CARREV-02353; No of Pages 10

Cardiovascular Revascularization Medicine xxx (xxxx) xxx

Contents lists available at ScienceDirect

Cardiovascular Revascularization Medicine

Efficacy and safety of intravascular lithotripsy in calcified coronary

lesions: A systematic review and meta-analysis
Mohammed Mhanna a,⁎, Azizullah Beran a, Salik Nazir b, Omar Sajdeya a, Omar Srour a,
Ahmed Elzanaty a, Ehab A. Eltahawy b
a
Department of Internal Medicine, The University of Toledo, Toledo, OH, USA
b
Department of Cardiovascular Medicine, University of Toledo, Toledo, OH, USA

a r t i c l e i n f o a b s t r a c t

Article history: Background: Intravascular lithotripsy (IVL) is a recently introduced therapeutic modality in the management of
Received 3 April 2021 calcified coronary lesions (CCAD). IVL delivers sonic pressure waves to modulate calcium, hence promote vessel
Received in revised form 11 May 2021 compliance and optimize stent deployment.
Accepted 11 May 2021 Methods: We performed a comprehensive literature search for studies that evaluated the utility of adjunctive IVL.
Available online xxxx
The primary outcomes of our study were the clinical success, defined as the ability of IVL to produce residual di-
ameter stenosis <50% (RDS < 50%) after stenting with no evidence of in-hospital major adverse cardiac events,
Keywords:
Intravascular lithotripsy
and the angiographic success, defined as success in facilitating stent delivery with RDS < 50% and without serious
Shockwave therapy angiographic complications. The secondary outcomes included post-IVL and post-stenting changes in lumen
Coronary artery area, calcium angle, and the maximum calcium thickness. Proportional analysis was used for binary data and
Calcification mean difference was used for continuous data. All meta-analyses were conducted using a random-effect
model and 95% confidence intervals (CIs) were included.
Results: A total of eight single-arm observational studies, including 980 patients (1011 lesions), were included.
48.8% of the patients presented with acute coronary syndrome. Severe calcifications were present in 97% of le-
sions. Clinical success was achieved in 95.4% of patients (95%CI:92.9%–97.9%). Angiographic success was achieved
in 97% of patients (95%CI:95%–99%). There was an overall increase in postprocedural lumen area as well as sig-
nificant reduction of calcium angle and maximum calcium thickness.
Conclusions: IVL seems to have excellent efficacy and safety in the management of CCAD. However, adequately
powered RCTs are needed to evaluate IVL compared to other calcium/plaque modifying techniques.
© 2021 Elsevier Inc. All rights reserved.

1. Introduction percutaneous coronary intervention (PCI) procedures more challeng-

Calcified coronary lesions (CCL) are not uncommon and frequently
observed during coronary angiography, with a reported prevalence
ranging between 18% and 26% [1]. The incidence of CCL increases with
age and other cardiovascular risk factors, particularly diabetes mellitus
(DM), hypertension, and renal dysfunction [2]. Coronary artery calcifi-
cation (CAC) is associated with increased arterial stiffness and highly
correlates to the rate of cardiac adverse events [3]. The presence of
CCL renders them resistant to conventional intervention making
Abbreviations: ACS, acute coronary syndrome; CAC, coronary artery calcification; CAD,
coronary artery disease; CCAD, calcified coronary artery disease; CCL, calcified coronary
lesions; DES, drug-eluting stent; IVL, intravascular lithotripsy; MACE, major adverse car-
diac events; MLA, minimal luminal area; MLD, minimal luminal diameter; MSA, minimal
stent area; PCI, percutaneous coronary intervention; RCT, randomized controlled trial;
RDS, residual diameter stenosis.
⁎ Corresponding author at: Department of Internal Medicine, University of Toledo, 2100
W. Central Ave, Toledo, OH 43606, USA.
E-mail address: Mohammed.Mhanna@utoledo.edu (M. Mhanna).
ing, with substantial failure to gain satisfactory artery expansion and
higher risks of dissection, perforation, and re-stenosis [4].
Several specialty balloons such as high-pressure non-compliant,
scoring, and cutting balloons have been developed to modify the calcific
plaque thereby promoting effective vessel dilatation and therefore en-
hance stent deployment [5]. However, these balloons are often associ-
ated with limited calcium debulking efficacy due to the eccentric
nature of calcification. The more effective rotational and orbital atherec-
tomy are even associated with inhomogeneous ablation leaving sub-
stantial areas of unmodified calcium plaques, particularly in eccentric
lesion [6]. Furthermore, these modalities are often associated with in-
creased risk of periprocedural complications including slow or no-
flow, coronary dissection, or perforation, which occur more frequently
with atherectomy techniques as compared to balloon techniques [5].
Intravascular lithotripsy (IVL) is a recently introduced therapeutic
modality in managing CCL to overcome limitations of the more com-
monly applied practices with non-compliant or cutting balloons or rota-
tional atherectomy. IVL promotes vessel compliance and optimizes

https://doi.org/10.1016/j.carrev.2021.05.009
1553-8389/© 2021 Elsevier Inc. All rights reserved.

