The future of interventional cardiology

WHAT DO WE KNOW ABOUT FRACTIONAL FLOW RESERVE AFTER STENTING?

The introduction of the concept of fractional flow reserve (FFR) in the mid 90s moved coronary physiology from experimental science to routine use at the cath lab.1-3 Added to the better understanding of basic physiological mechanisms such as self-regulation and compensatory vasodilation and the coronary flow reserve introduced 20 years earlier by Gould et al.,4 FFR has undeniably changed our interpretation of coronary angiograms and had a major influence on the clinical decision-making process, and patient outcomes.3,5,6 This has resulted in the unique adoption of FFR as the only physiological index with a class I A indication for use in the clinical practice guidelines produced by the most important cardiologic societies worldwide.7,8

FFR has taught us that coronary angiography and the anatomic images we can acquire at the cath lab only provide moderately reliable measures of the functional significance of coronary artery disease and myocardial ischemia. Also, there is undeniable proof that the decision-making process based on functional measurements leads to better outcomes compared to angiography alone.3,5,6

In contrast, the interpretation of FFR after coronary intervention is still ambiguous. Basically, we should be aware that the status of a coronary artery immediately after a percutaneous coronary intervention (PCI) changes and is prone to much more variability compared to a situation of chronic stable coronary artery disease. An excellent result of a PCI performed today can change rapidly within hours due to thrombus formation, progressive dissection or other unforeseen complications. Therefore, the FFR measured immediately after a PCI should be interpreted with caution. Also, whereas the ischemic FFR threshold (0.80) in the stable angina has been clearly established, FFR values within the first days, weeks or months after a PCI can change quickly due to the healing process in the coronary artery itself, intimal hyperplasia, thrombus formation, etc. This means that by definition, the FFR after a PCI is more dynamic and that an adequate FFR value immediately after a PCI should be considerably higher than 0.80 to compensate for any intravascular changes that may occur in the short-term.

Therefore, it is not surprising to see FFR values of at least 0.90 in medical literature as indicative of an acceptable PCI result.9,10 Having said that, at the same time we should realize that most post-stent FFR values in earlier studies were obtained in patients with focal stenosis and without much diffuse disease. It is plausible to think that if diffuse disease is present inside a coronary artery, FFR values ≥ 0.90 will probably not be achieved by just stenting a focal stenosis.

Most likely, in such cases, hyperemic pressure pullback recording (whether motorized or not) or a sophisticated variety called hyperemic pressure pullback gradient will better qualify the functional result after stenting. They will also reveal if the remaining gradients inside the coronary artery are due to insufficient stent deployment or more diffuse disease.11

Despite these limitations, the existence of a clear correlation between the FFR values measured immediately after PCI and long-term outcomes is undeniable. This was first described in the FFR-post-STENT Registry of 750 patients that revealed the existence of an inverse correlation between the FFR values measured immediately after the PCI and the rate of restenosis at the 6-month follow-up (figure 1). Such an inverse correlation between high FFR values post-stenting and the mid-term risk of restenosis has been confirmed ever since.12 Still, it is not completely clear if suboptimal FFR values after stenting are due to a focal problem in the stented segment or to diffuse disease elsewhere in the artery. Hyperemic pressure pullback recording and pressure pullback gradient recording have proven that a considerable pressure gradient across the stent is often associated with inappropriate deployments as seen on intravascular ultrasounds or optical coherence tomographies.

Figure 1. Superiority of functional testing compared to angiography alone to predict the outcomes after stenting. A: correlation between post-stenting fractional flow reserve (FFR) and the rate of adverse events at the 6-month follow-up in 750 patients from the FFR-Post-Stent registry. B: correlation between post-stenting angiography and the rate of adverse events at the 6-month follow-up. Reproduced with permission from Pijls et al.9

PATIENT AND VESSEL RELATED PREDICTORS OF POST-PROCEDURAL FFR

At this point, the study conducted by van Zandvoort et al. and recently published on REC: Interventional Cardiology comes into perspective.10 In this study, a large registry of 1000 consecutive patients from 1 large volume cardiac center, the FFR was consistently measured after an angiographically successful PCI without the intention of performing any additional procedures in cases of unexpectedly low FFR values. The authors should be praised for their adherence to this protocol. Afterwards, independent patient and vessel related characteristics were determined as associated with the post-procedural FFR values. Considering that in this study no information was available on the outcomes and that the relationships were not causal per se but associative, a few important lessons can be learned.

In the first place, a very strong predictor of lower FFR values was stent implantation in the left anterior descending coronary artery (LAD). In truly normal LADs, the FFR is not different from other arteries and is very close to 1.00.13 However, even in cases of mild disease, the FFR values measured in the LAD are often more damaged compared to other arteries. This is explained by the fact that the LAD perfusion territory is large. One of the major advantages of FFR with respect to other methodologies that only address a coronary artery injury is that the FFR does not only measure the stenosis itself, but also the extent of the perfusion territory. If a similar stenosis (with similar angiographic, intravascular ultrasound or optical coherence tomography characteristics) is located in a coronary artery with a larger perfusion territory, the FFR will be lower. In this regard, the FFR is actually the link between stenosis severity, coronary blood flow, extent of the myocardial perfusion territory, and myocardial ischemia.14 As such, it is plausible that after a successful PCI, the FFR of the LAD will be somehow lower compared to other coronary arteries.

