The future of interventional cardiology

INTRODUCTION

Transcatheter aortic valve implantation (TAVI) is a well-established procedure for severe symptomatic aortic stenosis. Previously, this procedure was used exclusively to treat inoperable and high-risk patients but is now a common approach for intermediate and low-risk populations. In parallel, there has been growing global experience in several off-label scenarios, as in bicuspid, valve-in-valve, and noncalcified aortic regurgitation (NCAR).1

AORTIC REGURGITATION

Due to abnormalities in the aortic leaflets or their supporting structures (ie, aortic root and annulus), or both, aortic regurgitation (AR) causes diastolic reflux of blood from the aorta into the left ventricle (LV). This leads to LV volume overload and dilatation, allowing the ejection of a larger stroke volume. However, over time, it results in a decline in systolic function causing symptoms conferring a poor prognosis.2 Current European and American guidelines recommend surgical intervention when significant AR is accompanied by symptoms, reduced LV ejection fraction, or severe LV dilatation.3-4 Although moderate or severe AR affects around 2.2% of the population aged 70 years or older, up to 30% of these individuals are deemed inoperable due to advanced age or comorbidities, with percutaneous options—including dedicated and nondedicated devices—gaining increased interest due to the absence of safe surgical alternatives.5

CHALLENGES OF TAVI IN NCAR

Specific challenges for transcatheter devices are due to the characteristics of patients with NCAR, including larger aortic annular dimensions, aortic root dilatation, insufficient annular calcification for anchoring, and larger stroke volume with backflow to the LV causing a “suction effect”. All of these factors create difficulties in selecting the appropriate device and positioning and deploying it correctly, and consequently increase the risk of embolization or malpositioning of the prosthesis, requiring a second valve implantation. Ultimately, these challenges are associated with increased mortality. In particular, the primary concern is valve embolization. To reduce the risk of this complication, prosthesis oversizing is routinely performed, but the exact degree of oversizing with each device has not been standardized. Furthermore, oversizing is associated with a high rate of conduction system disturbances and may carry a higher risk of annular rupture.

DEVICES AND EVIDENCE

There are 2 dedicated-devices for NCAR: The Trilogy system (JenaValve Technology Inc, California, United States) and the J-Valve (JC Medical Inc, California, United States). The most recent experience with these dedicated devices has been reported by Adam et al.6 and García et al.7 The Trilogy system was associated with a 30-day mortality rate of 1.7% (vs 3.7% with J-Valve) and both had 0% ≥ moderate residual AR. However, 7.4% required conversion to surgery with the J-Valve, leading to some technical changes in the technology. Of note, the pacemaker rate with both systems was above 10% (19.6% and 13%, respectively). These promising dedicated technologies still have certain shortcomings, the main one being the lack of sizes covering large annuli; indeed, for 10% oversizing, the proportion of AR patients whose aortic structures were above the recommended indications was up to ~50%.8

The first-in-human compassionate use of SAPIEN (Edwards Lifesciences, California, United States) was reported in 2012,9 followed by multiple case series and registries reporting the feasibility of TAVI in NCAR with new-generation nondedicated devices. The most recent summary of the experience was reported in a meta-analysis by Takagi et al.,10 and the pooled analysis at 30 days demonstrated 80.4% device success, 9.5% all-cause mortality, 7.4% ≥ moderate residual AR, and a pacemaker rate of 11.6%. Although these results were promising and significantly better than with early-generation devices in all aspects, there was still a substantial gap to achieve similar outcomes to TAVI in aortic stenosis and, indeed, the rate of valve embolization was high (above 9% with all the technologies, even the dedicated technologies).10

More recently, the new Myval balloon-expandable valve (Meril Lifesciences Ltd, Vapi, India) has demonstrated better outcomes than those reported by Takagi et al. likely due to the availability of extra-large sizes (30.5 and 32 mm), allowing a greater degree of oversizing and covering annuli up to 100.5 mm perimeter and 840 mm² area at its nominal volume, increasing the proportion of inoperable patients who can be treated percutaneously. Because of the high procedural success rate (94.7%), and the absence of severe anatomical complications (ie, annular rupture, aortic dissection, or coronary obstruction), the Myval balloon-expandable valve is a promising new approach to this condition until dedicated devices for these annular sizes become available. Nevertheless, prosthesis embolization occurs in 3.5% of patients, leaving room for improvement; according to this research, the interplay of the aortic annulus and the LV outflow tract could help to predict the risk of valve embolization, suggesting that, in borderline annular sizes, when 20% oversizing cannot be achieved and adverse (tapered) morphology is detected, the intervention should be avoided or might be carried out under mechanical circulatory support (figure 1).11

Figure 1. Anatomical predictor of valve embolization during transcatheter aortic valve implantation for noncalcified aortic regurgitation. LVOT, left ventricular outflow tract.

