The future of interventional cardiology

It comes as no surprise that the progression of medical training would eventually take a leap into the digital world where we would be able to access information without leaving our working place or the comfort of our homes. Our specialty, interventional cardiology, predominantly visual, has always benefited from the most advanced technology regarding communication. Actually, we have been doing this for years, even in our country: by the mid-1980s, the Madrid Interventional Course (MIC) organized by Dr. J.L. Delcán and Dr. E. García, was already broadcasting live cases via satellite to analyze and discuss new insights with larger audiences compared to those that can fit in a room. These days, live cases are an essential part of the meetings held in our setting (whether international like the ones organized by EuroPCR and TCT or national like the ones held by the Società Italiana di Cardiologia Interventistica [GISE] and the Interventional Cardiology Association of the Spanish Society of Cardiology [ACI-SEC])3. These cases are discussed remotely by panels of experts with a growing interaction with in-person and remote attendees thanks to specific computer tools and social media. But it is not only the broadcast of live cases which benefit from these advances. We have had access to information on late breaking clinical trials through the Internet many times even before in-person meeting where these trials are often presented. Also, we have had access to the recordings of many simultaneous sessions we couldn’t attend in-person but can review later when we have the time.

The situation of the pandemic caused by the new SARS-CoV-2 coronavirus has accelerated this cross over to virtual meetings due to the impossibility of travelling to places and holding large in-person meetings.1 The main in-person cardiology meetings sched­uled for 2020 have been suspended or turned into virtual meetings. The two largest international meetings already mentioned, EuroPCR and TCT, have become virtual meetings. Also, mass meetings like the ones held by the American College of Cardiology, the American Heart Association or the European Society of Cardiology (ESC) have followed in the footsteps of this digital transition. Our sister societies, the Italian GISE and the Portuguese Associação Portuguesa de Intervenção Cardiovascular (APIC) have done the same thing. But, when these restrictions are lifted, will in-person activities like large face-to-face congresses and meetings be gone for good? Let us look at the pros and the cons of virtual and in-person meetings2 (Figure 1).

Figure 1. Pros of virtual meetings compared to face-to-face meetings.

These are the basic strengths of virtual meetings:

Figure 2. Registration comparison of the annual meetings held by the European Society of Cardiology back in 2019 and 2020.

The downsides of virtual meetings are:

• - Dependency on technical factors: technical support systems are excellent, but still depend on variables like the Internet bandwidth, the quality of connectivity or the incompatibilities of presentations and videos. After 25 years of use of the DICOM standard for the communication and management of medical imaging we still have issues when we try to play video sequences in virtual meetings.

• - To a great extent, the format of these sessions keeps the same structure as face-to-face meetings. The adaptation to the new virtual environment has been more cosmetic than a true reality with the implementation of several technological advances to mimic the in-person experience (avatars, virtual common rooms, chats to replace direct communication). However, fully developed specific methods of communication have not been implemented yet.

• - More difficult personal interaction: asynchronous communication and other virtual borders like lack of types of nonverbal communication (beyond emoticons) complicate connectivity among speakers, moderators, and audience. Speakers feel some kind of «digital loneliness» because they don’t receive any feedback from the audience. In turn, the audience experience “digital fatigue” and they can’t remain focused on anything for more than 30 minutes. New systems to encourage audience participation are desperately needed, particularly in the virtual format.

• - Agendas, time zones, and time devoted to work: in these virtual meetings it is not unusual to find conflicting time schedules since participants come from all across the world. It is not unusual either that these time schedules invade our spare time or affect our working day. The proliferation of these activities is associated with digital overload that has sometimes been referred to as «death-by-webinars»

• - Program sustainability: although our political representatives can’t wait to stop the private sector from funding our medical training programs, the truth is that this is crucial if we want to develop this kind of activity. If some of the activities that used to take place at face-to-face meetings are gone, will support still be the same? Isn’t it more profitable to conduct sponsored meetings and not independent activities?

Those of us who have been trained in the “traditional” meeting environment have a hard time thinking that they can be totally replaced by the virtual format. Here are some of the reasons why:

• - Attending a scientific meeting is a comprehensive experience that includes training as well as other activities: research coordination meetings, building up professional relations, consultancy and counseling, etc. It is almost impossible to conduct these activities outside the context of a scientific meeting.