Please cite this article as: M. Mhanna, A. Beran, S. Nazir, et al., Efficacy and safety of intravascular lithotripsy in calcified coronary lesions: A
systematic review ..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2021.05.009
M. Mhanna, A. Beran, S. Nazir et al.
stent deployment by modulating calcium content and enhancing the
fragmentation of CCL via delivery of circumferential sonic pressure
waves to the vessel wall and applying pulsatile shockwaves to the sur-
rounding plaque [7]. Recently, few studies have been performed to in-
vestigate the use of IVL for calcified coronary artery lesions [8–15], but
data regarding its efficacy and safety remain sparse.
Therefore, we conducted a systematic review and meta-analysis to
evaluate all the available evidence to better assess the efficacy and
safety of IVL in the management of calcified coronary artery disease.
2. Methods
2.1. Data sources and search strategy
We performed a comprehensive search for published studies
indexed in PubMed/MEDLINE, EMBASE, and the Cochrane Central Reg-
ister of Controlled Trials from inception to April 26, 2021. We also per-
formed a manual search for additional relevant studies using
references of the included articles. The search items include medical
subject headings (MeSH) and the keywords: (“Intravascular litho-
tripsy”, “shockwave therapy”, “coronary lithotripsy” or “IVL” or “S-
IVL”), (“calcified”, “calcification”), (“failed percutaneous coronary inter-
vention,” “stent under expansion,” “drug-eluting stent,” and “failed ro-
tational atherectomy.”) and (“coronary artery disease”, “CAD”, “ST-
elevation myocardial infarction,” “non-ST elevation myocardial infarc-
tion,” “unstable angina,” “stable angina,”). These terms were combined
using Boolean operators (“AND” or “OR”), and results from all the possi-
ble combinations were downloaded into an EndNote library. Truncation
and wildcard strategies were applied. The search was limited by the En-
glish language, but not to the study design or country of origin. Online
Supplementary Table 1 describes the full search term used in each data-
base searched.
2.2. Study selection
We followed the preferred reporting items for systematic reviews
and meta-analyses (PRISMA) and the meta-analysis of observational
studies in epidemiology (MOOSE) guidelines to screen the studies
[16,17]. We included full texts of randomized controlled trials, cohort
studies, and case-control studies. We excluded abstracts, animal studies,
case reports, case series, reviews, editorials, and letters to editors. Two
investigators (MM and AB) independently screened and selected the
studies for the final review. Discrepancies were resolved by a third in-
vestigator (SN).
2.3. Eligibility criteria
Studies were included if they met all the following inclusion criteria:
1) studies that evaluated coronary intravascular lithotripsy (shockwave
therapy), 2) studies of patients with calcified coronary artery disease,
3) studies had to report data that evaluated the utility of IVL with clinical
success, angiographic success or pre and post-procedural calcified le-
sion changes in lumen area, calcium angle or maximum calcium
thickness.
2.4. Data extraction
We extracted the following data from the final studies: the last name
of the first author, publication year, study design, country of origin,
follow-up duration, sample size, inclusion criteria, efficacy endpoints,
and safety endpoints (including peri-procedural complications such as
coronary dissection and perforation with their subtypes). In addition,
we extracted patients' demographics, baseline comorbidities (including
diabetes mellitus, hypertension, hyperlipidemia, and chronic kidney
disease), and their clinical presentation. Finally, we extracted proce-
dural details and outcomes. Data presented with median and
2
Cardiovascular Revascularization Medicine xxx (xxxx) xxx
interquartile range (IQR) were converted to mean (±SD) using mathe-
matical formulas for meta-analysis [18].
2.5. Outcomes
The primary outcomes of our study included the clinical success
which was defined as the ability of IVL to produce residual diameter
stenosis <50% (RDS < 50%) after stenting with no evidence of in-
hospital major adverse cardiac events (MACE: composite of cardiac
death, myocardial infarction (defined as a CK-MB level > 3 times the
upper limit of lab normal value with or without new pathologic Q
wave), and target lesion revascularization (defined as revascularization
at the target vessel (inclusive the target lesion) after the completion of
the index procedure)) and the angiographic success which was defined
as success in facilitating stent delivery with RDS <50% and without
serious angiographic complications (significant (more than type
B) coronary dissection, perforation, abrupt closure, persistent slow
flow, or no-reflow).
The secondary outcomes included post-IVL lumen area change mea-
sured at the minimal luminal area (MLA) and post-stenting lumen area
change measures at the minimal stent area (MSA). We also included
post-IVL and post-stenting changes in calcium angle and the maximum
calcium thickness both measured at the maximum calcium site (MCS)
(MCS 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). All measurements were based on optical coherence to-
mography (OCT) or intravascular ultrasound (IVUS) assessment.
2.6. Statistical analysis
We used Open Meta Analyst (CEBM, Oxford, United Kingdom) and
Review Manager 5.3 (Cochrane Collaboration, Copenhagen, The Nordic
Cochrane Centre). The statistical analysis of binary data (including the
primary outcomes) was performed with proportional analysis, and the
final outcomes were presented as a percentage (proportion × 100)
with the corresponding 95% confidence intervals (95% CI) were calcu-
lated using a random-effects model. The statistical analysis for the con-
tinuous data (when presented with mean and standard deviation) was
conducted using a random-effect model (inverse variance) with the
mean difference (MD) and 95% confidence intervals (CIs) are presented
as summary statistics, and 95% confidence intervals (CIs) were included.
A P-value of <0.05 was considered statistically significant. The hetero-
geneity of effect size estimates among the included studies was assessed
using the Q statistic and I2 (I2 value >50% indicates high heterogeneity).
Sensitivity analysis using leave-one-out meta-analysis was performed
to confirm if there was a big change generated by a single study [19].
2.7. Quality and publication bias assessment
We assessed the quality of the included studies using the Newcastle-
Ottawa Scale for observational studies. Two authors (MM and SN) inde-
pendently assessed each study for bias. Discrepancies were resolved by
consensus. Publication bias was assessed visually by generating a funnel
plot of the studies that reported the clinical and angiographic success
rates. We also performed Egger's regression to quantitively assess pub-
lication bias, where p < 0.05 was considered statistically significant for
publication bias.
3. Results
3.1. Study selection
A total of 345 studies were retrieved by our search strategy. Subse-
quently, we excluded 263 studies that were not relevant, had insuffi-
cient data, were preliminary studies, or subgroup analysis. Eventually,
eight studies met our inclusion criteria and were included in the
M. Mhanna, A. Beran, S. Nazir et al.
meta-analysis [8–15]. Fig. 1 shows the PRISMA flow chart that illustrates
how the final studies were selected.
3.2. Study and patients' characteristics
Table 1 shows the characteristics of the eight studies that were in-
cluded in our meta-analysis. All included studies were full-text publica-
tions, observational studies without control groups.
A total of 980 patients were included in these eight studies (Table 2).
The mean age was 72.1 ± 9.1 years, and males represented 75.4% of
total patients; 32.2% were smokers, 87.6% had hypertension, 81.9%
with hyperlipidemia, 21.8% with chronic kidney disease (eGFR<60
ml/min), and 41.8% had the diagnosis of DM. 48.8% of the patients
Fig. 1. PRISMA flow diagram for the selection of studies.
3
Cardiovascular Revascularization Medicine xxx (xxxx) xxx
presented with acute coronary syndrome, while the others presented
with stable angina. A total of 52.3% of lesions were in the left anterior
descending artery, and 43.6% were proximal lesions with a mean length
of 24.3 ± 12.3 mm. Severe calcifications; defined either angiographic-
ally (radio-opacities involving both sides of the arterial wall and length
of at least 15 mm) or by intravascular ultrasound (IVUS) or optical co-
herence tomography (OCT) [presence of ≥270 degrees of calcium on at
least 1 cross-section] was present in 97% of lesions, with 58.4% being
concentric. Radial access was performed in 56.9% of cases with an aver-
age of 1.3 ± 0.58 stents placed per lesion (Table 3).
Regarding procedural characteristics, the mean value of balloon size
was (3.8 × 12 mm), the size of catheter used was (6fr), and maximum
IVL inflation pressure was 5.9 ± 0.53 atm. The average used contrast
M. Mhanna, A. Beran, S. Nazir et al. Cardiovascular Revascularization Medicine xxx (xxxx) xxx

