Intravascular Lithotripsy for Vessel Preparation in Calcified Coronary Arteries Prior to Stent Placement　― Japanese Disrupt CAD IV Study 2-Year Results ―

Shigeru Saito; Seiji Yamazaki; Akihiko Takahashi; Atsuo Namiki; Tomohiro Kawasaki; Satoru Otsuji; Shigeru Nakamura; Yoshisato Shibata

doi:10.1253/circrep.CR-23-0082

Abstract

Background: Intravascular lithotripsy (IVL) delivers acoustic pressure waves to modify calcification to enhance vessel compliance and optimize stent deployment. The Disrupt CAD IV study enrolled patients with severe coronary artery calcification. The primary safety (30-day major adverse coronary events [MACE], 6.3%) and effectiveness (procedural success, 93.8%) endpoints were achieved. The present analysis evaluated the 2-year outcomes of the study.

Methods and Results: Disrupt CAD IV (NCT04151628) was a prospective, single-arm, multicenter study designed for regulatory approval of the Shockwave Coronary C² IVL system in Japan. Angiographic outcomes were analyzed by an independent core laboratory and adverse events were adjudicated by a Clinical Events Committee. Kaplan-Meier analysis was performed for MACE (composite of cardiac death, MI or target-vessel revascularization [TVR]), target lesion failure (TLF: composite of cardiac death, TV-MI, and target lesion revascularization [TLR]), and stent thrombosis (ST). At 2 years, 62 subjects had completed follow-up. MACE occurred in 12.6% (cardiac death 0.0%, MI 6.3%, TVR 7.9%) and TLF occurred in 7.8% of patients, with both rates driven by non-Q-wave MI events (6.3%). TLR was 3.2%; no ST occurred through 2 years.

Conclusions: Treatment with IVL in patients with severely calcified coronary lesions was associated with low rates of MACE, TLR, and ST at 2 years, demonstrating continued durable safety and effectiveness of coronary IVL in a Japanese population.

Coronary artery revascularization is commonly performed by percutaneous coronary intervention (PCI) with placement of a drug-eluting stent. However, PCI can be complicated by the presence of coronary artery calcification (CAC), a complex challenge in the treatment of coronary artery disease (CAD) and associated with poor acute and long-term clinical outcomes.¹ Severe calcification can interfere with catheter crossing, balloon dilatation, and/or stent expansion, and consequently result in a higher risk of complications, procedural failure, stent underexpansion or malapposition, and an increased risk of major adverse cardiovascular events (MACE).¹^–³ Although specialized balloons and atheroablative technologies have been used to treat severe CAC, procedural complications remain a concern.² Specialty balloons rely on high luminal pressure to achieve adequate vessel dilatation, which can lead to barotrauma,⁴ and atherectomy effectiveness in treating severely calcified CAD is limited by the presence of deep calcification and has also been associated with an increased risk of angiographic complications and MACE.²^,⁴ Optimized vessel preparation for CAC should aim for both a low complication risk and a high procedural success rate.

Intravascular lithotripsy (IVL) is a vessel preparation treatment option that delivers atraumatic acoustic pressure waves to modify both superficial and deep calcification and enhance vessel compliance, thus facilitating PCI in complex CAC and optimize successful stent deployment.³ Importantly, coronary IVL has consistently shown high rates of stenosis reduction and low rates of procedural failure and complications in smaller cohort assessments as well as in larger global prospective studies.⁵^–¹² The Disrupt CAD IV study enrolled Japanese patients with severe CAC (100%) and with follow-up out to 2 years, assessing whether the acute outcomes of the primary endpoints translated into longer-term clinical benefit. The primary safety endpoint of 30-day MACE (6.3%) and effectiveness (procedural success, 93.8%) have been previously reported.¹⁰ Secondary endpoints at 1 year, including target lesion failure (TLF; 6.3%), MACE (9.4%), and stent thrombosis (ST; 0.0%), have also been published.¹³ The current analysis presents the final outcomes of the Disrupt CAD IV study and evaluated secondary endpoints at 2 years.

