Intravascular Lithotripsy for Vessel Preparation in Severely Calcified Coronary Arteries Prior to Stent Placement　― Primary Outcomes From the Japanese Disrupt CAD IV Study ―

Abstract

Background: Intravascular lithotripsy (IVL) delivers acoustic pressure waves to modify calcium, enhance vessel compliance and optimize stent deployment. The objective of this study was to assess the safety and effectiveness of IVL treatment of de novo stenoses involving severely calcified coronary vessels in a Japanese population.

Methods and Results: Disrupt CAD IV (NCT04151628) was a prospective, multicenter study designed for Japanese regulatory approval of coronary IVL (SWM-1234). The primary safety endpoint was freedom from major adverse cardiac events (MACE) at 30 days. The primary effectiveness endpoint was procedural success (residual stenosis <50% by QCA without in-hospital MACE). Noninferiority analyses for the primary endpoints were performed by comparing the CAD IV cohort with a propensity-matched historical IVL control group. Patients (intent-to-treat, n=64) were enrolled from 8 centers in Japan. Severe calcification by core laboratory assessment was present in all lesions, with a calcified length of 49.8±15.5 mm and a calcium angle of 257.9±78.4° by optical coherence tomography. Primary endpoints were achieved with non-inferiority demonstrated for freedom from 30-day MACE (CAD IV: 93.8% vs. Control: 91.2%, P=0.008), and procedural success (CAD IV: 93.8% vs. Control: 91.6%, P=0.007). No perforations, abrupt closures, or slow/no-reflow events occurred at any time during the procedures.

Conclusions: Coronary IVL demonstrated high procedural success with low MACE rates in severely calcified lesions in a Japanese population.

Calcified coronary lesions are increasingly prevalent in patients with advancing age, diabetes mellitus, and chronic kidney disease.¹ Between 38% and 73% of coronary lesions display calcification on angiography and intravascular ultrasound, respectively.² Coronary artery calcification is associated with inferior clinical outcomes in the general population,³ as well as in patients undergoing percutaneous revascularization.⁴ Adjunctive therapies, such as atherectomy, are often used in an attempt to promote stent expansion in the presence of heavy calcium, yet suffer from limitations. Rotational and orbital atherectomy selectively ablate superficial calcium, which facilitates stent delivery, but both techniques have limited ability to modify the deep calcification that reduces vessel compliance and restricts vessel expansion during stent implantation.^5,6 Periprocedural complication rates, including perforation, slow flow, and periprocedural myocardial infarction (MI), are significantly higher with atherectomy than with balloon-based therapies.^7–11 Additionally, major adverse cardiac event (MACE) rates with atherectomy are suboptimal, ranging from 10.4% to 15.0% at 30 days and from 16.9% to 24.2% between 9 and 12 months.^7,12,13

Editorial p ????

Intravascular lithotripsy (IVL) is intended for vessel preparation in the presence of coronary artery calcification prior to stent delivery. Single-arm studies of IVL in coronary arteries, including Disrupt CAD I,¹⁴ Disrupt CAD II,¹⁵ and Disrupt CAD III,^16,17 report high procedural success rates with low risk of complications in patient populations from the USA and Europe. However, results of IVL for vessel preparation in the calcified coronary arteries of Asian patients are lacking. The purpose of the Disrupt CAD IV study was to evaluate the safety and effectiveness of the Shockwave C² Coronary IVL System (Shockwave Medical Inc., Santa Clara, CA, USA) in a Japanese population with similar eligibility criteria as for the Disrupt CAD III pivotal study.

