Available online: 09/04/2019
Editorial
REC Interv Cardiol. 2020;2:310-312
The future of interventional cardiology
El futuro de la cardiología intervencionista
Emory University School of Medicine, Atlanta, Georgia, United States
INTRODUCTION
Preventive percutaneous coronary intervention (PCI) refers to the treatment of high-risk plaque before the occurrence of any adverse events. Typically, the decision to perform preventive treatment is made when the expected event rate of the underlying condition outweighs the potential short- and long-term complications of the procedure. This approach is also applicable to the treatment of coronary disease. In recent years, advances in understanding atherosclerotic plaque progression and identifying high-risk plaques, along with technological progress in coronary devices, have shifted the balance between the risks of the underlying condition and those of percutaneous treatment.
THE CONCEPT OF VULNERABLE PLAQUE
The understanding of high-risk coronary plaques, also known as vulnerable plaques, has evolved over the years. Initially, a vulnerable plaque was often considered an angiographically nonsignificant stenosis that was prone to rupture and cause acute coronary syndrome.1 The PROSPECT study was the first landmark trial to focus on the natural history of vulnerable plaques, assessed using intravascular ultrasound with virtual histology.2 This trial was the first to define specific criteria for plaque vulnerability, notably thin-cap fibroatheroma (TCFA). TCFA is characterized by a lipid-rich plaque with a necrotic core, separated from the vessel lumen by a thin fibrotic cap. The trial also identified 2 other quantitative criteria: a plaque burden > 70% and a minimum lumen area (MLA) < 4.0 mm2. Despite its major contributions, the study had limitations: a) the resolution of intravascular ultrasound with virtual histology was not sufficient to detect the cap thickness ≤ 0.65 µm (cutoff value for true TCFA), and b) the trial could not exclude the absence of ischemia in lesions that led to events.
THIN-CAP FIBROATHEROMA
The use of more sophisticated imaging modalities, such as optical coherence tomography (OCT), which has a resolution of 10 to 20 µm and is therefore able to detect TCFA, has paved the way for the true detection of vulnerable plaque. Indeed, the COMBINE OCT-FFR trial,3 a natural history study that compared the outcomes of nonischemic lesions, categorized as TCFA or non-TCFA based on OCT assessment, showed for the first time that even in the absence of ischemia, the presence of an OCT-assessed TCFA was associated with a 4-fold higher event rate compared with lesions without TCFA. This trial provided evidence that the morphological features of a lesion might be more important than ischemia in predicting future adverse events, opening the door to the potential treatment of nonischemic lesions.
Interestingly, our group has also shown that TCFA, rather than any lipidic plaque, is associated with future adverse events, while lipidic plaques with a thick cap have a benign outcome comparable to that of fibrotic plaques. This finding suggests that only about a third of all lipidic plaques and less than a quarter of all plaques might benefit from pre-emptive treatment.4 Other studies, such as CLIMA5 and PECTUS,6 have corroborated the role of TCFA in predicting future adverse events. Similarly, Kubo et al.7 have also shown that the presence of TCFA is associated with a high rate of future adverse events.
VULNERABLE PLAQUE NEW CONCEPTS
Recent studies have demonstrated that, contrary to previous beliefs, vulnerable plaques that lead to future adverse events typically have a large plaque volume and show a significant degree of luminal stenosis. COMBINE OCT-FFR and the FORZA trial8 both independently found that an MLA cutoff of 2.5 mm2 was a better predictor of future adverse events than the previously considered 4.0 mm2.
In addition to MLA, other plaque features are associated with vulnerability. A recent post hoc analysis from the COMBINE OCT-FFR study9 showed that, beyond MLA, other signs of plaque destabilization adjacent to TCFA, such as old plaque ruptures or healed plaques, are associated with a significantly increased rate of adverse events. When vulnerability features coexist, the event rate can progressively increase. For example, while TCFA alone was associated with a 20% future adverse event rate, a combination of TCFA with MLA < 2.5 mm2 adjacent to a healed plaque was associated with an event rate of 50%.
These findings are important as they introduce a new way of thinking about vulnerable plaques. The concept has shifted from a simple yes/no binary to a variable and progressive model. In this model, the vulnerability of a plaque increases based on the number of high-risk features present, with the most vulnerable plaques being those with more than 3 risk factors.
The notion that a plaque that ruptures without causing an acute event will heal and stabilize has also been challenged. “Healed” plaques often do not represent stable plaques but are prone to new ruptures in adjacent locations, making them one of the strongest predictors of vulnerability. Araki et al.10 have very nicely shown that multiple repeat plaque ruptures and healings are the true mechanisms behind atherosclerosis progression.
It is understandable that growth in the volume of intraluminal plaque parallels ischemia progression, as plaque progression will eventually lead to ischemic lesions. However, it is important to recognize that, based on this rupture and healing model of plaque progression, any future destabilization (rupture and/or healing) of a plaque with vulnerable features—whether angiographically borderline or already significant but not yet ischemic—could result in either an acute coronary syndrome or rapid progression (from one day to the next) of luminal stenosis, leading to ischemia and likely stable or unstable angina.
