Percutaneous treatment of the left main coronary artery in older adults. Impact of frailty on mid-term results

INTRODUCTION

The implementation of STEMI Code protocols, involving emergency and cardiology services, has led to improved care for ST-segment elevation myocardial infarction (STEMI) and lower morbidity and mortality rates.1 Correct diagnosis of STEMI, pretreatment with antiplatelet agents, and the organization of rapid and direct transfer to a center with an PCI-capable center for primary angioplasty are quality standards in the management of STEMI.1

Parenteral anticoagulation is generally recommended in acute coronary syndrome at the time of diagnosis.1 In STEMI, the use of unfractionated heparin (UFH) during primary angioplasty is recommended to prevent coronary thrombosis and device-related complications, but its use should be discontinued after the procedure.2

The precise role of UFH pretreatment at the time of first medical contact for patients diagnosed with STEMI remains to be fully defined. The 2023 clinical practice guidelines of the European Society of Cardiology1 allow attending physicians to decide when to administer UFH during treatment, as there is no solid evidence supporting its early use. This flexibility is based on the absence of conclusive data on the benefits of UFH at this stage of treatment.1,3

The most recent data published on the implementation of STEMI Code protocols and care networks in Spain reveal heterogeneity in response times and transport among the different autonomous communities (AC).4,5 This heterogeneity is also observed in the administration of anticoagulant and antiplatelet pretreatment across the 17 AC. A review of STEMI Code protocols as of December 2024 shows that in 6 of the 17 (35.3%) AC, pretreatment with UFH is recommended, representing coverage for 43.1% of the Spanish population (table 1 of the supplementary data). All AC, except for one, include dual antiplatelet therapy as pretreatment at the first medical contact in their protocols. Differences in the standardization of UFH use in STEMI Code protocols reflect the lack of evidence and concrete recommendations on this topic.

Table 1. Demographic data of populations and characteristics of the selected studies

The aim of this study is to perform a systematic review and meta-analysis of existing studies on UFH pretreatment in the context of primary angioplasty as a reperfusion treatment for STEMI in terms of TIMI (Thrombolysis in Myocardial Infarction) grade 2-3 flow at the start of the procedure and early 30-day in-hospital mortality.

The meta-analysis follows PRISMA guidelines to ensure transparency and quality (table 2 of the supplementary data).

Table 2. Events from the studies

METHODS

Literature search

We conducted a systematic search of scientific literature across Medline-PubMed and the Cochrane Controlled Register of Trials (CENTRAL) from May through September 2024. We accessed several observational studies and clinical trials comparing UFH pretreatment in the ambulance vs no pretreatment in patients diagnosed with STEMI treated with primary angioplasty. A lower date limit was set to 2002, and no language restrictions were applied. Studies were selected if they included information on initial TIMI grade flow, 30-day early mortality, and major bleeding complications. In the article by Emilsson et al.6 data from the propensity score cohort, which provides better adjustment, were used, and the same population was used in the study by Bloom et al.7. The references of the selected studies were analyzed to obtain additional articles via cross-referencing. Both the search and article selection methodology are shown in figure 1.

Figure 1. Flowchart of the literature search. STEMI, ST-segment elevation myocardial infarction.

The PRISMA guidelines were followed (table 2 of the supplementary data), and the meta-analysis was registered in PROSPERO (CRD420250655362).

Inclusion criteria

We included observational, retrospective, and clinical trials analyzing the use of UFH as pretreatment in patients diagnosed with STEMI, administered at the first medical contact, in the ambulance or at a non-PCI-capable center prior to arrival at the destination hospital where the percutaneous coronary intervention (PCI) would be performed along with a control group of patients without UFH pretreatment. Moreover, studies had to provide information on initial TIMI grade flow, the 30-day mortality rate, and major bleeding complications. Only studies with a population of at least 500 individuals were included.

Exclusion criteria

We excluded repeated series from the same group, studies prior to 2002, those on pretreatment with anticoagulants other than UFH, studies without a control comparator group, or those that included patients diagnosed with non-ST-segment elevation acute coronary syndrome, angina, or another cardiac event different from STEMI. Studies with less than 500 individuals were also excluded.