Table 1
Baseline characteristics of studies included in the meta-analysis.

Author, year Study design Follow up Total no. Severe calcification Inclusion criteria Success endpoint Safety endpoint
duration patients definition and
(lesions) assessment

Aksoy, 2019 [8] Prospective 30 days 71 (78) Radiopacities seen Moderately and severely Successful stent delivery and Procedural complication,
observational without cardiac calcified coronary lesions expansion with attainment of defined as coronary
multicenter motion before RDS <20% in the presence of dissection, slow or no
registry contrast dye TIMI 3 flow without stent reflow, new coronary
injection assessed failure. thrombus.
angiographically or MACE: (MI, TVF, or cardiac
with IVUS/OCT. Primary end point was based death)
on QCA.

23 lesions were assessed by

IVUS, and 12 lesions by OCT.
Ali, 2019 [10] Prospective 30 days 120 (120) Calcification within 1. Silent ischemia, unstable Post stenting RDS <50 In-hospital MACE defined
DISRUPT CAD II. multicenter, the lesion on both or stable angina, or stabi- as cardiac death, MI, or TLR
single-arm sides of the vessel lized ACS without eleva- Post stent OCT was used in 47
post-approval assessed by tion in cardiac patients.
study angiography. biomarkers.
2. A single target lesion
requiring PCI with a
diameter stenosis ≥50%,
lesion length ≤32 mm in
native coronary arteries.
3. Severe calcification
Aziz, 2020 [11] Retrospective 7.2 months 190 (200) NR NR Angiographic success defined Procedure related
observational as the ability to complete the complications: cardiac
study procedure with complete death, TVMI, TLR, and
expansion of balloon and/or MACE (composite of cardiac
stent with RDS <30% with TIMI death, TVMI, and TLR).
3 flow.

