The future of interventional cardiology

The article signed by García-Guimarães et al.1 recently published in REC: Interventional Cardiology is a living example of how a technical modification of a percutaneous device already being used with good clinical outcomes can have a significant impact not only from the standpoint of the parameters of technical results but also from the clinical viewpoint. Over the past 20 years of development of valves for transcatheter aortic valve implantation (TAVI) procedures we have witnessed a gradual technological progression where 2 different concepts—self-expanding valves and balloon-expandable valves—have initially achieved encouraging clinical outcomes in high-risk or inoperable patients,1,2 and gradually until achieving better short-term results compared to surgical aortic valve replacement in low-risk patients.3,4 This successful trajectory is partly due to the interest for developing and improving early and successive TAVI devices. The trials conducted among high-risk patients already found a higher rate of paravalvular leak after TAVI compared to surgical repair. As a matter of fact, it was a common event very much associated with a greater need for pacemaker implantation after TAVI2 in the early self-expandable valves.

Conceptually this is something that could have been expected since there is no native valve resection or washout of the calcium remaining in the leaflets or the annulus. The need for permanent pacemaker implantation increases due to the implicit mechanism of mechanical fixation due to pressure to the valve annulus and its adjacent structures. We should mention that both phenomena can be inversely associated, that is, the more annular overexpansion we have, the more chances of atrioventricular block and vice versa with paravalvular leak. If we accept that the clinical impact of residual leak—with disparate evidence available—5,6 can be associated with different degrees categorized as mild, all design changes and those associated with the implantation technique used aim at reducing its rate and severity.

The nature and mechanisms involved with paravalvular regurgitation are obviously different compared to the native valve, which is why several authors propose more categories, and a modification of the analysis technique of transthoracic echocardiography after implantation. This aims at the proper detection of different degrees of paravalvular regurgitation with some potential adverse prognostic effect.7 The fact of the matter is that the development of TAVI devices mostly aims at reducing the degree of paravalvular leak without compromising the rate of new pacemaker implantation after TAVI, that is, without changing the degree of pressure to the native annulus. Therefore, the «skirts» surrounding the metal structure of the devices where they come into contact with the annulus are not only here to stay but come in longer lengths and have more morphological variations. The history of ACURATE neo (Boston Scientific Corporation, United States) would be a good example of how a modified skirt that is 60% longer can have a benefit that, though may seem spurious, is really a breakthrough with a potential clinical benefit like García-Guimarães et al. proved.1.

Although the study has some limitations associated with its nature like comparing 2 different, non-homogeneous historic cohorts, it demonstrates something that operators who have tried different models have already confirmed in our routine clinical practice: the segment packaging in contact with the annulus has reduced the rates of leak in TAVI. Also, it proves that designing a device should be a positively toll-free packaging: the ACURATE Neo2 valve reduces paravalvular leak without compromising the rate of pacemaker implantation as another similar study that compared 2 consecutive cohorts with the 2 consecutive models of Accurate neo already demonstrated.8

In the process of developing new devices for TAVI we have learned to study the size of aortic annuli with the computed tomography (CT) scan much better and be more accurate when adapting the size of the device that should be implanted. More technical options have come up regarding the size of the valve have become available too regarding the size of the valve, its measurement, implantation height, and even the need for pre or postdilatation. The impact of each one of these factors could be statistically figured out, although this is not an easy task between 2 different historic cohorts.

If we conduct an in-depth study of what it means to assess aortic valves with the CT scan, especially the capacity to predict the rate of paravalvular leak after TAVI, we’ll find some contradictions along the way. Although the degree or spread of calcification can seem the culprits of paravalvular regurgitation, not everything is so clear or linear. This confusion can be attributed to the different ways valvular calcium can impact the sealing of the valve based on the type (balloon-expandable or self-expanding), specific design (with or without skirt, among other), size selected, and procedural technical issues (implantation height). In the studies of coronary calcification assessed via CT scan there is variability in the technique used to quantify coronary calcium (CT without contrast or coronary computed tomography angiography [CCTA]) and the methods of analysis (threshold for the detection of coronary calcium, assessment of Agatston score or calcium volume even the outflow tract, among other).

