Disrupt CAD III With the Shockwave Coronary IVL System
Research type
Research Study
Full title
Prospective, Multicenter, Single-Arm, Global IDE Study of the Shockwave Coronary Intravascular Lithotripsy (IVL) System with the Shockwave C2 Coronary IVL Catheter in Calcified Coronary Arteries (Disrupt CAD III Study)
IRAS ID
257081
Contact name
Jonathan Hill
Contact email
Sponsor organisation
Shockwave Medical, Inc
Clinicaltrials.gov Identifier
Duration of Study in the UK
3 years, 4 months, 0 days
Research summary
Summary of Research
Calcified coronary artery lesions increases risk for cardiovascular events and are associated with advanced age, diabetes and chronic kidney disease. These lesions are often bulky and negatively impacts coronary interventions such as stenting (procedure of placing a stent i.e. a metal or plastic tube into the artery) used for restoring blood flow through blocked arteries. Current therapies that are used to overcome this problem have their own limitations. Objective of this prospective, multicentre, single-arm study is to assess the safety and effectiveness of the device, Shockwave Coronary Intravascular Lithotripsy (IVL) System, to treat calcified coronary lesions prior to stenting. The device prepares the blood vessels for stenting by emitting short pulses of waves at the area of interest in the blood vessel. These waves puts pressure in calcium lesions leading to fracture of these lesions but passes through soft tissue, and facilitates blood vessel compliance for stenting.
Participants with calcified coronary artery suitable for coronary interventions consenting for participation and meeting all the inclusion and exclusion criteria will be enrolled to the study. Participants, if consents, will be included in three sub study. These sub study will be conducted to understand the mechanism of action of the device and its impact on implantable device and blood movement.
Approximately 392 subjects will be enrolled at 50 global sites. Participants will be followed up at 30days, 6, 12 and 24 months post procedure.
Summary of Results
The Disrupt CAD III clinical study was sponsored by Shockwave Medical, Inc. The goal of the Disrupt CAD III investigational clinical study was to determine the safety and effectiveness of the Shockwave Coronary IVL System to treat de novo (never been treated), calcified, stenotic, coronary lesions prior to stenting. Disrupt CAD III was a prospective, multicenter, single-arm, pivotal global investigational study. This study was carried out to show that the study device is safe and reliable in treating narrows coronary arteries and to receive FDA approval in the US. It was conducted per a protocol approved by the US FDA in compliance with Good Clinical Practices (GCP) and other applicable regulatory requirements including, ISO, the Declaration of Helsinki), and applicable local Ethics Committee (EC) or Institutional Review Board (IRB) requirements. An independent core laboratory provided an unbiased analysis of all images and an independent clinical events committee (CEC) made a formal judgment on all clinical events. A Data Safety Monitoring Board (DSMB) looked over the safety data regularly and checked the validity and scientific value of the study. The study was monitored according to the monitoring plan and provides a high-quality dataset that allows for a confident interpretation of results.
The main safety goal was the absence of major adverse cardiac events (MACE) through 30 days with MACE defined as cardiac death, myocardial infarction (MI) or target vessel revascularization (TVR). The main effectiveness goal of Procedural Success (defined as stent delivery with a residual stenosis < 50% without in-hospital MACE) was evaluated at discharge. Per the pre-specified Statistical Analysis Plan (SAP), the study was to be deemed a success if both the primary safety and effectiveness goals were met.
The subjects invited to take part in the study, had a narrowed blood vessel in their heart due to calcium. To treat this, their doctor scheduled a procedure called angioplasty to open the blocked arteries and restore normal blood flow to the heart muscle. To take part in the study, patients went to the following visits: Screening Visit (to see if the subject was eligible to participate), Procedure Visit (Angioplasty and monitoring after the procedure to make sure subjects were ready to go home) and Follow Up Visits (4 visits following the procedure; 6, 12 and 24months).
Patients began participating in the study in January 2019 and finished in March 2020. The first patient at each center was considered a roll-in to confirm the investigator’s expertise with the device. A total of 431 subjects (47 roll-in, 384 pivotal) participated from 47 centers in the United States, France, Germany, and the UK; most of the subjects (86.5%, 373/431) were from US centers. The Pivotal Analysis Set (n=384) was the group used to assess the primary safety and effectiveness goals. The dataset through 30 days was locked and exported for analysis on June 28, 2020, and study results through 30 days including assessment of the primary and secondary goals were submitted to FDA on August 22, 2020. All 24-month visits were completed as of April 2022. The database was locked and exported for review on June 20, 2022, for this report; and the study is complete.
Baseline characteristics for the pivotal group were consistent with those presenting with stable coronary artery disease. The average age of all subjects enrolled in the pivotal group was 71.2 ± 8.6 years, ranging from 43 to 95 years. The majority of the pivotal group (76.6%, 294/384) were male and white (82.8%, 318/384). Average body mass index (BMI) in the pivotal cohort was 29.2 ± 5.0 kg/m2. Diabetes was reported in 40.1% (154/384) of the pivotal subjects enrolled. Most of the pivotal subjects (89.1%, 342/384) suffered from hypertension (high blood pressure) and hyperlipidemia (high cholesterol), 46.9% (180/384) had prior percutaneous coronary interventions, 9.4% (36/384) had a prior coronary artery bypass graft (CABG), 18.0% (69/384) had a history of myocardial infarction and 12.0% (46/384) had renal insufficiency. Former smokers represented 43.0% (165/384) of pivotal subjects, while 12.2% (47/384) were current smokers. In the pivotal group, most of the subjects (54.7%, 210/384) were NYHA Class I and there were no subjects with NYHA Class III/IV heart failure. Most subjects (70.3%, 268/381) had baseline angina scores of CCS II or III. The average LVEF was 56.6 ± 9.2%. The left anterior descending artery (LAD) was the most common target vessel for treatment (56.5%, 217/384).