Following stent deployment,

34 patients underwent IVUS
and 6 underwent OCT.
Brinton, 2019 Prospective 6 months 60 (60) Calcification within 1. Age ≥18 years. Post stenting RDS <50% with 1. MACE: cardiac death,
[13] multicenter, the lesion on both 2. Troponin less or equal to no evidence of in-hospital MI or TLR at 30 days.
DISRUPT CAD I. single-arm sides of the vessel ULN within 12 h. prior to MACE. 2. Serious angiographic
feasibility assessed during the procedure. complications defined
study angiography by the 3. TIMI flow 3 at baseline QCA was utilized in all as severe dissection
operator. 4. Native CAD with ≥50% patients. (Type D to F),
diameter stenosis. perforation, abrupt
5. Single lesion stenosis n a closure, and persistent
reference vessel of 2.5 slow flow or persistent
mm–4.0 mm diameter no reflow
and ≤32 mm length.
6. Angiographically assessed
calcification within the
lesion on both sides of the
vessel.
Cubero-gallego, Prospective, 30 days 57 (66) NR 1. Age ≥18 years with stable <50% of RDS of the target Bleeding as defined
2020 [12] multicenter, angina or ACS suitable for lesion, successful deployment according to the Bleeding
single-arm PCI. of the stent. Academic Research
study 2. Had CCL with significant Consortium
stenosis (≥50% diameter 61 lesions were assessed with
stenosis) and a vessel QCA.
diameter ≥2.5 mm
assessed by visual esti-
mation and QCA.
Hill, 2020 [9] Prospective, 30 days 384 (384) Angiographya, or 1. Age ≥18 years. Procedural success defined as MACE: cardiac death, MI
DISRUPT CAD multicenter, by IVUS or OCT, 2. Native and de novo CAD. successful stent delivery with or TLR at 30 days.
III. single-arm with presence of 3. Troponin less or equal to RDS <50%
study ≥270 degrees of ULN within 12 h. prior to
calcium on at least the procedure. QCA was utilized in all
1 cross section. 4. The target vessel refer- patients.
ence diameter must be
≥2.5 mm and ≤4.0 mm.
5. The lesion length
<40 mm.
6. TIMI flow 3 at baseline.
Ielasi,2019 [14] Retrospective, 30 days 34 (39) Severe calcification Patients who underwent IVL Successful IVL dilatation MACE: cardiac death, MI,
The SMILE multicenter, assessed by to treat under expanded defined as IVL balloon TLR and stent thrombosis
Registry single-arm angiography coronary stents delivery and application at during the hospitalization.
study the target site followed by an
increase (after NC balloon
expansion failure) of at least

4
M. Mhanna, A. Beran, S. Nazir et al. Cardiovascular Revascularization Medicine xxx (xxxx) xxx

Table 1 (continued)

Author, year Study design Follow up Total no. Severe calcification Inclusion criteria Success endpoint Safety endpoint
duration patients definition and
(lesions) assessment

1 mm2 in MSA on
intracoronary imaging or an
increase of at least 20% in
MSD by QCA.
Saito, 2021 [15] Prospective, 30 days 64 (64) Same as DISRUPT Same as DISRUPT CAD III. Procedural success, defined as MACE: cardiac death, MI
DISRUPT CAD multicenter, CAD III. stent delivery with core or TLR at 30 days.
IV. single-arm laboratory-assessed RDS
study <50% and freedom from
in-hospital MACE.

Abbreviations: CAD: coronary artery disease, CCL calcified coronary lesion, IVUS: intravascular ultrasound, MACE: major adverse cardiac events, MI: myocardial infarction, MSA: minimal
stent cross-sectional area, MSD: minimal stent diameter, OCT: optical coherence tomography, QCA: quantitative coronary angiography, RDS: residual diameter stenosis, TIMI: thrombol-
ysis in myocardial infarction, TLR: target lesion revascularization, TVF: target vessel failure, TVMI: target vessel myocardial infarction, ULN: upper limit of normal.
a
With fluoroscopic radio opacities noted without cardiac motion prior to contrast injection involving both sides of the arterial wall in at least one location and total length of calcium of
at least 15 mm and extending partially into the target lesion.