Methods

Study Design

Disrupt CAD IV was a prospective, multicenter, single-arm study designed to assess the safety and effectiveness of IVL for the treatment of de novo, calcified, stenotic coronary arteries prior to stent placement. Disrupt CAD IV applied to the Pharmaceuticals and Medical Devices Agency (PMDA) to conduct the study in Japan. All participants provided written informed consent, and study procedures were in compliance with Good Clinical Practices (GCP), 21 CFR 50, 54, 56, 812, and 820, ISO 14155, the Declaration of Helsinki, and all applicable national requirements in Japan, as well as local Ethics Committee and Institutional Review Board requirements. The study was prospectively registered at ClinicalTrials.gov (NCT04151628). This paper reports the primary 30-day outcomes of the study; patients remain in follow-up for 2 years post-treatment.

Patients

Study eligibility criteria for the current study were similar to those in the Disrupt CAD III study.^16,17 Eligible patients were scheduled for percutaneous coronary intervention and presented with stable, unstable, or silent ischemia and severely calcified de novo coronary artery lesions. Target lesions were ≤40 mm length and the target vessel reference diameter ranged from 2.5 to 4.0 mm. Patients with New York Heart Association Class III or IV heart failure, renal failure, or recent MI, stroke, or transient ischemic attack were excluded. A listing of the study inclusion and exclusion criteria is provided in Supplementary Table 1.

Study Device and Procedures

Patients who met the eligibility criteria were enrolled in the study when the IVL catheter was inserted over a 0.014 guidewire that had previously crossed the target lesion. If the IVL catheter was unable to cross the lesion, adjunctive approaches (e.g., buddy wire, predilatation with a small diameter balloon [1.5–2.0 mm], or guide catheter extension) were used at the operator’s discretion before re-crossing the lesion. Atherectomy devices and cutting/scoring balloons were not permitted as prior lesion treatments per protocol. The study device was the Shockwave C² Coronary IVL System with a single-use Shockwave C² Coronary IVL Catheter, which contains multiple lithotripsy emitters enclosed within an integrated balloon. The lithotripsy emitters create acoustic pressure waves that produce a circumferential field effect to selectively fracture calcium and improve vessel compliance. The 12-mm fluid-filled balloon angioplasty IVL catheter, available in diameters ranging from 2.5 to 4.0 mm, is connected via a dedicated connector cable to the generator that is programmed to deliver 10 sequential pulses at 1 pulse/s for up to 80 pulses per catheter. The IVL balloon was sized 1 : 1 in relation to the reference vessel diameter, inflated to 4 atm, and 10 IVL pulses were delivered; the balloon was then inflated to 6 atm, and this process was repeated until complete balloon inflation was achieved. Subsequent stent placement was followed by high pressure (>16 atm) post-dilatation using a noncompliant balloon. Optical coherence tomography (OCT) imaging was performed before IVL, after IVL, and after stent deployment to characterize the extent of calcification and provide insights into the mechanism of IVL in facilitating stent expansion. Anticoagulation and antiplatelet regimens were administered according to established guidelines.^18,19

Outcomes

Study endpoint and MACE definitions were identical to those utilized in the Disrupt CAD III study.^16,17 The primary safety endpoint of the study was freedom from MACE within 30 days. MACE was defined as cardiac death, MI, or target vessel revascularization as adjudicated by an independent Clinical Events Committee. The primary effectiveness endpoint of the study was procedural success, defined as stent delivery with core laboratory-assessed residual stenosis <50% and freedom from in-hospital MACE. Secondary endpoints included: device crossing success (defined as delivery of the IVL catheter across the target lesion and delivery of lithotripsy without serious angiographic complications immediately after IVL), angiographic success (defined as stent delivery with <50% or ≤30% residual stenosis and without serious angiographic complications), procedural success (defined as stent delivery with residual stenosis ≤30% and freedom from in-hospital MACE), and the frequency of serious angiographic complications, target lesion failure, death (all-cause and cardiac), procedural and non-procedural MI (all-cause, target vessel, and target lesion), revascularization procedures, and stent thrombosis. Serious angiographic complications included type D-F dissection per the NHLBI classification system,²⁰ perforation per the Ellis classification for coronary perforation,²¹ abrupt closure, and persistent slow flow/no-reflow. Key outcomes derived from OCT imaging were lumen area, area stenosis, maximum calcium angle, maximum calcium thickness, stent area, stent expansion percentage, and the frequency of calcium fracture.