Based in this rationale, revascularization based on OCT imaging, which has the potential to detect these plaques, becomes an appealing strategy, rather than relying solely on ischemia-guided intervention. The FORZA trial was the first to show a benefit for imaging-guided PCI vs ischemia-guided PCI. However, the trial used only quantitative OCT criteria rather than a combination of quantitative and qualitative OCT vulnerability criteria. As explained above, the benefit of OCT guidance lies in its ability to identify lesions with a high degree of vulnerability that do not yet cause symptoms, thereby paving the way for preventive PCI.
IMPROVED PCI OUTCOMES
Improvements in stent technology, PCI techniques, and intravascular imaging guidance have led to very low complication rates with PCI, especially in nonseverely stenosed lesions. The PREVENT trial,11 which compared a medical therapy vs PCI in lesions with a diameter stenosis of ≥ 50% but which were otherwise nonischemic, showed very low event rate in the PCI arm (< 1%). This suggests that PCI can currently provide lower event rates than medical therapy for these high-risk vulnerable lesions.
IMPROVING THE CURRENT REVASCULARIZATION STRATEGY BY INTEGRATING A PREVENTIVE VULNERABLE PLAQUE INTERVENTION
Interestingly, while at first glance, an approach similar to that of the PREVENT trial might seem to open the door to stenting all intermediate lesions, the reality is different. The ability of OCT to detect truly vulnerable features has significantly limited the number of lesions that might benefit from preventive PCI. In patients without ischemia but with a lesion that has a diameter stenosis of more than 50%, the prevalence of vulnerable lesions according to OCT criteria may range between 10% and 20% compared with > 90% in the PREVENT trial.
On the other hand, large trials like ISCHEMIA12 and FAME 2,13 have shown that approximately 20% of patients with ischemic lesions are unresponsive to medical treatment and require PCI to control angina symptoms. Interestingly, this 20% corresponds to the percentage of truly ischemic lesions, defined as having a fractional flow reserve (FFR) of < 0.75.14 Therefore, it can be deduced that there is still a role for ischemia detection and revascularization of these lesions with true ischemia (FFR < 0.75), regardless of the presence of vulnerability features. Meanwhile, the role of preventive PCI could be reserved for plaques with highly vulnerable features that show at least an intermediate degree of stenosis but are otherwise nonischemic.
If such a combined decision-making strategy is correctly applied, the number of lesions that may benefit from PCI treatment could be similar to or even lower than those identified through the current ischemia-driven revascularization strategy alone. Indeed, with this new combined strategy, the only lesions requiring PCI would be those with true ischemia (FFR ≤ 0.75), which represent about 20% of lesions, and those with high-risk vulnerable plaque, which represent another 10% to 20% of all lesions. This compares with the 40% of lesions that currently undergo PCI based on an ischemia-driven revascularization strategy (FFR ≤ 0.80).
This combined FFR- and OCT-guided treatment strategy in patients with multivessel disease (lesions with angiographic stenosis > 50%) presenting with stable or acute coronary syndromes is now being tested in the COMBINE-INETREVENE trial (NCT05333068), a global randomized controlled trial. This new strategy involves reserving PCI to lesions with an FFR of ≤ 0.75, as well to to all lesions with an FFR > 0.75 that show vulnerable features such as TCFA, ruptured plaque, or plaque erosions with significant lumen reduction (MLA < 2.5 mm2).
Another trial implementing a purely preventive percutaneous treatment is the VULNERABLE trial (NCT05599061), an ongoing multicenter study in Spain that tests a similar concept but focuses solely on nonischemic, ST-segment elevation myocardial infarction nonculprit lesions with high-risk vulnerable features. We believe that the results of these trials, as well as new imaging technologies that could lead to automatic detection of vulnerable plaques, combined imaging and hemodynamic assessment modalities, and improved intracoronary treatment devices (whether implantable or not), will provide new insights into the role of preventive PCI.
FUNDING
There was no funding for this manuscript.
CONFLICTS OF INTEREST
E. Kedhi has received institutional research grants from Medtronic and Abbott and is a proctor for Abbott.
REFERENCES
1. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47:C13-C18.
2. Stone GW, Maehara A, Lansky AJ, et al. PROSPECT Investigators. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364:226-235.
3. Kedhi E, Berta B, Roleder T, Hermanides RS, et al. Thin-cap fibroatheroma predicts clinical events in diabetic?patients with normal fractional flow reserve:the COMBINE OCT-FFR trial. Eur Heart J. 2021;42:4671-4679.
4. Fabris E, Berta B, Roleder T, et al. Thin-Cap Fibroatheroma Rather Than Any Lipid Plaques Increases the Risk of Cardiovascular Events in Diabetic Patients:Insights from the COMBINE OCT-FFR Trial. Circ Cardiovasc Interv. 2022;15:011728.
5. Prati F, Romagnoli E, Gatto L, et al. Relationship between coronary plaque morphology of the left anterior descending artery and 12 months clinical outcome:the CLIMA study. Eur Heart J. 2020;41:383-391.
6. Mol JQ, Volleberg RHJA, Belkacemi A, et al. Fractional Flow Reserve-Negative High-Risk Plaques and Clinical Outcomes After Myocardial Infarction. JAMA Cardiol. 2023;8:1013-1021.
7. Kubo T, Ino Y, Mintz GS, Shiono Y, Optical coherence tomography detection of vulnerable plaques at high risk of developing acute coronary syndrome. Eur Heart J Cardiovasc Imaging. 2021:jeab028.
