Advance Publication

Circulation Journal ORIGINAL ARTICLE

doi: 10.1253/circj.CJ-20-1174

Intravascular Lithotripsy for Vessel Preparation in Severely

Calcified Coronary Arteries Prior to Stent Placement
― Primary Outcomes From the Japanese Disrupt CAD IV Study ―

Shigeru Saito, MD; Seiji Yamazaki, MD; Akihiko Takahashi, MD, PhD; Atsuo Namiki, MD, PhD;
Tomohiro Kawasaki, MD; Satoru Otsuji, MD; Shigeru Nakamura, MD;
Yoshisato Shibata, MD for the Disrupt CAD IV Investigators

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 ste-
noses 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.

Key Words: Calcification; Coronary artery disease; Intravascular lithotripsy

C
alcified 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 angiogra-
phy and intravascular ultrasound, respectively.2 Coronary
artery calcification is associated with inferior clinical out-
comes 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
Editorial p ????
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 myo-
cardial infarction (MI), are significantly higher with ather-
ectomy than with balloon-based therapies.7–11 Additionally,
major adverse cardiac event (MACE) rates with atherec-
tomy 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

Received November 15, 2020; revised manuscript received December 4, 2020; accepted December 9, 2020; J-STAGE Advance
Publication released online February 5, 2021   Time for primary review: 9 days
Department of Cardiology, Shonan-Kamakura General Hospital, Kamakura (S.S.); Department of Cardiology, Sapporo Higashi
Tokushukai Hospital, Sapporo (S.Y.); Department of Cardiology, Sakurakai Takahashi Hospital, Kobe (A.T.); Department of
Cardiology, JOHAS Kanto-Rosai Hospital, Kawasaki (A.N.); Department of Cardiology, Tenjinkai Shin-Koga Hospital,
Kurume (T.K.); Department of Cardiology, Higashi-Takarazuka Satoh Hospital, Takarazuka (S.O.); Department of Cardiology,
Kyoto-Katsura Hospital, Kyoto (S.N.); and Department of Cardiology, Miyazaki Medical Association Hospital, Miyazaki
(Y.S.), Japan
Mailing address: Shigeru Saito, MD, Director of Cardiology and Catheterization Laboratories, Shonan-Kamakura General Hospital,
1370-1 Okamoto, Kamakura 247-8533, Japan.   E-mail: saito@shonankamakura.or.jp and transradial@kamakuraheart.org
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp
ISSN-1346-9843
 Advance Publication
2 SAITO S et al.
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 coro-
nary arteries, including Disrupt CAD I,14 Disrupt CAD
II,15 and Disrupt CAD III,16,17 report high procedural suc-
cess rates with low risk of complications in patient popula-
tions 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 popu-
lation 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 exclu-
sion 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 estab-
lished guidelines.18,19
Outcomes
Study endpoint and MACE definitions were identical to
those utilized in the Disrupt CAD III study.16,17 The pri-
mary 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 proce-
dures, and stent thrombosis. Serious angiographic compli-
cations 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 expan-
sion percentage, and the frequency of calcium fracture.
Data Quality
Study data were regularly reviewed for accuracy and com-
pleteness 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
 Advance Publication
IVL for Calcified Coronary Stenosis 3

