The future of interventional cardiology

While on his first hospital duty, a second-year cardiology resident receives a message in his pager about a patient who has just been admitted to the emergency room with chest pain. Specifically, he is asked to discard that the pain is of coronary origin. The resident questions the patient on his symptoms, examines his risk factors, and analyzes the electrocardiogram (ECG). With the ECG data, the qualitative information of pain provided by the patient, together with his past medical history, the presence of coronary pain is eventually discarded. The patient’s past medical history reads «the symptoms described by the patient, the presence of hypertension as the only risk factor, and the lack of specific changes on the ECG suggest that the chances of coronary pain are extremely low». Intuitively, the resident considers that the chances the pain is due to coronary artery disease (CAD) with the data available (qualitative data of pain, risk factors, ECG) is lower than, let’s say, 5%. In other words, the resident instinctively concludes that:

p(CAD |qualitative data, risk factors, ECG) < .05,

that is, the probability of having CAD according to all the abovementioned information (qualitative data, risk factors, and ECG) is < 5%.

However, before the patient is discharged, the resident decides to consult with the fifth-year cardiology resident who is at the Coronary Care Unit. He arrives to the emergency room and asks the patient about his symptoms, examines his medical history, and crosschecks his ECG once again. The much more experienced fifth-year resident considers that, although there are no risk factors other than hypertension, certain characteristics of the pain could have a coronary origin. And not only that, the analysis of the ECG reveals minimal repolarization alterations that appear as a mild—almost unnoticeable—rectification of the ST-segment. Intuitively, the resident considers that the chances that the pain is due to coronary artery disease (CAD) is undoubtedly > 5%, and possibly > 20%. In other words, the fifth-year resident intuitively concludes that:

p(CAD |qualitative data, risk factors, ECG) > .02

that is, the probability of having CAD according to all the information provided above (qualitative data, risk factors, and ECG) is > 20%.

With this early assessment, the fifth-year resident decides to perform a transthoracic echocardiogram (TTE) that reveals alterations in segmental contractility. With this new information available, the resident believes that the chances that the pain is of coronary origin have increased significantly:

p(CAD |qualitative data, risk factors, ECG, TTE) > .05

The intuition of a moderate-high probability of the coronary origin of the pain plus the information provided by the TTE suggest that high-sensitivity troponin (Tp) level should be tested, as Tp appears slightly elevated. Therefore, the intuitive probability that the patient’s chest pain is of coronary origin increases even more:

p(EC |qualitative data, risk factors, ECG, TTE, Tp) > .08

The previous example—though rather simplistic—illustrates several factors associated with conditioned probability and, more specifically, with traditional Bayes’ theorem.

Firstly, it illustrates how Bayes’ theorem is possibly a very appropriate mathematical approach to update our natural and intuitive decision making in medicine: we take an effect—which is what we find at the patient’s bedside—(chest pain), and make a decision on its cause with diagnostic, prognostic or treatment purposes, and then intuitively assign a probability to the cause under consideration (coronary artery disease). We do this with the information available we believe to be the effects of this cause while considering other variables closely associated with the cause such as the characteristics of pain, the ECG, the risk factors, etc.

Secondly, it illustrates how different sources of information added sequentially provide a more accurate definition on the probability of a given cause, always intuitively. And not only that, in the routine clinical practice, interpreting different sources of information varies from observer to observer, which will determine that the probability assigned to a given cause will vary significantly among observers. Here the clinician’s experience undoubtedly plays a key role.