Data Quality

Study data were regularly reviewed for accuracy and completeness by an independent monitoring group (IQVIA Services Japan KK, Tokyo, Japan). Independent core laboratories analyzed the angiography and OCT images (Cardiovascular Research Foundation, New York, NY, USA). Data management (MedPace, Cincinnati, OH, USA) and data analysis (Cardiovascular Research Foundation) were performed by independent organizations. Adverse events were adjudicated by an independent Clinical Events Committee (Cardiovascular Research Foundation). An independent Data Safety Monitoring Board reviewed safety data on a regular basis and monitored the validity and scientific merit of the study.

Statistical Analysis

The primary safety and effectiveness endpoints of the study were compared with those of the patients in the Disrupt CAD III study¹⁶ (hereafter referred to as the IVL control group) who were enrolled under similar study eligibility criteria and treated with the same IVL study device. Disrupt CAD III treated 431 patients; a propensity score-matched subgroup of 384 patients served as the IVL control group for the current study. In order to account for possible imbalances in baseline patient characteristics, propensity-score matching using a greedy, nearest-neighbor matching algorithm in a 1 : 5 ratio was performed. The variables used for matching were selected a priori and included patient age, sex, history of diabetes mellitus, history of coronary artery bypass graft, estimated glomerular filtration rate, reference vessel diameter, lesion length, and presence of a bifurcation lesion. Propensity scores were derived from these variables, and logistic regression was used to estimate the probability that patients would be selected for each treatment. We compared the distribution of covariates between treatment groups after propensity score adjustment using the average standardized difference (ASD) statistic, calculated as the difference in means or proportions between groups divided by the pooled standard deviation. An ASD <0.2 indicates a small difference between treatment groups.²²

The primary safety and effectiveness study comparisons were designed in consultation with the PMDA. The primary safety hypothesis was that freedom from 30-day MACE in the current study would be non-inferior (estimated at 89.6% in each group, margin=9.36%, one-sided α=0.10) to that of the IVL control group. The primary effectiveness hypothesis was that procedural success in the current study would be non-inferior (estimated at 88.9% in each group, margin=10.0%, one-sided α=0.10) to that of the IVL control group. A minimum of 60 evaluable patients provided 72% statistical power for the primary safety hypothesis and 75% statistical power to evaluate the primary effectiveness hypothesis. To account for a possible 5% attrition rate, 64 patients were enrolled. Safety and effectiveness analyses were performed on an intent-to-treat (ITT) population that excluded the first treated patient as a roll-in at each site. Baseline patient characteristics are reported as means and standard deviations for continuous variables, and counts and percentages for categorical variables. The primary endpoints were analyzed using the Farrington-Manning test of non-inferiority of 2 proportions. Predefined subgroup analyses of the primary safety and effectiveness endpoints were reported as an odds ratio and 95% confidence interval (CI). All analyses were prespecified in a statistical analysis plan and performed using SAS v9.4 (SAS Institute, Cary, NC, USA).

Results

Patients were enrolled at 8 sites in Japan between November 2019 and April 2020. The safety population included all 72 treated patients and the ITT population included 64 patients, excluding the first enrolled patient at each site. No patient died or withdrew from the study and all patients returned for clinical follow-up at 30 days.

Baseline clinical and angiographic characteristics are presented in Table 1. Most patients were male with a high prevalence of cardiovascular risk factors. Baseline characteristics were well-balanced when comparing the study participants to the propensity-score matched IVL control group (Supplementary Table 2). The target lesion was predominantly located in the left anterior descending artery (75.0%), mean lesion length was 27.5 mm, and 34.4% of lesions were located at a bifurcation. Severe calcification was present in all patients, with a mean calcified length of 49.8 mm, and OCT imaging confirmed a high burden of calcification with a mean calcium angle of 258° and calcium thickness of 0.96 mm at the site of maximum calcification.