were compared with those of the patients in the Disrupt Table 1. Baseline Patient Characteristics
CAD III study16 (hereafter referred to as the IVL control
Characteristic Value (n=64)
group) who were enrolled under similar study eligibility
Demographics
criteria and treated with the same IVL study device. Disrupt
CAD III treated 431 patients; a propensity score-matched   Age (years) 75.0±8.0
subgroup of 384 patients served as the IVL control group   Male sex 75.0 (48/64)
for the current study. In order to account for possible Medical/surgical history
imbalances in baseline patient characteristics, propensity-   Hyperlipidemia 85.9 (55/64)
score matching using a greedy, nearest-neighbor matching   Hypertension 82.8 (53/64)
algorithm in a 1 : 5 ratio was performed. The variables used    History of tobacco use 62.5 (40/64)
for matching were selected a priori and included patient   Diabetes mellitus 48.4 (31/64)
age, sex, history of diabetes mellitus, history of coronary    Prior coronary intervention 46.9 (30/64)
artery bypass graft, estimated glomerular filtration rate,
   Prior stroke or transient ischemic attack 20.3 (13/64)
reference vessel diameter, lesion length, and presence of a
   Prior myocardial infarction 20.3 (13/64)
bifurcation lesion. Propensity scores were derived from
these variables, and logistic regression was used to estimate    Peripheral vascular disease 17.2 (11/64)
the probability that patients would be selected for each   Arrhythmia 12.5 (8/64)
treatment. We compared the distribution of covariates    Congestive heart failure 9.4 (6/64)
between treatment groups after propensity score adjust-    Prior coronary artery bypass graft 3.1 (2/64)
ment using the average standardized difference (ASD) sta-   Prior cardiovascular implantable 1.6 (1/64)
tistic, calculated as the difference in means or proportions electronic device
between groups divided by the pooled standard deviation.   Renal insufficiency 23.4 (15/64)
An ASD <0.2 indicates a small difference between treat- (eGFR <60 mL/min/1.73 m2)
ment groups.22     eGFR (mL/min/1.73 m2) 78±22
The primary safety and effectiveness study comparisons    Chronic obstructive pulmonary disease 0.0 (0/64)
were designed in consultation with the PMDA. The primary Functional characteristics
safety hypothesis was that freedom from 30-day MACE in    New York Heart Association classification
the current study would be non-inferior (estimated at     I 82.8 (53/64)
89.6% in each group, margin=9.36%, one-sided α=0.10) to     II 17.2 (11/64)
that of the IVL control group. The primary effectiveness     III/IV 0.0 (0/64)
hypothesis was that procedural success in the current study
  Canadian Cardiovascular Society angina
would be non-inferior (estimated at 88.9% in each group, classification
margin=10.0%, one-sided α=0.10) to that of the IVL control     0 26.6 (17/64)
group. A minimum of 60 evaluable patients provided 72%
    I 39.1 (25/64)
statistical power for the primary safety hypothesis and 75%
    II 32.8 (21/64)
statistical power to evaluate the primary effectiveness
hypothesis. To account for a possible 5% attrition rate, 64     III 1.6 (1/64)
patients were enrolled. Safety and effectiveness analyses     IV 0.0 (0/64)
were performed on an intent-to-treat (ITT) population    Left ventricular ejection fraction 62.2±10.6
that excluded the first treated patient as a roll-in at each Angiographic characteristics
site. Baseline patient characteristics are reported as means    Target lesion vessel
and standard deviations for continuous variables, and     Left anterior descending artery 75.0 (48/64)
counts and percentages for categorical variables. The     Right coronary artery 17.2 (11/64)
primary endpoints were analyzed using the Farrington-     Circumflex artery 6.3 (4/64)
Manning test of non-inferiority of 2 proportions. Predefined     Left main coronary artery 1.6 (1/64)
subgroup analyses of the primary safety and effectiveness
   Reference vessel diameter (mm) 2.9±0.4
endpoints were reported as an odds ratio and 95% confi-
   Diameter stenosis (%) 65.8±10.9
dence interval (CI). All analyses were prespecified in a
statistical analysis plan and performed using SAS v9.4    Lesion length (mm) 27.5±10.4
(SAS Institute, Cary, NC, USA).    Calcification length (mm) 49.8±15.5
  Severe calcification 100.0 (64/64)
  Bifurcation/trifurcation 34.4 (22/64)
Results
Values are mean ± SD or % (n/N). eGFR, estimated glomerular
Patients were enrolled at 8 sites in Japan between Novem- filtration rate.
ber 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 dominantly located in the left anterior descending artery
patients returned for clinical follow-up at 30 days. (75.0%), mean lesion length was 27.5 mm, and 34.4% of
Baseline clinical and angiographic characteristics are lesions were located at a bifurcation. Severe calcification
presented in Table 1. Most patients were male with a high was present in all patients, with a mean calcified length of
prevalence of cardiovascular risk factors. Baseline charac- 49.8 mm, and OCT imaging confirmed a high burden of
teristics were well-balanced when comparing the study calcification with a mean calcium angle of 258° and calcium
participants to the propensity-score matched IVL control thickness of 0.96 mm at the site of maximum calcification.
group (Supplementary Table 2). The target lesion was pre- Arterial access was gained most commonly through the
 Advance Publication
4 SAITO S et al.