8. Burzotta F, Leone AM, Aurigemma C, et al. Fractional Flow Reserve or Optical Coherence Tomography to Guide Management of Angiographically Intermediate Coronary Stenosis:A Single-Center Trial. JACC Cardiovasc Interv. 2020;13:49-58.
9. Del Val D, Berta B, Roleder T, et al. Vulnerable plaque features and adverse events in patients with diabetes mellitus:a post hoc analysis of the COMBINE OCT-FFR trial. EuroIntervention. 2024;20:707-717.
10. Araki M, Yonetsu T, Kurihara O, et al. Predictors of Rapid Plaque Progression:An Optical Coherence Tomography Study. JACC Cardiovasc Imaging. 2021;14:1628-1638.
11. Park SJ, Ahn JM, Kang DY, et al. PREVENT Investigators. Preventive percutaneous coronary intervention versus optimal medical therapy alone for the treatment of vulnerable atherosclerotic coronary plaques (PREVENT):a multicentre, open-label, randomised controlled trial. Lancet. 2024;403:1753-1765.
12. Maron DJ, Hochman JS, Reynolds HR, et al. ISCHEMIA Research Group. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med. 2020;382:1395-1407.
13. De Bruyne B, Pijls NH, Kalesan B, et al. FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367:991-1001.
14. Davies JE, Sen S, Dehbi HM, et al. Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI. N Engl J Med. 2017;376:1824-1834.
The management of symptomatic coronary artery disease in older adults presents a conundrum. Depending on their residual life expectancy, treatment is focused more on quality of life and symptomatic relief than on the improvement of long-term prognosis. Consequently, coronary artery bypass grafting (CABG) often is not an option, not only because of an increased and sometimes prohibitive risk but also because of the slow or even incomplete recovery after major surgery in older adults. On the other hand, medical treatment alone is of limited efficacy and may result in polypharmacy, with associated problems of adherence and drug interaction. Thus, percutaneous coronary intervention (PCI) may remain the only reasonable option. Nevertheless, PCI in older adults is often technically challenging and carries a substantially increased risk compared with PCI in younger patients.1 The extent and location of coronary artery disease appear to be even more important in older adults than in younger patients. Specifically, the risk of PCI in older patients is increased by more than twofold, if it involves the left main coronary artery as compared with PCI in other territories.1
Thus, guidance on left main PCI in older adults is particularly needed. There is, however, a paucity of data to aid treatment decisions in this setting. Older age groups are scarcely represented in the randomized trials that inform current guidelines.2 As a first approach to this problem, it may be important to learn how the outcomes of left main PCI in older adults differ from those in the younger age groups included in pivotal trials.
The study by Gallo et al.,3 recently published in REC: Interventional Cardiology, is an important first step in this direction. This retrospective, single-center observational study investigated all older adult (≥ 75 years) patients undergoing left main PCI at the Cardiology Service of the Hospital Universitario Reina Sofía (Córdoba, Spain) between 2017 and 2021. Gallo et al. identified 140 patients with a median age of 80 years and a median SYNTAX score of 21, similar to those in published randomized studies. Highlighting the clinical relevance of the issue, these patients represented as much as 32% of their left main PCI cohort.
With a median follow-up of 19 months (interquartile range, 5-35 months), Gallo et al. found substantial differences in outcomes for their left main PCI cohort of older adults compared with published outcomes in pivotal randomized trials comparing left main PCI with CABG (figure 1). In these trials, patients had to be eligible for CABG and were approximately 14 years younger.4 As shown by a recent individual patient data meta-analysis, outcomes in the pivotal trials were driven by nonfatal cardiac events rather than mortality.4 In the current cohort of Gallo et al., however, only 2.1% had a spontaneous nonfatal myocardial infarction during the 2-year follow-up and reintervention was indicated in only 4.3%, whereas 2-year mortality was 27.1%.3
Figure 1. Two-year outcomes of left main percutaneous coronary intervention (PCI) in older adults in the study by Gallo et al.3 compared with younger patients included in randomized studies comparing PCI with coronary artery bypass grafting.4 Percentages were derived from numbers of events divided by total number of patients for older adults and from Kaplan-Meier estimates for younger patients. The incidence of noncardiovascular death in younger patients was imputed based on the reported proportion of 44% for noncardiovascular death at 5 years. MI, myocardial infarction.
The younger patients in the randomized trials had a substantially better prognosis with a 2-year mortality of only 4.5%. In these patients, outcomes were dominated by spontaneous myocardial infarction and reintervention, with 2-year incidences of 3.0% and 9.6%, respectively.4 According to the individual patient data meta-analysis, CABG substantially reduced these latter events—to 1.6% and 3.4%, respectively—but did not significantly improve survival.
In this context, the results of the study by Gallo et al. are important. They show that the contribution of those events where CABG clearly outperforms PCI (ie, spontaneous myocardial infarction and reintervention) is less relevant in older adults than in the younger patients of the randomized trials.
In the population of older adults in the study by Gallo et al., deaths that could be clearly attributed to noncardiac causes were more frequent than in younger patients. The incidence of noncardiac death was 7.1% at the 2-year follow-up after left main PCI in older adults, while it ranged around 2% in the younger patients of randomized studies on left main PCI (figure 1). This indicates a higher number of deaths not amenable to any cardiovascular treatment in older patients compared with younger patients.