This example also indirectly illustrates how difficult it is to obtain numerical—though approximate—estimates of the actual probability of the real cause for the effect (CAD) from the effects seen and other variables associated with this cause. As Armero et al.1 state in an article recently published in REC: Interventional Cardiology, the accurate probability estimate of the example would require solving the equation of Bayes’ theorem:

p(CAD |information available) =

where information available, in the example, would be the qualitative data of pain, the risk factors, the ECG, etc. But here is where problems begin. Like Armero et al.1 say, the first problem is to obtain the prior distribution to estimate probabilities. Although estimates can be made on the probability of CAD in a population based on its prevalence or on the probabilities of hypertensive patients or on the probabilities of having an abnormal ECG, estimating the probability of the qualitative data of pain doesn’t have a clear distribution on which to lean on. Like Armero et al.1 say the second problem is implementing an analytical expression for the posterior distribution of parameters and estimating the function of verisimilitude. Again, although the probability of knowing that a hypertensive patient has CAD or that an ECG shows certain characteristics of coronary artery disease is feasible, the problem becomes more complicated when several sources of information are combined; what are the chances of having chest pain with certain characteristics in a hypertensive patient with a given ECG knowing that he’s got CAD? Although it is true that distribution samples can be simulated, the analytical method becomes complicated and—as Armero et al.1 say—interpretation probably stops being intuitive.

We should also add the problem of «expert knowledge» to the mix for the definition of prior distribution. Like the example illustrates, knowledge can depend on the expert’s interpretation. But also, to a great extent, prior knowledge can significantly be affected by publication bias or it can be erroneous, which is why the associated informative distribution will give rise to biased probability estimates.

Due to all of this, although it is very possible that doctors can use Bayes’ theorem naturally for his decision-making process regarding diagnosis, prognosis, and treatment, this does not seem to have translated into a significantly wider use of this methodology in research. In an exercise of indirect approach to corroborate the this, we used PubMed to analyze «clinical trial» or «randomized clinical trial» publications in the cardiovascular field over the last 10 years. Then, we selected those where the term «Bayesian» was included somewhere in the text field. Like figure 1 shows—although it has increased significantly over the last few years—the overall rate of possible use of Bayesian methodology in clinical trials in the cardiovascular field is well under 7‰.

Figure 1. Clinical trials published over the last 10 years in the cardiovascular field with possible Bayesian methodology (for every 1000 cardiovascular publications).

If, like Armero et al.1 say, the Bayesian protocol is easy-to-use, robust, and conceptually powerful, why is it used so marginally compared to frequentist statistics? We believe there are several reasons for this. In the first place, frequentist statistics was the first ever used to answer research questions in medicine possibly because right from the start the most common probability distributions had already been perfectly defined, and it was easy to apply the inferential method for decision-making based on such distributions with perfectly defined parameters. However, analytical and computer problems associated with the use of Bayes’ theorem to estimate probabilities were not initially resolved. Secondly, because of the simplicity of being able to make decisions on whether a treatment, diagnostic method, procedure, etc. is effective or not based on the selection of P value < .05 so popular in the frequentist method also referred to by Armero et al. Finally, because the Bayesian conception of probability allocation to parameters and being able to establish direct probabilistic assessments means that the parameter is not an immovable fixed reference anymore. From the analytical standpoint this is a change of paradigm we are not used to. But maybe this loss also generates certain anxiety: parameters are not unchangeable anymore.

FUNDING

None reported.

CONFLICTS OF INTEREST

The authors did not declare any conflicts of interest in relation to this manuscript.

REFERENCES

Over the last 3 decades, the percutaneous treatment of congenital heart diseases has made significant progress. Currently, it is the therapy of choice to treat many of these diseases like atrioventricular septal defects, pulmonary valve stenosis or coarctation of the aorta. Multiple procedures throughout the life of a patient are required to treat complex heart disease like stenting and, more recently, percutaneous valves, which have become additional alternatives to surgery.

Since 1990, cath lab activity is regulated in the registries published by the Interventional Cardiology Association of the Spanish Society of Cardiology (ACI-SEC).1 In the annual publications of these registries there is a small section dedicated to congenital heart disease in the adult population with details on the activity performed, but without an in-depth analysis of the outcomes, complications or mortality.

The ACI-SEC and the Spanish Society of Pediatric Cardiology and Congenital Heart Disease Working Group on Hemodynamics have joined forces—for the first time in our country—to conduct a registry of the procedures performed in patients of all ages with congenital heart disease since the fetal stage until the adult age with the collaboration of pediatric and adult cardiologists.2 The Spanish Society of Cardiovascular and Endovascular Surgery has recently published a registry of surgical procedures performed in patients with congenital heart disease from 2019, and retrospectively, of the past 8 years.3 Therefore, we should mention that, to this date, in Spain, we have surgical and percutaneous activity registries in the specific field of congenital heart disease.