agent was 175 ± 77.6 ml, with 24.1 ± 17 min spent during fluoros-
copy. Adjunctive calcium modifying techniques were used in 9.6%
of the patients' population (4.2% had additional rotational atherec-
tomy, 1.6% had cutting/scoring balloons, and 3.8% had non-
compliant balloons).
3.3. Angiographic characteristics
Post-procedural quantitative coronary angiography (QCA) measures
were reported by all studies except Aziz et al. as shown in Supplemen-
tary Table 2. Post-IVL in-segment RDS <50% was achieved in 99.3%
(95% CI: 98.6%, 100.01%) and <30% was achieved in 97.4% (95% CI:
94.4%, 100.4%) of lesions. Post-PCI in-stent RDS <50% was achieved in
99.8% (95% CI: 99.5%, 100.2%) and <30% was achieved in 99.5% (95%
CI: 98.6%, 100.5%) of lesions. Final in-stent residual stenosis was
11.24% (95% CI: 9.32%, 13.16%) and final in-stent acute gain was
1.81 mm (95% CI: 1.65, 1.97).
3.4. Primary outcomes
The clinical success was achieved in 95.4% of patients (95% CI:
92.9%–97.9%) (Fig. 2A) and angiographic success was achieved in 97%
of patients (95% CI: 95%–99%). (Fig. 2B). The statistical heterogeneity
was substantial for the given outcomes (I2 = 70.68% and 75.75%, P <
0.05). The sensitivity analysis did not show any significant difference
by an individual study on the clinical and the angiographic success
rates (Online Supplementary Fig. 1A and B).
3.5. Secondary outcomes
A total of 289 patients were enrolled in the OCT/IVUS sub-study. The
pre-procedure minimal lumen area (MLA) was 2.1 ± 0.96 mm2, the cal-
cium angle was 270.3° ± 81.3°, and calcium thickness was 0.95 ±
0.25 mm at the site of maximum calcification.
Post-IVL imaging demonstrated a significant increase in lumen area
at MLA site compared to the baseline (mean difference (MD 1.58, 95% CI
1.28, 1.88, P < 0.001, I2: 32%)) (Fig. 3A). Furthermore, there was a signif-
icant reduction in post-IVL calcium angle (MD -30.9, 95% CI -47.08,
−14.73, P < 0.001, I2: 0%) (Fig. 3B). No significant change was observed
in post-IVL calcium thickness (MD −0.03, 95% CI −0.08, 0.02, P = 0.098,
I2: 0%) (Fig. 3C).
Post-stent imaging demonstrated a significant increase in MSA
compared to baseline lumen area (MD 2.78, 95% CI 2.14, 3.43,
P < 0.001, I2 : 74%) (Fig. 4A). A sensitivity analysis was conducted
by removing one study at a time to reduce heterogeneity and found
no significant heterogeneity after removal of the Ielasi et al. study
(I2 = 0%, P heterogeneity = 0.69), with the results continuing to be sta-
tistically significant (MD 2.53, 95% CI 2.17–2.89, P < 0.001). The high
heterogeneity by including Ielsai et al. can be explained by under-
reporting of the post-stent lumen area due to limited utilization of
OCT view of vessels to measure lumen area (Online Supplementary
Fig. 2).
Furthermore, there was a significant reduction in post-stent calcium
angle (MD −56.08, 95% CI −70.15, −42.00, P < 0.001, I2: 0%) (Fig. 4B)
and in post-stent calcium thickness (MD −0.05, 95% CI −0.09, 0.01, P =
0.02, I2: 0%) (Fig. 4C).

Table 2
Baseline patients characteristics included in the meta-analysis.

Variables, number Aksoy, 2019 Ali, 2019 Aziz, 2020 Brinton, 2019 Cubero-gallego, 2020 Hill, 2020 Ielasi, 2019 Saito, 2021 All, % or mean ± SD

No. of patients 71 120 190 60 57 384 34 64 980

Age (years) 76 ± 9.7 72.1 ± 9.8 72 ± 9.5 72 ± 9.7 72.6 ± 9.3 71.2 ± 8.6 69.6 ± 10.1 76 ± 9.7 72.1 ± 9.08
Male 66 96 172 48 53 342 26 48 75.4% (739/980)
Hypertension 45 86 NR 48 43 342 29 53 87.6% (859/980)
Hyperlipidemia 26 16 127 48 34 47 28 55 81.9% (647/790)
Smoking 51 94 137 9 41 294 17 40 32.2% (316/980)
Diabetes mellitus 24 38 95 18 32 154 18 31 41.8% (410/980)
Prior MI 42 31 101 24 20 69 14 13 32% (314/980)
Prior CABG 11 8 31 14 5 36 NR 2 11.3% (107/946)
LVEF 51 ± 13 NR NR NR 53.6 ± 11 NR NR NR 52.2 ± 12.14
Stroke 12 4 NR 8 6 29 NR 13 9.5% (72/756)
CKD 25 10 30 6 20 101 NR 15 21.8% (207/946)
Stable angina 33 NR 99 NR 20 NR 19 NR 48.9% (172/352)
ACSa 32 NR 91 NR 37 NR 15 NR 48.8% (172/352)

Note: Data are presented as mean ± SD (n) or % (n/N).

a
Acute coronary syndrome includes unstable angina, non-ST-Elevation myocardial infarction, and ST-elevation myocardial infarction.

5
M. Mhanna, A. Beran, S. Nazir et al. Cardiovascular Revascularization Medicine xxx (xxxx) xxx

Table 3
Lesions and procedural characteristics.