A second interesting observation is that in women, the FFR measured after apparently successful stenting was often higher compared to the males. Van Zandvoort et al. suggest that this might be due to the fact that in women, microvascular disease plays a more predominant role compared to men. Also, that the generation of a hyperemic gradient within the epicardial coronary artery may be blunted by the presence of microvascular disease.10 To confirm that position, more detailed studies of coronary microvasculature are needed. For many years, the assessment of microvascular disease in a true quantitative way has been too hard to pin down. However, recently developed methodology has changed that as follows.15

SIMULTANEOUS ASSESSMENT OF EPICARDIAL AND MICROVASCULAR DISEASE

Recently, the technique for measuring absolute coronary blood flow and microvascular resistance has been introduced as an adjunctive to FFR measurement. This technique is based on the continuous infusion of a saline solution at a low rate and thermodilution. The technique is simple, elegant, accurate, and operator independent.15

In short, immediately after measuring the FFR, a specifically designed infusion catheter (Rayflow, Hexacath, Paris) is advanced while mounted on the pressure guidewire and placed inside the stent (to study the microvascular resistance of the territory distal to the stent). Then, the infusion of a saline solution at a low rate is started and the absolute coronary blood flow in mL/min is measured in the area of interest using this equation:

Q = Q_i × T/T_i × 1.08

where Q is blood flow in the myocardial territory distal to the stent, Q_i is the infusion rate of the saline solution (mL/min), T_i is the temperature of the infused saline solution (°C), and T is the temperature in the distal coronary artery after mixing blood and the saline solution. T and T_i are expressed as the difference with respect to body temperature.

With infusion rates = 8 to 10 mL/min, resting blood flow values are obtained and with infusion rates = 20 mL/min, maximum hyperemic values are obtained since the saline solution itself at that rate induces maximum hyperemia in a matter of seconds (figure 2; unpublished data).

Figure 2. Example of absolute coronary blood flow and microvascular resistance measurement in left anterior descending coronary artery following routine fractional flow reserve measurement. On the figure upper side, aortic pressure (P_a), and distal coronary pressure (P_d) are shown in red and green, respectively. The blue line represents coronary temperature as a difference with respect to body temperature (T = 0). After starting the infusion of 20 mL/min of a saline solution (Q_i) at room temperature through a dedicated infusion catheter, maximum hyperemia occurs within seconds. Then, after a complete mix of blood and saline solution, a steady-state distal coronary temperature T of 0.32 ^oC below body temperature is achieved. After withdrawing the pressure/temperature sensor from the tip of the infusion catheter, the infusion temperature (T_i) measured is 4.11 ^oC below body temperature. Absolute flow (Q) in the coronary artery is calculated using the equation shown in this article (274 mL/min). Microvascular resistance is simply calculated now by Pd/Q and equals 297 Wood units, which is a normal value for the anterior wall. Since the fractional flow reserve value is also known, the normal reference value of coronary flow can be calculated. All parameters are shown online supported by dedicated software (Coroventis, Sweden).

Immediately after the simultaneous measurement of distal coronary pressure and blood flow values, quantitative microvascular resistance R_µ (Wood units) is estimated. In this same way, epicardial disease (indicated by FFR) and microvascular disease (indicated by R_µ) can be assessed and independently distinguished. The position taken by van Zandvoort et al. suggesting that higher FFR values after PCI are related to a higher microvascular resistance in women could be elegantly validated this way.

WHAT IS THE BEST TECHNIQUE TO MEASURE THE FFR VALUES AFTER A PCI?

In the study conducted by van Zandvoort et al. the FFR values measured after the PCI are only briefly described.10 The authors do not report if hyperemic pressure pullback recordings were performed or other techniques used to assess the entire artery. Also, we should mention that to measure intracoronary pressure, not a single true pressure guidewire was used, but the Navvus system instead (ACIST Medical Systems, Eden Prairie, MN, United States). This system is known to overestimate pressure gradients and underestimate FFR mildly in cases of minimal disease or moderately in cases of more severe disease.16 Also, this system is not validated against regular pressure guidewires in post-PCI vessels.

Nevertheless, the measurements were taken meticulously using IV adenosine at a rate of 140 µg/kg/min, giving the opportunity of an easy and reliable estimation of the FFR under stable conditions. We should mention that only 2 out of 1000 patients showed adenosine intolerance, meaning that the infusion of adenosine had to be interrupted due to harmless adenosine-induced, angina-like chest pain. This underlines the safety profile of IV adenosine infusions as seen in tens of thousands of patients in a myriad of other studies.

In future studies on the meaning and interpretation of post-PCI FFR, it would be adviseable to perform hyperemic pressure pullback recordings as outlined in the first part of this article or use the even more sophisticated technique for whole vessel evaluation after PCI recently introduced by Collet et al. and called hyperemic pressure pullback gradient.11 Obviously, all pressure analyses performed inside the stented coronary artery should preferably be performed at maximum hyperemia since gradients at rest inside the artery are 2 to 3 times smaller. Consequently, the signal-to-noise ratio of a resting pullback recording is 2 to 3 times less sensitive.

In conclusion, although outcome data were not presented which, by the way, was not the objective of the study, the interesting trial conducted by van Zandvoort et al.10 teches us about several interesting patient and vessel related predictors of post-procedural FFR measurement. Also, it anticipates the need for future physiological studies to unravel the different factors involved using new research methods on coronary circulation like hyperemic pressure pullback gradients and truly quantitative microvascular resistance (R_µ) measurements.

FUNDING

No funding whatsoever with regards to this article.

CONFLICTS OF INTEREST

N.H.J. Pijls has received institutional research grants from Abbott and Hexacath. Also, he is a consultant for Abbott, Opsens, and General Electric, and a minor stockholder of Philips, GE, ASML, and Heartflow. L.X. van Nunen declared no conflicts of interest whatsoever.

REFERENCES

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