Methods

Study Design

Disrupt CAD IV (NCT04151628) was a prospective, single-arm, multicenter study designed for regulatory approval of the Shockwave Coronary C² IVL system in Japan. Study design and endpoints have been previously described.¹⁰^,¹³ Study participants provided written informed consent, and study procedures accorded with the Declaration of Helsinki, Good Clinical Practice guidelines, ISO 14155, applicable national requirements in Japan, and local institutional review boards and ethics committees. Angiographic outcomes were analyzed by an independent core laboratory (Cardiovascular Research Foundation, New York, NY, USA) and adverse events were adjudicated by a Clinical Events Committee (Cardiovascular Research Foundation). The study investigators had full access to data, controlled the decision to publish, and agreed to be accountable for the accuracy and completeness of the reported data. This paper reports the 2-year outcomes from Disrupt CAD IV, which concluded the follow-up for this study.

Patients

A complete list of study entry criteria has been previously published.¹⁰ Briefly, study participants scheduled for PCI who presented with stable, unstable, or silent ischemia, and severely calcified de novo coronary artery lesions, with a target lesion length ≤40 mm and target-vessel reference diameter between 2.5 and 4.0 mm were eligible. Patients with New York Heart Association Class III or IV, renal failure, active systemic infection, uncontrolled diabetes or severe hypertension, and recent myocardial infarction (MI), stroke, or transient ischemic attack were excluded.

Study Device and Procedure

The treatment of severely calcified coronary vessels prior to PCI with a single-use coronary IVL catheter (Shockwave Medical, Inc. Santa Clara, CA, USA) in CAD IV has been described previously.¹⁰ Briefly, the coronary IVL catheter contains multiple lithotripsy emitters and an integrated, fluid-filled balloon. The emitters create acoustic pressure waves to selectively disrupt both superficial and deep calcification in situ. A 0.014-inch (0.36-mm) Rapid Exchange (Rx) guidewire was used to introduce the IVL catheter into the target vessel and to position it across the target lesion. An appropriately sized IVL balloon (1 : 1 ratio to the reference vessel diameter) was inflated to 4 atm to optimize vessel wall apposition. An initial 10 IVL pulses were then delivered before the balloon was temporarily inflated to 6 atm, then deflated to re-establish blood flow. This process was repeated until complete balloon inflation was achieved for optimal vessel preparation. Subsequent stent placement was performed, followed by high-pressure post-dilatation with a non-compliant balloon. Optical coherence tomography before and after IVL, as well as after stent placement, was used to characterize pre-existing calcification, and the degree of calcium fracture and stent expansion after treatment. Guideline-directed anticoagulation and antiplatelet regimens were administered, and patient follow-up was scheduled at discharge for 30 days, 6 months, and for 1 and 2 years after the procedure.

Outcomes

The primary safety (30-day freedom from MACE, a composite of cardiac death, MI, or target-vessel revascularization [TVR]) and effectiveness (procedural success) endpoints, as well as the complete 30-day and 1-year outcomes, have been previously reported.¹⁰^,¹³ Serious angiographic complications included Type D–F dissection (National Heart, Lung, and Blood Institute classification system), perforation (Ellis classification), abrupt closure, or persistent slow/no flow. All 2-year outcome measures were secondary endpoints. TLF was a composite of cardiac death, target vessel MI, and target lesion revascularization (TLR). Periprocedural MI was defined as a peak post-PCI CK-MB concentration >3-fold the upper limit of normal with or without new pathologic Q waves at discharge; the Fourth Universal Definition was used to define MI beyond discharge. Angina severity was assessed using the physician-reported Canadian Cardiovascular Society (CCS) angina classification system, which grades the relationship of angina symptoms with physical activity level.