The standard method to quantify coronary calcium includes a baseline study often before the injection of the iodinated contrast material needed to perform the cardiac and aortic CCTA. When this baseline determination is lacking, the calcium quantification used in the article signed by García-Guimarães et al.1 includes a dichotomic detection threshold based on the opacification obtained in the outflow tract of CCTA images;9,10 an easy method with an acceptable correlation that was homogeneously applied to both cohorts.

The size of the valve selected, implantation height, and the distribution of calcium both in the annulus and left ventricular outflow tract may have shared some protagonism in this study and on this regard.

Sealing limitations with TAVI compared to surgical aortic valve replacement may still persist for some time despite the advances made with the former. However, the supravalvular position of coaptation and the worse profile of the bare-metal stents vs surgical valve can be favorable assets for TAVI regarding the study of long-term durability.

Finally, although for the time being there is not a cause-effect correlation, it’s striking to see that the group with more residual leak in the aforementioned study1 and others9,10 also shows more bleeding at follow-up. It is obvious that since they’re historic cohorts, this could be due to other factors involved in the learning curve and the development of the technique like vascular access treatment or use of drugs that may affect bleeding. It could also be that the leak has deleterious rheological effects like some studies have already suggested.11

We should say that although there’s always a toll to pay with new packagings, this doesn’t seem to be the case.

FUNDING

None whatsoever.

CONFLICTS OF INTEREST

B. García del Blanco is a proctor for Edwards, and has declared to have received funding for counselling jobs for Medtronic, and Boston Scientific. H. Cuéllar Calabria declared no conflicts of interest whatsoever.

REFERENCES

The time has come. Over the past few years, we have been living a constant increase in the number of patients with aortic stenosis who are treated with transcatheter aortic valve implantation (TAVI). Although the latest indications of the clinical practice guidelines from the European Society of Cardiology1 are somehow more restrictive than those of the American College of Cardiology2 regarding age cut-offs and surgical risk we’ve seen a growing demand for TAVI in low-risk patients and, progressively, in younger patients in almost all anatomical settings.

Up until now, randomized clinical trials had mostly focused on comparing the TAVI technique to conventional aortic valve replacement surgery.3^,4 And although these studies with different models of transcatheter aortic valves laid the foundation for the indications published by the guidelines, very few of them make head-to-head comparisons among the different TAVI models currently available. As a matter of fact, most are observational, non-randomized or non-inferiority clinical trials. On the other hand, the variability of the different models currently available has been growing with technological advances to perform easier, safer, and more durable transcatheter heart valves. However, can we assume that there will be some sort of class effect in all TAVI models currently available?

In an article recently published in REC: Interventional Cardiology, Elnaggar et al.5 compared 2 models of top transcatheter heart valves currently available (the Evolut PRO, Medtronic, United States, and the SAPIEN 3, Edwards Lifesciences, United States) using an easy randomized design. Although the study has significant limitations (a rather clinical compared to methodological protocol), it seems reasonable to start discussing whether the different TAVI models available have similar results in non-selected and randomized populations. As it occurred with coronary stents, presumably in no time, we’ll be seeing more comparative trials like this studying not TAVI vs surgery, but TAVI vs TAVI in different clinical and anatomical settings. In the study conducted by Elnaggar et al.5 no significant differences regarding in-hospital mortality between both models were seen, but a difference regarding paravalvular leak favorable to the SAPIEN 3 vs the Evolut PRO device in a population not previously screened through coronary computed tomography angiography. As described in the methodology and further discussion, the method used in the study to assess annular size and anatomy was unusual. The protocol included an intraoperative transesophageal echocardiography plus in-situ balloon inflation to measure the annulus and select the size of the valve based on the coverage index. This may have impacted implantation results following size selection and coronary artery calcium assessment as predictors of paravalvular leak, and not based on today’s gold standard (computed tomography). Regarding the need for pacemaker implantation after TAVI, the authors say that this difference was not significant (7.1% vs 5.8% favorable to the SAPIEN 3) although a difference was seen in the rate of baseline right branch bundle block (16.9% in the SAPIEN 3 group vs 0% in the Evolut PRO group). Therefore, we should mention that the baseline population was more favorable regarding the predictors of pacemaker implantation in the Evolut PRO compared to the SAPIEN 3. The latter, however, showed a lower—although not statistically significant—absolute rate of pacemaker implantation. Finally, the composite endpoint defined by the authors as device success was favorable to the SAPIEN 3 (98%) vs the Evolut PRO (86%) and included lack of mortality, paravalvular leak grade ≥ II at discharge, the need for a second valve, conversion to surgical aortic valve replacement or valve embolization. The study focused on procedural results with a follow-up limited to the length of stay (median of 7 days).