Poletti et al.12 recently compared latest-iteration nondedicated devices and suggested that Myval might provide the best outcomes compared with other devices; indeed, the subanalysis (not published yet) comparing the 2 balloon-expandable platforms suggested that, despite being used in patients with significantly smaller aortic annuli, SAPIEN-3 had a lower device success rate (72% vs 90%) and a higher rate of prosthesis migration/embolization (SAPIEN 17% vs MyVal 5%).12 A summary of the PURE-AR study11 with the Myval device is shown in figure 2. The current evidence on different devices is summarized in table 1.

Figure 2. Main outcomes reported in the Myval registry for treatment of noncalcified aortic annuli with large annuli. AR, aortic regurgitation; LVOT, left ventricular outflow tract; TAVR, transcatheter aortic valve regurgitation.

Table 1. Comparison of outcomes between the international registries

In conclusion, although the surgical approach remains the standard-of-care in NCAR patients, the outcomes of new-generation dedicated and nondedicated TAVI devices are rapidly improving. The main caveats include the lack of large-sized dedicated devices and the risk of valve embolization with nondedicated devices, although this risk can be minimized by extra-large sizes and morphological analysis of the LV outflow tract. The rate of conduction disturbances is still higher than for TAVI in aortic stenosis and its decrease will require specific technology and strategies, given its potentially negative impact in LV remodelling. Clinical trials comparing surgery and TAVI in this setting for high-risk patients are an urgent need.

FUNDING

None.

AUTHORS’ CONTRIBUTIONS

I.J. Amat-Santos and J.P. Sánchez-Luna equally contributed in the design, data gathering, analysis, and final approval of the manuscript.

CONFLICTS OF INTEREST

I.J. Amat-Santos is proctor for Boston Scientific, Medtronic, and Meril Life. There are no other potential conflicts of interest related to this work.

REFERENCES

Transcatheter aortic valve implantation (TAVI) is an established treatment for elderly patients with severe symptomatic aortic stenosis. Currently, most procedures are performed through transfemoral transcatheter aortic valve implantation (TF-TAVI) under conscious sedation via vascular access with safe and effective closure.1 Nonetheless, large-bore transcatheter arterial accesses are inherently associated with a higher risk of vascular and hemorrhagic complications.2

The use of vascular closure devices (VCDs) in endovascular procedures has grown exponentially. Their emergence has reduced time to hemostasis, facilitated early ambulation and discharge, and reduced hospitalization costs.2-4

However, failed VCDs are not an uncommon finding (1%-8%), and vascular and hemorrhagic complications—most commonly found at the access site—can sometimes determine procedural success or failure.5,6 Vascular complications significantly contribute to clinical outcomes in the short- and long-term, including length of stay, rehospitalizations, need for blood transfusions, and all-cause mortality.2,4 Therefore, successful arterial access and closure is critical in TAVI.2,7,8

CURRENT DEVICES

The most widely used VCDs for large-bore arteriotomy closure are the suture-mediated closure system, Perclose ProGlide system (Abbott Vascular, United States), and the most recent plug-based MANTA vascular closure device (Teleflex/Essential Medical, United States).

