary nitrate is recommended to avoid periprocedural coronary vasospasm. In general, there is no specific adjunctive pharmacotherapy required when ELCA is attempted. The essential role of a continuous saline flush during laser application has been emphasised before.

Clinical studies with ELCA

After several small observational studies documented the feasibility of ELCA in the treatment of stable coronary lesions with procedural success rates of about 90% [17], two randomised trials were conducted to compare ELCA with PTCA. In the multicentre AMRO study [18], 308 patients with stable angina were found to have no significant differences in angiographic success (79% versus 80%), however there was a 10-fold higher transient occlusion rate in the ELCA group (0.7% versus 7%) in periprocedural complications, and a trend towards higher restenosis rate in the ELCA group (41.3% versus 51.6%) at 6 months, but no difference in angiographic net lumen gain (0.40 mm versus 0.48 mm). Patients with tandem lesions, lesions in vessels < 2.5 mm, or lesion location in the left circumflex coronary artery appear to have significantly poorer outcomes with ELCA compared to PTCA [19, 20]. The ERBAC study [21] was originally a three arm trial comparing PTCA with ELCA and rotational atherectomy in 685 patients with stable angina. Procedural success rates were comparable, with 77% and 80% between the ELCA and PTCA groups as well as in-hospital complication rates of 4.3% and 3.1%. The periprocedural cross-over rate was almost three times higher with ELCA (5.0% versus 15.1%). At 6-month follow-up the target vessel revascularisation rate was significantly higher in the ELCA group compared to the PTCA group (46.0% versus 31.9%). The results of both studies must be interpreted bearing in mind that saline flushing at that time was not part of the lasing protocol.

In a large registry of 9,222 patients with different percutaneous coronary interventional techniques, including 500 patients with laser angioplasty and 4,104 patients with PTCA, a significantly higher likelihood of developing restenosis with an odds ratio of 1.55 was documented [22].

Since these results did not support the broad use of ELCA and in parallel, coronary stents showed better angiographic, acute, and long-term clinical results compared to PTCA, the application of ELCA was limited to certain subgroups of lesions despite technological and procedural improvement of this technology.

Lesion subsets

THE UNDILATABLE LESION

In some lesions resistance is so high that an adequately sized balloon is not able to expand completely despite high pressures of up to 20 atm or more ( Figure 6). These so-called undilatable lesions are a target for ELCA [23, 24]. It is not only the ablative aspect of ELCA but also the creation of fast-expanding and imploding vapour bubbles, despite saline flush, that create microfissures to the obstructive plaque which allow complete balloon inflation during post-dilatation. Without such forms of technology, PCI of undilatable lesions would not be possible. Thus ELCA competes for this indication with rotational atherectomy or cutting-balloon catheters.

CHRONIC TOTAL CORONARY OCCLUSIONS

Even after successful wire passage across a chronic total coronary occlusion (CTO), PCI is sometimes limited similarly by the inability to pass with a balloon catheter . In this particular setting ELCA is a valuable option since, in contrast to rotational atherectomy, it can be advanced along standard guidewires ( Figure 7 parts 1 and 2). The laser can create a channel through the CTO which allows a balloon catheter to pass afterwards in order to facilitate final vessel reconstruction by stent implantation [24, 25]. Meticulous attention should be paid to a correct distal intraluminal wire position before ELCA is performed in order to avoid perforations.

A subgroup analysis of the randomised AMRO trial in patients with functional or total coronary occlusions >10 mm evaluated the safety and efficacy of ELCA plus PTCA versus PTCA alone [26]. Angiographic success rates were similar in both groups at 65% and 61%. Net lumen gain at six months was also not significantly different (0.81±0.74 mm versus 1.04±0.68 mm), whilst there was at least a trend towards a lower restenosis rate in the PTCA group alone (48.5% versus 66.7%; p=0.15).

A special 0.018 inch laser wire was introduced to address those CTOs which cannot be passed with standard or dedicated crossing wires [27, 28]. This wire was quite rigid and wire exits during the crossing attempt were not infrequent.

In the Total Occlusion Trial with Angioplasty by using Laser guidewire (TOTAL), 303 patients with CTOs were randomly assigned to the laser guidewire or conventional guidewires [29]. Treatment success as the primary endpoint, defined as successful crossing within 30 minutes of fluoroscopic time, was not different between both arms (52.8% in the laser wire group versus 47.2% with conventional wires). Angiographic and clinical results up to 12 months were not different with 79% of patients receiving a stent. This device is no longer available and has been replaced by dedicated mechanical crossing wires and techniques [30].

Despite a lack of data supporting the broad use of ELCA for this indication, it can still be a valuable option for patients in whom conventional techniques failed to recanalise a CTO [31].

IN-STENT RESTENOSIS

The development of in-stent restenosis after the implantation of bare metal stents occurs in 10% to 20% of treated lesions. Long stented segments especially have a higher likelihood of developing in-stent restenosis. ELCA has been tested in this setting as a treatment option to debulk first before adjunctive PTCA in contrast to PTCA alone [32, 33, 34, 35, 36, 37]. Figure 8 illustrates an example. Intravascular ultrasound-based data documented effective ablation of neointimal tissue [32]. Nevertheless, acute procedural as well as long-term angiographic and clinical results for ELCA plus PTCA were not superior to the PTCA alone strategy.
In a meta-analysis of 3,012 patients with in-stent restenosis, 474 patients receiving ELCA as the treatment presented the highest probability, 34.8%, to develop major cardiac events (death, myocardial infarction or revascularisation) at follow-up [38].
Today, ELCA is rarely used even in diffuse in-stent restenosis with a large neointimal burden. Drug-eluting stents, or more recently, drug-eluting balloons have shown superior angiographic and clinical results for the treatment of this condition compared to PTCA alone ( View chapter and View chapter ).
This is underlined in the most recent guidelines on myocardial revascularisation of the European Society of Cardiology, where ELCA is cited explicitly as not being useful for the treatment of in-stent restenosis [39].