Table 1. Baseline Patient Characteristics

Characteristic	Value (n=64)
Demographics
Age (years)	75.0±8.0
Male sex	75.0 (48/64)
Medical/surgical history
Hyperlipidemia	85.9 (55/64)
Hypertension	82.8 (53/64)
History of tobacco use	62.5 (40/64)
Diabetes mellitus	48.4 (31/64)
Prior coronary intervention	46.9 (30/64)
Prior stroke or transient ischemic attack	20.3 (13/64)
Prior myocardial infarction	20.3 (13/64)
Peripheral vascular disease	17.2 (11/64)
Arrhythmia	12.5 (8/64)
Congestive heart failure	9.4 (6/64)
Prior coronary artery bypass graft	3.1 (2/64)
Prior cardiovascular implantable electronic device	1.6 (1/64)
Renal insufficiency (eGFR <60 mL/min/1.73 m2)	23.4 (15/64)
eGFR (mL/min/1.73 m2)	78±22
Chronic obstructive pulmonary disease	0.0 (0/64)
Functional characteristics
New York Heart Association classification
I	82.8 (53/64)
II	17.2 (11/64)
III/IV	0.0 (0/64)
Canadian Cardiovascular Society angina classification
0	26.6 (17/64)
I	39.1 (25/64)
II	32.8 (21/64)
III	1.6 (1/64)
IV	0.0 (0/64)
Left ventricular ejection fraction	62.2±10.6
Angiographic characteristics
Target lesion vessel
Left anterior descending artery	75.0 (48/64)
Right coronary artery	17.2 (11/64)
Circumflex artery	6.3 (4/64)
Left main coronary artery	1.6 (1/64)
Reference vessel diameter (mm)	2.9±0.4
Diameter stenosis (%)	65.8±10.9
Lesion length (mm)	27.5±10.4
Calcification length (mm)	49.8±15.5
Severe calcification	100.0 (64/64)
Bifurcation/trifurcation	34.4 (22/64)

Values are mean±SD or % (n/N). eGFR, estimated glomerular filtration rate.

Arterial access was gained most commonly through the radial artery (84.4%). Target lesion predilatation was performed in 20.3% of procedures and IVL was successfully delivered in all cases (mean IVL pulses: 104±56). Stent implantation was successful in all patients (mean 1.1±0.3 stents per patient) (Table 2).

Table 2. Procedural Details

Characteristic	Value (n=64)
Access site
Radial artery	84.4 (54/64)
Femoral artery	14.1 (9/64)
Brachial artery	1.6 (1/64)
Predilatation with PTA	20.3 (13/64)
IVL catheter size
2.5 mm	22.5 (23/102)
3.0 mm	51.0 (52/102)
3.5 mm	22.5 (23/102)
4.0 mm	3.9 (4/102)
No. IVL pulses	104±56
Maximum inflation pressure (atm)	6.0±0.0
Post-dilatation with PTA	1.6 (1/64)
No. stents per patient	1.1±0.3
Stent length (mm)	30.6±10.2
Procedure time (min)	62.5±23.1
Fluoroscopy time (min)	22.2±11.1

Values are mean±SD, or % (n/N). IVL, intravascular lithotripsy; PTA, percutaneous transluminal angioplasty.

The primary safety and effectiveness endpoints of the study were met (Table 3). Freedom from 30-day MACE, the primary safety endpoint, was non-inferior compared with the IVL control group (93.8% vs. 91.2%, lower 90% CI=−3.8%, P=0.008). Of the 4 study patients who experienced MACE, all were in-hospital non-Q-wave MI that did not result in additional adverse events, and the patients were discharged by post-procedure day 1. No cardiac deaths, Q-wave MI, or target vessel revascularizations were reported. Procedural success, the primary effectiveness endpoint, was non-inferior compared with the IVL control group (93.8% vs. 91.6%, lower 90% CI=−4.2%, P=0.007). The same 4 patients experienced in-hospital MACE (as for the primary safety endpoint) and were deemed primary effectiveness endpoint failures. No cases of stent delivery failure or residual in-stent stenosis ≥50% were reported.