Statistical Analysis

The present descriptive analysis reports 2-year outcomes from the Disrupt CAD IV study. Kaplan-Meier analysis was performed for the outcome of MACE, TLF (cardiac death, TV-MI, or TLR), and ST (definite and probable) at 2 years. Data analysis was performed using SAS v9.4 (SAS Institute, Cary, NC, USA) and GraphPad Prism 9.5 (GraphPad software, San Diego, CA, USA).

Results

Between November 2019 and April 2020, 72 patients were enrolled at 8 centers in Japan, with 64 patients comprising the intent-to-treat population (Figure 1). Two patients died between the 1- and 2-year follow-up (non-cardiac deaths), but all others (n=62) were eligible for 2-year follow-up and 98.4% (n=61) completed the visit. At 2 years, MACE had occurred in 12.6% of patients (cardiac death 0.0%, MI 6.3%, TVR 7.9%) and TLF in 7.8% (cardiac death 0.0%, TV-MI 6.3%, ID-TLR 3.2%), with both rates driven by early non-Q-wave MI (NQWMI) events (6.3%) (Figure 2).

Figure 1.

Patient flow through 2-year follow-up. The first subject enrolled at each site was considered a roll-in patient and was not included in the intention-to-treat (ITT) analysis cohort.

Figure 2.

Kaplan-Meier rates for major adverse cardiac events (A), target lesion failure (B) and selected endpoint components (C–E). ID-TLR, ischemia-driven target lesion revascularization; MI, myocardial infarction; TVR, target-vessel revascularization.

As shown in previous reports,¹⁰^,¹³ 4 NQWMIs occurred within 1 month of coronary IVL. However, there were no additional NQWMI events after this subsequently and no cases of Q-wave MI occurred after coronary IVL throughout the follow-up. Three TVR events had occurred by 1-year follow-up, with 2 additional events occurring between the 1- and 2-year follow-up. There were no ST events through the 2 years and 90.2% of patients were asymptomatic at the end of the study based on the CCS Angina Grade (Figure 3).

Figure 3.

Canadian Cardiovascular Society (CCS) Angina Grade over the 2-year follow-up; 90.2% of patients were asymptomatic at the end of the study.

Discussion

The Disrupt CAD IV study represents the longest follow-up of Japanese patients with severely calcified and stenotic coronary lesions treated with IVL. This study previously demonstrated the safety and effectiveness of coronary IVL treatment, with low rates of procedural complications, excellent stenosis reduction, and favorable TLF and ST rates after 1 year.¹⁰^,¹³ This final report on CAD IV expands on these results, highlighting continued safety and effectiveness out to 2 years, evident by an absence of additional MI events, cardiac deaths, or any ST events during the entire study, with just 2 TVR events between the 1- and 2-year follow-up, and fully resolved anginal symptoms in ≈90% of patients.

Vascular calcification becomes increasingly prevalent with increasing age and is especially frequent in patients with diabetes or chronic kidney disease, with chronic kidney disease being a frequent comorbidity in the Japanese population.¹⁴ Approximately 8% of patients undergoing PCI present with severe calcification, which can affect catheter delivery, balloon expansion, and stent deployment.³^,¹⁵ Coronary IVL can help facilitate PCI in such severely calcified lesions by fracturing both superficial and deep layers of calcium to improve vessel compliance, allowing maximum stent expansion, and possibly improving drug delivery after drug-coated balloon therapy.³ Prior reports have demonstrated excellent short-term outcomes of coronary IVL in Asian patients with calcified coronary arteries prior to PCI.¹⁰^–¹²^,¹⁶ In addition, the global CAD III study has recently published 1-year and presented 2-year results¹⁷ showing that the benefits of calcium modification with IVL for optimized stent deployment were sustained to at least 2 years.¹⁸^,¹⁹ TLF rates were continuously acceptable and driven by target-vessel NQWMI (10.3%), which mostly occurred prior to 30 days. Frequencies of ID-TLR (6.4%), cardiac death (2.7%), and ST (1.4%) remained low out to 2 years.¹⁸ The results of CAD IV corroborate those findings in Japanese patients and support the long-term safety and effectiveness of coronary IVL-facilitated PCI regardless of geographic region.