In the pivotal cohort, 98.2% (377/384) of subjects received IVL therapy and 99.2% (381/384) received a stent. The average number of IVL catheters used per subject was 1.2 ± 0.5 and average number of pulses delivered was 68.8 ± 31.9. An average of 1.3±0.5 Drug Eluting Stents were implanted per subject.
A total of 341 subjects in the pivotal cohort (88.8%, 341/384) had post-IVL images available for analysis with an average residual stenosis of 37.2 ± 13.5%. All subjects in the pivotal cohort that received a stent during the index procedure (n=381) had final (post-stent) images available for analysis. In the pivotal cohort, the average stented length was 31.00 ± 12.01 mm. The in-stent final residual stenosis was 11.9 ± 7.1%. In the pivotal cohort, 12 subjects (3.1%, 12/384) experienced a serious angiographic complication at any time, nine (9) subjects (2.6%, 9/341) experienced a serious angiographic complication immediately following IVL, and two (2) (0.5%, 2/384) had an ongoing serious angiographic complication at the end of procedure.
The study met its primary safety goal. The observed absence of 30-day MACE was 92.2% (353/383) and the lower bound of the one-sided 95% confidence interval was 89.9%, greater than the performance goal of 84.4%. As such, the null hypothesis was rejected and the primary safety endpoint was met (p<0.0001). Most of 30-day MACE were in-hospital events (27/30, 90.0%) which were predominantly non-Q-wave MIs (22/27, 81.5%) due to elevated biomarkers.
The study also met its primary effectiveness goal. The observed rate of Procedural Success was 92.4% (355/384) and the lower bound of the one-sided 95% confidence interval was 90.2%, greater than the performance goal of 83.4%. As such, the null hypothesis was rejected and the primary effectiveness endpoint was met (p<0.0001).
The safety and effectiveness endpoints were met even under the worst-case scenario wherein all subjects with missing endpoint data were assumed as failures.
The secondary goals were also favorable. Device Crossing Success, defined as the ability to deliver the IVL catheter across the target lesion and deliver lithotripsy without serious angiographic complications immediately after IVL, was achieved in 95.8% (368/384) of pivotal subjects. Angiographic Success, defined as stent delivery with < 50% residual in-stent stenosis and without serious angiographic complications (at any time), was achieved in 96.4% (370/384) of pivotal subjects. Using a more contemporary threshold of 30% residual stenosis, Angiographic Success was achieved in 96.1% (369/384) of pivotal subjects, Procedural Success was achieved in 92.2% (354/384) of pivotal subjects, and there was a low frequency of serious angiographic complications 3.1% (12/384).
A summary of additional secondary endpoint outcomes are as follows:
MACE:
The estimate for 24-month MACE was 18.9%, which is consistent with PCI procedures in calcified patients.
Death:
There were 22 total deaths reported in the study, out of which 10 deaths were adjudicated as cardiac, resulting in an estimated 24-month cardiac death rate of 2.7%.
Protocol Defined MI:
A total of 47 subjects in the pivotal cohort experienced a protocol-defined MI event, corresponding to an estimated 24-month rate of 12.6%. Most events were attributable to the target vessel (TV-MI) rate of 8.1%. There were a total of 52 protocol-defined MI events across these 47 subjects: 26 peri-procedural events based on elevated cardiac enzymes and 26 MI events after discharge based on the 4th Universal Definition of MI.
Alternate Definitions for Periprocedural MI:
In the pivotal cohort, 28 (7.3%) subjects experienced a peri-procedural MI that met the Fourth Universal Definition (Type 4a) and 10 subjects (2.6%) experienced a peri-procedural MI event that met the SCAI definition.
Target Lesion Failure (TLF):
In the Pivotal analysis set through 24 months, 60 of 384 subjects met the criteria for TLF resulting in an estimated rate of 16.1%.
Revascularization:
A total of 57 subjects had undergone a revascularization procedure with estimated rate of 15.4%. Most procedures (34 total) in the 24-month period were non-target revascularizations with the rate of 9.1%. The estimated rate of Target Vessel Revascularization at 24 months was 8.5% (31 total events); of these, all were deemed to be ischemia-driven (ID-TVR) per the CEC (8.5% (31)) and 23 were ischemia-driven target lesion revascularization (ID-TLR) procedures resulting in a 24-month event rate of 6.4%.
Stent Thrombosis (ST):
A total of 10 ST events occurred, resulting in an estimated 24-month stent thrombosis rate of 2.7%; total of five (5) subjects experienced a definite or probable stent thrombosis, resulting in a 24-month estimated event rate of 1.4% and five (5) subjects experienced a definite stent thrombosis resulting in estimated event rate of 1.4%.
In conclusion, the Disrupt CAD III Study was successful by meeting both the main safety and effectiveness goals. The Shockwave Medical Coronary IVL System showed compelling safety with a low rate of major adverse cardiac events and angiographic problems. Acute performance results showed high procedural success with a large acute gain and low residual stenosis in this difficult-to-treat population. These results show the ongoing safety and effectiveness of the Shockwave Medical Coronary IVL System for the treatment of subjects with calcified lesions in coronary arteries before stent placement.REC name
London - Dulwich Research Ethics Committee
REC reference
19/LO/0106
Date of REC Opinion
8 Apr 2019
REC opinion
Further Information Favourable Opinion