In any case, and beyond any methodological constraints, comparative trials show the strengths and weaknesses of different transcatheter aortic valve models even with experienced operators, which probably debunks the theory that a single model in expert hands fits every patient. If we want excellent results in patients and longer life expectancies, we’ll probably need to profit from what each model has to offer depending on the patient’s anatomy. Also, in high-volume centers that treat young or low-risk patients, the use of different TAVI models should be mandatory for better valve selection regarding the patients’ clinical and anatomical characteristics. As a matter of fact, there is compelling evidence that the hemodynamics of supra-annular models is better compared to that of annular coaptation models, especially, in small annuli6^,7 or that, with a significant load of calcium, latest generation balloon-expandable models have better results regarding paravalvular leak,8 etc. Still, several questions remain unanswered that can all be summarized in the headline of this editorial: is there a class effect in all TAVI models currently available?

In view of the reports that compare the results of different models,9^,10 similar immediate results are likely during primoimplantation with all of them since the technique is highly reproducible. However, like we said before, the population where indications are trying to be expanded requires excellent results and small differences that seem irrelevant in absolute terms but are very important in this context of excellence if we want TAVI to become the gold standard to treat aortic stenosis regardless of age and surgical risk. Considering the durability data available to this date (median of nearly 8 years)11 when offering this therapy to young patients with longer life expectancies compared to this expected durability, the term «lifetime plan» comes into play. Now the index TAVI needs much more than excellent results regarding severe cardiovascular complications, paravalvular leak, need for pacemaker implantation or rate of stroke. Now, valve selection needs to be planned and carefully individualized to better suit the patient’s anatomy anticipating a possible second TAVI in the future (TAVI-in-TAVI). Come to this point, very few will still advocate for class effect. The different designs and adaptations made to the patient’s anatomy will be key in a crucial aspect regarding planning a second procedure years after the index one: access to coronary arteries following the risk of sinus sequestration or occlusion due to outer skirts and height of the first and second valves. This is where intra- or supra-annular designs, the valve total height, strut amplitude, the possibility of commissural alignment, laceration techniques, prosthesis-patient mismatch, etc. come into play. In conclusion, a significant combination of factors that still need to be studied before answering some of these questions. Undoubtedly, virtual, and three-dimensional simulation technologies play a key role in research and clinical application with decision-making algorithms to choose the best alternative for our patients. Therefore, former studies have already discussed these aspects while trying to elucidate how different models behave in this complex TAVI-in-TAVI setting.12 Also, comparisons have been made with surgical explantation of TAVI with structural failure.13^,14 Currently, the rate of these events is not high, but the most plausible thing is that as the patients’ mean age drops, the rate of valve degeneration will increase parallel to the need for dealing with this problem.

All things considered it seems highly likely that there will be no class effect in TAVI considering how different the designs currently available behave beyond implantation. There is, however, great reproducibility of the transfemoral transcatheter technique with excellent short- and mid-term results. Some questions remain, though, on the long-term outcomes that will surely be answered as scientific evidence as it has been the case since this technique was born 20 years ago.

FUNDING

None whatsoever.

CONFLICTS OF INTEREST

C.A. Urbano Carrillo is a proctor for Edwards Lifesciences and participates in consulting groups for Medtronic España.

REFERENCES

Two decades of transcatheter aortic valve implantation (TAVI) changed the history of contemporary medicine and became a reference model in cardiovascular disease. Percutaneous structural heart disease (SHD) therapies emerged to treat the entire heart valve and vessel spectrum, as well as congenital or acquired wall and muscular defects.