Although cross-trial comparisons have limitations, understanding the historic context of longer-term results after complex PCI in Japanese patients is important to assess the presented results of the CAD IV study. The J2T Registry was a multicenter registry of rotational atherectomy for calcified coronary lesions that enrolled 1,090 Japanese patients with similar characteristics to those in CAD IV. The 1-year outcomes for MACE (23%), all-cause death (8%), TVR (14%), and TLR (17%) following rotational atherectomy were markedly greater than those observed in CAD IV,¹³ with the incidence of MACE continuing to rise to 46.7% during a median follow-up period of 3.8 years.²⁰ Similar findings were reported in the Coronary Orbital Atherectomy System Study (COAST), which reported 1-year rates of MACE, TVR, and TLR of 22.2%, 9.4%, and 6.3%, respectively.²¹ Disrupt CAD IV demonstrated high procedural success and low long-term rates of MACE (12.6%), ID-TLR (3.2%), and ST (0.0 %) relative to historical studies. One explanation might be the IVL mode of action, which, different from atherectomy, uses a low-pressure balloon (4 atm) and the atraumatic delivery of lithotripsy that selectively modifies superficial and deep layers of calcium, with a demonstrated low risk of vascular injury or angiographic complications.³

Lastly, in a recent consensus document from the Japanese Association of Cardiovascular Intervention and Therapeutics on the use of drug-coated balloon treatment in CAD, the experts highlighted the need for optimal lesion preparation and included the use of lithotripsy in moderate-severe calcified vessels in their recommended treatment algorithm.²¹

Study Limitations

The limitations of the CAD IV study have been previously described and are inherent to the study design and include the lack of a control group.¹⁰^,¹³ In addition, head-to-head comparisons with other calcium-modifying modalities or the use of individualized therapy (e.g., combination therapy approaches or specific treatment algorithms, including PCI with drug-coated balloon) as an alternative “leave nothing behind” strategy,²² remain to be systematically studied in future trials. Lastly, we did not systematically collect information on the medical management of patients.

Conclusions

Overall, the CAD IV study demonstrated low 2-year rates of MACE and TLR, and no cardiac deaths or ST in patients treated for severely calcified CAD. The study demonstrated continued durability of favorable acute procedural safety and effectiveness of coronary IVL in a Japanese population.

Acknowledgments

The authors thank Maureen J Ostaff, PhD for medical writing and Ryan Shields, MS and Suzanne Wilson, MS for statistical support.

Disclosures

S.S. reports consultancy annual income from a single company or organization, as an officer or consultant, which exceeds an annual total of 1,000,000 yen from Elixir Medical and Medinol Ltd. T.K. reports remuneration for attending meetings (presentations), paid for the time and effort of the activity, which exceeds an annual total of 500,000 yen, per company or organization from Abbott Japan, Boston Scientific Japan, Amgen, Medtronic Japan, Japan Lifeline. Shockwave Medical Inc. (Santa Clara, CA, USA), provided financial support for this research.

IRB Information

Reference number: 024-19-08. Tokushukai Group Joint Institutional Review Board, Kyoto-Katsura Hospital Institutional Review Board, Tenjinkai Shin-Koga Hospital, Institutional Review Board, Iryohojin Koyukai Nishi Byoin, Institutional Review Board, JOHAS Kanto-Rosai Hospital, Director, Institutional Review Board, Miyazaki Medical Association Hospital, Institutional Review Board, Sakurakai Takahashi Hospital, Institutional Review Board.

Data Availability

The deidentified participant data will not be shared.

References

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