Although higher in absolute numbers, the proportion of deaths that could be attributed unequivocally to noncardiac causes was lower in older adults than in younger patients (figure 1). This finding is, however, difficult to interpret. In line with common practice, deaths of unknown cause were counted as cardiac deaths. Thus, we do not know how many of these deaths were from true cardiac causes, let alone what proportion of deaths were due to treatment failure of left main PCI.
Despite these uncertainties, the study by Gallo et al. shows that in older adults with left main PCI, the causes of death not related to myocardial revascularization were more frequent than in younger patients undergoing left main PCI.
Mortality was driven less by calendar age and more by frailty. Gallo et al. stratified their cohort into nonfrail and frail groups, as defined by a frailty score of 3 or higher. As many as 57% of the frail patients had died at the 3-year follow-up compared with 23% of the nonfrail patients (P = .001) (for 2-year mortality, see figure 1). After inverse probability of treatment weighting with a number of variables including age, this difference in all-cause mortality remained substantial and statistically significant (23 % vs 44%; P = .046). Thus, frailty, but not age or SYNTAX score, was a significant independent predictor of mortality (multivariable hazard ratio = 2.4; 95% confidence interval, 1.2-5.0; P = .018).These findings are in line with a recently published study on PCI in older adults that identified frailty, but not calendar age, as a strong predictor of mortality.5
The high mortality of older adults with left main coronary disease despite PCI poses the question of futility, particularly in frail patients. While PCI may indeed be futile in terms of prolonging life, it may still alleviate symptoms. In this regard, it is important to note that PCI in the study by Gallo et al. could be accomplished without complications in 94% of the patients (92% of frail patients and 97% of nonfrail patients), and 91% of the patients left the hospital alive, even though 50% of them had presented with acute myocardial infarction. Thus, there is no prohibitive complication rate that justifies withholding left main PCI in older adults as an attempt to improve symptoms. Moreover, the randomized After Eighty study found that myocardial revascularization reduced the risk of myocardial infarction and urgent revascularization in older patients with acute coronary syndromes.6 Thus, PCI in older adults, particularly for the left main, may offer more than just relief from angina or angina equivalents. The low incidences of spontaneous myocardial infarction and reintervention found by Gallo et al. after left main PCI may thus reflect the positive effects of the procedure. However, in the absence of a control group such interpretation remains speculative. Moreover, the number of patients in this retrospective observational study is limited. Together, with the single-center design of the study, this weakens the generalisability of the current findings.
Nevertheless, 3 important messages of the study by Gallo et al. prevail: a) left main PCI in older adults is a reasonable option with a fair procedural success rate; b) the clinical course after left main PCI differs substantially from that in younger patients with death being far more common than nonfatal cardiovascular events; c) frailty is more relevant to prognosis than calendar age, being a central determinant of mortality after left main PCI. Further studies are needed to determine how best to integrate these findings into individualized treatment decisions in older adults presenting with symptomatic left main disease.
FUNDING
None.
CONFLICTS OF INTEREST
F-J. Neumann has received consultancy honoraria from Novartis and Meril, speaker honoraria from Boston, Amgen, Daiichi-Sankyo and Meril and reports speaker honoraria paid to his institution from BMS/Pfizer as well as research grants paid to his institution from Boston and Abbott.
REFERENCES
1. Jalali A, Hassanzadeh A, Najafi MS, et al. Predictors of major adverse cardiac and cerebrovascular events after percutaneous coronary intervention in older adults:a systematic review and meta-analysis. BMC Geriatrics. 2024;24:337-349.
2. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J. 2019;40:87-165.
3. Gallo I, Hidalgo F, González-Manzanares R, et al. Percutaneous treatment of the left main coronary artery in older adults. Impact of frailty on med-term results. REC Interv Cardiol. 2024. https://doi.org/10.24875/RECICE.M24000460.
4. Sabatine MS, Bergmark BA, Murphy SA, et al. Percutaneous coronary intervention with drug-eluting stents versus coronary artery bypass grafting in left main coronary artery disease:an individual patient data meta-analysis. Lancet. 2021;398:2247-2257.
5. Shimono H, Tokushige A, Kanda D, et al. Association of preoperative clinical frailty and clinical outcomes in elderly patients with stable coronary artery disease after percutaneous coronary intervention. Heart Vessels. 2023;38:1205-1217.
6. Tegn N, Abdelnoor M, Aaaberge L, et al. Invasive versus conservative strategy in patients aged 80 years or older with non-ST-elevation myocardial infarction or unstable angina pectoris (After Eighty study):an open-label randomised controlled trial. Lancet 2016;387:1057-1065.
In 1998, in response to a comment on the limited durability of an aortic valvuloplasty performed during the last Madrid Interventional Cardiology (MIC) course, Alain Cribier insightfully stated: “We’ll mount a stent on the valvuloplasty balloon, attach the leaflets, and problem solved.” Four years and countless hours of work later, both at his hospital in Rouen, France, and at the animal experimentation center in Lyon, France, the recently deceased Alain Cribier (1945-2024) achieved a groundbreaking milestone.1 On April 16, 2002, he performed the world’s first surgery-free transcatheter aortic valve implantation (TAVI), prolonging the patient’s life and revolutionizing heart valve surgery. This innovation dramatically improved the quality of life of a high percentage of patients with severe aortic stenosis who were ineligible for conventional heart surgery. Since then, more than a million patients have benefited from his technological innovation.
