Intravascular Lithotripsy for the Treatment of Calcium-Mediated Coronary In-Stent Restenoses

Abstract

Background. Coronary intravascular lithotripsy (IVL) has recently been evaluated for the treatment of severely calcified native coronary lesions. Evidence for its use in in-stent restenosis is sparse and is still an off-label indication. Therefore, we aimed to evaluate the feasibility, safety, and acute and mid-term angiographic outcomes after IVL for the treatment of calcium-mediated coronary in-stent restenosis. Methods. A retrospective, single-center analysis was performed for 6 cases with undilatable in-stent restenosis due to calcium-mediated stent underexpansion and/ or calcified neointima from January to November 2019. Lesions were treated with IVL (Shockwave Medical) and subsequent drug-eluting stent or drug-coated balloon. Angiographic success was defined as residual lumen stenosis <20% and Thrombolysis in Myocardial Infarction 3 flow. Follow-up angiography was performed at a median of 141.5 days. Results. Six patients presented with symptomatic in-stent restenoses (65.8% to 87.9%) at 11 to 175 months after implantation. Intravascular and angiographic imaging detected calcium-mediated stent underexpansion (n = 2), calcified neointima (n = 2), or a combination of both (n = 2) as cause of restenosis. In-stent IVL, subsequent high-pressure balloon dilation, and drug-eluting stent or drug-coated balloon implantation were performed successfully in all cases. Acute angiographic success and angina relief were achieved in 5 of 6 cases and sustained during follow-up. No major acute cardiovascular events occurred. Conclusions. The application of IVL for the treatment of calcium-mediated coronary in-stent restenosis was feasible and safe, and yielded promising short- and mid-term results in the majority of cases.

J INVASIVE CARDIOL 2021;33(1):E25-E31.

Key words: angina, calcified lesions, drug-eluting stent

In patients undergoing percutaneous coronary intervention (PCI), heavily calcified coronary lesions are associated with elevated rates of myocardial infarction and death.¹ Furthermore, severe coronary calcium plaques complicate sufficient lesion preparation, stent delivery, and optimal stent expansion during PCI.^2,3 High-pressure angioplasty with non-compliant balloons, the application of cutting or scoring balloons, and rotational or orbital atherectomy may facilitate lesion preparation.^2,4 Nevertheless, certain anatomic considerations (eg, severe vessel tortuosity), particular calcium-distribution patterns, and previously implanted stents at the target site may yield patients less suitable for these approaches. Intravascular lithotripsy (IVL) has recently been evaluated for the treatment of severe coronary artery calcifications to induce calcium fracture, leading to an improved stent delivery and apposition.^5,6 The Disrupt Coronary Artery Disease I and II studies demonstrated high procedural success rates and low complication rates for this novel technology in native coronary lesions.^5,6 Evidence for the application of IVL to treat in-stent stenoses remains sparse and angiographic follow-up to demonstrate sustainable results is particularly limited.^7-11 We aimed to evaluate acute and mid-term angiographic results of IVL for the treatment of calcium-mediated undilatable in-stent restenosis in a series of 6 patients.

Methods

Patient population and follow-up. Six consecutive patients were admitted to our university hospital for the treatment of calcium-mediated in-stent restenoses from January to November 2019. Previous attempts to sufficiently expand the target lesion using non-compliant and super-high-pressure balloons had failed. Lesion type was defined as in-stent stenosis caused by calcium-mediated stent underexpansion, calcified neointima in patients with adequately expanded stents, or a combination of both. Indication for PCI and periprocedural care, including antithrombotic regimens, were based on current guidelines.¹² Follow-up angiography was performed for the treatment of remaining coronary stenosis or as part of clinical routine after complex coronary interventions with a high risk for restenosis.