The failure mechanisms associated with the Perclose ProGlide device include suture-related malfunction, unsuccessful deployment, and incomplete vessel wall apposition. Potential errors associated with the MANTA device include failed deployment, intraluminal or subcutaneous deployment, collagen detachment, delivery handle-related arterial occlusion, and incomplete handle apposition.5,6,8

The first feasibility studies ever conducted on the MANTA device showed promising safety and efficacy. Afterwards, several registries have presented their findings that compare favorably with suture techniques.8-11

Two recent randomized clinical trials have compared the 2 techniques. The MASH trial included 210 patients and found no differences in its primary endpoint: puncture site-related major and minor complications (10% with the MANTA vs 4% with the ProGlide; P = .16).6 In contrast, in the CHOICE-CLOSURE trial of 516 patients, the MANTA device was associated with a higher rate of puncture site-related major and minor vascular complications (19.4% vs 12% with ProGlide; P = .029), and a similar incidence of puncture-site bleeding (11.6% vs 7.4%; P = .133).12

In an article published in REC: Interventional Cardiology, Martinho et al.13 present an interesting single-center observational study on the largest real-world experience with the MANTA device. The aim of the study was to evaluate the safety and efficacy profile of the device in a consecutive unselected cohort of patients referred for TF-TAVI. The registry included 245 patients from March 2020 through February 2022. The participants’ median age was 81 years, 52.7% were women, and the median EuroSCORE II was 3.15%. The 30-day TF-TAVI puncture site-related vascular complications were studied according to the Valve Academic Research Consortium (VARC) criteria. Regarding the primary outcome measure of the study—efficacy according to the VARC-3 criteria—successful puncture-site closure was achieved in 92.2% of participants. There were no major vascular or hemorrhagic complications, and only 8.6% experienced minor vascular complications according to the VARC-3 criteria (secondary safety outcome measure). The main predictors of device failure were a minimum femoral artery diameter and, consequently, a higher sheath-to-femoral artery diameter ratio, and the presence of more tortuous and calcified arterial accesses.13

Compared with the most recent clinical trials, the study by Martinho et al.13 found rates of device failure that were lower than those in the MASH trial (7.8% vs 20%), but higher than those reported by the CHOICE-CLOSURE trial (4.7%). According to the authors, some of these differences may be attributed to the varying and inconsistent definitions of device failure across the studies.6,12

According to researchers, the study limitations include its single-center retrospective design, the absence of comparisons with other closure devices, and the lack of postoperative ultrasound scans for some of the participants (which were mandatory in the CHOICE-CLOSURE trial, potentially contributing to a higher detection rate of access site-related complications).12 We should also mention that the registry included only patients considered eligible for closure with the MANTA device and excluded those with “unsuitable” anatomies.

To date, the available information, which includes numerous observational studies, 2 current randomized controlled trials, and more than 1 meta-analysis, suggests that vascular and hemorrhagic complications associated with collagen-based VCDs are quite similar to those of suture-based devices. No significant differences in the VCD failure rate have been reported, with identical 30-day all-cause mortality rates in the 2 groups.

CONCLUSIONS

The gradual reduction in the rate of vascular complications is the result of better preoperative assessment and technological support. Meticulous preoperative planning, with multidetector computed tomography for iliofemoral arterial axis study and ultrasound-guided access, should allow for an optimal approach to the access site and avoidance of incorrect cannulations.

Undoubtedly, cannulation of severely calcified arteries is associated with worse outcomes because of the difficulty involved in attaching the suture systems, and the higher risk of poor plug device apposition. Conversely, puncture sites without wall calcification should consistently yield better results, regardless of the type of VCD used.

Finally, regardless of the system used, angiographic or ultrasound confirmation after closure is always necessary to identify undetected VCD failures, vascular occlusions, or subcutaneous deployments, and expedite the implementation of corrective measures.5,13

In the search for the ideal VCD, several criteria have been proposed: successful deployment with immediate hemostasis in ≥ 98% of procedures, reduction of device-related major vascular complications to ≤ 1%, versatility to adapt to challenging anatomies, universal applicability with minimal exclusions, user-friendliness, easy access to the arterial site after closure, and the potential for early ambulation.5 Such a perfect closure device, however, is still far from being a reality, which is why VCD innovation must continue to minimize vascular complications and achieve such goals.

A less well studied yet undoubtedly pivotal variable to achieve favorable outcomes with any VCD is the operator’s experience, which is key to guaranteeing closure success and reducing VCD-related complications. However, measuring, quantifying, and analyzing this variable across different studies is a daunting task. Thus, although the perfect device may never become a reality, there will always be experienced operators who prefer certain types of VCDs.