After this pivotal first case of TAVI,1 isolated procedures were performed in selected patients in the following years, with few technical variations, and all via antegrade access. While interventional cardiologists were enthusiastic and had high expectations, critics predicted apocalyptic disasters due to alleged complications, such as vascular complications, valve instability and migration, coronary occlusion, strokes, annular and aortic rupture, paravalvular regurgitation, and concerns about the durability of the valve. In 2006, the first clinical trials (REVIVAL2 in the United States and REVIVE3 in Europe) changed the procedure strategy. The adoption of retrograde access, facilitated by the versatility of a flexible carrier catheter, considerably simplified the technique and contributed to its widespread adoption.
After a stay in Vancouver, Canada to acquire theoretical and practical training in the technique, and with Cribier’s assistance, a team of interventional cardiologists from Hospital Gregorio Marañón, Madrid, Spain successfully implanted the first 2 aortic valves via transfemoral access in Spain on April 23, 2007 (figure 1). Throughout 2007, the team contributed to the REVIVE trial, successfully treating 10 patients with transfemoral TAVI, with no perioperative mortality or major complications. This success, with contributions from other European centers, paved the way for the approval of this technology for clinical use.
Figure 1. First transcatheter aortic valve implantation performed in Spain, on April 23rd, 2007. In the photograph, from left to right, Dr. Alain Cribier, Dr. Eulogio García, and Dr. Javier Ortal.
After standardizing and defining the complications associated with the procedure,4 the randomized PARTNER clinical trials were conducted in inoperable patients and high-risk surgical patients.5,6 These trials confirmed the safety and efficacy of TAVI, establishing it as the treatment of choice for high-risk patients.7 Eventually TAVI became the preferred treatment for all patients with aortic stenosis older than 75 years.8-10
In this exciting journey, we contributed a few technical improvements, demonstrating the safety of direct implantation without prior valvuloplasty11 and improving the management of vascular access via contralateral access.12 The gradual simplification of TAVI led to its classification as a “minimally invasive procedure”. It is now available in all cath labs, with more than 1 million valves implanted in all 5 continents.13
Alain Cribier was technically elegant and efficient; meticulous, systematic, and generous in his teaching. His perseverance in the management of aortic stenosis drove him to seek a definitive solution. Bernard Guiraud-Chaumeil, former president of the French health assessment department, highlighted Cribier’s exceptional contribution to the management of valvular heart disease, stating: “Revolutionary advances in medicine must be accessible to patients as soon as possible.” Cribier’s dedication, perseverance, and ingenuity changed the history of severe aortic stenosis; his legacy will not only save thousands of lives but will also improve the clinical practice of present and future generations of interventional cardiologists.
FUNDING
None declared.
CONFLICTS OF INTEREST
None declared.
REFERENCES
1. Cribier A, Eltchaninoff H, Bash A, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis:First human case description. Circulation. 2002;106:3006-3008.
2. Kodali SK, O'Neill WW, Moses JW, et al. Early and late (one year) outcomes following transcatheter aortic valve implantation in patients with severe aortic stenosis (from the United States REVIVAL trial). Am J Cardiol. 2011;107:1058-1064.
3. Garcia E, Pinto AG, Sarnago Cebada F, et al. Percutaneous Aortic Valve Implantation: Initial Experience in Spain. Rev Esp Cardiol. 2008;61:1210-1214.
4. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials:a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol. 2011;57:253-269.
5. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363:1597-1607.
6. Schymik G, Heimeshoff M, Bramlage P, et al. A comparison of transcatheter aortic valve implantation and surgical aortic valve replacement in 1,141 patients with severe symptomatic aortic stenosis and less than high risk. Catheter Cardiovasc Interv. 2015;86:738-744.
7. Baumgartner H, Falk V, Bax JJ, et al.;ESC Scientific Document Group. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;38:2739-2791.
8. Vahanian A, Beyersdorf F, Praz F, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2022;43:561-632.
9. Reardon MJ, Van Mieghem NM, Popma JJ, et al.;SURTAVI Investigators. Surgical or Transcatheter Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med. 2017;376:1321-1331.
10. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients. N Engl J Med. 2019;380:1695-1705.
11. García E, Almería C, UnzuéL, Jiménez-Quevedo P, Cuadrado A, Macaya C. Transfemoral implantation of Edwards Sapien XT aortic valve without previous valvuloplasty:Role of 2D/3D transesophageal echocardiography. Catheter Cardiovasc Interv. 2014;84:868-876.
12. García E, Martín-Hernández P, UnzuéL, Hernández-Antolín RA, Almería C, Cuadrado A. Usefulness of placing a wire from the contralateral femoral artery to improve the percutaneous treatment of vascular complications in TAVI. Rev Esp Cardiol. 2014;67:410-412.