In the first official report from the Spanish Cardiac Catheterization in Congenital Heart Diseases Registry—recently published in REC: Interventional Cardiology—Ballesteros Tejerizo et al.2 reported the activity of 16 public centers, 7 of which have exclusive dedication to pediatric patients in an unaudited voluntary registry through an online database. The number of participant centers can be representative of pediatric activity. However, this seems like a very low number of hospitals to be representative enough of the activity developed in adult congenital heart disease. As a matter of fact, by 2014, there were already 24 PCI-capable centers with specialized consultations on the management of congenital heart diseases.4 Also, other centers perform interventional procedures to treat simple congenital heart disease like interatrial shunt and patent foramen ovale closures without specialized consultations. These 2 aspects can explain the huge difference seen between the ACI-SEC national registry that reported a total of 1341 interventional procedures performed in the adult population compared to the 367 procedures reported in this registry.2,5 This low representativity of interventional procedures in adult patients should be included in future registries to get an actual snapshot of the activity performed in this field.

The higher rate of almost 5% reported in the activity performed in the management of congenital heart disease in 2000—the pandemic year—compared to 2019 is not easy to explain either even though fewer hospitals (2) participated that year. This contrasts with other registries—like the Italian one—where 6 out of the 11 participant centers saw how their activity dropped over 50%, especially among adults and teenagers.6 Also, during the pandemic, patients with congenital heart disease were a susceptible population with a higher morbidity and mortality risk due to appointment cancellations, and delays in the diagnosis and treatment of complications.7

Another significant and debatable aspect is the definition of congenital heart disease included in the registry. The patent foramen ovale can be present in over 25% of the general population and has become part of the interventional procedures performed to treat congenital heart disease. In fact, it is the most prevalent one among the adult population. However, interventional procedures to treat bicuspid aortic valve— considered the most common congenital heart disease and present in 1% to 2% of the general population—was not included in this registry. Although valve disease following calcification often occurs at a younger age compared to the tricuspid aortic valve—at around 50 to 60 years old—current registries show that transcatheter aortic valve implantation is performed in 4% to 5% of the patients with bicuspid aortic valve.8 Also, bearing in mind that 4241 percutaneous aortic valves were implanted in Spain, it somehow seems logical to agree that nearly 190 were implanted in the bicuspid aortic valve, but this figure was never reported in this registry.

The pulmonary angioplasty section includes interventional procedures on pulmonary branches, the native right ventricular outflow tract, and prosthetic valve conduits. These are different procedures regarding complexity and potential complication, which is why they should be included in separate sections.

We should mention the low rates of serious complications (2%), and mortality (0.1%) reported, which are similar to the ones reported by the best international registries. The exception to this was interventricular shunt closure with a high rate of complications reported—over 10%—which emphasizes the technical difficulty of this procedure.

The availability of a national registry on pediatric percutaneous procedures and adult congenital procedures with a prospective database is essential for patients, and their families. Also, for doctors who treat and advice patients on the risks and outcomes of a given procedure, and for interventional cardiologists to improve their clinical practice. It allows us to analyze results and draw comparisons among hospitals, autonomous communities, and even countries to eventually implement process management upgrades.

Also, this is closely associated with the need for establishing the optimal conditions to perform percutaneous procedures to treat congenital heart disease, and with the accreditation of both centers and interventional cardiologists. A consensus document was drafted on the need to establish the infrastructure standards and experience that both centers and interventional cardiologists should have by the different working groups and associations on pediatric and adult congenital heart disease, and the European Society of Cardiology.9 Two different levels of centers were established based on the number of procedures performed each year. Therefore, in level 1 centers, the lead operator should perform, at least, 70 procedures with, at least, 10 percutaneous valve implantations, 10 angioplasties, and stenting to treat coarctations of the aorta, pulmonary arteries, surgical conduits or baffles (for a total of 10 in any of these areas). Also, the second operator should perform ≥ 30 procedures (over 100 in 1 year). Level 2 centers would need to perform over 60 procedures each year. Although these figures can seem arbitrary, it is essential to perform a high volume of procedures per center, and have onsite cardiac surgery teams expert in the management of congenital heart disease to solve potential and emergency complications that may arise. Heart teams including several specialties and experience in this field are required too. Therefore, this type of procedures should only focus on interventional cardiologists and experienced centers to obtain optimal results.

