The future of interventional cardiology

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.

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

INTRODUCTION

Therapies for the management of heart failure have been responsible for the great benefit experienced by the population in terms of hope and quality of life. However, they are nothing more than palliative measures that have not resolved the tissue destruction due to this problem whose malignity causes 20 million cardiac deaths worldwide every year.1 Reparative and regenerative medicine was born over 2 decades ago as a biological response to the pressing need for innovation in this field. Its objective is to orchestrate diagnostic tools and therapeutic strategies to restore the molecular, cellular, and tissue health of the cardiac organs damaged.2

Although we can categorically say that the adult heart has a limited capacity for regeneration that depends on the formation of new cardiac muscle, endothelial and smooth muscle cells from a reservoir of existing heart stem cells,3 we can also say that this capacity is marginal and insufficient to repair cardiac organs after sustaining ischemic, toxic, valvular or inherited damage,4 even after physiological aging.5 On the contrary, the myocardium major repair response consists of cellular hypertrophy, in some cases, and replacement of damaged functional tissue by more or less dense fibrous tissue (scar) in most cases. Process that causes the adverse ventricular remodeling that defines the advanced stages of heart failure (systolic ventricular disfunction and cardiac cavity dilatation) of both ischemic and non-ischemic origin (figure 1).

Figure 1. Common biopathological mechanisms indicative of myocardial damage in its vascular, muscular, extracellular components due to different types of tissue damage including the role of neurohormonal compensatory mechanisms and inflammatory response. The bottom shows the 3 main componentes of heart failure (angina, ventricular arrhythmias and ventricular remodelling). In green, the 5 beneficial action mechanisms confirmed by basic, preclinical research through which reparative and regenerative therapies work.

FUNDAMENTALS OF PATHOBIOLOGY AND PRECLINICAL EXPERIENCES

Ever since the 1990s, different types of cells have been studied in the lab in small and large animal models; in chronological order: skeletal myoblasts, hematopoietic end endothelial cells (in most cases harvested from the bone marrow), mesenchymal cells (harvested from bone marrow or adipose tissue), cardiac cells and, recently, embryonic or adult somatic induced pluripotent stem cells.6 All these types of cells have been studied mostly in ische­mic heart disease models. In some cases, they have been explored in their allogenic origin of healthy donors of the same species (unlike autologous stem cells that are harvested from the same recipient). As years have gone by, new products have appeared with regenerative or reparative capabilities. Added to gene therapy that has coexisted with cell therapy almost since the beginning, “non-cellular” products have been developed (growth factors, cytokines, proteins or types of ribonucleic acid—microARN). Many of them contained in microvesicles or exosomes that release stem cells or adult cells when they suffer an aggression. These products together with tissue engineering platforms (nanoparticles, gels, and matrices), have recently become part of regenerative medicine; and clinical research is still in its infancy.

Lab experiments and animal model experimentation have been useful because they have proved that: a) the process of myocardial and vascular repair is incredibly complex, both on the molecular, cellular, and tissue levels, which to this day, it is mostly unknown; b) the contribution made by cardiac stem cells to this process is marginal as it is the re-entry process of mature cardiomyocytes to the cellular cycle; c) the beneficial effects of the different products in the myocardium are due to the effect of the proteins and cytokines released by the cells administered (paracrine effect). They are not due to cellular fusion, proliferation or differentiation of these cells into cardiomyocytes, endothelial cells or smooth muscle cells (this has only been confirmed with pluripotent and embryonic cells that are still not used in clinical research); and d) these positive effects include protection from apoptosis, reduced fibrous tissue resulting from myocardial damage, modulation of the inflammation that precedes or is associated with such damage, creation of new blood vessels or formation of small amounts of cardiomyocytes (figure 1).