Selection of publications

The article search was conducted across Medline-PubMed and CENTRAL databases using the following terms: “preclinical,” “cardiac,” “heparin,” “analysis, early,” “unfractionated,” “STEMI,” “prehospital,” and “pretreatment.” A total of 275 relevant articles were identified, from which, after initial exclusion based on inclusion and exclusion criteria, 16 were selected, and 7 finally remained6-12 (6 of them conducted in European populations and 1 in Australia.7) All were observational and retrospective studies, except for the one conducted by Karlsson et al.11, which is a subanalysis of a randomized clinical trial.

Primary and secondary endpoints

The primary endpoint was to analyze the association of UFH pretreatment with the presence of initial TIMI grade 2-3 flow in the infarct-related artery on diagnostic coronary angiography, prior to the start of PCI, in patients for whom PCI was indicated. The secondary endpoints were to analyze the association of UFH pretreatment with 30-day mortality in STEMI patients with an indication for PCI, and the presence of major bleeding complications13 (clinically significant bleeding events, such as bleeding requiring medical intervention or blood transfusion, or resulting in a significant hemoglobin decrease).

Data collection and management

Abstracts and methods sections of selected publications were systematically reviewed to ensure they met the inclusion criteria. Disagreements were resolved by consensus. Measures were taken to avoid duplication of articles.

Risk of bias

The risk of bias in the studies included in the meta-analysis was assessed using a combination of robust statistical approaches and widely recognized visual methods. The Harbord test (table 3 of the supplementary data), specifically designed to detect publication bias in meta-analyses reporting risk ratios (RR), was used. Additionally, funnel plots were analyzed, allowing a visual assessment of asymmetry in the distribution of study effects. The funnel plots for each variable are included in figures 1-3 of the supplementary data.

Figura 2. Forest plot of the prevalence of TIMI grade 2-3 flow. References cited in this figure: Fabris et al.10, Emilsson et. al.6, Bloom et al.7, McGinley et al.8, Karlsson et al.11, Giralt et al.9, and Zijlstra et al.12. 95%C, 95% confidence interval; M-H, Mantel-Haenszel’s method; UFH, unfractionated heparin.

In this meta-analysis, the variables of interest include TIMI grade 2-3 flow, 30-day mortality, and major bleeding. Furthermore, their potential bias was analyzed using the above-mentioned statistical procedures.

Statistical analysis

For statistical analysis, version 4.2.1 of R was used, using the metabin function from the meta package to synthesize the results of studies comparing UFH pretreatment vs UFH administered in the cath lab. Binary event data and totals for each group were analyzed using the RR model, with the inverse variance method, which weights studies based on precision, giving more weight to those with lower variance. A forest plot was generated using a random-effects model; the graph shows point estimates and corresponding 95% confidence intervals (95%CI) for each individual study, along with an overall RR estimate. The graph design followed the RevMan format, with customized labels indicating the groups of interest (UFH and non-UFH) and direction of effects (favors UFH and favors non-UFH), improving clinical interpretation. Heterogeneity analysis included calculation of the I² value, which quantifies the proportion of variability among studies not attributable to chance, due to observed heterogeneity. As indicated by the τ² value from the Harbord test analysis (table 3 of the supplementary data), the random-effects model is most appropriate in this situation.

Figure 3. Forest plot of the prevalence of 30-day mortality. References cited in this figure: Fabris et al.,10 Emilsson et al.,6 Bloom et al.,7 McGinley et al.,8 Karlsson et al.,11 Giralt et al.,9 and Zijlstra et al.12. 95%C, 95% confidence interval; M-H, Mantel-Haenszel’s method; UFH, unfractionated heparin.