The future of structural and congenital heart procedures is guaranteed and looks bright thanks to the technological advances made in this field that will invariably improve the quality of life and increase the survival rate of patients with heart disease. Although there is large room for improvement in the quality of data curation for future registries, the first Spanish registry on interventional procedures for the management of congenital heart disease is a major first leap that should be interpreted as a snapshot of the state of interventional procedures to treat congenital heart disease, the activity, and results obtained nationwide. This will help standardize procedures and obtain excellent results.

FUNDING

None whatsoever.

CONFLICTS OF INTEREST

None reported.

REFERENCES

Severe tricuspid regurgitation (TR) is known to be independently associated with adverse prognosis.1 Its importance is further emphasized by the prevalence of this entity, particularly in the aging population.2 Until the past few years, surgical management was the only available effective treatment for isolated severe TR. Operative mortality, nonetheless, remains high.3 Moreover, surgery is associated with a 45% recurrence rate after 5 years,4 and recent data suggest that surgery may not improve the survival rate in isolated severe cases of TR.5 Accordingly, guidelines recommend TR surgery as a class 1 indication only with concomitant left-sided valvular surgery.6 Conversely, patients with prohibitive surgical risk managed conservatively were shown to have dismal outcomes.7 Fortunately, the emergence of percutaneous devices expanded the horizon of TR treatment.

TACKLING THE MULTI-MECHANISTIC PATHOLOGY

TR is the product of various pathophysiological mechanisms including right ventricular (RV) dilatation with consequential leaflet tethering, tricuspid annular dilatation with subsequent mal-coaptation, atrial fibrillation causing further annular dilation through atrial enlargement, and abnormalities in the tricuspid valve leaflets and apparatus. At a certain point, regurgitation itself becomes an etiology through a vicious circle of RV and atrial remodeling. Accordingly, numerous percutaneous devices are being developed for transcatheter tricuspid valve repair (TTVr) and replacement (TTVR). They can be classified according to their mechanism—leaflet approximation, direct suture or ring annuloplasty and valve implantation that can be orthotopic—implantation in the anatomic tricuspid location or heterotopic implantation in the cavoatrial junction. The long-term stability of the orthotopic valve may be compromised due to the structural changes of the valvular apparatus over time that faces increased postoperative afterload. Some valves minimize this effect by not entirely relying on radial forces such as the Lux-Valve (Ningbo Jenscare Biotechnology, China) that attaches to the septum. Of note, a shortcoming of the Lux-valve is the thoracotomy requirement. An approach to relief RV pressure due to increased afterload is the Trisol valve (TriSol Medical, Israel) that induces leaflet coaptation by using a dome-shaped structure that enables larger RV closing volume. Additional orthotopic valves like the Intrepid (Medtronic, United States)—that received the Food and Drug Administration Breakthrough Device designation—and the Evoque (Edwards Lifesciences, United States) are showing encouraging results. Heterotopic valve implantation had been reported as double-valve implantation (inferior and superior vena cava), as well as single valve solely into the inferior vena cava. Nevertheless, the vena cavae can show substantial dynamic variations in size as well, particularly in self-expanding valves applying radial force on the compliant vessel, whereas right atrial enlargement can generate a funnel-shaped cavoatrial junction, thus increasing the risk of valve migration. Since the procedure results in the ventricularization of the right atrium, persistent overload can cause morphological changes and adversely impact the cardiac function.