• - In this sense, attending a face-to-face meeting is time-bound. It is not always easy to disassociate attendance to these meetings from working or face-to-face obligations (especially when the meeting is held in our own town), but it is actually easier compared to virtual meetings. In our setting there are work permits that can be issued to attend training sessions: could this be applicable to virtual meetings particularly with the current extended time schedules of such events?6

• - Most of the advantages seen in the broadcast of contents have long been part of face-to-face meetings. Consequently, most sessions are recorded for immediate broadcast and further reproduction. The same thing happens with in-person and remote audience interaction where the use of social media has proven very useful.

Will the digital gap between the analogical and the digital world, between immigrants and digital natives, between boomers and millennials grow? I don’t think so. Their coexistence will prevail and bring us the best of both worlds: hybrid meetings. If these two worlds were actually ever there…

FUNDING

No funding was received for this work.

CONFLICTS OF INTEREST

A. Pérez de Prado declared having received professional fees for his consultancy work or meetings held for iVascular, Boston Scientific, Terumo, BBraun, and Abbott totally unrelated to this article; he is the current president of the education and learning organization Fundación Epic.

REFERENCES

Mitral regurgitation (MR) is one of the most prevalent valvular heart diseases in the world.1 Although surgical mitral valve replacement has shown to improve clinical outcomes in patients with severe primary MR, surgery is still being denied in a significant number of patients due to their multiple clinical comorbidities.2 The current clinical practice guidelines for the management of severe secondary MR recommend the surgical valve intervention only in cases where concomitant coronary revascularization is indicated.3

Transcatheter mitral valve repair using the edge-to-edge technique (MitraClip, Abbott Menlo Park, CA, United States) has shown to improve quality of life and reduce all-cause mortality in patients with heart failure and secondary MR refractory to the optimal medical treatment.4 However, the level of MR reduction achieved by MitraClip is inferior compared to the surgical techniques, and its overall use is limited by several anatomical factors.5 Transcatheter mitral valve implantation is emerging as a potential therapeutic alternative that could overcome some of the current limitations of edge-to-edge repair.6 Due to their technical design features, most transcatheter mitral valve implantation systems use the surgical transapical approach. Limited experience has been gathered on the use of dedicated transseptal systems. Finally, complex anatomical features such as the possibility of left ventricular outflow tract obstruction and presence of mitral annular calcification have limited the fast clinical adoption of this technology.

The field of catheter-based mitral valve intervention is rapidly expanding, and translational experimental models are seriously needed for the proper validation of these technologies. Unlike aortic valve disease, MR is due to several pathological conditions that result in different anatomical substrates that are not easy to reproduce in experimental models. Catheter-based technologies are designed taking into consideration specific anatomical targets such as annular dilatation or chord elongation, which are also challenging to reproduce in experimental animal models. Significant differences exist between humans and animal models. In the first place, one of the most important challenges we face is annular size. Devices developed for human use are typically larger compared to the annulus seen in common experimental models, which at times, requires developing customized valve sizes. Secondly, the aortomitral curtain is particularly small, which often leads to device interaction with the aortic valve. Thirdly, the mitral tissue is thin and friable providing little support to technologies that require the use of anchors or pads to remain in position. Finally, the left atrium is flat and shallow and provides little room for the validation of technologies via transseptal access.

The use of diseased animal models is not typically required to validate structural heart technologies and most of the validation work can be done on the bench or on healthy animal models. Healing and thrombogenicity of valve materials is particularly important and can be validated in healthy animals. The stability of the frame and durability of the leaflets can also be tested and is of particular significance in the transcatheter mitral valve implantation space. The mechanism of the deployment and delivery system can also be tested but, overall, the retention of the valve depends on the mechanism of anchoring used, which could be challenging due to the lack of structural support. In these cases, the surgical placement of the valves is needed for the long-term stability of the implant.

The use of diseased animal models is often spared to assess the efficacy of the device or test particular device features (ie, anchoring). Several animal species, primarily dogs suffer from primary MR due to leaflet prolapse and have been used to test several catheter-based technologies.7 However, these models are expensive and difficult to provide. Several groups have already developed secondary MR models by inducing ischemia of the posteromedial papillary muscle.8-9 These models have resulted in a high periprocedural mortality rate and moderate levels of clinically relevant MR. The study conducted by Rodríguez-Santamarta et al. recently published on REC: Interventional Cardiology presents a variation of this model by adding volume overload and creating an aorto-pulmonary fistula following the myocardial infarction of the circumflex artery.10 The number of animals was small, but researchers were able to prove the feasibility of model development. In this study, the level of MR was moderate (at most) and other features associated with MR such as annular dilatation were present. These morphological features, although obvious on the image assessment, were subtle in nature and probably in their early stages compared to patients who suffer from severe MR.