13. Akodad M, Lefèvre T. TAVI:Simplification Is the Ultimate Sophistication. Front Cardiovasc Med. 2018;5:96.
Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 was published to regulate medical devices with the aim of bolstering the safety, quality, and efficacy of medical products in Europe.1
The regulation covers medical products intended for the diagnosis and treatment of numerous cardiovascular conditions, including high-risk devices such as pacemakers, defibrillators, artificial hearts, stents, cardiovascular sutures, heart valves, catheters, cardiovascular wires, and cardiac ablation instruments. According to the classification rules outlined in the regulation, all these high-risk medical products are classified as Class III.
The process for obtaining the CE mark for a medical device requires the manufacturer to demonstrate that the product meets the established safety and performance requirements and to conduct a clinical evaluation to validate the intended indication and purpose of use. For Class III product certification, a notified body designated by a member state authority must verify that the manufacturer has the objective technical and clinical documentation required to demonstrate that the product meets all the claims made by the manufacturer on the product. The authorized body issues a “CE Declaration of Conformity” including the manufacturer’s information, the product’s unique identifier, class, intended purpose, test reports and documentation, date and issue of validity, and details of the notified body involved in the process of granting the CE mark. The manufacturer’s company must also implement a quality management system to ensure that the manufactured products meet specified standards. After auditing the manufacturer’s facilities, the body issues an “EU quality management system certificate” detailing the scope of the quality system and type of manufactured products.
In other words, for the marketing of Class III medical products, the manufacturer must hold 2 different EU certificates issued by a notified body: one for the product and one for the quality management system.
Health care workers or users of a medical product can easily identify which notified body participated in its assessment by checking the product label, which is identified by a 4-digit number appearing alongside the CE mark. The name of the organization behind that number can be found on the European Commission’s website.2 For example, if the digits 0318 appear next to the CE mark on the label or the instructions for use of a medical product, it indicates that the evaluation was conducted by the National Certification Center for Medical Product, the sole notified body designated by the Ministry of Health.
The main change introduced in the regulation on product requirements involves the clinical evaluation. The assessment is especially strict for Class III products, which, as previously mentioned, are high risk. The first requirement is that the clinical evaluation validating the indication for use must be based on clinical data obtained from clinical investigations conducted with the product itself or a product that is technically, biologically, and clinically equivalent. The second requirement is that manufacturers must have access to the primary clinical data supporting the clinical evaluation of the medical product in question, either because they own them, or because the data have been published, or because they have a contractual agreement with the owner allowing permanent access and availability.
Although it may seem trivial, since the publication of the regulation, the availability of a compliant clinical evaluation has been the Achilles’ heel for manufacturers of medical products intending to market their products in Europe in the coming years.
During the 3 decades since the implementation of the directives, special emphasis has been placed on ensuring the safety and quality of medical products, while the available objective evidence supporting their clinical benefit has been relegated to a secondary role. Consequently, manufacturers of medical products that have been on the market for years have had to make considerable efforts and investments to obtain sufficient clinical data with the necessary level of evidence to support the clinical risk-benefit ratio esta- blished by the new legislation. Many have had to devise new clinical evaluation plans or review existing ones, including conducting specific postmarket clinical follow-up studies to provide clinical data with an adequate level of evidence. Therefore, we could say that a culture of the need for clinical research and publication of the obtained data is emerging in the medical products sector.
On the other hand, to minimize potential discrepancies between notified bodies in the assessment of the clinical evaluation of Class III implantable medical products (such as pacemakers), the regulation has established a centralized supervision procedure by a panel of experts in medical products from the European Medicines Agency (EMA). The role of this panel is to review and confirm the adequacy of both the clinical evaluation conducted by the manufacturer and the assessment made by the notified body, and provide any recommendations deemed appropriate regarding the decision on certifying the medical product. These recommendations may include proposing to certify or not certify the product, or to limit or restrict indications, among others.
An interesting point is that 18 out of the 43 applications received by the panel so far correspond to medical products within the “circulatory system” clinical area. In particular, the clinical evaluations of some stents, implantable defibrillators, and various types of heart valves have already undergone this procedure, and the resulting public opinions can be consulted in a list within the framework of the European Commission’s clinical evaluation consultation procedure.3
In addition, manufacturers of these types of products can seek guidance from the panel of experts before starting clinical development to confirm that the strategy designed for clinical development is appropriate and ensure that the resulting clinical evaluation will fully comply with the current legislation. If manufacturers decide to submit this voluntary query, the response issued by the panel will be binding. In other words, manufacturers will not be able to implement a different clinical evaluation plan from that recommended by the panel if they want to obtain the CE mark for the product.
The cornerstone of the CE certification model described is the competence of the personnel conducting the evaluation tasks. The personnel involved in the process of conducting or assessing the clinical evaluation of a medical product must have adequate knowledge. At the forefront of this chain are the manufacturers because they have had to review the competence of their staff to ensure that clinical evaluations are conducted by personnel experienced in clinical evaluation, competent in bibliographic searches, and with sufficient clinical knowledge and use of the products. Next are the notified bodies, which have to ensure that they have sufficient personnel with relevant clinical knowledge to issue a clinical judgment on the product’s risk-benefit ratio after analyzing and scientifically testing the clinical data collected in the clinical evaluation provided by the manufacturers. Furthermore, clinicians internal to the notified bodies must verify that the personnel conducting the clinical evaluations provided by the manufacturers are qualified to perform the task. Further along the review chain, notified bodies are audited by European teams of qualified professionals, who, in turn, must verify that the competencies of the personnel conducting the assessments of the clinical evaluations in the notified bodies meet the criteria of experience and training established in the regulation.
