The future of interventional cardiology

Mitral regurgitation (MR) is the most prevalent form of valve disease in developed countries1 and its prevalence increases with age affecting ~10% of people > 75 years.2MR is a very heterogenous disease that damages not only the mitral valve apparatus but also its surrounding structures. In primary MR, mitral valve surgery is the therapy of choice in symptomatic patients or asymptomatic patients with left ventricular dysfunction. Surgical repair is generally preferred over replacement if technically feasible.3^,4 In secondary MR, the surgical approach is still under discussion5 and it is spared for patients with indications for other surgical cardiac procedures (ie, coronary artery bypass graft).3^,4

Several studies suggest that a large proportion of MR patients are never treated due their high surgical risk6 and that such a conservative approach results in high re-hospitalization (~90%) and mortality rates (50%) within 5 years following the initial diagnosis.7This population has become a clear unmet need and a target for the development of less invasive therapeutic approaches. Several transcatheter mitral valve repair (TMVR) technologies inspired by well-established surgical techniques have been developed and have already been approved for clinical use. The most commonly used, the MitraClip device (Abbott Vascular, United States) has reached more than 100 000 implants and demonstrated safety and efficacy in several MR subsets.8^-10 Although clinical adoption continues to increase, edge-to-edge repair does not fully resolve MR and has some anatomical limitations too (ie, calcified leaflets) that prevent a wider use. Transcatheter mitral valve replacement (TMVR) offers a more universal concept for the management of mitral valve disease with a more predictable abolition of MR severity in a procedure that could be less invasive compared to current surgical techniques.11

Important lessons have been learned from ongoing TMVR clinical studies. First, the patients screened for these trials, considered of high or prohibitive surgical risk display more complex anatomical substrates than originally thought that lead to very high rejection rates. Imaging sizing algorithms used to confirm patient eligibility are patient- and valve-design specific, but have not been standardized in all valve programs. The availability of different device sizes has also limited the wider adoption of this technology.

One of the biggest earliest technical concerns was the ability to achieve valve stability in the absence of sutures. To tackle this issue, several anchoring mechanisms have been developed resulting in high periprocedural success and low early dislodgment rates.12 The potential for left ventricular outflow tract obstruction is still the biggest Achilles’ heel of this technology. Several factors including13 aorto-mitral-annular angle, degree of septal hypertrophy, the left ventricle size, and device protrusion into the cavity may contribute to left ventricular outflow tract obstruction. The short and mid-term valve leaflet performance has not been an issue to this day. Mean transvalvular gradients and paravalvular leaks have been similar to those obtained after surgical mitral valve replacement.

The rate of periprocedural complications varies based on the valve program we are dealing with. The mean 30-day all‐cause mortality reported is ~13.6%.14 Approximately 4.6% of periprocedural death rate mainly due to unsuccessful TMVR deployment that ends up leading to conversion to open heart surgery. Also, issues with the management of access site are responsible for some deaths mainly associated with myocardial tears. The remaining deaths occur following the TMVR procedure. Transapical access has been associated with a higher rate of periprocedural complications (particularly bleeding) and mortality in TMVR procedures.14 The negative effects of thoracotomy in frail populations and the higher degree of myocardial injury associated with the transapical approach may be particularly deleterious in patients with reduced left ventricular ejection fraction.14 Finally, acute hemodymamic changes due to valve implantation in patients with severely depressed left ventricular ejection fraction (< 30%) is a very well-known phenomenon in the surgical field that worsens the prognosis of these patients.

Long-term data in a large cohort of patients is still lacking. In the largest series reported so far, no cases of structural valve degeneration, new occurrence of paravalvular leaks or valve dislocation requiring reintervention have been reported.14 However, a more systematic clinical and echocardiography follow-up of patients undergoing TMVR is crucial to provide consistent data on valve durability and structural valve failure in the future. Data on the risk of long-term thrombosis is scarce too. No episodes of clinically relevant valve thrombosis have been reported with other TMVR devices. Three-month anticoagulation therapy is currently recommended although no long-term data on the real thrombogenic profile of these devices has been reported yet.3^,4^,15

TMVR is evolving to become a new alternative for treating patients with severe MR of very high or prohibitive surgical risk. The complexity of the mitral valve apparatus and the heterogeneity of the disease have limited the wide adoption of these technologies. Several devices are under clinical evaluation and the early experience gained with some of them proves the feasibility of their implantation. Larger studies including a larger number of patients are still needed to test the clinical performance of these technologies. Emerging transseptal TMVR systems have the potential to overcome some of the limitations of current transapical devices. However, technical and anatomical challenges will remain the same. The TMVR field is rapidly evolving, what is somehow clear now is that it will benefit a specific population subset and that there is no such thing as a one-size-fits-all solution.

