Background. Coronary intravascular lithotripsy (IVL) is an emerging therapy for the modification of coronary artery calcification (CAC). Data on its use in several clinical and lesion subsets are limited due to their exclusion from preapproval trials. Methods. We performed a retrospective review of patients who were excluded from preapproval trials of coronary IVL and underwent CAC modification with the off-label use of a peripheral IVL system. The primary outcome was a composite of procedural success, defined as residual stenosis <10%, and no major adverse cardiac event (MACE), ie, cardiac death, myocardial infarction, or target-vessel revascularization, in hospital and at 30 days. Results. Between June 2019 and April 2020, a total of 9 patients who underwent off-label coronary IVL were identified. Exclusion criteria from preapproval trials included a target lesion within an unprotected left main coronary artery (ULMCA; n = 3) and/or ostial location (n = 5), a target lesion involving in-stent restenosis (n = 3), a second target-vessel lesion with >50% stenosis (n = 1), and/or New York Heart Association class III/IV heart failure (n = 5). The primary outcome was achieved in 8 patients. MACE rate was 0% in hospital and at 30 days. For ULMCA lesions (n = 3), residual stenosis was 0% in 2 patients and 10% in 1 patient. For right coronary artery lesions (n = 3), residual stenosis was 0% in 2 patients and 40% in 1 patient. For left anterior descending coronary artery lesions (n = 3), residual stenosis was 0% in all patients. Conclusion. Coronary IVL with a peripheral IVL system may be an effective therapy for CAC modification within ULMCA disease, ostial disease, in-stent restenosis, and New York Heart Association class III/IV heart failure.
J INVASIVE CARDIOL 2021;33(4):E245-E251. Epub 2021 March 10.
Key words: intravascular lithotripsy, unprotected left main coronary artery
The degree of drug-eluting stent (DES) expansion in percutaneous coronary intervention (PCI) is a major determinant of procedural outcome.1,2 Given that coronary artery calcification (CAC) within a site of DES implantation may adversely affect stent expansion and subsequent function,3-6 multiple therapies for CAC modification have been developed. Current United States Food and Drug Administration (FDA)-approved therapies include balloon angioplasty, scoring and cutting balloons, and atherectomy in the orbital, rotational, and laser forms. However, these therapies are not without limitation. Balloon angioplasty may lack the ability to safely produce the radial pressure required to alter culprit-lesion anatomy,7 and atherectomy may be associated with a higher complication rate.8-11 The latter may be due to direct thermal or mechanical injury to the arterial wall12 and/or guidewire bias causing eccentric CAC modification.13-15
Coronary intravascular lithotripsy (IVL) is a novel emerging therapy for CAC modification prior to DES implantation in PCI.16-19 In coronary IVL, an integrated balloon-catheter (Shockwave Medical) delivers a series of circumferential sonic pressure waves that microfracture intimal and medial arterial wall calcifications within a region of CAC. These microfractures have been proposed to increase compliance of the target vessel, thereby easing DES delivery, enhancing DES apposition, and improving DES expansion.16,18 Given the relatively low pressure required of the coronary IVL balloon at the time of therapy and its uniform distribution of energy in the acoustic form, coronary IVL may overcome many of the inherent limitations of its balloon-only and atherectomy-based counterparts.
Two studies have recently demonstrated the safety and efficacy of coronary IVL as an adjunctive therapy in PCI. The Disrupt Coronary Artery Disease (CAD) I study was a single-arm pilot study that evaluated coronary IVL in a cohort of 60 patients with CAC requiring revascularization.16 It showed an acute luminal diameter gain of 1.7 mm when utilizing a stepwise approach of coronary IVL followed by DES implantation, with a clinical success rate (defined as the ability of coronary IVL to produce a residual stenosis of <50% after stenting with no evidence of in-hospital major adverse cardiac event [MACE]) of 95%. A larger single-arm postapproval study (Disrupt CAD II) affirmed these findings in a comparable cohort of 120 patients, showing an acute luminal diameter gain of 1.67 mm with a clinical success rate of 94%.18 A third prospective study (Disrupt CAD III) to further evaluate the safety and efficacy of coronary IVL in calcified de novo native coronary stenoses recently completed enrollment.
In the United States, an analogous IVL system for the treatment of peripheral arterial disease (Shockwave Medical) gained FDA approval in 2016. Herein, we report our single-center experience with the off-label use of this peripheral IVL system as an adjunctive therapy during coronary revascularization, with a focus on its use in cohorts historically excluded from preapproval trials of coronary IVL.
We conducted this study at Northwestern Memorial Hospital (NMH), a large, urban, academic medical center located in Chicago, Illinois. Electronic health record and cardiac catheterization data were retrospectively collected and analyzed for all patients who were admitted to NMH, excluded from available preapproval trials of coronary IVL, and who subsequently underwent PCI with the off-label use of a peripheral IVL system. Prior to PCI, all patients and/or a designated legally authorized representative underwent a thorough informed consent process for the potential off-label use of a peripheral IVL system for coronary IVL. Patients who were potential candidates for surgical revascularization additionally underwent a formal surgical assessment, and the decision to pursue PCI was based on a patient-centered heart team evaluation. Individual procedural decisions, such as the use of intravascular imaging, were left to operator discretion. Northwestern University’s institutional review board granted a waiver of patients’ informed consent for data collection.