Additional anatomical considerations play a role in device selection including the course of the right coronary artery, proximity to the atrioventricular node, and or/bundle of His (in this regard, the NaviGate valve—NaviGate Cardiac Structures, United States—has short graspers, and termed atrial winglets to prevent compression of the conduction system8), the dimensions of the inferior vena cava and its orientation relative to the right atrium (that can impact device stability and introduce difficulties achieving coaxiality), the size of the tricuspid annulus (large annuli may be modified as with the TriCinch—4Tech Cardio, Ireland—,9 that mimics the Kay procedure), the distance between the tricuspid annulus and the RV apex, the size of the iliac vein (eg, the Cardiovalve—Cardiovalve, Israel—and the Evoque utilize a relatively low profile), the presence of an intracardiac shunt, short leaflet length (with an insufficient grasping area), thickened nonpliable leaflets, coaptation gap and depth (usually over ~7mm is a predictor of leaflet approximation failure), tethering severity, the tenting area and height, the location of the regurgitant jet, the number of leaflets (eg, 3 or 4), a proper annular shelf, and the juxtaposed noncoronary sinus relative to the device anchoring to the anterior and septal leaflet commissures (that may be compromised by the anchoring mechanism).

Multiple factors must, therefore, be taken into observed when considering a patient for TTVr/TTVR, and a thorough evaluation is warranted. In advanced stages of the disease manifesting as severe RV enlargement, considerable tethering or very large annuli, TTVr and TTVR may not be technically feasible. The anatomical characteristics can exceed the device capabilities, eg, the maximum length of Cardioband (Edwards Lifesciences, United States) tricuspid system is 120 mm. Even if the intervention is technically possible with advanced disease, irreversible damage to the RV structure and function may impede clinical improvement. Nevertheless, the point of no return is not clear, and patients with RV dysfunction and pulmonary hypertension have the potential to improve.10

Finally, the patient’s characteristics must be reviewed as certain trials excluded patients with specific comorbidities like chronic kidney disease or systolic pulmonary artery pressure > 70 mmHg.

OUTCOMES OF PERCUTANEOUS TRICUSPID VALVE INTERVENTIONS

TriValve is the largest TTVr registry available predominantly describing edge-to-edge repair with MitraClip (Abbott Vascular, United States) in the tricuspid position. Use of MitraClip was described as bicuspidization of the tricuspid valve,11 by approximating the posterior or anterior leaflet to the septal leaflet (while anterior to the posterior leaflet clipping may distort the valvular apparatus). Devices operating with similar mechanisms are the TriClip (Abbott Structural Heart, United States), and the PASCAL (Edwards Lifesciences, United States).

Patients from studies describing the various devices were heterogenous and vary significantly from one to the other. Also, the 30-day mortality rate ranges from 0% to 13% with significant improvement in TR grade, and in the quality of life according to published data (table 1). Notable longer-term outcomes include a 20% mortality rate at 1-year follow-up in the MitraClip cohort,12 and a 26% mortality rate after 2 years in the Cardioband cohort.18 Currently, prospective efficacy data mostly rely on quality-of-life scores and TR grade. However, it was shown that patients with procedural failure have a significantly higher mortality rate,30 suggestive that patients would fare worse without the procedure. Moreover, a registry-based propensity-matched study that compared TTVr to conservative treatment showed symptomatic and survival benefits.31 Currently, 3 TTVr devices have received the CE marking: Cardioband, TriClip, and PASCAL system for the management of TR, but none have been approved by the U.S. Food and Drug Administration. Consequently, most percutaneous tricuspid interventions are applicable in trial settings or as compassionate use.

Table 1. Outcome data with transcatheter tricuspid valve devices

In conclusion, TTVR/TTVr devices are becoming considerably more viable options. Surgical, and most certainly, conservative treatment of patients with severe TR are not ideal choices and expanding treatment possibilities towards percutaneous approaches is, therefore, an obvious choice. Results from ongoing trials have been anticipated, which will hopefully be followed by the approval of additional devices.

FUNDING

None whatsoever.