Table 3. Primary Endpoints

Characteristic	IVLa	IVL controlsa,b	Difference (Lower CIc)	Non-inferiority margin	P value
Primary safety endpoint
Freedom from MACE at 30 days	93.8 (60/64)	91.2 (291/319)	2.53% (−3.79%)	−9.36%	0.008
Cardiac death	0.0 (0/64)	0.6 (2/319)
Non-Q-wave MI	6.3 (4/64)	6.9 (22/319)
Q-wave MI	0.0 (0/64)	1.6 (5/319)
Target vessel revascularization	0.0 (0/64)	1.9 (6/319)
Primary effectiveness endpoint
Procedural success	93.8 (60/64)	91.6 (293/320)	2.19% (−4.16%)	−10.00%	0.007
Stent delivery failure	0.0 (0/64)	0.9 (3/320)
≥50% residual in-stent stenosis	0.0 (0/64)	0.0 (0/317)
In-hospital MACE	6.3 (4/64)	7.8 (25/320)

^aValues are % (n/N). ^bDerived from a propensity score-matched subset of patients treated with IVL in the Disrupt CAD III study. ^cOne-sided 90% Lower CI. CI, confidence interval; IVL, intravascular lithotripsy; MACE, major adverse cardiac event; MI, myocardial infarction.

Device crossing success and angiographic success rates (<50% and ≤30%) were all 98.4% (Table 4). Comparing pretreatment to final in-stent angiographic results, the core-lab adjudicated mean diameter stenosis decreased from 65.8% to 9.9% and that minimal lumen diameter increased from 1.00 to 2.67 mm, yielding a mean acute gain of 1.67 mm. The single serious angiographic complication was a type D dissection following IVL that resolved with placement of a drug-eluting stent. There were no reports of perforation, abrupt closure, persistent slow flow, no-reflow, or stent thrombosis (Table 5, Supplementary Table 3).

Table 4. Secondary Endpoints

Characteristic	Value (n=64)
Device crossing success	98.4 (63/64)
Angiographic success (residual stenosis <50%)	98.4 (63/64)
Angiographic success (residual stenosis ≤30%)	98.4 (63/64)
Target lesion failure	6.3 (4/64)
Death	0.0 (0/64)
Myocardial infarction
Target vessel	6.3 (4/64)
Procedural	6.3 (4/64)
Nonprocedural	0.0 (0/64)
All revascularizations	0.0 (0/64)
Stent thrombosis	0.0 (0/64)

Values are % (n/N).

Table 5. Angiographic Outcomes

Characteristic	Value (n=64)
Final in-segment angiographic outcomes
Acute gain (mm)	1.42±0.42
Minimum lumen diameter (mm)	2.42±0.40
Residual diameter stenosis (%)	15.9±7.9
<50%	98.4 (63/64)
≤30%	98.4 (63/64)
Final in-stent angiographic outcomes
Acute gain (mm)	1.67±0.37
Minimum lumen diameter (mm)	2.67±0.36
Residual diameter stenosis (%)	9.9±5.7
<50%	100.0 (64/64)
≤30%	100.0 (64/64)
Final serious angiographic complications*
Severe dissection (Type D to F)	0.0 (0/64)
Perforation	0.0 (0/64)
Abrupt closure	0.0 (0/64)
Slow flow	0.0 (0/64)
No flow	0.0 (0/64)

Values are mean±SD, or % (n/N). *Serious angiographic complications include severe dissection (Type D to F), perforation, abrupt closure, slow flow, and no flow. IVL, intravascular lithotripsy; OCT, optical coherence tomography.