The primary outcome was a composite of procedural success, defined as a residual stenosis of <10% following PCI, and no MACE (defined as cardiac death, myocardial infarction, or target-vessel revascularization) in hospital and at 30 days. Principal secondary outcomes of interest included minimal luminal cross-sectional area (MLA) gain by intravascular ultrasound (IVUS) and angiographic complications, including coronary artery dissection, aortocoronary cusp dissection, coronary artery perforation, abrupt stent closure, slow or no stent flow, cerebrovascular accident, or blood loss requiring transfusion.
Baseline patient and lesion characteristics. Between June 2019 and April 2020, a total of 9 patients underwent coronary IVL with a peripheral IVL system. Baseline patient characteristics are provided in Table 1. Method of presentation was stable ischemic heart disease in 2 patients, unstable angina in 3 patients, and non-ST segment myocardial infarction in 4 patients. The mean SYNTAX score was 25.2 ± 9.5%.20 Exclusion criteria from preapproval trials included a target lesion within an unprotected left main coronary artery (ULMCA; n = 3) and/or ostial location (n = 5), a target lesion involving in-stent restenosis (ISR; n = 3), a second lesion with >50% stenosis in the same target vessel (n = 1), and/or New York Heart Association (NYHA) class III or IV heart failure (n = 5). Indications for revascularization included de novo native coronary artery disease in 6 patients and ISR in 3 patients. Mechanisms of ISR included restenosis due to stent underexpansion (patients #5 and #6) and de novo ISR (patient #7). The target lesion in patient #5 had previously undergone laser atherectomy, and the target lesion in patient #6 had previously undergone balloon angioplasty, scoring balloon atherectomy, and laser atherectomy.
Baseline lesion characteristics and major procedural outcomes by patient are provided in Table 2. Target vessels included ULMCA (n = 3), right coronary artery (RCA; n = 3), and left anterior descending coronary artery (LAD; n = 3). The majority of cases (n = 5) involved ostial locations. IVUS was performed in 6 cases (67%) prior to any intervention and in 8 cases (89%) post PCI. For ULMCA lesions (n = 3), the initial percent diameter stenosis was 83.3 ± 5.8%, with a mean MLA by IVUS of 3.8 ± 0.8 mm2. For RCA lesions (n = 3), the initial percent diameter stenosis was 88.3 ± 7.6%, with a mean MLA by IVUS (n = 2) of 3.2 ± 0.3 mm2. For LAD lesions (n = 3), the initial percent diameter stenosis was 75.0 ± 5.0%.
Procedural characteristics. General procedural characteristics are provided in Table 3. Primary access was at the operator’s discretion and was common femoral artery (CFA) in 7 cases (78%), which allowed for the use of a 7 or 8 Fr guide catheter. Contralateral CFA access with a 4 Fr sheath was also pre-emptively obtained in 2 patients as a placeholder for provisional mechanical circulatory support (MCS) given concomitant low left ventricular ejection fraction (patient #4) or a target lesion subtending a large region of myocardium (patient #1). A strategy of planned MCS-supported PCI was utilized in 2 ULMCA cases (patients #2 and #3) in order to maintain hemodynamic stability during anticipated prolonged IVL balloon inflation times. In these cases, Impella CP (Abiomed) was utilized, and guide-catheter access was obtained via micropuncture of the diaphragm of the Impella CP 14 Fr peelaway sheath, which allowed for use of a single arterial access point. If the target lesion was located within the RCA, a temporary pacemaker was also placed given the potential for malignant bradyarrhythmia secondary to distal CAC plaque embolization.
When preparing to deliver IVL therapy to ostial lesions, only the distal third of the peripheral IVL balloon was positioned within the diseased segment vessel and the guide catheter was subsequently retracted. Since available peripheral IVL balloon catheters are longer than the dedicated investigational coronary IVL device and have 4 emitters that can be activated sequentially, only the distal emitters were activated when there was a need to concentrate therapy on a focal region. The total number of IVL pulses delivered was at the operator’s discretion.
Procedural outcomes. Procedural outcomes by lesion location are provided in Table 3, and detailed case studies are provided in Figures 1 and 2. Peripheral IVL balloon-catheter delivery across the target lesion was successful in all cases. DES implantation and/or expansion of the pre-existing stent was also successful in all cases. A percent residual stenosis of <10% was achieved in 8 cases (89%). For ULMCA lesions (n = 3), the percent residual stenosis was 0% in 2 patients and 10% in 1 patient, with a mean MLA gain by IVUS of 7.2 ± 6.1 mm2. For RCA lesions (n = 3), the percent residual stenosis was 0% in 2 patients and 40% in 1 patient, with a mean MLA gain by IVUS (n = 2) of 7.3 ± 5.2 mm2. For LAD lesions (n = 3), the percent residual stenosis was 0% in all patients.