With the current results, the decision to choose one VCD over another should be based on the patient’s anatomy and basically on the operator’s preferences and experience. An important consideration is that, to date, the MANTA device is more expensive than ProGlide, which, added to the substantially larger number of patients treated with TAVI, could pose a major obstacle to its selection in preference to suture-based systems.

In the meantime, we should consider innovations and technological advancements in the field of VCDs as welcome news for the interventional community. Soon, these advancements will likely position TF-TAVI as the technique of choice for most patients with symptomatic aortic stenosis.

FUNDING

None declared.

CONFLICTS OF INTEREST

None declared.

REFERENCES

Are the radiation doses we use in interventional procedures appropriate? Cardiologists should be able to answer this question, which is particularly important in pediatric patients. However, the answer matters not only to patients but also to the health professionals involved in these procedures. The occupational radiation doses received by health staff are associated with the doses received by patients, and “optimization” (keeping radiation doses to the minimum needed to achieve the clinical objective of the procedures involved) should be managed comprehensively for patients and professionals alike.1

The International Commission on Radiological Protection (ICRP) recommends using “diagnostic reference levels” (DRLs) to help in the optimization of imaging modalities with ionizing radiation (including interventional procedures).2

DRLs are indicative of “good clinical practice”. It is recommended that they be established for specific clinical indications and can be estimated for the local, national, or regional level by using the third quartile of the distribution of the median values of the dose indicators for patients from various centers representative of these clinical practices.2

The term “achievable dose value” has been proposed in the United States for the 50th percentile instead of the third quartile. Although the ICRP has stated that the median could be used as an additional step in optimization, the recommendation of using the third quartile recommendation to estimate DRLs still stands.2

For interventional procedures, the most widely used radiological measure is the kerma-area product (KAP), which is numerically equivalent to the dose-area product (DAP), and serves as one of the main indicators of the radiation doses received by patients. Secondary indicators that can also be used are the kerma at the patient entrance reference point (15 cm below the isocenter), fluoroscopy time, and the number of cine images acquired. These latter 2 indicators are becoming less relevant because doses depend on different image acquisition modes.

The ICRP recommends taking into consideration the complexity of interventional procedures, since it can increase DRLs significantly. Because complexity can vary widely for a single procedure, carried out for the same or similar clinical indications, it is important to assess its impact on the doses delivered to patients.3,4

The ICRP recommendations have been included in the European regulations (Directive 59/2013 EURATOM)5 and the corresponding practical guidelines of the European Union.6,7 For pediatric procedures, it is suggested that DRLs be estimated based on patient age and weight categories.2

The radiation doses received by pediatric patients vary widely depending on their size and weight. Although variations are inevitable, we should try to avoid those stemming from inappropriate use of imaging modalities (different fluoroscopy or cine modes) or protocols. DRLs help optimize radiation protection.

Different fluoroscopy and cine modes with varying dose rates (and image quality) can be used, substantially impacting the radiation doses received by patients. Factors that play a key role in delivered radiation doses are collimation, C-arm x-ray machine angles, fluoroscopy sequence recording to save cine sequences, and rotational acquisitions.

Ways to significantly reduce the radiation doses received by patients and health professionals are knowing the quality control results of x-ray machines (to understand dose differences between cine and fluoroscopy acquisitions) and fostering collaboration between hospital radiologists and cardiologists, along with continuous medical education programs on radiation safety.

All these variables associated with different operating modes can substantially change the doses delivered to patients and the quality of diagnostic information. Therefore, cardiologists’ knowledge and experience of their imaging equipment are crucial. In general, state-of-the-art machines reduce radiation doses while maintaining similar or improved diagnostic information. Quantifying all these factors and deciding whether corrective actions are needed involves comparing radiation doses for specific procedures with the DRLs.

The Royal Decree that transposes part of the European Directive to the Spanish legislation8 demonstrates the implementation and regular review of DRLs. If these DRLs are consistently and significantly exceeded, or if image quality deteriorates repeatedly, the corresponding local reviews should be undertaken and appropriate corrective measures should be implemented without delay.

Some automated dose management systems allow real-time reception and processing of the radiation doses received by patients and operators. These systems can create alerts for safer interventional practices.9,10

Several studies have been published on DRLs in interventional cardiology for adult patients (DOCCACI program) in Spain11,12 with collaboration from the Spanish Society of Cardiology.