Based on OCT imaging, calcium fracture was identified in 53.5% of the lesions after delivery of IVL, and multiple fractures were observed in 60.5% of these cases. Fracture frequency, depth, and angle were similar when comparing post-IVL with post-stent imaging. However, maximum fracture width significantly increased from 0.59±0.56 mm to 1.13±0.95 mm (P=0.003). Post-stent imaging demonstrated a minimal stent area (MSA) of 5.65±1.45 mm², with a significant reduction in area stenosis to 13.5±16.9% at the site of MLA (P<0.001), and final stent expansion of 99.5±23.5% at the maximum calcium site (Table 6). Calcium fractures were circumferentially distributed and were observed in multiple longitudinal planes. MSA, area stenosis, and stent expansion were similar regardless of calcium fracture identification by OCT (MSA: fracture [5.7±1.3 mm²], no fracture [5.6±1.7 mm²], P=0.79; area stenosis: fracture [14.7±14.7%], no fracture [11.6±19.9%], P=0.46; stent expansion: fracture [98.7±17.7%]; no fracture [100.7±31.0%, P=0.74]). Representative calcium fractures and stent expansion after IVL are provided in the Figure.

Table 6. Optical Coherence Tomography Results

	Pre-IVL (n=69)	Post-IVL (n=71)	Post-stent (n=71)	P value
				(Pre-IVL vs. Post-IVL)	(Pre-IVL vs. Post-stent)	(Post-IVL vs. Post-stent)
At MLA site
Lumen area, mm2	1.63±0.69 [69]	3.24±1.36 [71]	5.85±1.55 [71]	<0.001	<0.001	<0.001
Area stenosis	74.5±9.2 [62]	51.3±16.4 [66]	13.5±16.9 [67]	<0.001	<0.001	<0.001
Calcium angle, °	152.1±82.2 [53]	136.2±76.4 [43]	129.9±76.4 [53]	0.33	0.15	0.69
Max. calcium thickness, mm	0.85±0.30 [53]	0.84±0.28 [43]	0.86±0.25 [53]	0.87	0.85	0.71
Stent area, mm2			5.69±1.44 [71]	–	–	–
Stent expansion, %			84.4±16.6 [67]	–	–	–
At pre-IVL max. calcium site*
Lumen area, mm2	3.65±1.50 [69]	5.06±1.49 [69]	7.38±1.95 [69]	<0.001	<0.001	<0.001
Area stenosis, %	43.9±30.5 [62]	20.8±29.7 [64]	−9.3±27.7 [65]	<0.001	<0.001	<0.001
Calcium angle, °	257.9±78.4 [69]	227.0±80.0 [68]	209.5±76.4 [69]	0.02	<0.001	0.19
Max. calcium thickness, mm	0.96±0.27 [69]	0.92±0.26 [68]	0.92±0.26 [69]	0.38	0.38	1.0
Stent area, mm2			6.72±1.82 [67]	–	–	–
Stent expansion, %			99.5±23.5 [63]	–	–	–
At final MSA site
Lumen area, mm2	3.19±1.83 [65]	4.10±1.54 [71]	5.91±1.57 [71]	0.002	<0.001	<0.001
Area stenosis	51.4±24.1 [61]	36.6±21.8 [66]	12.5±17.5 [67]	<0.001	<0.001	<0.001
Calcium angle, °	159.3±88.5 [53]	145.2±85.8 [57]	130.5±78.0 [57]	0.40	0.07	0.34
Max. calcium thickness, mm	0.89±0.25 [53]	0.85±0.26 [57]	0.84±0.25 [57]	0.41	0.30	0.84
Stent area, mm2			5.65±1.45 [71]	–	–	–
Stent expansion, %			83.6±16.1 [67]	–	–	–
Calcified nodule	11 (15.9)
Calcium fracture analysis
Calcium fracture, %	–	38 (53.5)	43 (60.6)	–	–	0.50
1 fracture	–	15 (21.1)	19 (26.8)
2 fractures	–	5 (7.0)	5 (7.0)
≥3 fractures	–	18 (25.4)	19 (26.8)
Max. fracture depth, mm	–	0.49±0.23 [37]	0.51±0.24 [43]	–	–	0.71
Max. fracture width, mm	–	0.59±0.56 [37]	1.13±0.95 [43]	–	–	0.003
Min. calcium angle at fracture site, °	–	201.5±73.2 [43]	182.9±69.7 [43]	–	–	0.23
Max. calcium angle at fracture site, °	–	243.5±81.7 [43]	223.9±82.1 [43]	–	–	0.27