Percutaneous coronary IVL procedure. Initial lesion preparation with non-compliant (NC Quantum Apex; Boston Scientific) or super-high-pressure balloons (OPN NC; SIS Medical) was again performed, but did not yield sufficient inflation at the lesion site due to heavily calcified coronary in-stent restenosis. Subsequently, an advanced lesion preparation was required. For this purpose, the commercially available IVL system (Shockwave Medical) was applied. This system consists of a portable IVL generator and a connector cable to activate lithotripsy pulsing. The IVL balloon catheter is delivered through a 6 Fr guide catheter using a standard 0.014˝ guidewire (monorail technique). The IVL balloons are 12 mm long, with diameters ranging from 2.5 to 4.0 mm. Oversizing of up to 10% compared with the reference segment is recommended to achieve efficient energy transfer through optimized wall apposition. The IVL balloons contain multiple lithotripsy emitters, creating a circumferential field effect on the calcified lesion by sonic pressure waves.⁵ A total of 80 pulses can be emitted by 1 IVL balloon catheter, with a maximum of 10 continuous pulses (1 pulse per second) per cycle (8 cycles with 10 pulses each and a minimum pause of 10 seconds between cycles). Following the instructions of use, the balloon was inflated subnominally at 4 atm for emission of lithotripsy waves followed by inflation to a nominal pressure of 6 atm (rated burst pressure at 10 atm) for lithoplasty. After IVL, postdilation was performed again using high-pressure or super-high-pressure non-compliant balloons to achieve optimal calcium modification. This was followed by drug-coated balloon (DCB) treatment or drug-eluting stent (DES) implantation.

Data management and quantitative coronary angiography. Baseline, procedural, and follow-up data were retrospectively assessed and analyzed. Offline quantitative coronary angiography was performed from digitally recorded coronary angiograms. Measurements were performed in the same single-worst-view projection and calibrated against the contrast-filled guiding catheter tip. According to the literature, angiographic success was defined as residual diameter stenosis <20% of the target lesion and Thrombolysis in Myocardial Infarction (TIMI) 3 flow.¹⁰

Ethics. All patients were fully informed about the off-label use of IVL for this indication and provided signed written consent forms.

Results

Baseline characteristics. Patient baseline characteristics are provided in Table 1. All patients were symptomatic with stable or unstable angina, and had previously undergone unsuccessful PCI for the treatment of calcium-mediated in-stent restenoses. Target-lesion characteristics are shown in Table 2. Briefly, target lesions were located in the left anterior descending (LAD) coronary artery in 2 cases and in the right coronary artery (RCA) in 4 cases (Table 2; Figures 1 and 2). The initial PCI had been performed 11 to 175 months before, now demonstrating in-stent restenosis from 65.8% to 87.9% with minimum lumen diameters of 0.4 to 1.1 mm (Table 2).

Procedural information and acute outcomes. Procedural details and outcomes are provided in Table 3. Median fluoroscopy time and applied contrast volume were 24.3 minutes and 150.0 mL. Three of the 6 procedures were guided by intravascular imaging (optical coherence tomography [OCT] or intravascular ultrasound), while 3 were guided by angiography and high-resolution fluoroscopy alone (Table 3). In-stent restenosis due to calcified neointima in sufficiently expanded stents was found in 2 patients. Calcium-mediated stent underexpansion without significant neointima was found in another 2 patients. The remaining 2 patients featured a combination of calcified neointima and calcium-mediated stent underexpansion as cause of in-stent restenosis (Table 2). Figure 1 and Figure 2 illustrate angiographic and intravascular images in these cases. Before IVL therapy, extensive lesion preparation was performed with non-compliant, cutting, or scoring balloons based on the interventionist’s decision, however, with incomplete expansion of the target lesion in all cases. In only 1 patient (case 3), delivery of non-compliant balloon was not feasible and lesion preparation of the mid-RCA required the support of a coronary microguide catheter to achieve a stepwise predilation with 1.1 x 10 mm and 2.0 x 12 mm compliant balloons (Table 3 and Figure 2). After predilation, the IVL catheter was delivered successfully in all cases. In all procedures, the maximum of 80 pulses were emitted at the calcified lesion (Table 3). Therefore, the IVL balloon was inflated at 4 atm emitting 10 pulses (1 pulse per second) followed by inflation to 6 atm for 5 to 10 seconds and final deflation of the balloon. If necessary, the balloon was repositioned along the lesion site followed by another IVL cycle, as described above (8 cycles in total). Subsequent postdilation was performed with non-compliant or super-high-pressure balloons up to 40 atm for optimal calcium fractioning and lesion modification in all cases (Table 3, Figures 1 and 2). Finally, delivery and implantation of drug-eluting stent or drug-coated balloon yielded an acute gain of >2 mm at the target lesion in 5 of 6 patients (Table 3). Angiographic success was achieved in 5 patients (Table 3). Confirming an optimal apposition and deployment of the implanted stent by OCT, 1 patient (case 1) (Figure 1) was left with 27.5% residual stenosis despite extensive postdilation due to an eccentric plaque (Table 3). Intraprocedural complications, eg, dissections, perforations, or slow-flow/no-reflow phenomena, did not occur in any of the procedures. The hospital course was uneventful, without any major acute cardiovascular events or need for urgent target-lesion revascularization.