No nationwide results have been published on the doses received by pediatric patients in interventional cardiology until now. However, Rueda Núñez et al.13 recently presented the results of the Radcong-21 Registry conducted by the Cardiac Catheterization Working Group of the Spanish Society of Pediatric Cardiology and Congenital Heart Disease (GTH-SECPCC) on the overall values from a sample of 1090 procedures across 10 different hospitals. This registry represents a significant initiative that could encourage other centers to compare their values with dose indicators obtained from a representative sample of multiple Spanish hospitals in patients with congenital heart disease treated with cardiac catheterization and categorized by type of procedure and estimated radiation risk (ERR).

The study authors used medians, although DRL values refer to the third quartile of the distribution of the median values in the different centers involved. Specific DAP/kg values are provided for certain specific procedures to treat prevalent conditions such as aortic coarctations, atrial septal defects, ductus arteriosus occlusions, aortic and pulmonary valvuloplasties and pulmonary valve implantations following the methodology proposed by Quinn et al.14 in the United States.

DAP/kg/fluoroscopy is a parameter that can be confusing when comparing radiation doses. This is because the total DAP includes contributions from fluoroscopic imaging—corresponding to different fluoroscopy modes with very different dose values—and cine acquisitions.

To facilitate comparisons and potential optimization efforts, the authors could provide dose indicator values (DAP/kg) tailored to a wider range of procedure types in future updates of the results. They could also use the third quartiles of the distribution of the median values for each center for the weight categories recommended by the ICRP and European guidelines.2,6,7

We could speculate whether it would be better to perform a global analysis across groups of different procedures or an analysis specifically designed for procedures with specific clinical indications. Quinn et al.14 choose the former, while managing the DAP/kg values as the primary dose parameter. However, a global approach does not allow analysis of specific procedures requiring corrective measures when the doses delivered to some patients may be very high. These doses exceeding the “good clinical practice” threshold can be used in certain procedures, but not in others, within the 3 REC (Radiation Exposure Category) groups proposed by Quinn et al.14 in their methodology. The advantage of using DRLs per weight group is that these DLRs are estimated for specific clinical indications, thus enabling easy comparisons with the dose indicators used in different hospitals for these procedures.

The global KAP/kg values for groups of different procedures may be balanced if there are procedures using higher radiation doses than necessary (due to excessive cine acquisitions, high-dose fluoroscopy modes, lack of collimation, etc) and other procedures requiring standard doses. This could indicate overall improvement (fewer doses in procedural groups), but does not necessarily indicate improvement in all types of procedures.

The effort made by the GTH-SECPCC to obtain and process PDA/kg values represents a significant advancement that could be further expanded in the future. This could involve establishing initial DRLs (KAP values) in Spain, based on weight and age groups, following the recommendations of the European guidelines and ICRP.

FUNDING

None.

CONFLICTS OF INTEREST

None reported.

REFERENCES

Cardialysis was founded in 1983 by visionary professionals from the Thoraxcenter at Erasmus University Medical Center (EMC) in Rotterdam, The Netherlands. This initiative emerged to address the need for a specialized research organization able to plan, execute, and report European cooperative clinical investigations in the field of cardiovascular research.1 The mission of Cardialysis is “to be at the heart of cardiovascular research” in the fullest sense of the phrase. To achieve this mission, the organization strives to collaborate with clinicians, trialists, research professionals, regulators, industry partners, and research organizations that share the same passion. Throughout the first 40 years, its well-established reputation has been based on dedication, diligence, and industry-leading standards. This has been made possible by attracting and retaining talented employees, as well as by cultivating long-standing relationships with investigators, clients, and partners.

Organizations similar to Cardialysis are typically classified as either academic research organizations (AROs) or contract research organizations (CROs). AROs, such as clinical trial units and epidemiology departments, are typically affiliated with universities or university hospitals, and usually design and manage investigator-initiated single-center or multicenter national clinical trials. These organizations are academically-driven and their traditional objectives are to facilitate research and education, publish innovative research in peer-reviewed journals, and support PhD programs. In contrast, CROs are private entities performing sponsor-driven clinical trials across all phases of clinical development. These organizations are business-driven, and expected to remain self-sustaining by establishing research contracts with the medical industry in a strict regulatory environment.