The field of structural heart procedures is changing very rapidly, and experimental models are essential for the proper validation of these technologies. Healthy animal models are perhaps enough to test the mechanism of the device delivery system, healing, and durability. Diseased animal models can help validate device efficacy, mechanisms of anchoring, and the long-term stability of the device. However, due to the high anatomical variability seen in humans compared to animals, long-term results may be confusing and require careful analysis by multidisciplinary teams before starting the first tests in humans. A multi-modality approach is highly desirable in the validation process of structural heart technologies. Although animal data are key, proper validation including human tissue and imaging correlation studies may help minimize the misinterpretation of experimental signals and define the developmental pathway of structural heart technologies.

FUNDING

No funding was received for this work.

CONFLICTS OF INTEREST

J. Granada is co-founder of Cephea Valve Technologies.

REFERENCES

According to data from the National Statistics Institute, life expectancy has increased from 73.5 years in 1975 to 83.6 years in Spain in the year 2019. Also, the mean age of the population has gone up 10 years during this same period.1 In this sense, the results from the study conducted by Dégano et al.2 in 2013 come as no surprise. They already anticipated a strong increase in the rate of acute coronary syndrome (ACS) within the next 35 years when the Spanish population > 75 years will represent almost a quarter of the national census. This study anticipated that between 2013 and 2049, the cases of ACS in elderly patients would increase over 70%, but keep a discrete growth in patients under 75 years. These data are but a glimpse of a not so distant future when our patients will be older and their life expectancy longer. Also, the association between aging and comorbidity means that we will have to treat more complex patients.

Elderly patients with comorbidities are misrepresented in clinical trials studying the efficacy of both early invasive strategy for the management of non-ST-segment elevation acute coronary syndrome (NSTEACS) and the most suitable antithrombotic treatment.3 Therefore, despite the fact that clinical practice guidelines recommend early invasive strategy in most patients,4 its generalization to these patients is controversial. It is often decided to individualize the decision-making process by weighing risks and benefits and taking into consideration the treating physician’s perception on the possible complications. Hence, conducting clinical trials focused on this subpopulation as creating large registries representative of the actual clinical practice is of paramount importance.

In an article recently published by Pernias et al.5 on REC: Interventional Cardiology, the authors present a wide registry of elderly patients with NSTEACS conducted thanks to the collaborative work of different cardiology units from several Spanish autonomous communities. With over 7000 patients included, this study evaluated the impact of comorbidities on the indication to perform coronary angiographies. The 6 comorbidities studied (cerebrovascular disease, anemia, kidney disease, peripheral arteriopathy, chronic pulmonary disease, and diabetes mellitus) turned out to be independent predictors of a non-invasive approach. Also, it was confirmed that patients with more comorbidities had lower the chances of undergoing an invasive strategy despite having higher GRACE scores.

The comorbidities reported in this study are associated with a worse prognosis in this clinical setting.6 However, this does not necessarily involve low short-term life expectancy per se. Therefore, given the futility of an eventual revascularization a conservative strategy would not be justified. This clearly shows the need for a proper comprehensive geriatric assessment of these patients, since the accumulation of concomitant comorbidities is often followed by frailty, cognitive impairment, and functional dependency. These variables are key finding out why there is a paradoxically reverse correlation in these patients between the risk of ischemic events and the frequency of performing coronary angiographies. In this sense, we should mention the LONGEVO-SCA, a registry conducted in our setting that studied in detail the impact of frailty and geriatric syndromes on the therapeutic approach and vital prognosis of elderly patients with NSTEACS. Important conclusions can be drawn from this registry, like the negative impact of frailty both on the prognosis of elderly patients with NSTEACS and on the benefits of an invasive strategy.7,8

The usefulness of the invasive strategy in elderly patients is not well established. The randomized clinical trial After Eighty included 457 patients > 80 years with non-ST-elevation acute myocardial infarction (NSTEMI). It confirmed a lower incidence rate of the composite endpoint of death or cardiovascular events at the 1.5-year follow-up with the invasive strategy.9 However, this clinical trial did not consider frailty and included less than 25% of the possible candidates, indicative of bias in favor of elderly patients in better general health conditions and with fewer comorbidities.9 The MOSCA clinical trial10 included 106 elderly patients with NSTEMI and comorbidities. Although there were fewer chances of death or ischemic events in this study at the 3-month follow-up in patients randomized to the invasive strategy, no benefits were seen with this strategy at the end of the follow-up (2.5 years).