Variables Aksoy, 2019 Ali, 2019 Aziz, 2020 Brinton, 2019 Cubero-gallego, Hill, 2020 Ielasi, 2019 Saito, 2021 All, % or mean ± SD
2020

Total no of lesion 78 120 190 60 66 384 39 64 1011

Lesion localization
Left main 13 1 29 1 8 6 4 1 6.2% (63/1011)
LAD 34 75 78 28 31 217 18 48 52.3% (529/1011)
CX 5 14 38 8 16 49 3 4 13.5% (137/1011)
RCA 26 30 50 23 11 112 5 11 26.5% (268/1011)
Ostial 18 NR NR NR NR 13 NR NR 6.7% (31/462)
Proximal 31 NR NR NR 32 167 NR NR 43.6% (230/528)
Medial 26 NR NR NR 28 121 NR NR 33.1% (175/528)
Distal 3 NR NR NR 6 80 NR NR 16.9% (89/528)
CTO 2 NR 14 NR 2 NR NR NR 5.4% (18/334)
Length of lesion 21 ± 16 19.5 ± 9.8 NR 19.1 ± 8.3 26.9 ± 15.1 26.0 ± 11.7 NR 27.5 ± 10.4 24.3 ± 12.3

Calcification
Moderate 14 7 NR 0 NR 0 1 0 3% (22/740)
Severea 64 113 NR 60 NR 384 33 64 97% (718/740)
Lesion assessment
Eccentric lesion 43 34 NR 13 45 NR NR NR 41.6% (135/324)
Concentric lesion 35 86 NR 47 21 NR NR NR 58.4% (189/324)

Vascular access
Femoral artery 47 NR NR NR 20 154 NR 9 38.8% (230/592)
Radial artery 23 NR NR NR 33 227 NR 54 56.9% (337/592)

Procedural characteristics
Contrast agent, mL 165 ± 63 181.9 ± 66.4 NR NR 222.07 ± 115.7 167.9 ± 71.9 164.3 ± 84.7 NR 175 ± 77.6
Fluoroscopy time, min 27.34 ± 18.95 18.0 ± 11.1 NR 28.7 ± 17.5 31.6 ± 21 16.7 ± 9.7 26.5 ± 16.1 22.2 ± 11.1 24.1 ± 17
Total procedural time, min NR 68.3 ± 34.2 NR 90.2 ± 29.6 NR 55.1 ± 26.8 NR 62.5 ± 23.1 61.7 ± 30.2
No. of stents used 1.3 1.3 ± 0.6 NR 1.35 ± 0.76 1.29 ± 0.55 1.35 ± 0.74 NR 1.1 ± 0.3 1.3 ± 0.58
MIP, atm NR 5.8 ± 0.7 NR 6 ± 0.0 NR 6.0 ± 0.3 6.03 ± 3.1 6.0 ± 0.0 5.9 ± 0.53

Note: Data are presented as mean ± SD (n) or % (n/N).

Abbreviations: CTO: chronic total occlusion, CX: circumflex artery, LAD: left anterior descending artery, MIP: maximum inflation pressure, RCA: right coronary artery.
a
Severe calcification defined as defined either angiographically (radio-opacities involving both sides of the arterial wall and length of at least 15 mm) or by intravascular ultrasound
(IVUS) or optical coherence tomography (OCT) [presence of ≥270 degrees of calcium on at least 1 cross-section].