CONFLICTS OF INTEREST

The CRF Skirball Center for Innovation has received research grant support from Edwards Lifesciences, Neovasc, Abbott Vascular, Sinomed and Cephea. J.F. Granada is one of the co-founders of Cephea.

REFERENCES

Scientific dissemination has always been at the forefront of medicine. It consists of bringing the advances made in research to all professionals and the general population. The traditional way to do this was through books. However, the growing accumulation of knowledge and the need to communicate it in a timely manner prompted the appearance of periodic publications: the scientific journals.

Currently, the enormous speed at which knowledge is generated and the lust for knowledge have found an ally in the Internet and the inevitable social media. The possibilities are just amazing, and they allow the spread of ideas and opinions with greater impact in education, networking, and public health. 1^,2

In our journal, Jurado-Román reviewed the role of social media in the educational setting and highlighted its importance without obviating its potential risks and limitations.3^,4 Some have already coined the term “twitterology” to refer to the medical use of this social network.5

Over the last year an example of this have been the ISCHEMIA and PARTNER-3 landmark clinical trials that have prompted ongoing discussion and debate on social media.6^,7 But new studies do not have the monopoly on this. We have also witnessed fierce debates about a not so recent trial that gave rise to methodological considerations; I am referring to the EXCEL trial and the update of its 5-year results.8^-11

The recent pandemic of COVID-19 has been the largest dissemination of medical-scientific information on social media ever. We have learned so much from this world-shocking experience in this regard.

CHARACTERISTICS AND PREVALENT VALUES OF COMMENTS POSTED ON SOCIAL MEDIA

Here is a brief description of the characteristics of communication in social media based on what is being posted on a daily basis.

Totally open access

Anybody can post their opinion or comment on social media. This means that the capacity to spread knowledge has been democratized with the corresponding benefits and risks involved. There is no peer review nor filters on authors or content. Rigor and truth are not guaranteed either, only if imposed by the author himself.

Communication on real time and immediacy

The comments are published and available online immediately. There are no delays anymore. Communication needs to happen as quickly as possible after public exposure or after the publication of the study or even better during its presentation at the congress. Being the “first to shoot” is the only thing that matters.

Concision

These comments are limited in size and thoughts on a particular study have to be summarized in a few words. Regarding Twitter, complexity has to be summarized in just 280 characters. Simplicity over concision is the rule to follow.

Impact

Communication needs to generate sensations and induce reactions whether of agreement or of rejection; anything goes but indifference.

The group: tribalism

The study results perceived as favorable are cheered by the group and those considered negative are ignored, questioned or even rejected in a sort of medical tribalism already identified and questioned by some.12 This mimics the fierce style of political or football discussions.

The influencer

The communicator becomes the “man of the hour”; it is not about the actual value of the message anymore but about the messengers themselves. The author feels compelled to comment on all studies. These comments are awaited by those who receive them with sympathy or rejection. These influencers have followers who can’t wait to give their feedback as well; this division is related to the author’s profession and the group represented by the author.

The reactions

Reactions are subject to similar conditions. However, in this case, they may not be preceded by the acquisition of information and reflection on the opinion given; feedback is posted in a rather direct way often guided by feelings and emotions rather than reason. There are times that the comment is posted simply because a certain opinion is expected to be given by the author’s professional group.

 

 

THE REAL VALUES OF SCIENTIFIC DISCUSSION

Having said all this, we should not forget about the real values of scientific communication. The interpretation of a study requires a detailed analysis of methods and results, confirmation through previous studies, and the assessment of the different interpretations given. All of it requires elaborating and presenting one’s personal opinion in the most basic way possible. This process takes time, space, and moderation. That is the only way to achieve precise and balanced results.