This regulation also encourages the manufacturers of medical products to hire health care workers with clinical experience, who have their own opinions on the products they use in their routine clinical practice. These professionals can participate in the early stages of product design, engage in usability testing, and, naturally, as occurs with drugs, promote clinical research both before and after product marketing. This helps to confirm the clinical benefit of medical products throughout their life cycle.
Health care workers must be aware of the value of their experience and clinical knowledge in ensuring that the medical products entering the market are truly innovative and meet the needs of patients.
The responsible and committed contribution made by each of the parties involved in conducting and reviewing the clinical evaluation of medical products will, on the one hand, provide greater assurance of the rigor, robustness, and sufficiency of the clinical data supporting a product’s indication. On the other hand, it will serve to standardize the criteria applied in the evaluation and ensure that the level of evidence required for all medical products bearing the CE mark under the new regulation is the same. These measures will restore confidence in the legislative model of medical products, ensuring that all manufacturers marketing their medical products in the European common market play by the same rules. Therefore, that the CE certification under which products are marketed will provide identical safeguards to patients, regardless of the country of origin, manufacturer, or issuing body.
FUNDING
None declared.
STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE
No artificial intelligence has been used in the preparation of this article.
CONFLICTS OF INTEREST
None declared.
REFERENCES
1. Parlamento Europeo. Reglamento (UE) 2017/745 del Parlamento Europeo y del Consejo, de 5 de abril de 2017, sobre los productos sanitarios, por el que se modifican la Directiva 2001/83/CE, el Reglamento (CE) n.º178/2002 y el Reglamento (CE) n.º1223/2009, y por el que se derogan las Directivas 90/385/CEE y 93/42/CEE del Consejo. DOUE. 2017;117:1-175.
2. European Commission. New Approach Notified and Designated Organisations -NANDO. Available at: https://webgate.ec.europa.eu/single-market-compliance-space/%23/notified-bodies/notified-body-list?filter=legislationId%3A34%2CnotificationStatusId%3A1. Accessed 18 Dec 2023.
3. European Commission. List of opinions provided under the CECP. Available at: https://health.ec.europa.eu/medical-devices-expert-panels/experts/list-opinions-provided-under-cecp_en#p2.
INTRODUCTION
When scientific projects or articles are evaluated, objections are often raised that may prevent their performance or publication. Sometimes, the flaws noted may not be correct or relevant to the study. In this article, we review the most common types of objections that can hinder the progress of medical research and suggest ways to reduce them.
CLINICAL (OR PROCEDURAL) OBJECTIONS AND STATISTICAL/METHODOLOGICAL OBJECTIONS
The objections an evaluator can make to a research project can be grouped into 2 broad categories: clinical (or procedural) and statistical/methodological.
The former can be addressed and, if necessary, refuted by the author of the project as they relate to the clinical problem per se. In this regard, the author of the project has more expertise and sometimes more up-to-date knowledge than the evaluator on the issue in question. A common example could be the objection, “the project does not specify under which conditions baseline blood pressure should be measured, or the criteria chosen to define hypertension.” The researcher can acknowledge the flaw in his/her protocol and correct it or argue that the objection is incorrect.
The situation is different with statistical/methodological objections. Researchers, whether acting as evaluators or persons who are evaluated, are not usually experts in research methodology and biostatistics. Below are a few examples of this type of objection.
Common erroneous statistical/methodological objections
Sample size
Contrary to what most researchers believe, the objection of an insufficient sample size is only relevant in highly specific situations. In some cases, it is not accurate; for example, if the result has a very small P value that constitutes strong evidence against the null hypothesis. It does not make any sense either in somewhat more complex situations.1
Statistical power
Statistical power depends on 4 parameters, whose value is often not predefined, so by choosing suitable values for these parameters, researchers can obtain almost any value for statistical power. In fact, when researchers are asked about the figure for statistical power, it is often insufficient to give a specific value, because the values of other parameters associated with such power are also necessary. Moreover, it is obvious that by slightly modifying these values within reasonable ranges, very different power values can be obtained.2
Test on the normal distribution of the response variable
In many cases, this objection may be doubly mistaken: either because the response variable is dichotomous and will be treated as such in the analysis, or because the sample size used is greater than, say, 30, and the central limit theorem guarantees a very good approximation to the normal distribution of the statistic used in the test. Naturally, it can never be guaranteed whether the variable has a normal distribution or not. Thus, in cases with a confirmed lack of normal distribution, the robustness of some parametric tests vs nonnormality must be taken into account.3 In cases with a strong association and an extremely small P value in the test, it should be noted that if the true P value of the test were, say, 10 times larger or 10 times smaller than that found in the parametric test, the practical conclusion would be the same.
Control group and study validity
While a control group is a great asset in many situations, demanding its presence should not be a universally or undisputed mantra. In some situations—and when used appropriately—historical controls provide enough information to draw very interesting conclusions. In other cases, each patient serves as his/her own control, thus allowing the use of intraindividual variability, which is often less than interindividual variability and, therefore, provides more powerful tests in many cases.