CONFLICTS OF INTEREST

A. Latib has served on advisory boards or as consultant for Medtronic, Boston Scientific, Edwards Lifesciences, Abbott, and VDYNE. The remaining authors have no relations to disclose.

REFERENCES

Although mechanical reperfusion has been shown to achieve epicardial recanalization in almost all acutely occluded arteries, the optimal myocardial reperfusion still remains a major issue, and it is only achieved in barely 50% to 70% of the patients with ST- segment elevation myocardial infraction (STEMI).1 Several factors have been demonstrated to have an impact on myocardial reperfusion including preoperative Thrombolysis in Myocardial Infarction (TIMI) flow, ischemia time, ageing, diabetes, thrombus burden, and vessel size.1-3 Therefore, over the last few decades, several studies have been conducted on adjunctive therapies and devices to improve reperfusion such as antithrombotic therapies,4-5 and thrombectomy.6

The use of coronary stents, in particular drug-eluting stents, currently represents the standard of care,7 and considerable attention has been paid over the last decade on stenting techniques,8 and their impact on procedural results and outcomes.

In a paper recently published in REC: Interventional Cardiology, Vega et al.9 conducted a randomized trial to address the impact of the delivery system speed deflation on myocardial perfusion and the outcomes of patients with STEMI treated with direct stenting.

In fact, fast balloon deflation has been suggested to cause abrupt changes in coronary flow that may trigger the detachment of thrombotic material, and plaque fragments, disrupted by the stent strut coverage.10 Also, variations of intravascular pressure may increase the wall shear stress, which has been shown to promote plaque destabilization, endothelial dysfunction,11 and also the hydrostatic pressure inside the interstitial space favoring myocardial oedema, and cellular damage.12

Indeed, in post-conditioning strategies, balloon inflation has been proposed as a mechanism of protection against ischemic damage by inducing repeated sequences of ischemia-reperfusion that have been proven to reduce the infarct size.13

In a previous randomized study that recruited 211 patients, Gu et al.14 reported an improvement of coronary flow with the stent delivery system slow deflation strategy, yet with a not significant reduction of the no-reflow phenomenon, and null effects on the long-term outcomes.

However, this study primary endpoint was the corrected TIMI frame count, an index of coronary flow, whereas Vega et al.9 assessed the myocardial blush grade (MBG) and the ST-resolution, both parameters of myocardial perfusion that may be conditioned by several other factors.

In fact, the Spanish study9 was consistent with previous larger reports,8 and diabetes, hypertension, kidney disease, hemodynamic parameters, and lesion location emerged as independent predictors of MBG. Therefore, it may be argued that slow balloon deflation may have facilitated a successful epicardial reperfusion, although this did not translate into microcirculation differences or myocardial salvage.

Furthermore, although the extensive use of thrombectomy and glycoprotein IIb/IIIa inhibitors in the overall cohort of patients, as the authors very well pointed out, is not representative of the current guidelines-indicated strategies regarding primary percutaneous coronary intervention (PCI), it may have prevented such complications and minimized any potential benefits with the delivery system slow deflation strategy. Indeed, former studies and meta-analyses have demonstrated that the administration of these potent antiplatelet agents during a primary PCI, mainly as a downstream strategy,15 could translate into better myocardial perfusion, and reduce mortality.

In addition, the recruitment restriction to those lesions eligible for direct stenting in the study conducted by Vega et al.9 may have led to the selection of a very low-risk population where the occurrence of an impaired MBG was extremely low (observed in about 25% of the study population).

Finally, since the study was stopped after the recruitment of 50% of the predefined sample size for futility, we cannot discard that, with a larger population and different endpoints, any differences would have emerged. Future larger studies with a more heterogeneous and higher-risk population of patients with STEMI, more complex lesions, a higher rate of comorbidities, less extensive use of glycoprotein IIb/IIIa inhibitors, are certainly justified to better define the potential role of slow balloon deflation during primary PCI in terms of periprocedural complications, myocardial reperfusion, short- and long-term outcomes.

FUNDING

None whatsoever.

CONFLICTS OF INTEREST

None declared.

REFERENCES