Values are mean±SD [n] or % (n/N). *Max calcium site was defined as the site with maximum calcium arc: if multiple sites had the same arc, the site with both maximum arc and thickness was selected. IVL, intravascular lithotripsy; MLA, minimal lumen area; MSA, minimal stent area.

Figure.

Multiplane calcium fracture by optical coherence tomography (OCT). (A) OCT cross-sectional image acquired before intravascular lithotripsy (IVL) demonstrates circumferential calcium in the area of stenosis. (B) Post-IVL OCT cross-sectional image demonstrates multiple, deep calcium fractures (arrows) and large luminal gain. (C) Post-stent OCT cross-sectional image demonstrates further fracture displacement and widening (arrows), with full stent expansion and additional increase in the acute area gain.

Discussion

The Disrupt CAD IV study evaluated the utility of IVL for lesion preparation of severely calcified coronary stenoses prior to stent implantation. Several major findings were derived from the study results. First, both the primary safety and effectiveness endpoints of the study were met, indicating that clinical outcomes with coronary IVL in Japanese patients were non-inferior to those from a study of patients treated with IVL in the USA and Europe. Second, coronary IVL prior to stent implantation was well tolerated, with a low rate of major periprocedural clinical and angiographic complications. Third, the rate of 30-day MACE in this Japanese patient population with complex anatomy was low and similar to previous results with the same study device in other populations. Finally, OCT imaging provided evidence that calcium fracture was the underlying mechanism of action for coronary IVL.

Disrupt CAD I was the first study to demonstrate the feasibility of IVL in the presence of coronary calification.¹⁴ In 60 patients in the USA and Europe who were treated with IVL, delivery success was 98.5%, mean residual stenosis was 13%, and freedom from 30-day MACE was 95.0%. In a subset of those patients, OCT imaging demonstrated calcium modification via in vivo fracture as the primary mechanism of action of IVL.²³ The Disrupt CAD II study was a prospective post-market study designed to determine the performance of IVL in a larger ‘real-world’ population in the USA and Europe.¹⁵ Among 120 patients (94% with severe calcification), IVL delivery success was 100%, mean residual stenosis after IVL was 8%, and freedom from in-hospital MACE was 94.2%. Disrupt CAD III was a single-arm study of 431 patients treated with IVL in the USA and Europe.¹⁶ Among 320 propensity score-matched patients in Disrupt CAD III used for comparison, freedom from 30-day MACE was 92.2%, procedural success was 92.4%, and OCT imaging demonstrated calcium fractures after IVL in 67.4% of lesions and mean stent expansion of 101.7%. The major findings of the current Disrupt CAD IV study performed in Japan were that, similar to previous studies in Western populations, IVL was able to cross and treat lesions with a high success rate, residual stenosis was significantly reduced after IVL, major angiographic complications were rare, and 30-day MACE was driven by non-Q-wave MI. Further, OCT imaging in the current study confirmed the mechanism of action by IVL identified in a previous study,¹⁶ whereby calcium fracture facilitated increased vessel compliance and favorable stent expansion. The absence of OCT-demonstrable calcium fracture in all patients likely represents the presence of microfractures or out-of-plane fractures beyond the recognized limitations of imaging resolution of OCT.^24,25 Ultimately, IVL is an efficient vessel preparation strategy in the presence of a heavy coronary calcium burden, and these results appear to be consistent regardless of ethnicity or geography.