The rule of the 3 Rs to have a scientific debate on social media: rigor, responsibility, and respect

The contrast between the characteristics and values of success on social media and the real values that should inspire scientific discussion is obvious. The only way to bring together the true virtues of both is through the commitment to communicate with rigor, responsibility, and respect:

 

 

RECOMMENDATIONS FOR SCIENTIFIC COMMUNICATORS ON SOCIAL MEDIA

Before posting anything on social media you should inform yourself, delve into the studies, think about your interpretation, and reflect on the reactions your post might generate. Take your time and don’t be obsessed with the topic under discussion right away. Don’t try to amaze everyone at all times, but shake consciences to a certain point, appeal to reason rather than feeling, and respect other people’s opinions.

To mitigate the effects of tribalism it is essential to recognize the natural tendency to create an us-vs-them-based state of opinion and to move away from such a state towards a more problem-focused approach. Group-based approaches should be left aside to favor a more positive collaboration and interaction with others.12

Finally, take your time to fight back, but do not do it right away. The true value should be in the message, not the messenger. If you respect privacy, listen more than you talk, see things from the other people’s perspective, and focus only on doing good to others, then you cannot go wrong.13

I would like to conclude with a quote by social media expert Erik Qualman that perfectly summarizes this editorial: «We don’t have a choice on whether we do social media, the question is how well we do it».

CONFLICT OF INTERESTS

J. M. de la Torre Hernández has received funding to conduct his study from Abbott Medical, Biosensors, Bristol Myers Squibb, and Amgen; he has also received funding for his work as a consultant for Boston Scientific, Medtronic, Biotronik, and Daiichi-Sankyo.

REFERENCES

INTRODUCTION

The history of coronary balloon angioplasty began in 1997 with the first percutaneous transluminal coronary angioplasty (PTCA) ever performed by Andreas Grüntzig.1 Some of the limitations of this technology were solved with the introduction of stents.2 Added to an improved pharmacological concomitant therapy in the form of dual platelet inhibition,3 the local drug delivery initially through stents (drug-eluting stents, DES)4 and then balloons (drug-coated balloons, DCB)5 improved long-term outcomes significantly. The history of coronary angioplasty was summarized in detail in various articles on the 40th anniversary of this technology.6^,7

The local application of paclitaxel through DCB had begun to revolutionize the treatment of peripheral arterial disease (PAD).8 This advance was very helpful for patients regarding primary patency and quality of life, but received a severe setback in a meta-analysis that claimed that the use of paclitaxel DES and DCB was associated with a higher mortality rate at the 2- and 5-year follow-up.9

The objective of this editorial is to discuss the safety profile of drug-coated devices in the historical context of the 2006 “European Society of Cardiology (ESC) firestorm” on coronary DES, data available on the coronary use of paclitaxel coated devices, and the potential role of limus-based agents in DCB.

FIRST-GENERATION DES AND THE 2006 “ESC FIRESTORM”

After the publication of the RAVEL clinical trial on the Cypher sirolimus-eluting stent4 and the TAXUS trials on the Taxus paclitaxel-eluting stent,10 the DES rapidly gained momentum thanks to their significantly lower rate of restenosis compared to uncoated bare metal stents (BMS). In a direct comparison with the Cypher stent, the Taxus showed a higher rate of recurrence at the 9- to 12-month follow-up.11 The common view that sirolimus is more effective than paclitaxel is essentially based on these data. However, it should be emphasized that the Taxus stent was almost as effective as the Cypher stent beyond the 12-month follow-up and up to 10 years.12 The progress made by these first-generation DESs compared to modern DESs was based on the nowadays better controlled coating processes especially after improving stent platforms with thinner stent struts.13