Table 2. Procedural Details

The same 4 patients experienced in-hospital MACE (as for
the primary safety endpoint) and were deemed primary
Value
Characteristic
(n=64) effectiveness endpoint failures. No cases of stent delivery
Access site
failure or residual in-stent stenosis ≥50% were reported.
Device crossing success and angiographic success rates
  Radial artery 84.4 (54/64)
(<50% and ≤30%) were all 98.4% (Table 4). Comparing
  Femoral artery 14.1 (9/64)
pretreatment to final in-stent angiographic results, the
  Brachial artery 1.6 (1/64) core-lab adjudicated mean diameter stenosis decreased
Predilatation with PTA 20.3 (13/64) from 65.8% to 9.9% and that minimal lumen diameter
IVL catheter size increased from 1.00 to 2.67 mm, yielding a mean acute gain
  2.5 mm 22.5 (23/102) of 1.67 mm. The single serious angiographic complication
  3.0 mm 51.0 (52/102) was a type D dissection following IVL that resolved with
  3.5 mm 22.5 (23/102) placement of a drug-eluting stent. There were no reports of
  4.0 mm 3.9 (4/102) perforation, abrupt closure, persistent slow flow, no-reflow,
No. IVL pulses 104±56
or stent thrombosis (Table 5, Supplementary Table 3).
Based on OCT imaging, calcium fracture was identified
Maximum inflation pressure (atm) 6.0±0.0
in 53.5% of the lesions after delivery of IVL, and multiple
Post-dilatation with PTA 1.6 (1/64)
fractures were observed in 60.5% of these cases. Fracture
No. stents per patient 1.1±0.3 frequency, depth, and angle were similar when comparing
Stent length (mm) 30.6±10.2 post-IVL with post-stent imaging. However, maximum
Procedure time (min) 62.5±23.1 fracture width significantly increased from 0.59±0.56 mm
Fluoroscopy time (min) 22.2±11.1 to 1.13±0.95 mm (P=0.003). Post-stent imaging demonstrated
Values are mean ± SD, or % (n/N). IVL, intravascular lithotripsy; a minimal stent area (MSA) of 5.65±1.45 mm2, with a
PTA, percutaneous transluminal angioplasty. 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). Cal-
cium fractures were circumferentially distributed and were
radial artery (84.4%). Target lesion predilatation was per- observed in multiple longitudinal planes. MSA, area stenosis,
formed in 20.3% of procedures and IVL was successfully and stent expansion were similar regardless of calcium
delivered in all cases (mean IVL pulses: 104±56). Stent fracture identification by OCT (MSA: fracture [5.7±1.3 mm2],
implantation was successful in all patients (mean 1.1±0.3 no fracture [5.6±1.7 mm2], P=0.79; area stenosis: fracture
stents per patient) (Table 2). [14.7±14.7%], no fracture [11.6±19.9%], P=0.46; stent
The primary safety and effectiveness endpoints of the expansion: fracture [98.7±17.7%]; no fracture [100.7±31.0%,
study were met (Table 3). Freedom from 30-day MACE, P=0.74]). Representative calcium fractures and stent
the primary safety endpoint, was non-inferior compared expansion after IVL are provided in the Figure.
with the IVL control group (93.8% vs. 91.2%, lower 90%
CI=−3.8%, P=0.008). Of the 4 study patients who experi-
enced MACE, all were in-hospital non-Q-wave MI that Discussion
did not result in additional adverse events, and the patients The Disrupt CAD IV study evaluated the utility of IVL for
were discharged by post-procedure day 1. No cardiac lesion preparation of severely calcified coronary stenoses
deaths, Q-wave MI, or target vessel revascularizations were prior to stent implantation. Several major findings were
reported. Procedural success, the primary effectiveness derived from the study results. First, both the primary
endpoint, was non-inferior compared with the IVL control safety and effectiveness endpoints of the study were met,
group (93.8% vs. 91.6%, lower 90% CI=−4.2%, P=0.007). indicating that clinical outcomes with coronary IVL in

Table 3. Primary Endpoints

Difference Non-inferiority
Characteristic IVLa IVL controlsa,b P value
(Lower CIc) margin
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)
aValuesare % (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.
 Advance Publication
IVL for Calcified Coronary Stenosis
Table 4. Secondary Endpoints
Value
Characteristic
(n=64)
Device crossing success 98.4 (63/64)
 ngiographic success (residual stenosis
A 98.4 (63/64)
<50%)
 ngiographic success (residual stenosis
A 98.4 (63/64)
≤30%)
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).
Japanese patients were non-inferior to those from a study
of patients treated with IVL in the USA and Europe. Sec-
ond, 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 steno-
sis 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 com-
plications 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 effi-
5
Table 5. Angiographic Outcomes
Value
Characteristic
(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 compli-
cations include severe dissection (Type D to F), perforation,
abrupt closure, slow flow, and no flow. IVL, intravascular litho-
tripsy; OCT, optical coherence tomography.
cient 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 revasculariza-
tion 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 dif-
ferences 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 com-
pare 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 pro-
vided by a diffuse acoustic pulse delivered through a low-
pressure balloon as opposed to other devices that induce
 Advance Publication
6 SAITO S et al.

Table 6. Optical Coherence Tomography Results

P value
Pre-IVL Post-IVL Post-stent
(n=69) (n=71) (n=71) (Pre-IVL vs. (Pre-IVL vs. (Post-IVL vs.
Post-IVL) Post-stent) 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 – 201.5±73.2 [43] 182.9±69.7 [43] – – 0.23
site, °
  Max. calcium angle at fracture – 243.5±81.7 [43] 223.9±82.1 [43] – – 0.27
site, °
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 dem-
onstrates further fracture displacement and widening (arrows), with full stent expansion and additional increase in the acute area gain.
 Advance Publication
IVL for Calcified Coronary Stenosis
mechanical tissue injury. The resulting potential clinical
benefits of IVL include uniform plaque modification in
which fractured calcium remains in situ with no microcir-
culation embolization, thereby safely facilitating stent
apposition and expansion.31 Comparisons of IVL with
atherectomy for coronary artery calcification should, how-
ever, be made cautiously because no direct comparative
studies are available. Therefore, the suggestion that IVL
provides for safer vessel preparation relative to atherec-
tomy should be considered as hypothesis-generating.
Study Limitations
There were several limitations of this study that warrant
further discussion. The first limitation relates to propen-
sity-score matching of study participants to a historical
IVL control group. Although utilization of the same study
device and study eligibility parameters strengthen the valid-
ity 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 pos-
sible 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 frac-
tures 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 rep-
resent 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. Refer-
ence no. 024-19-08
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Supplementary Files
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-20-1174