Patterns and outcomes of coronary artery revascularization differ between Asian and Western populations.²⁶ Thus, it was important to assess the generalizability of the primary endpoint results in the current study to those obtained from patients treated in the USA and Europe. Although the prevalence of coronary artery calcification is lower among Japanese adults compared with all ethnic groups in the USA,^27,28 the burden of calcification development and progression is comparable among ethnic groups when adjusting for recognized risk factors.²⁹ There are also important differences in coronary artery plaque morphology between Asian and Western populations. Japanese patients tend to present with shorter lesions and smaller coronary luminal areas compared with Western patients; however, the burden of coronary calcification is comparable between the groups.³⁰ In the current study, patients with heavy calcium burden in a coronary artery undergoing stent placement had similarly favorable acute outcomes relative to the IVL control group comprising Western patients. These findings suggest that despite underlying ethnic differences in risk factors and the differing prevalence and morphology of coronary artery plaques, clinical outcomes of vessel preparation using IVL prior to stent placement are comparable among ethnic groups.

The results of coronary IVL in Japanese patients compare favorably to atherectomy. With extended follow-up, atherectomy outcomes remain suboptimal, with MACE rates ranging from 10.4% to 15.0% at 30 days and from 16.9% to 24.2% between 9 and 12 months.^7,12,13 A unique advantage of IVL is that the mechanism of action is provided by a diffuse acoustic pulse delivered through a low-pressure balloon as opposed to other devices that induce mechanical tissue injury. The resulting potential clinical benefits of IVL include uniform plaque modification in which fractured calcium remains in situ with no microcirculation embolization, thereby safely facilitating stent apposition and expansion.³¹ Comparisons of IVL with atherectomy for coronary artery calcification should, however, be made cautiously because no direct comparative studies are available. Therefore, the suggestion that IVL provides for safer vessel preparation relative to atherectomy should be considered as hypothesis-generating.

Study Limitations

There were several limitations of this study that warrant further discussion. The first limitation relates to propensity-score matching of study participants to a historical IVL control group. Although utilization of the same study device and study eligibility parameters strengthen the validity of the design, propensity score methods cannot account for variables that were unreported or excluded from the model. These unmeasured variables may have influenced patient outcomes and, thus, are important sources of possible bias in the primary endpoint comparisons. Second, vessel preparation was limited to IVL and, therefore, the current results may not be representative of those of patients treated with other revascularization procedures such as atherectomy. Third, OCT identified calcium fractures in 53.5% of lesions after IVL, which was lower than in the Disrupt CAD III data; however, excellent MSA, area stenosis, and stent expansion outcomes were observed regardless of calcium fracture visualization. This may represent a limitation of OCT to detect subtle morphologic changes in calcified plaque that are beyond the resolution limits of current OCT technology.^24,25 Finally, we present 30-day results from the current study. Longer term data are necessary to determine whether safety and durability of treatment effect with IVL is maintained.

Conclusions

Coronary IVL demonstrated high procedure success with low MACE rates in severely calcified lesions in a Japanese population.

Acknowledgments

The authors thank Larry Miller, PhD, PStat for editorial assistance and critical review. Shockwave Medical Inc. (Santa Clara, CA, USA), provided financial support for this research.

Data Availability

The deidentified participant data will not be shared.

Disclosure of Conflict of Interest

Consultancy

Annual income from a single company or organization, as an officer or consultant, which exceeds an annual total of 1,000,000 yen:

(1) Shigeru Saito, TERUMO and Japan Lifeline

(2) Satoru Otsuji, Nipro and ASAHI Intecc

(3) Shigeru Nakamura, Nipro, ASAHI Intecc, Orbus Neich

The other authors and spouses have no conflicts of interest.

IRB Information

Name of IRB: Tokushukai Group Institutional Review Board. Reference no. 024-19-08

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-20-1174

References

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