However, there were also critical remarks to be made on the safety profile of coronary DESs. It has been reported that the delayed drug delivery from the stent struts prevents the implant endothelialization and increases the risk of thrombotic occlusion of the stent.14 The BASKET-LATE trial reported between 3 and 4 times more late deaths or myocardial infarctions15 with first-generation DESs. A hotline session held in Barcelona at the ESC congress of 2006 reported on 2 meta-analyses on a safety risk after sirolimus DES implantation.16^,17 In both meta-analyses the events published at study level were divided by the total number of patients with intention-to-treat without observation of cross-over treatments and lost to follow-up numbers. This is similar to the recently controversial meta-analysis on paclitaxel coated devices for the management of PAD.9 The first DES meta-analysis showed significant differences in the mortality and Q-wave myocardial infarction rate at the late follow-up when the Cypher and bare metal stents were compared.16 This finding may be explained by a possibly higher rate of late stent thrombosis. However, the second meta-analysis showed that the higher mortality rate associated with the Cypher stent was due to a higher non-cardiac mortality rate, thus contradicting the mechanism of stent thrombosis.17 Despite these conflicting results, the government regulatory agencies worldwide were alarmed. The Food and Drug Administration (FDA) published several warning letters that eventually limited the indications for DESs.18 However, further analyses did not confirm such an increased risk.19 Also, the clinical trials that compared the Taxus stent to the BMS or the Cypher did not show higher rates of myocardial infarction or death.10^,12 Thus, DES became the standard treatment for the management of coronary heart disease.20 Similarly, large contemporary registry studies and randomized studies have not confirmed any mortality signals for paclitaxel devices for the management of PAD21^-24 It remains to be seen whether a similar comeback as with coronary DES will eventually happen.

PACLITAXEL-COATED BALLOONS

Currently, the clinical practice guidelines recommend DCBs for the management of in-stent restenosis (ISR) only.20 However, there is an increasing number of positive data on the treatment of de novo stenoses, particularly in small coronary vessels25^,26 and risk indications.27^,28 A patient-based meta-analysis of the trials that compared DCBs and DESs in DES-treated ISRs showed a similar 3-year safety profile for DCBs and DESs with numerically lower rates of events with DCB.29 Even individual studies that compared DCB with first-generation DES,30 BMS,27 or plain old balloon angioplasty31^,32 reported significantly lower mortality rates after DCB implantation in the long term. However, these studies did not have enough statistical power to analyze this question. A recent meta-analysis of all randomized data on DCBs showed no differences in the mortality rate of DCBs and alternative treatments at the 1- and 2-year follow-up, but a significant survival benefit for DCBs regarding all-cause mortality and cardiac mortality at the 3-year follow-up.33

SIROLIMUS VS PACLITAXEL FOR LOCAL DRUG DELIVERY

When comparing paclitaxel and sirolimus regarding local drug delivery it is often said that sirolimus has a wider therapeutic window and paclitaxel is cytotoxic. However, these statements are not correct.

Cell culture experiments tell us that the exposure of smooth muscle cells or endothelial cells to paclitaxel leads to more pronounced dose-depending growth inhibition compared to sirolimus.34^,35 There is an increasing release of cytosolic lactate dehydrogenase—a marker for cell death—when incubating the cells with paclitaxel from a concentration of ≥ 100 ng/mL.34 It should be mentioned that the paclitaxel DES only released 10% of the total amount of drug just as the comparable sirolimus DES because of this stronger antiproliferative effect. Regarding DCB, there are typically acute tissue levels of less than 100 ng/mg in the vessel wall.36 Also, only about 10 ng/mg of paclitaxel are biologically active. Otherwise, the solubility product in the tissue is exceeded. While toxic concentrations may well be reached in the DES in the area of the stent struts, distribution in the vessel wall is very homogeneous with local drug delivery through DCB.37 Also, tissue concentration decreases very rapidly after DCB treatment.36 Therefore, the theoretically possible cytotoxicity of paclitaxel is not a factor in the clinical use of DCB.

The second myth is the therapeutic window. A typical total dose of a paclitaxel DCB equals 0.4 mg (3 µg/mm², 20 mm length, 3 mm diameter). The single dose per cancer treatment cycle is 100-175 mg/m² of body surface area through intravenous administration,38 usually 300 mg per infusion. This results in a factor of 750 for paclitaxel as therapeutic window compared to systemic therapy. The typical daily oral dose of sirolimus for restenosis prevention is 2 mg.39 Depending on the specific sirolimus DCB used, the balloon dose is somewhere between 0.2 and 0.6 mg (1-4 µg/mm², 20 mm length, 3 mm diameter). So far, clinical efficacy could only be proved for the high dose of sirolimus,40 which means a factor of 3 only compared to systemic therapy, a clearly smaller therapeutic window. If a sirolimus DCB is implanted on the superficial femoral artery, the dose delivered through the balloon is already above the systemic dose and should be contraindicated (table 1).