(R)evolution happened back in 2002 with Alain Cribier’s human aortic valve disease percutaneous milestone treatment.1 A progressive and impressive range of therapeutic alternatives for patients grew parallel to the population’s longevity given the most prevalent etiology of aortic stenosis is degenerative. In fact, cardiovascular diseases remain the leading causes of death and hospitalization and represent an enormous clinical and public health burden, which disproportionately affects older adults. The World Health Organization expects octogenarians to quadruple up to 396 million by 2050. Although rheumatic heart disease has become rare in industrialized countries, its overall burden is still significant. It comes as no surprise that complex patients who can benefit from combined valvular procedures are increasingly common.

The TAVI impact on cardiology and cardiac surgery surpassed the clinical field and imposed a restructure as the path taken in aortic valve disease is transposed, progressively, to other structural clinical areas, namely mitral, tricuspid, and acute stroke prevention.

WHAT’S THE STORY?

Initially, safety and efficacy were the main requirements for TAVI, same as for any other cardiovascular technique. Mortality and complications were important from a clinical point of view resulting in prolonged admissions and increased hospital costs. Intensive use of imaging and general anesthesia were the default procedure for most. Patient selection became the concern and frailty assessment, risk stratification, futility, and the imponderables were the main issues. Bench simulation provided relevant information while studies and registries depicted the actual TAVI expression across countries.2-4

Progressively, innovative techniques and devices led to cautious simplified protocols that run parallel to image expertise replication in the non-aortic space, especially in the mitral valves. Patient subgroups were the main topic, namely the history of cardiac valve surgery –aortic, mitral, and tricuspid– as well as octogenarians. The economic burden of incremental cost on health economics emerged as a concern, as well as device selection, hybrid techniques, alternative access routes, and standardized approaches for complications. Concomitant medical therapy and longevity were also captured.5,6

Therefore, the field of aortic procedures expanded, grew, and consolidated. TAVI procedures became daily routine with hands-on training for fellows. The need for preparing interventional cardiologists for this area became clear, which was reflected in industry proctoring programs and by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) Core Curriculum. Simultaneously, expansion to other SHD areas like percutaneous mitral and tricuspid valve procedures, left atrial appendage and valve leak closures emerged from this maturity as a natural (r)evolution in the field of SHD.7-10

WHAT DID WE LEARN?

Aortic valve procedures reflect, first, contemporary longevity and modern medicine. Their expansion constitutes a role model in cardiology and cardiac surgery by inducing changes adopted in other SHD areas.

Several SHD procedures have the extraordinary ability to ameliorate heart failure, prevent and treat thromboembolic diseases, and improve survival.11 We should recognize and acknowledge the common features that bring their current prestige, success, and expansion. Among immense factors, the following may be considered the most relevant:

• – Basic research
• – Comprehensive patient management
• – Multidisciplinary approach
• – Patient and subset selection
• – Access route mastering
• – Interventional cardiology background
• – Device iteration and innovation
• – Structured education and training
• – Complementary medical therapy
• – Long-term assessment of care and outcomes

Progress is endless and these are valuable assets to guide the next steps (figure 1).

Figure 1. Influence of aortic and mitral procedures in structural heart disease. ASD, atrial septal defect; IC, interventional cardiology; LAAC, left atrial appendage closure; PFO, patent foramen ovale; PTE, pulmonary thromboembolism; PVR, paravalvular regurgitation; TV, tricuspid valve; VSD, ventricular septal defect.

WHAT DOES THE FUTURE LOOK LIKE?

Physicians, caretakers, industry, and policy makers conquered a huge responsibility in the field of SHD.

To match societal and patient’s expectations, the interventional cardiologist needs a holistic approach:

• – To define the role of SHD interventional cardiologists. As a medical cardiologist who manages patients from diagnosis to follow-up of SHD and performs percutaneous procedures in this domain. As members of heart teams that interact closely with other cardiologists, cardiac surgeons, and other medical specialties, nurses, paramedics, and other healthcare professionals.11 All these considerations are based on the EAPCI Core Curriculum of 2020 and on the upcoming EAPCI Core Curriculum on percutaneous SHD procedures (submitted for publication).10
• – To harmonize SHD interventional cardiology practice. Data from health surveys, administrative records, cohort studies, and registries show persisting geographic inequity across Europe. The EAPCI certification that includes a national mutual recognition system, attempts to validate a proper level of knowledge and practice to protect patients from undergoing interventional cardiology procedures performed by unqualified professionals and set up a European standard for competency and excellence in this field.10
• – To promote and assess quality of care by adopting standardized data definitions for the quantification of quality of care and outcomes. Recently, the EuroHeart methodology reached consensus on a set of variables, 93 categorized as mandatory (level 1) and 113 as additional (level 2) based on their clinical importance and feasibility.11 That facilitates quality improvement, observational research, registry-based randomized trials, benchmarking and post-marketing surveillance of devices, and pharmacotherapies.12
• – To perform TAVI in centers without permanent onsite cardiac surgery by establishing straight-forward protocols that provide patient safety and ensure that both operators and hospitals are committed to high quality outcomes. Though TAVI in centers without permanent onsite cardiac surgery is not endorsed at present, the dramatic growth of candidates outpaced the efforts, prompting increased waiting times with negative and severe clinical consequences. Models should include an optimal heart team around the patient from periodic visiting teams to an overall exchange partnership.13,14
• – To expand SHD procedures to low-risk and/or younger patients who present distinct challenges in their stratification, comorbidities, clinical presentation, anatomy, and potential longevity supported by recent trials. Also, by promoting responsible research and enhancing patient-centered solutions.14
• – To develop awareness regarding valvular heart disease since it is not commonly acknowledged by the population and because aortic, mitral, and tricuspid valves present overlapping functions, and differences regarding diagnostic and therapeutic methods. The EAPCI Valve for Life initiative detects barriers, identifies stakeholders, and implements strategic plans to overcome difficulties in different areas.15
• – To provide the referral network a simple, expeditious, and efficient articulation from the patient and the referring physician perspective by deploying and/or developing dedicated information technology solutions for treatment pathways and reshaping the future cardiovascular department (eg, by fusion or rotative leadership between cardiology and surgery).

CONCLUSION

In conclusion, percutaneous SHD procedures are highly demanding and rewarding. Lessons from the past are precious and interventional cardiology must use them wisely as access and volume are increasing significantly. A comprehensive approach is warranted to face this surge.

FUNDING

None whatsoever.

CONFLICTS OF INTEREST

R. Campante Teles declared no conflicts of interest associated with this manuscript.

REFERENCES

Ischemic postconditioning (iPost) was first described in 2003 as a strategy capable of reducing the size of infarction after prolonged coronary occlusion in dogs through the immediate application of reperfusion after 3 cycles of 30 seconds of coronary reocclusion followed by 30 seconds of reperfusion.1 These results were soon confirmed independently, and the potential mechanisms involved described including, among others, a delayed normalization of pH levels, less accumulation of intracellular calcium, inhibition of the mitochondrial permeability transition pore, and less oxidative stress.2 Compared to the robust protective effect of ischemic preconditioning, it was confirmed that iPost was only beneficial if the procedure started right after reperfusion. However, it was attenuated in elderly subjects or in the presence of comorbidities or certain drug therapies.2,3

Despite these limitations, iPost soon called the attention of interventional cardiologists because it was easy to apply during primary percutaneous coronary intervention. Back in 2005 the very first study ever conducted in humans was published. In this study, iPost reduced the size of creatine kinase release compared to the control group in patients with ST-segment elevation myocardial infarction (STEMI).4 However, successive trials that estimated the size of infarction using similar methods or was more reliably measured by contrast-enhanced cardiac magnetic resonance imaging showed contradictory results. Some of these confirmed iPost protective effect while others revealed the opposite or even less myocardial salvage in patients treated with iPost compared to those who were iPost-naive.5^-7 So far, no clinical trial has been able to demonstrate that iPost reduces clinical events. The largest trial ever conducted is the DANAMI-3–iPOST that included 1234 patients with STEMI treated with primary percutaneous coronary intervention within the first 12 hours of disease progression and with the culprit artery occluded at the beginning of the procedure. These patients were randomized to receive iPost or a conventional percutaneous coronary intervention.8 After a median of 38 months of follow-up, the rate of the primary endpoint (death or hospitalization due to heart failure) was similar in both the iPost and the control group (10.5% vs 11.2%, respectively; non-significant P value) with no differences being reported in their individual components, other events, ST-segment elevation resolution or in the size of infarction measured by cardiac magnetic resonance imaging in a subgroup. A follow-up meta-analysis confirmed the lack of tangible clinical benefits in iPost in an aggregate population of 3619 patients with STEMI.9