Similar to other world-leaders in cardiovascular research, Cardialysis has successfully adopted a hybrid ARO/CRO model, combining the best of the 2 models. First, the organization participates in innovative research that has played a pivotal role in the development and improvement of therapies in cardiology. This involvement has resulted in numerous high-impact publications and the completion of more than 100 theses through its support of in-house academic research. Figure 1 lists notable trials in which Cardialysis participated, including research in coronary artery disease, structural heart disease, heart failure, hypertension, and peripheral artery disease. Second, the organization proudly maintains a global network of renowned investigators who play key roles in the academic leadership of trials (eg, within steering committees), independent clinical events committees (CECs),2 independent data and safety monitoring boards,3 and imaging core lab supervision. Third, Cardialysis operates as a private, independent entity that serves both university hospitals worldwide, as well as leading pharmaceutical and medical device industry partners. Fourth, the organization maintains state-of-the-art infrastructure and follows standardized procedures, ensuring efficiency and quality. Finally, Cardialysis consistently adheres to applicable regulatory requirements for trial execution in all active regions, including Europe, the United States of America, and China.

Figure 1. Timeline of landmark trials conducted with Cardialysis.

THE CARDIALYSIS CORE LAB

Over the past half century, clinical research has had an enormous impact on clinical outcomes, which was eloquently summarized by Nabel and Braunwald.4 These advancements are inextricably linked to the development of therapeutic and diagnostic devices, especially in interventional cardiology. The development of coronary angioplasty involved progressive iterations in coronary stent technologies and continuous innovation in intracoronary imaging.5 Similarly, advancements in transcatheter therapies for aortic, mitral, and tricuspid conditions have paralleled the progress in imaging modalities and techniques.6 Independent and consistent assessments of imaging outcomes are an important component of dossier evaluations when commercialization approvals are sought for new devices.7

Cardialysis started as a central reading facility for electrocardiography-Holter monitoring. However, over time it has validated and implemented rigorous analysis methodologies for various imaging techniques within the coronary core lab. These include quantitative coronary angiography (n = 67 000+), intravascular ultrasound (n = 16 000+), near-infrared spectroscopy (n = 1500+), and optical coherence tomography (n = 5000+). Notably, Cardialysis also launched and maintains the globally used SYNTAX score (n = 10 000+) website.8 Due to a shift toward structural heart research, its echocardiography core lab has become its largest laboratory and serves large European and global investigations (n = 39 000+). Additionally, the organization operates magnetic resonance imaging (n = 1000+), cardiac computed tomography (n = 1000+), and electrocardiography-Holter core laboratories (n = 270 000+).

CARDIALYSIS CLINICAL TRIAL ACTIVITIES

The workload involved in a clinical investigation should not be underestimated. For example, the ongoing IVUS CHIP randomized clinical trial (NCT04854070) involves 40 sites in Europe and more than 200 professionals in the execution of the study, excluding the members of the Ethics Committees. Managing and coordinating more than 200 professionals across 7 countries for a minimum of 5 years requires high levels of availability, dedication, consistency, and well-established standardized procedures. Having an all-inclusive research organization performing ambitious trials increases efficiencies. Table 1 lists the activities performed at Cardialysis, which are those expected of any all-round professional research organization. Further information is available on the Cardialysis website.8

Table 1. List of activities performed at a cardiovascular research organization

THE ACADEMIC RESEARCH CONSORTIUM

In 2006, with the increasing need for consistent endpoint definitions in coronary artery disease research, and specifically due to the challenges posed by the classification of stent thrombosis, leading AROs in the United States and Europe, including Cardialysis, collaborated to found the Academic Research Consortium (ARC).8 The primary mission of the ARC is to promote informed and collaborative dialogue among stakeholders, with the goal of developing consensus definitions and nomenclature for targeted areas of new medical device development, and to disseminate such definitions in the public domain.8 The first initiative focused on endpoint definitions and classifications for coronary intervention trials and was published in 2007.9 This consensus document was developed in consultation with regulatory agencies in both the United States and Europe, and became one of the most cited articles in interventional cardiology. To date, the ARC has successfully launched and completed 20 programs and is currently running 15 new initiatives based on an unprecedented level of global scientific collaboration.8

EUROPEAN CARDIOVASCULAR RESEARCH INSTITUTE

Europe is known for its stringent regulations on academic research. Importantly, the sponsor of a clinical investigation is the legal entity (or individual) that ensures that regulations are met and that monitors patient safety either directly or through a data and safety monitoring board. The sponsor holds full rights to the study data (ie, has sole ownership) and is responsible for verifying data integrity, ensuring that published results are consistent with the locked final analysis database. Although prominent academic centers possess the expertise to sponsor clinical trials, the size of certain studies requires external support for manageability.