Currently underway, the MOSCAFRAIL clinical trial11 will assess the efficacy and safety of the invasive strategy and its prognostic effect within the first year after NSTEMI in elderly patients with confirmed frailty. This trial, that included over 10 tertiary and secondary Spanish hospitals, is a systematic geriatric and comorbidity study conducted with widely validated scales. Its results should provide valuable information and greatly impact clinical practice in the coming future.

Another controversial issue with studies of elderly patients with ACS is what clinical outcomes should be assessed. Most randomized and observational studies focus on “traditional” clinical outcomes like mortality or ischemic events. However, on many occasions there are no data on the impact on symptoms, perceived quality of life, and need for readmission, which may indicate better the clinical benefits of this population. In this sense, we should mention the After Eighty clinical trial found no differences regarding quality of life between patients treated with the invasive strategy and those treated conservatively.12

In conclusion, elderly patients with high comorbidities who are hospitalized due to NSTEACS are a common problem today and will remain so in the future. Given the scarce scientific evidence on the therapeutic approach of these patients, studies like the one conducted by Pernias et al.5 improve our understanding of this complicated clinical scenario and remind us of the importance of collaborative research to conduct large registries that show the reality of this emerging problem in our setting.

FUNDING

No funding was received for this work.

CONFLICTS OF INTEREST

None reported.

REFERENCES

During the second half of 2019, cangrelor started selling in our country, a “new” antiplatelet drug with especial pharmacological properties that make it especially appealing for the management of certain clinical situations in the percutaneous coronary intervention (PCI) setting. The adjective “new” is in quotation marks because the clinical trial conducted proved its superiority compared to clopidogrel with ICP. The CHAMPION PHOENIX trial1 was published in 2013 and it was approved by regulatory authorities back in 2015. This delay has probably caused the scientific evidence to lose relevance and, in consequence this drug might not be widely accepted within the cardiology community. Also, the indication specified in the technical label is only based on the conditions of the clinical trial that prompted its approval—which is mandatory—not on real-world practices. This may be confusing when selecting those patients who may benefit from this drug.2

In short, cangrelor is an intravenous reversible, high-affinity antagonist of the platelet P2Y₁₂ receptor of adenosine diphosphate to which it binds directly (without need for conversion into an active metabolite). In pharmacodynamic terms, the properties of cangrelor are: a) rapid onset of action (3 to 6 minutes); b) powerful dose-dependent effect (inhibition > 90% of the P2Y₁₂ receptor signaling pathway) in relation to the dose used in the PCI; and c) rapid offset of action (shot half-life of 3 to 5 minutes) with recovery of the baseline platelet function in 60 to 90 minutes after infusion.3

Given its pharmacological properties, cangrelor may help solve some of the problems posed by other antiplatelet agents. For example, oral P2Y₁₂ receptor inhibitors (iP2Y₁₂), especially clopidogrel and to a lesser extent prasugrel and ticagrelor, have a delayed optimal platelet inhibition, which is even more significant in the ST-segment elevation myocardial infarction (STEMI) setting, where the bioavailability of oral drugs may be compromised (worse intestinal absorption, vomiting, use of opioids or situations like intubation, therapeutic hypothermia or cardiogenic shock).3,4 Also, despite their efficacy in reducing thrombotic events, the use of parenteral glycoprotein IIb/IIIa inhibitors, may be associated with a higher risk of bleeding.

The clinical development of cangrelor as a coadjuvant therapy in the PCI setting is based on the CHAMPION program, in which the first 2 studies conducted (CHAMPION PCI5 and CHAMPION PLATFORM6) were prematurely interrupted due to their futility, in part attributed to a restrictive definition of myocardial infarction.3,7 On the contrary, the CHAMPION PHOENIX clinical trial did prove the superiority of cangrelor vs clopidogrel reducing the main variable of efficacy (a composite of death, myocardial infarction, ischemia guided revascularization or stent thrombosis) after 48 hours in patients who underwent PCI to treat stable angina or any type of acute coronary syndrome (ACS) and who were not eligible for oral iP2Y₁₂ pretreatment.1 We should mention that in a combined analysis of the 3 trials, cangrelor was associated with a slightly higher risk of bleeding mainly at the cost of minor bleeding;8 this good safety profile is probably due to the fact that the drug is administered over a very limited span of time and its effect rapidly goes away after infusion.