Given these results, clinicians have consequently lost interest in this strategy. Therefore, iPost has not joined the therapeutic arsenal for the management of patients with STEMI. However, the reason behind the contradictory results of the mentioned trials is worth analyzing to identify, if any, subgroups of patients who could benefit from the protective effect of iPost. A possible explanation could be that the benefit of iPost depends on the duration of previous ischemia.10

In an article recently published in REC: Interventional Cardiology, Nuche et al.11 put this hypothesis to the test by comparing the effect of iPost on the size of infarction in a series of pigs undergoing left anterior descending coronary artery occlusion through 30-min balloon inflation (N = 19) to a different series from a previous report12 where occlusion went on for 40 min (N = 10). Except for the duration of ischemia, the experimental protocol was identical. iPost consisted of 4 cycles of balloon reinflation and deflation (1 min each) started 1 min after reperfusion. The area at risk was measured on the contrast-enhanced multidetector computed tomography scan with contrast during ischemia while the size of infarction was measured on the contrast-enhanced cardiac magnetic resonance imaging at 7 days.

iPost did not reduce the size of infarction in animals with 30-min coronary occlusion (0.3% [0.0-3.9] vs 0.9 [0.0-2.6] of left ventricular mass in animals treated with iPost or in the control group, respectively) or 40-min coronary occlusion (31.1% [27.3-32.8] vs 27.3 [25.1-27.5], respectively; both with non-significant P values]). Overall, T1 relaxation times were longer in animals treated with iPost. Authors conclude that iPost did not reduce the size of infarction in any of the 2 series, which goes against the possible interaction between its effect and the duration of previous ischemia. Also, longer T1 relaxation times—a marker of interstitial fibrosis—in animals with iPost suggests potential damage associated with the procedure.

The trial11 comes from a group of researchers with solid experience in the area, it is technically demanding, and has been conducted following a highly sophisticated methodology, for which the authors should be credited. Results go against an interaction between the benefit of iPost and the duration of previous ischemia. However, before this becomes the definitive conclusion, some methodological considerations should be made. In the first place, to assess the effect of any protective procedures, the size of infarction in the control group should have certain variability and, on average, should not be too large or too small.13 However, in this trial, after 30 min of ischemia barely any infarction was reported (3.8% [0.0-8.5] of the area at risk) while after 40 min infarctions were massive (98.2% [70.7-98.8] of the area at risk). Although these ischemia times were selected because they had caused medium-sized infarctions in former trials,14 homogeneity of the infarction size seen in both series and the almost non-existent infarctions in the 30 min series complicate discarding a possible beneficial effect of iPost in the results reported. Secondly, and on this regard too, it was surprising to see that by increasing ischemia time in just 10 min we went from almost non-existent infarctions to infarctions that occupy the entire area at risk. Although the experimental protocol was the same, as both series were conducted in different moments in time, variations in the conditions of the experiment such as animal breed, room temperature, materials used, etc, may have impacted the results and, therefore, cannot be ruled out. In this sense, results stress out the possible setback associated with the use of historic series. Finally, for the lack of a targeted anatomopathological study, a possible explanation for the massive infarctions reported in the 40 min series is that maybe some animals had coronary reocclusions between the end of the experiment and when the size of infarction was estimated 7 days later. Reocclusion is a common occurrence in this experimental model, especially when ischemia has been prolonged, and although the risk of ischemia drops with antiplatelet therapy (3 doses of clopidogrel were used in this trial) it does not go away completely.15

Despite these considerations, the truth is that the results of this study11 do not offer any signs of a potential cardioprotective effect of iPost by changing the ischemia times in this experimental model. This, added to the lack of clinical benefits reported in the previously mentioned trials confirms that, currently, iPost should not be used in patients with STEMI. This anticipates that it will be difficult to find a population of target patients in whom this procedure might be beneficial.

FUNDING

J.A. Barrabés received research funds from Instituto de Salud Carlos III (PI20/01681 project) and Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV) co-financed by the European Regional Development Fund.

CONFLICTS OF INTEREST

None reported.

REFERENCES