In response to this need, the European Cardiovascular Research Institute (ECRI) was founded in 2012 by the Cardialysis group as an academic research platform capable of overseeing the execution of large, multicenter clinical trials and of fulfilling sponsor responsibilities. Since April 2023, the ECRI has become an independent foundation (Stichting) under Dutch law. This institute combines 3 elements of success: its outstanding academic leadership represented by its pro bono scientific advisory board (figure 2), a well-established network of investigators and research professionals, and the possibility to conduct clinical research activities in partnership with Cardialysis. Through this collaborative model, the ECRI-Cardialysis joint venture has successfully conducted some of the largest interventional cardiology trials, with the GLOBAL LEADERS trial being the most representative.10 This trial enrolled 15 968 patients at 130 sites across 18 countries. Another example is the MASTER DAPT trial,11 which enrolled 4579 high-bleeding risk patients at 140 sites in 30 countries.

Figure 2. European Cardiovascular Research Institute foundation and its scientific advisory board. ECRI, European Cardiovascular Research Institute.

The ECRI-Cardialysis partnership is currently conducting 3 landmark investigations on the use of coronary imaging and coronary physiology to guide percutaneous coronary interventions. Up-to-date details are available on the Cardialysis website.8

A LANDMARK FIGURE

Numerous clinicians and clinical research professionals have passed through the door of Cardialysis, with some staying for a lifetime and others for a short period. Undoubtedly, the most salient contributor to the organization’s innovations and successes has been Prof. Patrick W. Serruys. His mentor, Prof. Paul Hugenholtz, acknowledged as the father of the European Society of Cardiology, and one of the founding members of Cardialysis, recognized Prof. Serruys as a natural talent and luminary in clinical research. Prof. Serruys joined Cardialysis during its early days and since then played a decisive role in the organization. His innovations and contributions included the development of coronary imaging techniques (eg, he was coinventor of quantitative coronary angiography); the establishment of best practices in interventional clinical trials, including the design and execution of the BENESTENT study,12 which was the first of its kind and remains one of the most cited publications in interventional cardiology; research in bioresorbable scaffolds; and an illustrious career that garnered multiple distinctions and awards.13 Although Prof. Serruys left the organization in 2019, his scientific legacy remains highly esteemed.

Currently, a new generation is shaping the present and future of the organization with unwavering commitment to innovation, collaborative research, and, above all, commitment to improved patient outcomes. The 40-year timeline of Cardialysis (figure 1) starts with the CARPORT trial led by Prof. Serruys from the Thoraxcenter, and concludes with the FAST II study led by Dr Joost Daemen14 and the MONITOR HF trial led by Dr Jasper Brugts,15 both also from the Thoraxcenter. While Cardialysis envisions expanding its European and global collaborations in the coming decades, its scientific partnership with EMC has remained strong and will continue to flourish.

THE FUTURE

Cardialysis pledges to continue contributing to the design, execution and reporting of clinical trials as an independent and scientifically-driven cardiovascular research organization and core laboratory. Its priorities are patient safety, data integrity, and the production of high-quality data, which have been achieved by committed employees, passionate investigators, and long-standing collaboration with its valued partners.

Additionally, Cardialysis remains committed to further advancing continued standardization of clinical trial definitions, design principles, and core laboratory methods, given that standardization has proven to be a catalyst in clinical research. Current innovations at Cardialysis focus on implementing artificial intelligence, streamlining clinical trial processes, harnessing the potential of real-world data, and mastering applicable regulatory science.

FUNDING

None.

CONFLICTS OF INTEREST

E. Spitzer is a board member and shareholder of Cardialysis and a board member of the ECRI.

ACKNOWLEDGMENTS

Our 40th anniversary is dedicated to our beloved colleague Eline Montauban van Swijndregt^†.

REFERENCES