Table 1. Systemic vs local treatment. Therapeutic window of paclitaxel and sirolimus.

	Paclitaxel	Sirolimus
Systemic treatment	300 mg Single IV dose of 100-175 mg/m2 per cancer treatment cycle38	2 mg Daily oral dose for restenosis prevention39
Local treatment (DCB)	0.4 mg CAD 3.0/20 mm at 3 µg/mm2 5.5 mg PAD 5.0/80 mm at 3.5 µg/mm2	0.2-0.6 mg CAD 3.0/20 mm at 1-4 µg/mm2 1.6-6.4 mg PAD 5.0/80 mm at 1-4 µg/mm2
Therapeutic window	CAD × 750 PAD × 55	CAD x 3-10 PAD none
CAD, coronary artery disease; DCB, drug-coated balloons; IV, intravenous; PAD, peripheral arterial disease.

DISCUSSION AND FINAL REMARKS

The 2006 “ESC Firestorm” can be seen as a blueprint for the current paclitaxel controversy on the management of PAD. Interestingly enough, discussion at that time focused on sirolimus and not on paclitaxel. The current meta-analysis on the management of PAD with paclitaxel devices has several methodical flaws and has already been refuted. In any case, it has caused great damage to the entire field of local drug delivery for restenosis prevention. Too many patients are currently not receiving the therapy that works best for them and have to receive unnecessary revascularizations.

Regarding coronary paclitaxel DCB no associated mortality signals were seen. Just the opposite, there are indications that the therapy could even offer survival advantages in the longer term by avoiding permanent implants. The alternative of a sirolimus-coated balloon endorsed by many interventional cardiologists still has to prove its clinical efficacy. However, considering the necessary local doses compared to systemic therapy, the use of a sirolimus DCB for the management of PAD is questionable.

CONFLICTS OF INTEREST

B. Scheller is a shareholder of InnoRa GmbH, Berlin, and co-inventor on patent applications filed by Charité university hospital, Berlin, Germany.

REFERENCES

Over the last few years, the risk profile of patients referred to receive a coronary angiography has deteriorated and angiographic findings as well. Therefore, the progressive aging of the population and the development of better techniques to address the complexity of the different angiographic scenarios have conditioned the current situation of percutaneous coronary interventions. The balance between demand and supply in this field is in an ongoing expansion. The management of these delicate situations—which is often competence of cardiac surgery—requires profound knowledge of dedicated techniques and a precise clinical judgment.1^-3 This population is often discarded for coronary artery bypass graft surgery. There are times that even percutaneous treatment is denied because of a high clinical risk or unfavorable angiographic profile.

According to different series,4 to this day complex calcified coronary lesions are a common finding in up to 25% to 30% of all percutaneous coronary interventions. De Maria et al.5 published a review on the management of calcified lesions. They portrayed an accurate, contemporary big picture on the treatment of these lesions. The review basically focused on the technologies in intravascular imaging and tools available to solve today’s technical complexities. The authors emphasize that today the objective of percutaneous coronary intervention when treating these lesions is to modify the plaque. If it fails to do so, the procedure is more likely to fail also in the clinical and technical aspects. Clinically because there would be more major complications, and techni- cally because the result would compromise stent expansion and apposition, with the resulting increase in the rates of in-stent restenosis and thrombosis, etc.6^,7

Intracoronary lithotripsy (ICL) is the latest technology available for the management of severely calcified lesions. Its mechanism of action has been well described in the document. Basically, ultrasound energy interacts with the atherosclerotic plaque causing vibrations that crack and tear the calcified components of superficial and deep layers. Compared to ablation techniques, since it is based on balloons, it is easy to use and there is a short learning curve. This, together with an early apparent evidence of efficacy, suggests that it will soon become the standard of care for the management of many severely calcified lesions. Similarly, this effect on deep calcium is an important benefit of ICL compared to other plaque-modifying techniques. Compared to rotational and orbital atherectomies, both of which reduce the plaque burden, ICL does not ablate or reduce it but cracks it supposedly improving stent apposition and expansion. The long-term follow-up will confirm whether this is enough to see long-term benefits.