However, as in other areas of cardiovascular research,7 there has also been a significant “translational gap” in regenerative medicine, and the closer animal research has been to human clinical features the lower the impact of the therapies applied. For example, a meta-analysis of 80 studies showed that in small animal models, the average reduction of the infarction size with different products was 11%.8 However, in large animals, this reduction was only 5%, and it is well-known that in humans it is between 2% and 4%.9 This discrepancy in the results obtained in animals and humans is partly explained by the complexity of cellular processes that regulate cardiac repair, the enormous size difference among species, and the amount of cells (or products) needed to revert it. Other areas with room for improvement and other concepts that require further study regarding preclinical research are doses, administration times, and combination of products. Lastly, the rigor of clinical research is not always thoroughly applied to animal research. This means that it is required to standardize animal models and protocols to obtain and prepare repair products and develop multicenter, randomized and previously registered studies.2

CLINICAL EVIDENCE

The pressing need for innovation in the management of heart failure promoted research in human regenerative therapies early on. Phase I and pilot studies would soon be followed by clinical trials with small numbers of patients. Some products reached phase III in clinical research, particularly in patients with acute myocardial infarction, refractory angina or ischemic and non-ischemic heart failure. Of all the evidence available to this day these conclusions can be drawn: a) except for exceptional well-identified cases (ventricular arrhythmias with initial cellular types), all products administered in humans have proven safe and no cases of rejection (not even with allogenic products), oncogenesis, worsening of the patients’ cardiovascular status or major complications during the administration have been reported; b) the real clinical efficacy of these therapies has not been undeniably confirmed through hard endpoints. While some studies have shown neutral results, others have confirmed a reduction of the infarction size, increased myocardial perfusion or ejection fraction, and better soft endpoints; c) the most promising scenarios are heart failure with systolic ventricular dysfunction and refractory angina; and d) a large and very sophisticated array of administration strategies, including surgical, has been developed (mostly percutaneous) to allow the injection of biological materials in certain cardiac regions using conventional or special catheters and navigational systems to accurately guide the administration.

Like the preclinical setting, the clinical evidence available allows us to identify some of the variables that should be confirmed and better defined before conducting large-scale clinical trials; among them, the selection of the type of product, the total dose, and the optimal administration time for every particular condition. Also, comparative studies of products, repeated administration, and improvement of myocardial retention in the products infused or injected. All these aspects should be rigorously analyzed through basic and preclinical research before conducting new studies in humans. At this point, the rigorous design of clinical trials with well-defined endpoints, adequate sample sizes, and strict regulatory control should be mentioned here.

INTERNATIONAL ALLIANCES AND SPECIFIC WORKING GROUPS

As part of the development of regenerative medicine, and to go deeper in its study and organize and structure a still marginal research, 2 main organizations have been created:

The common initial objective of both associations is to analyze the evidence available on cardiovascular regenerative and reparative medicine, establish future research lines, and ultimately, facilitate the development of therapies to improve the patients’ cardiovascular health.

CONCLUSIONS

Although the clinical efficacy of regenerative and reparative medicine has not been confirmed yet to be able to include it in the routine clinical practice, it has overwhelmingly contributed to broaden our knowledge on the molecular biological, cellular, and tissue processes that govern functional loss, homeostasis, and cardiovascular system repair. By analyzing and planning future studies using multicenter, multidisciplinary, coordinated, evidence-based, rigorous methodology we will be closer to obtaining therapies capable of partially or totally reversing irreversible myocardial tissue damage and improving cardiovascular health.

CONFLICTS OF INTEREST

The authors declared no conflicts of interest whatsoever.

REFERENCES

Talking about innovation can be confusing. The term “innovation” is used to refer to many different things and proof of this is the large number of different definitions currently available. In any case, innovation is almost a magical word often hiding huge expectations of possible solutions to the great challenges posed by society and that have a dramatic impact on healthcare. We present some of the current trends and reflections affecting the Spanish healthcare system providers.

INNOVATION: GENERATING THE PRODUCT

At this point in time, talking about lists in relation to research and development (R+D) and its situation in Spain is an obvious and overused argument these days. Figures are well-known, have already been confirmed, are widely accepted, and have showed room for improvement over the last few decades: our country ranks high in research but runs low on R+D funding (high efficiency), especially in the private sector (mainly related to the business structure of small and medium-sized enterprises) but innovation still lags behind. Coming to terms with the specific weight of the different possible causes for this gap between research and innovation (culture, funding, education, regulation, etc.) is even harder.1