THROMBUS-CONTAINING LESION

Experimental work has shown that ultraviolet excimer laser fluence at a 308 nm wavelength decreases platelet aggregation and reduces platelet force development capability [40, 41]. In addition to its ablative properties, ELCA has been used to address thrombus-containing lesions primarily in patients with acute coronary syndromes [42, 43, 44, 45, 46, 47]. In the CARMEL trial, ELCA showed a significant mean increase in TIMI flow from 1.2 at baseline to 2.8. The same finding was observed in the subgroup of patients with very large thrombus burden [44]. Nevertheless, laser-induced major dissections occurred in 3% despite saline flushing, whilst laser-induced distal embolisation or no reflow were rare at 0.6% and 0.6% respectively. In a small randomised trial of 27 patients with ST segment elevation, myocardial infarction ELCA as an adjunct to PTCA plus stenting did not impact post-procedural TIMI flow or surrogate parameters of microvascular perfusion such as myocardial blush score or final corrected TIMI frame count [45].

SAPHENOUS VEIN GRAFT LESIONS

In an observational study ELCA alone (17%) or as an adjunct to PTCA (83%) was tested in the treatment of 106 patients with 125 saphenous vein graft bypass (SVG) lesions [48]. Despite angiographic improvement in lesion dimensions, periprocedural dissections occurred in 45% of lesions after ELCA treatment, including graft occlusion in 7%. The angiographic success rate was 54% after ELCA which increased to 91% after adjunct PTCA. In-hospital rates of death, myocardial infarction or bypass surgery were 0.9%, 4.5% and 0.9% respectively. At follow-up, the restenosis rate was 52%, including graft occlusions in 24%. Event-free survival was 48.2% at 1 year with a mortality rate of 8.6%.
Similar angiographic results were documented in a matched control study of ELCA plus PTCA versus PTCA alone in SVG lesions with no difference in acute recoil or acute lumen gain [49]. Even in the subgroup of patients with aorto-ostial SVG lesions, ELCA plus PTCA did not show superior angiographic or clinical results over PTCA alone [50].

Consequently, it may be argued that supportive angiographic or clinical data is lacking for a broad use of ELCA in the setting of SVG lesions.

Currently, distal or proximal protection devices have gained broad acceptance as a means of avoiding embolisation in this lesion subset. The potential of ELCA in this context has never been tested against these protection devices.

FOCUS BOX 3Potential indications for ELCA
  • The undilatable lesion
  • CTO with successful wire crossing
  • (diffuse) in-stent stenosis
  • Thrombus-containing lesions
  • Saphenous vein graft lesions

Complications with ELCA

Specific ELCA-related complications in the pre-saline flush era included dissections in up to 24% and perforations in about 4% of cases resulting in periprocedural or postprocedural myocardial infarctions in up to 5 % with a mortality rate of up to 1% [51, 52, 53, 54, 55]. The likelihood of developing periprocedural perforations was up to ten times higher with ELCA compared to other PCI techniques [52]. In a large registry these complications could be limited with increasing experience.

At follow-up, major cardiac events occurred in up to 18% with a mortality rate of 1.4%, myocardial infarctions in 1.5% and repeat interventions in 15% [53, 54].

With the introduction of saline flushing during laser application and slow catheter advancement without excessive push, these complications can now be limited.

Proper guidewire placement in the vessel lumen can avoid ELCA complications, especially when CTOs are addressed.
Eccentric laser catheters should be used with caution in angulated vessel segments with a severely eccentric plaque burden since this device can cause perforation of the less diseased vessel wall in this particular setting.

Future developments

Since the introduction of the eccentric ELCA catheter no other developments have emerged over the past years to improve the efficacy and safety of this technology in coronary applications. Furthermore because the potential coronary indications as outlined above are rare in practice, it is unlikely that ELCA technology will be pushed forward.

With the existing technology, well designed prospective randomised trials could be designed to elaborate the role of ELCA as a debulking technique before optimal stent placement or in CTOs. Additionally, the potential thrombus dissolution properties of ELCA need support from scientific data derived from randomised trials with either surrogate parameters of myocardial perfusion, salvage or clinical endpoints in acute coronary syndrome patients.

Personal perspective - Michel Haude

With the current technology and the available data on its safety and efficacy ELCA will remain a tool for niche indications in the coronary field. In our opinion, three situations stand out. The undilatable coronary lesion (following successful wire passage) is a very good indication to use ELCA and in terms of efficacy competes with rotational atherectomy. Diffuse in-stent restenosis due to excessive neointimal proliferation (which has become a less frequent event in the era of DES) could be another good indication for ELCA to debulk first before applying drug-eluting balloon technology or another DES. Finally, CTOs (again following successful wire passage) are a target for ELCA to enable balloon positioning and stent implantation.
Outside of the coronary circulation in peripheral artery disease, especially below the knee with diffusely diseased long vessel segments, ELCA has potential to gain broader acceptance.
Above all experience, and proctorship during the initial learning curve, is paramount to ensure safe and efficacious use of this interesting technology.

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