Follow-up outcomes. Follow-up coronary angiography was performed at a median of 141.5 days in all patients (Table 3). All 6 patients reported angina relief after IVL therapy. Excellent angiographic results without any relevant restenosis or need for reintervention were documented in 4 patients. Two patients underwent elective target-lesion revascularization during follow-up angiography. The first patient (case 1) initially had angiographic failure and was found with a progression to 59.5% in-stent restenosis at the target lesion after 202 days of follow-up, yielding additional PCI with a non-compliant high-pressure balloon and DCB with finally good result (Table 3). In the second patient (case 3), non-significant progression of target-lesion in-stent restenosis from 12.3% to 17.1% was observed after 148 days of follow-up. Because OCT demonstrated incomplete stent apposition at the target lesion, high-pressure non-compliant balloon postdilation was performed with subsequent good stent apposition and a residual diameter stenosis of 13.5% (Table 3). Both patients were asymptomatic with regard to chest pain or dyspnea on exertion.

Discussion

In this case series, we describe the successful use of coronary IVL for the treatment of calcium-mediated in-stent restenosis. The main findings are:

(1) IVL was intuitive, safe, and feasible in all cases, yielding acute angiographic success in 5 of 6 patients with previously unsuccessful PCI and without any complications.

(2) Lesion types were calcified neointima, calcium-mediated stent underexpansion, or a combination of both.

(3) In patients with acute angiographic success, sustainable angiographic results were observed without any relevant restenosis during a median follow-up of 141.5 days.

(4) In 1 patient without acute angiographic success, a significant and progressing in-stent restenosis was observed during follow-up, underlining the importance of excellent acute results to avoid later complications.

(5) Target-lesion revascularization (postdilation) was required for incomplete stent apposition during follow-up in 1 case without intravascular imaging at the index procedure, emphasizing the importance of intravascular imaging to guide PCI in these complex cases.

Stent underexpansion is an important risk factor for the development of in-stent restenosis or acute thrombosis and is often caused by severely calcified coronary lesions.¹³ Hence, optimal lesion preparation remains key to avoid this scenario and several techniques to modify or debulk calcium plaques before stent implantation are available to the interventional cardiologist.¹⁴

Despite these options, in-stent restenosis resulting from calcium-mediated undilatable stent underexpansion or calcified neointima remains a clinically relevant problem with few treatment options; cutting or scoring balloons facilitate successful PCI in only select cases.^13,15 Super-high-pressure balloon dilation poses a risk for vessel perforation, particularly in eccentric calcium lesions. In-stent rotablation (“stentablation”) may achieve good acute outcomes, but carries a significant risk for burr entrapment and should hence be considered with caution.^16,17 In addition, high rates of target-lesion revascularization have been described.^13,18 Orbital atherectomy and excimer-laser atherectomy constitute additional debulking tools that are limited to selected centers only.^18,19

Based on circumferential calcium modification and fracturing,²⁰ coronary IVL may be a valuable addition to the interventional toolbox to treat calcium-mediated in-stent restenosis. In addition, its short learning curve, intuitive use, and low complication rates have led to recent widespread use of the device.

IVL has only been systematically evaluated for calcified de novo stenosis.^5,6 An increasing number of cases suggest promising results also in the presence of calcium-mediated undilatable stent underexpansion.^7–11 The application of IVL for the treatment of calcified neointima has not yet been evaluated, but as illustrated in this report, in-stent restenoses often feature both entities.