Two patients had intraprocedural complications. Patient #6 (ostial RCA target lesion) developed transient Mobitz type II second-degree atrioventricular block and a hemodynamically insignificant Dunning class I aortocoronary cusp dissection.21 This arrhythmia was self limited, and the aortocoronary cusp dissection required no further intervention. Patient #7 (proximal to middle segment RCA target lesion) developed transient apnea and hypotension associated with the insertion of the peripheral IVL balloon catheter into the RCA, although this did not impede PCI completion and rapidly resolved with the removal of intracoronary equipment. There were no coronary artery perforations, luminal dissections, abrupt closures, slow-flow, or no-reflow phenomena. Emergent use of MCS was not required in any patients, and no patients experienced cerebrovascular accident or acute blood loss requiring transfusion. The MACE rate both in hospital and at 30 days was 0%.
To our knowledge, this is the first series to report the successful off-label use of an FDA-approved peripheral IVL system for CAC modification in PCI. In addition, coronary IVL with a peripheral IVL system was effective in several patient and lesion subsets that are not currently represented in the published or ongoing trials of coronary IVL. IVL therapy in this study allowed for successful DES implantation and/or expansion of a pre-existing stent in all cases, with minimal postprocedural residual stenoses and robust MLA gains by IVUS. Furthermore, coronary IVL with a peripheral IVL system was safe. All procedural complications were transient and self limited, and there were no incidences of MACE in hospital or by 30 days.
Treatment of heavily calcified coronary lesions continues to be a major challenge in PCI. Rotational and orbital atherectomy have several limitations, including their deliverability and associated complications, particularly in tortuous or angulated lesions. In addition, while these devices are beneficial for treating luminal and/or superficial calcium, they lack the ability to modify deeper arterial wall calcification. In theory, the circumferential sonic pressure waves produced by IVL can propagate through the arterial wall and microfracture intimal and medial calcification, thereby increasing vessel compliance and allowing for optimal stent expansion. While more data are needed, we speculate that this is the mechanism by which we achieved procedural success in the presented cases.
The Disrupt CAD III study is an ongoing prospective, multicenter, single-arm, global investigational device exemption study to further evaluate the safety and effectiveness of coronary IVL for CAC modification in PCI.22 With an enrollment of 392 participants, it will be the largest study to date evaluating the use of coronary IVL in patients undergoing coronary revascularization. However, analogous to those studies preceding it, the Disrupt CAD III study excludes target lesions that involve ISR, ostial, and/or ULMCA locations, and/or NYHA class III or IV heart failure; these are particularly challenging clinical and lesion subsets.
In ISR, there are limited options available for the treatment of restenosis due to stent underexpansion following failure of high-pressure dilation with a non-compliant balloon. Although laser angioplasty with contrast infusion has been used to create acoustically mediated calcium microfracture analogous to IVL in this setting, this strategy is not widely available and has been associated with an increased rate of serious angiographic complications.23 In calcific aorto-ostial lesions, maintaining coaxial orientation during conventional atherectomy device engagement is technically challenging, and non-coaxial alignment increases the risk of aortocoronary injury. Likewise, in patients with heart failure and/or a target vessel subtending a large region of myocardium, PCI portends a high risk for hemodynamic instability. Slow-flow or no-reflow phenomena in these subsets, which are most commonly associated with the use of rotational and orbital atherectomy, can be particularly catastrophic. Conversely, coronary IVL may be associated with prolonged balloon inflation times during therapy, thereby also increasing the risk of hemodynamic instability. This risk may be mitigated through the supportive use of MCS as part of a planned strategy, as demonstrated in 2 of the presented ULMCA cases. Following intervention, all patients had Thrombolysis in Myocardial Infarction 3 flow.
Study limitations. This case series has certain limitations, including its size, retrospective nature, and lack of a comparator group. Other specific limitations include operator discretion in determining which patients would be most likely to benefit from coronary IVL and variation in the use of intravascular imaging.
We report the safe and effective use of a peripheral IVL system as an adjunctive therapy for CAC modification, with a particular emphasis on its utility within the contexts of ULMCA disease, ostial disease, ISR, and NYHA class III/IV heart failure. Larger studies of coronary IVL within these unique clinical contexts are needed, particularly if its use becomes widespread following the publication and international response to the Disrupt CAD III study.
Acknowledgments. We thank the patients of Northwestern Memorial Hospital who participated in this retrospective study and their families and caregivers.
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From the 1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and 2Department of Medicine, Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
The authors report that patient consent was provided for publication of the images used herein.
Manuscript accepted July 24, 2020.
Address for correspondence: Daniel R. Schimmel, MD, MS, Bluhm Cardiovascular Institute, Northwestern Medicine, Galter Pavilion, 675 N St Clair St, Ste 19-100, Chicago, IL 60611. Email: email@example.com