In a recent article published in REC: Interventional Cardiology, Vilalta del Olmo et al.8 commented on their first experience with an ICL device in a high-risk population. Their data provide useful information to assess the role, safety, and feasibility profile of ICL in high-risk patients not included in other studies. The authors report on procedural success and the short-term clinical outcomes of a non-randomized registry. The data published show the utility of ICL improving the clinical and angiographic results of complex patients with advanced, diffuse, multivessel, and calcified atherosclerotic disease. Their patients often presented with critical conditions such as acute coronary syndrome or left ventricular dysfunction.

Since they recruited their first patient, many things have changed and new information has come to light. By performing OCTs in 31 patients, Ali et al.9 confirmed that ICL cracks the calcified arch in 43% of the patients with multiple fractures caused in over 25% of the cases. According to these authors, the efficacy of this technique is proportional to the burden of calcium with a higher rate of calcium fractures (77%) in cases with a higher degree of coronary calcifications. Serious safety issues or technical complications (coronary perforations, important dissections or slow flow/no reflow) have not been reported in the studies. Unlike former reports,10 Vilalta del Olmo et al.8 share encouraging data on a high-risk population with results that are as good as those from other authors.

Although the use of ICL has grown rapidly, the experience published on this device is limited, especially that coming from randomized clinical trials, and some considerations should be made on this regard. The first one is that the navigation capabilities of the device are an important limitation of this technique. Although Vilalta del Olmo et al.8 reported that the ICL balloon crossing rate was 100%, our data show that 89% of the lesions required preconditioning with balloon angioplasty (62%) or rotational atherectomy (27%). Therefore, with the current design of the ICL device, in most cases a coadjuvant technique is required prior to the ICL so it can be used effectively which increases the cost of both procedures. Secondly, since the population of the Disrupt CAD II clinical trial10 included stable patients with concentric lesions, the role of this technique in unstable patients and eccentric calcified lesions should be studied in a randomized controlled trial. Although it is a registry with a small sample size, the data from Vilalta del Olmo et al.8 are encouraging on this regard. In the third place, life often outruns science. Although it is a friendly, easy to use technique, randomized clinical trials should be performed to select the patients and establish the indications. For instance, because of the simultaneous presence of compression and decompression forces (pull and push) and the fact that flow is compromised with ICL, its role should be studied in detail in different clinical and angiographic contexts like ST-segment elevation myocardial infarction, chronic total coronary occlusion via subintimal pathway, patients with pacemakers, etc. Other contexts suggested are patients with in-stent restenosis or to facilitate transfemoral access in patients with transcatheter aortic valve implantation. The fourth consideration to make is closely associated with the previous one and is inherent to any new technique: the lack of data on its use and long-term benefit. With the ICL rapid expansion we run the risk of using it in non-studied settings making it a useless and unsafe technique that may increase the rate of complications or lead to worse results. For example, a few isolated clinical cases have been reported on the role of ICL on in-stent restenosis due to stent underexpansion. The study conducted by Vilalta del Olmo et al.8 did not report on any of this. Maybe the underlying mechanism of restenosis may explain the oberved differences (underexpansion, malapposition, neoatherosclerosis, etc.). Nevertheless, we still need time to study these issues in randomized and controlled clinical trials. ICL balloon tears have also been reported with the resulting added risk.11 In the fifth place, a very important aspect is that ICL may complement other plaque- modifying techniques; its use is feasible and safe with different angioplasty balloons (non-compliant balloons, cutting balloons, and other), rotational atherectomy, etc.12

In conclusion, the ICL is a new, attractive, easy-to-learn and use technique for the management of calcified lesions. Randomized clinical trials and further data are needed to establish its indications and benefits. In the coming future this technique will probably simplify the complex procedures associated with percutaneous coronary interventions and improve the outcomes of patients.

CONFLICTS OF INTEREST

None reported.

REFERENCES