This case series adds to the growing body of evidence supporting the safety and feasibility of IVL for the treatment of in-stent restenosis due to calcium-mediated stent underexpansion or calcified in-stent neointima. Intravascular imaging suggested fracture of calcium and disruption of calcified neointima as mechanisms of expansion; however, this warrants further investigation. Acute results were promising in patients with otherwise limited treatment options. More importantly, it demonstrated sustained angiographic improvement after several months in patients with acute angiographic success. This was in line with a case report that reported excellent OCT results at 4-month follow-up,¹¹ adding evidence that IVL treatment effects persisted after acute success. The root cause for an insufficient acute angiographic outcome in 1 case remains unclear, but eccentric calcium lesions have been particularly discussed as a potential limitation for IVL. In severely calcified lesions, it may be helpful to perform some lesion preparation before the IVL catheter is advanced to avoid damage of the fragile balloon. Furthermore, combining IVL with subsequent high-pressure or super-high-pressure non-compliant balloon postdilation, as performed in all cases in the present report, may be important to achieve optimal calcium modification.

Currently, IVL remains an off-label treatment for in-stent restenosis. Concerns have been raised that IVL may affect stent integrity and polymer coating, particularly in recently implanted devices, suggesting the avoidance of this technique in the early phase after stent implantation. Meanwhile, intravascular imaging and prolonged clinical follow-up should be employed to anticipate potential and delayed stent-related complications. It also remains unclear whether drug-eluting stent or drug-coated balloon should be used after IVL at the target-lesion site. Current guidelines likewise recommend drug-eluting stent or drug-coated balloon for the treatment of in-stent restenosis.¹² Intravascular imaging may be particularly valuable in these cases to evaluate stent integrity. In our series, drug-eluting stent or drug-coated balloon yielded good outcomes; however, long-term follow-up in larger samples will be required to confirm this finding.

Study limitations. The main limitation of this analysis relates to its small number of patients and the absence of sufficient intravascular imaging in 3 of 6 patients, making the detection of failure mode more difficult. Fortunately, patients with this particular complex indication remain scarce due to improved lesion preparation. Large-scale systematic prospective studies and long-term follow-up are now required to gain sufficient evidence for IVL in the treatment of calcium-mediated in-stent restenosis due to stent underexpansion and/or calcified neointima.

Conclusion

The application of IVL for the treatment of calcium-mediated coronary in-stent restenosis was feasible and safe, and yielded promising short- and mid-term results. Intravascular imaging appeared to be crucial for sustained procedural success in these complex lesions.

From the ¹University Heart & Vascular Center, Department of Cardiology, Hamburg, Germany; and ²German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.

Disclosure statement: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Blankenberg reports grant support and personal fees (lectures) for Abbott Diagnostics and Siemens; grant support and personal fees (lectures, advisory board) for Bayer and Thermo Fisher; grant support from Singulex; personal fees (lectures) from Abbott, Astra Zeneca, Amgen, Medtronic, Pfizer, Roche, and Siemens Diagnostics. Dr Clemmensen reports personal fees from Boehringer Ingelheim; personal fees and grant support from Acarix; grant support from Philips. Dr Schnabel reports personal fees (lecture) from BMS/Pfizer. Dr Seiffert reports travel support from Abbott Vascular, Biotronik, Edwards Lifesciences, Nicolai Medizintechnik, and OrbusNeich Medical; personal fees (lecture) from Abiomed, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Medtronic, and Amgen; personal fees (consultant) from Shockwave Medical; study grant support and personal fees (lecture) from Philips; personal fees (lecture and travel support) from Boston Scientific. Dr Waldeyer reports lecture honoraria from Amgen, Novartis, Daiichi Sankyo, and Sanofi. Dr Westermann reports personal fees from AstraZeneca, Bayer, Novartis, Boehringer Ingelheim, and Berlin-Chemie. The remaining authors report no conflicts of interest regarding the content herein.

The authors report that patient consent was provided regarding use of the images herein.

Final version accepted June 16, 2020.

Address for correspondence: Fabian J. Brunner, MD, University Heart & Vascular Center, Department of Cardiology, Hamburg, Germany. Email: fa.brunner@uke.de

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