Pilot trials
Randomized clinical trials (RCTs) add highly useful methodological refinements to effectively determine the safety and efficacy profile of a new drug or procedure. However, pilot trials can add these same methodological refinements and be controlled, randomized, and blinded to a point that the level of scientific evidence they provide can be equivalent to that of RCTs, with significant advantages regarding time and cost savings. In addition, in general, their size is not a determining factor that compromises their validity. Then, what is the main difference between the 2 designs? The difference lies not in the level of evidence they provide, but in the administrative process involved. RCTs require approval from external hospital, regional, or national committees, while pilot trials are endorsed by the expertise of the medical team involved in their design. For external evaluators, it is more challenging to make accurate assessments of each aspect of the project and provide a sound judgment. Moreover, if they have the authority to veto the study, there is a possibility of rejecting it based on insufficiently founded considerations.
Observational trials
Blinded RCTs are widely accepted as the best source of evidence on drug and treatment efficacy. However, observational studies can also provide information on long-term safety and efficacy, which is often lacking in RCTs. Additionally, they are less expensive, allow the study of rare events, and provide information more quickly than RCTs. New and ongoing developments in analytical and data technology offer a promising future for observational studies, which already play a key role in researching treatment outcomes. Data from large observational studies can clarify the tolerability profile of drugs and are particularly suitable for large and heterogeneous populations of patients with complex chronic diseases. RCTs and observational trials should, therefore, be considered to complement each other.
Case-control trials
Rothman4 states that case-control trials have gone from “being the Cinderella of medical research to one of its brightest stars.” In case-control designs, it is much more challenging to avoid the distortion caused by confounding factors. However, these issues are partially mitigated by segmentation, matching, and multivariate analysis techniques. In some cases, they can provide significant statistical evidence much faster and more cheaply than clinical trials. Let’s consider an example of a disease that affects 1% of the population who do not follow a particular diet, and 5% of those who do follow it, knowing that 40% of the population follows that diet. A prospective trial would take 80 people from the diet group and another 80 from the control group, and after the agreed-upon time, we would measure the incidence of the disease in each of the 2 groups. The statistical power of this study for an alpha value of 0.05 would be 8%. A case-control trial would take 80 patients with the disease and 80 without it, and with very detailed health records, we would be able to determine the percentage of people who follow that diet in each of the 2 groups. The statistical power would be 93%.
The list of erroneous objections is much longer, however, and each would require a dedicated article to explain it.
CONCLUSIONS
Some of the methodological objections raised by the evaluators are incorrect. In most cases, the evaluated party assumes that his/her project has a major flaw and ends up abandoning it. Consequently, many projects that could have provided valuable information are unfairly discarded slowing down the progress of medicine.
We believe that this anomaly would largely be avoided if: a) evaluators raised methodological objections only in areas in which they have in-depth knowledge; b) whenever possible, the judgment issued by the evaluators from health agencies and bioethics committees was a suggestion instead of a veto; c) the fundamental role of observational trials, which can be highly effective and generally cheaper than clinical trials, was recognized; d) pilot trials were conducted in many cases where they are indicated, because they can be controlled, randomized, and blinded but without the restrictions associated with RCTs (figure 1).
Figure 1. Measures to expedite medical research by promoting the autonomy of qualified physicians, avoiding unjustified methodological objections, and promoting the use of currently underrated designs.
FUNDING
None declared.
CONFLICTS OF INTEREST
None declared.
REFERENCES
1. Egbuchulem KI. The basics of sample size estimation:an editor's view. Ann Ib Postgrad Med. 2023;21:5-10.
2. Prieto-Valiente L, Carazo-Díaz C. Potencia estadística en investigación médica. ¿Quépostura tomar cuando los resultados de la investigación son significativos?Rev Neurol. 2023;77:171-173.
3. Roco-Videla A, Landabur Ayala R, Maureira Carsalade N, Olguín-Barraza M. ¿Cómo determinar efectivamente si una serie de datos sigue una distribución normal cuando el tamaño muestral es pequeño?Nutr Hosp. 2023;40:234-235.
4. Rothman KJ. The origin of Modern Epidemiology, the book. Eur J Epidemiol. 2021;36:763-765.
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Subcategories
Original articles
Review Articles
Original articles
Editorials
Ventricular pressure-volume loop and other heart function metrics can elucidate etiology of failure of TAVI and interventions
aDepartment of Mechanical Engineering, McMaster University, Hamilton, Ontario, Canada
bSchool of Biomedical Engineering, McMaster University, Hamilton, Ontario, Canada
Special articles
Role of computed tomography in transcatheter coronary and structural heart disease interventions
aServicio de Cardiología, Hospital Universitario Álvaro Cunqueiro, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Pontevedra, Spain
bServicio de Cardiología, Hospital de la Santa Creu i Sant Pau, Instituto de Investigación Biomédica Sant Pau (IBB Sant Pau), Barcelona, Spain
cServicio de Cardiología, Complejo Asistencial Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
dCentro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
Debate
“Orbiting” around the management of stable angina
The interventional cardiologist’s perspective
aServicio de Cardiología, Complejo Asistencial Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
bCentro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
The clinician’s perspective
aInstituto Cardiovascular, Hospital Clínico San Carlos, Madrid, Spain
bDepartamento de Medicina, Facultad de Medicina, Universidad Complutense, Madrid, Spain