3.6. Safety outcomes
The proportional analysis with 95% confidence intervals (CIs) of
complications, including MACE and its individual components (cardiac
death [CD], myocardial infarction [MI], and target lesion revasculariza-
tion [TLR]) during hospitalization, at 30-day, and at 6-month follow-
up, are shown in Online Supplementary Fig. 3 and summarized in a
bar chart in Fig. 5. Coronary dissections (more than type B) were ob-
served in 0.5% (95%CI: 0.0%–1.0%) and perforations were observed in
0.4% of the cases (95%CI: 0.0%–0.9%), and the 30-days MACE occurred
in 4.9% (95%CI: 2.5%–7.3%) of the cases. Supplementary Table 3 shows
the safety outcomes for each study.
3.7. Quality and publication bias assessment
We assessed the quality of the included studies using the Newcastle-
Ottawa Scale [20] for observational studies, as shown in Supplementary
Table 4. All studies scored low to moderate in quality assessment. There
was a visible asymmetry in the funnel plot of the studies that reported
the clinical and the angiographic success rates suggesting publication
bias (Supplementary Figs. 4a & b). However, Egger's regression tests
were not statistically significant, implying no publication bias in both
the clinical success rate (P = 0.06) and the angiographic success rate
(P = 0.18).
4. Discussion
Our study is a systematic review and meta-analysis to discuss the
clinical and the angiographic success of adjunctive intravascular litho-
tripsy in managing calcified coronary lesions. Our findings suggest
that the IVL-guided strategy is effective with high clinical and
procedural success rates. Furthermore, there were no safety concerns
regarding intraprocedural complications, short-term and mid-term
outcomes.
CCL presents in almost 30% of patients presenting with ACS or stable
disease [21] and up to 50% of revascularization procedures in peripheral
vascular disease [22]. CCLs are independently associated with worse
procedural success, leading to increased risks of the peri-procedural
major adverse events, stent thrombosis, re-stenosis, and revasculariza-
tion rates [23]. IVL is a promising technique for severely CCL [24]; litho-
tripsy waves are delivered through IVL balloon-catheter available in
diameters from 2.5 mm to 4.0 mm (in 0.5-mm increments) and are
12 mm in length, with the balloon size is selected in a 1:1 ratio to the
reference coronary diameter, usually guided by intracoronary imaging.
The system generator is programmed to dispatch ten consecutive pulses
at a frequency of 1 pulse/s for a maximum of 80 pulses per catheter [24].
The desired effect of IVL is gained through calcific lesions fragmentation
achieved through axial splitting by compressive circumferential forces
and the violent collapse of cavitation bubbles, thus lead to progressive
extension of microfractures into macro-fractures and ultimately into
CCL shattering [24].
In our study, successful stent delivery was possible in 99.4%, and re-
sidual diameter stenosis <50% after stenting was achieved in 99.8%. Fur-
thermore, IVL achieved RDS <30% in 99.5% of patients after stenting. The
pre-procedure mean luminal diameter (MLD) was 1.02 ± 0.4 mm, in-
creased to 2.34 ± 0.55 mm after IVL and to 2.79 ± 0.45 mm after
stenting, yielding an acute luminal gain of 1.3 ± 0.64 mm and 1.8 ±
0.5 mm after IVL and stenting, respectively. Moreover, the overall
post-stent lumen area was significantly higher than the pre-IVL with a
significant reduction in luminal calcium angle and thickness after
stenting. Finally, of the study population, 95% achieved 30-day freedom
from major adverse cardiac events. Intraprocedural complications