The impact of a disadvantaged situation in innovation is relevant: we do not invent, so we never own what we need (understood as a product manufactured and marketed by Spanish companies), which means we have to import it. Regarding health—where the impact of technology and drugs is huge—the effect the trade balance may have is considerable. Undubitably, this is a field where the activity of the Spanish healthcare system as a country that generates products, patents or companies may have a significant economic impact.2^,3

INNOVATION: INTRODUCING THE PRODUCT

Advances in medicine are the key to improve disease management and prevention. The speed at which new products like drugs, devices, machines, diagnostic procedures, etc. are available is now greater than ever. These advances are considered innovation and they become part of the therapeutic arsenal available after an often very expensive process of development where proprietary companies make big investments. The cost of these new products is sometimes considerable and their benefits in terms of incremental net health benefit do not usually match costs and are often limited. Two examples of striking innovations that have recently impacted the media because of their potential cost are the CAR T-cell therapy and proton radiotherapy. Another recent example of great therapeutic innovation is the curative treatment of hepatitis C. The total artificial heart is unquestionably relevant innovation in cardiology. The developing speed of technologies like 3D printing, artificial intelligence, big data, digital health or tele-healthcare forces us to understand what they are good for before implementing them in health organizations and also to assess their impact in the system. In these innovations, price, complexity, conditions of use, and effects greatly condition their use.

INNOVATION: USING THE PRODUCT

Management experts have been anticipating the arrival of a sustainable prevention healthcare model for decades because of the constant growth of healthcare spending due to a number of reasons: higher costs in healthcare innovation, increased chronicity and longevity, and greater expectations from the population.

Patients live longer but they also remain sick longer, and every month of life gained equals higher costs. Although this statement has several exceptions, it forces us to identify those patients who can live disease-free for longer, or, at least, not dependant on the healthcare system. Also, it shows what innovations bring real value both in general and particular terms. Precision medicine and innovation in management play a big role. Both concepts can be con­sidered a spectral continuum in the decision-making process. On the other hand, knowing that these innovations are cost-effective is no longer enough; now it is required to know what their real impact is on population health outcomes like quality of life and disease progression. This is how the Spanish healthcare system is moving forward with the great challenge posed by value-based medicine.4

INNOVATION: ORGANIZATION AND HEALTH PROFESSIONALS

There are 3 different scenarios regarding innovation: production, introduction, and use. These 3 settings require 3 different fields of expert knowledge —innovation manager, health professional, and healthcare manager— with significant overlapping that still coincides in information systems and new data management. In this context, the great expectations generated by big data and artificial intelligence should not be a surprise. These are true innovations to help us make decisions, prioritize efforts, speed up healthcare processes, reduce the load of tasks with no added value for health professionals, and eventually focus on personal attention.5

Beyond the traditional concept of product understood as technology—devices or drugs—healthcare providers have always been involved by generating solutions in their setting adapted to their working framework and using the existing resources based on process innovation. Healthcare providers can change the way things are done, most of the time intuitively, and then adapt them to their setting thanks to years of experience. They often give their opinion on current needs and possible solutions to different settings. They also happen to be right most of the time.

This may be an organizational innovation we must face: to hear what health professionals have to say to share the decision-making process with them. Also, to support them in complex priority decision-making processes caused by limited resources in a society with growing well-being demands. It is the healthcare institutions that need to move towards more intelligent and collaborative ecosystems to promote a culture of innovation. Innovative ideas have always been there; time has come to listen to the people who had these ideas, evaluate them rigorously, focus on the impact they have on health outcomes, and promote innovation.6^-8

FUTURE PERSPECTIVES

The road towards innovation is a long one and changing the productive model and the culture of an entire country is a huge challenge. However, over the last few decades, it has been proven that we can change the Spanish model of producing science together. Why not do the same thing with innovation?

Let’s give ourselves the time and opportunity to innovate in health, instead of letting others do the job. Let’s be us who, with our own knowledge, improve our healthcare system, one of the world’s most efficient healthcare systems now facing huge challenges ahead.9

FUNDING

The authors have received funding from the Medical Technology Innovation Platform (ITEMAS) (PTR2018.001071, PT17/0005/0036) sponsored by the Instituto de Salud Carlos III. Project co-funded by the European Regional Development Fund (ERDF).

CONFLICTS OF INTEREST

None declared.

REFERENCES