The CHAMPION PHOENIX trial has received 2 important criticisms that may condition its implementation in our routine clinical practice. The first is that cangrelor was never compared to prasugrel or ticagrelor (more powerful and effective than clopidogrel and drugs of choice in patients with ACS). The second is that iP2Y₁₂ pretreatment before the PCI was considered an exclusion criterion. We should remember that, although there are serious doubts about its pretreatment benefit in the ACS setting, especially in the non-ST-segment elevation acute coronary syndrome setting,9 this strategy is widely used in our country. As a matter of fact, the European technical label of this drug specifically says that cangrelor is indicated in association with acetylsalicylic acid in patients “who undergo PCI and have not received an oral P2Y₁₂ inhibitor before the PCI, and in whom oral treatment with P2Y₁₂ inhibitors is not possible or desired”.2 Still, the pharmacological properties of cangrelor make it especially interesting in situations where not only the aforementioned pretreatment has not occurred, but also in circumstances where it is considered insufficient. Proof of this is the experience published from the Swedish national registry (SCAAR) during the first 2 years of drug use that found an almost exclusive use of cangrelor in patients with STEMI who underwent primary percutaneous coronary intervention; in this real-world study, cangrelor was combined with ticagrelor mainly, although the latter had already been administered in over 50% of the times in the prehospital setting, which is why in such cases the use of cangrelor would be considered an off-label indication.10

The clinical settings where, in our opinion, cangrelor can be useful both in the PCI setting (most of the cases) and in other situations are shown on figure 1. The most relevant setting would be the primary percutaneous coronary intervention in the management of STEMI, where its use is appropriate in the absence of proper pretreatment with iP2Y₁₂ due to the impossibility or difficulty administering oral drugs (intubation or incoercible vomiting); it may also be considered if the loading dose of iP2Y₁₂ is ineffective during the procedure (short span of time elapsed from its administration until the PCI is performed). Another acceptable situation (much less common than the latter) would be non-emergent high-risk PCIs (such as bifurcations using the dual stent technique, multivessel interventions, in the presence of great thrombotic load, etc.) in patients without iP2Y₁₂ pretreatment. In any case, the drug potential benefit should always be weighed to prevent intraprocedural thrombotic events associated with the procedure and the patient’s bleeding risk. Also, we should remember that the use of cangrelor is ill-advised if glycoprotein IIb/IIIa inhibitors are going to be administered.

Figure 1. Potential favorable clinical settings for the use of cangrelor. ACS, acute coronary syndrome; CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy; iP2Y₁₂, platelet P2Y₁₂ receptor inhibitors; PCI, percutaneous coronary intervention; STEMI, ST-segment-elevation acute myocardial infarction.

a) The dose in the percutaneous coronary intervention setting should be 30 µg/kg in bolus followed by an infusion at rate of 4 µg/kg/min.

b) The dose studied in the bridging therapy is an infusion of 0.75 µg/kg/min.

Other relevant aspects are the duration of infusion that can be reasonably maintained for at least 2 hours after the PCI. According to the drug technical label, it should be started before the procedure and the infusion lasting at least 2 hours or for as long as the pro- cedure lasts, which ever is longer. Still, this may not be enough in situations where the oral drugs early action is delayed. Also, special care is needed when transitioning to oral drugs; in general, the recommendation here is that ticagrelor can be administered at all times (before, during or after infusion) while thienopyridines can be prescribed after infusion (to avoid an interaction that would imply a time lapse without the proper antiplatelet therapy).3

Taking all this into consideration, cangrelor should be primarily used in the cath lab in situations of periprocedural high thrombotic risk when oral iP2Y₁₂ pretreatment has not occurred, is ill-advised or insufficient. The availability of the drug will probably not change our antiplatelet strategy radically in the short term in the PCI setting. However, in some situations (especially primary percutaneous coronary interventions) its particular pharmacological profile will be very useful. Therefore, its use will probably grow in the interventional cardiology community as we become more familiar with it. In conclusion, cangrelor is an interesting addition to our therapeutic armamentarium in the PCI setting because it can individualize and, therefore, optimize our antithrombotic strategy.

CONFLICTS OF INTEREST

J.L. Ferreiro has declared he has received funds for his lectures for Eli Lilly Co., Daiichi Sankyo, Inc., AstraZeneca, Roche Diagnostics, Pfizer, Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, and Ferrer; also, he has received funds for his counselling for AstraZeneca, Eli Lilly Co., Ferrer, Boston Scientific, Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Inc., Bristol-Myers Squibb; he has also receive research grants from AstraZeneca. J.A. Gómez-Hospital has declared he has received funds for his counselling for Abbott, Medtronic, Boston Scientific, Terumo, and IHT.

REFERENCES