6
M. Mhanna, A. Beran, S. Nazir et al.
Fig. 2. Forest plot showing the primary outcomes; (A): the clinical success rate and (B) the angiographic success rate of intravascular lithotripsy in the management of calcified coronary
artery disease.
(including coronary dissection or perforation) were observed in 1.3% of
the cases. Of the seven reported events of perforation, six of them were
attributed to Aziz et al. study (on Ellis classification; one was type I,
three were type II, and the remaining two were type III). However,
none of them were directly related to the IVL use (occurred after stent
insertion or during post-dilatation). The higher-grade perforations re-
quired covered stents, while the rest were treated with prolonged bal-
loon tamponade. Only one perforation was associated with in-hospital
mortality [11].
Our study comes on the heel of the publication of the DISRUPT CAD
III and IV [9,15], studies designed for regulatory approval of IVL. We in-
cluded a large, diverse patient population with more statistical power to
investigate the clinical efficacy and safety of IVL. Furthermore, this anal-
ysis included patients with ACS. Our findings emphasize the clinical use-
fulness of IVL in a more heterogeneous group of patients and confirm
the safety of the IVL treatment strategy.
A conventional option for CCL therapy is rotational or orbital ather-
ectomy that modifies CAC to deliver drug-eluted stent (DES). Two ran-
domized control trials compared rotational atherectomy and standard
PCI (ROTAXUS and PREPARE-CALC trials) [25,26]. Although the proce-
dural success was lower in the routine therapy arm, the rate of late
loss was higher in the atherectomy arm in the ROTAXUS trial [25]. In
the PREPARE-CALC trial [26] rate of intraprocedural complications was
3–4%, with in-hospital MACE occurred in 2% of cases. In the ORBIT II
study [27], 443 patients underwent adjunctive orbital atherectomy,
clinical and angiographic success defined by the same measures in the
current study, were achieved in 88.9% and 91.4%, respectively, com-
pared to 95.4% and 97% in our study (OR 2.23 and 2.73 respectively)
7
Cardiovascular Revascularization Medicine xxx (xxxx) xxx
(Fig. 5). Successful stent delivery rate was similar to our analysis
(99.2%), with <50% RDS achieved in 98.6% of subjects; however, the
30-day MACE rate was almost twice (10.4%) compared to our meta-
analysis and severe angiographic complications occurred at a rate of
7.2% (vs. 1.3% in our study). Other modalities used in CCL include cutting
or scoring balloons; in a meta-analysis (included more than 9000
patients) comparing cutting or scoring balloon devices to standard
PCI, no reduction in MACE or re-stenosis was noted, and the risk of cor-
onary perforation was higher with these devices [28]. The first future
randomized controlled trial, RAINBOW (NCT04013906), will compare
rotational atherectomy vs. IVL efficacy in plaque modification prior to
stent deployment.
Our meta-analysis is the second meta-analysis to investigate the
utility of IVL in calcified coronary artery lesions. The first meta-
analysis was conducted by Sattar et al. that showed an overall increase
in the post-IVL lumen diameter and reduction in post-stent luminal cal-
cium angle [29]. However, our meta-analysis included DISRUPT CAD III
and IV and three more studies, with a larger number of included pa-
tients (n = 980 patients vs. 282). In our study, severe calcification was
present in 97% of the observed lesions, thus lead to a more robust con-
clusion on the efficacy of IVL. Moreover, the patient population in our
study was sicker, with 50.3% presenting with ACS. Furthermore, we in-
vestigated the clinical and the angiographic success of IVL guided man-
agement of CCL and compared our results with the adjunctive orbital
atherectomy strategy utilized in the ORBIT II study.
Despite having severe calcification on most of our cohort, IVL
showed great effectiveness on its clinical and angiographic success end-
points. Furthermore, IVL before stent deployment was well tolerated
M. Mhanna, A. Beran, S. Nazir et al.
Fig. 3. Forest plot showing post-intravascular lithotripsy (IVL) changes in (A) lumen area, (B) calcium angle, and (C) maximum calcium thickness.
with a low rate of major peri-procedural clinical and angiographic com-
plications. In a recently published article; Kassimis et al. wrote a com-
prehensive review on IVL and included an algorithm for the
contemporary management of heavily calcified lesions in which IVL
could potentially be a fundamental practice to facilitate calcified plaque
modification in which fractured calcium stays in situ without distal em-
bolization, hence safely facilitates stent deployment and expansion. Fur-
thermore, authors concluded that the growing evidence of IVL utility
could expand its usage beyond coronary intervention; for example, in
transfemoral access facilitation, endovascular aneurysm repair and in
the management of carotid calcifications [30].
Our study has certain limitations. First, this meta-analysis is limited
by the small number of studies with small sample sizes and a low rate
of events. Second, only observational single-arm studies were available
in our analysis, and no randomized controlled trials (RCTs) were in-
cluded. Third, patient-level data was lacking, and IVUS and OCT were
underutilized in the included studies. Fourth, although analysis using a
random-effect model was performed, significant heterogeneity was
found in the study outcomes. However, sensitivity analysis showed sim-
ilar results. Therefore, the substantial heterogeneity could not be attrib-
uted to a single study. This heterogeneity might be explained by the
small number of included studies with small sample sizes.
5. Conclusion
IVL seems to have excellent efficacy and safety in the management of
severe CCL lesions. However, adequately powered RCTs are needed to
evaluate IVL compared to other calcium/plaque modifying techniques.
Funding
None.
8
Cardiovascular Revascularization Medicine xxx (xxxx) xxx
Author contributions
MM and AB conceived and designed the study and critically revised
the manuscript. MM, EE, and SN designed the study, collected, analyzed,
and interpreted the data, and drafted the manuscript. AE, O. Sajdeya,
and O. Srour collected the data and reviewed the literature. All authors
read and approved the final manuscript.
IRB approval
This study was deemed exempt by the Institutional Review Board of
the University of Toledo, as it was a meta-analysis of published studies
that included de-identified patient information.
Abbreviations: ACS: acute coronary syndrome, CABG: coronary ar-
tery bypass grafting, CKD: chronic kidney disease, LVEF: left ventricular
ejection fraction, MI: myocardial infarction.
CRediT authorship contribution statement
Mohammed Mhanna: Conceptualization, Methodology, Soft-
ware, Data curation, Writing – original draft, Visualization, Investi-
gation, Validation, Writing – review & editing. Azizullah Beran:
Data curation, Investigation, Validation, Visualization, Writing –
review & editing. Salik Nazir: Methodology, Supervision, Writing –
review & editing. Omar Sajdeya: Writing – review & editing. Omar
Srour: Writing – review & editing. Ahmed Elzanaty: Writing –
review & editing. Ehab A. Eltahawy: Conceptualization, Supervision,
Writing – review & editing.
Declaration of competing interest
None.
M. Mhanna, A. Beran, S. Nazir et al. Cardiovascular Revascularization Medicine xxx (xxxx) xxx

Fig. 4. Forest plot showing post-stent changes in (A) lumen area, (B) calcium angle, and (C) maximum calcium thickness.

Fig. 5. (Right) Bar chart showing the proportional event rates of major adverse cardiac events after intravascular lithotripsy (IVL) and its components at different follow-up durations.
(Left) Bar chart with included OR and 95%CI that compares our study outcomes to ORBIT II study. Abbreviations: MACE: Major Adverse Cardiac Events, CD: Cardiac death, MI:
Myocardial infarction, TLR: Target lesion revascularization, IH: In hospital, 30D: At 30 days, 6 M: At 6 months. OR: Odds ratio, CI: Confidence interval. IVL: Intravascular lithotripsy,
ORBIT II: Orbital Atherectomy System in Treating De Novo, Severely Calcified Coronary Lesions. https://doi.org/10.1016/j.jcin.2014.01.158.

9
M. Mhanna, A. Beran, S. Nazir et al.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.carrev.2021.05.009.
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