RESULTS

A total of 36 831 patients were included, of whom 17 751 (48.2%) received pretreatment with UFH and 19 080 (51.8%) did not, the latter representing the control group for comparison. Of note, data from the article by Emilsson et al.6 were obtained from the propensity score-matched cohort, which provides better adjustment; therefore, the study population was 22 376 rather than 41 631 patients. Additionally, this adjusted cohort was used in the study by Bloom et al.7 with 2746 instead of 4720 patients. The data shown in table 1 correspond to the propensity score-matched cohort and include a summary of the demographics and characteristics of each study. A substantial portion of the population was male (70–80% of the total), with mean ages ranging from 60 to 67 years. Only 5 of the 7 studies reported the UFH dose, which ranged from 4000 to 5000 IU.

Primary endpoint

A total of 6202 (31.6%) patients pretreated with UFH achieved TIMI grade 2-3 flow vs 5106 (23.0%) from the non-pretreated group (table 2).

The meta-analysis of data from the 7 studies6-12 demonstrated a significant increase in the likelihood of TIMI grade 2-3 flow, with a hazard ratio (HR) of 1.35 (95%CI, 1.25–1.45; P < .0001) (figure 2). Although all studies showed statistically significant differences, except for the one by McGinley et al.8, heterogeneity in the magnitude of association was high (I² = 53%).

Secondary endpoints

A total of 490 (3.9%) patients pretreated with UFH died within 30 days vs 673 (5.1%) from the non-pretreated group (table 2). The meta-analysis of data from the 7 included studies6-12 showed a reduction in 30-day mortality in patients who received pretreatment with UFH (HR, 0.80; 95%CI, 0.72–0.90; P = .0002) vs those who did not. Two studies showed a significantly lower mortality rate in the UFH group individually, including the one with the largest sample size6 (65.8% of patients included in the meta-analysis). Heterogeneity in the magnitude of association was high (I² = 55%) (figure 3).

Regarding the association between UFH pretreatment and the rate of hemorrhagic complications, there were no significant associations in the meta-analysis of the 7 studies6-12 (HR, 0.87; 95%CI, 0.72–1.05; P = .1502). None of the studies showed a significant association, either beneficial or harmful, regarding bleeding complications. Heterogeneity among the studies was low (I² = 0%) (figure 4).

Figure 4. Forest plot of the prevalence of major bleeding. References cited in this figure: Fabris et al.,10 Emilsson et al.,6 Bloom et al.,7 McGinley et al.,8 Karlsson et al.,11 Giralt et al.,9 and Zijlstra et al.12. 95%C, 95% confidence interval; M-H, Mantel-Haenszel’s method; UFH, unfractionated heparin.

DISCUSSION

This meta-analysis demonstrates that for STEMI patients, administering UFH as pretreatment at the point of first medical contact is more beneficial than doing so at the PCI-capable center.

The observed benefit consists of a higher percentage of initial TIMI grade 2-3 flow (absolute increase of 8.6% and relative increase od 37.4%) and a lower 30-day mortality rate (absolute reduction of 1.2% and relative reduction of 23.5%). While most studies individually indicated a benefit of UFH pretreatment for open arteries, only 2 of the 7 studies primarily supported a mortality benefit. In terms of safety, pretreatment at first medical contact had a neutral effect on the risk of bleeding complications, and results were homogeneous across all 7 studies.

A recently published meta-analysis of 14 studies14 with different inclusion criteria and endpoints, incorporated studies on UFH and on a mix of other anticoagulants, such as low molecular weight heparin (enoxaparin), bivalirudin, and fondaparinux, along with additional events like cardiogenic shock, in-hospital mortality, and 1-year mortality. Both analyses showed consistent results on the benefit of pretreatment on open artery rates and early mortality, although they differed in the rate of bleeding complication. The referenced meta-analysis14 found a beneficial association between pretreatment with UFH or fractionated heparin in the reduction of bleeding complications. Moreover, the meta-analysis also analyzed the impact of pretreatment on the percentage of patients with cardiogenic shock, showing a positive association between pretreatment with UFH or fractionated heparin and this outcome. Of note, the heterogeneity in design, timing, and concomitant antiplatelet therapy among the studies included in the 2 meta-analyses. Notably, a small observational study conducted in Spain reported benefits from UFH pretreatment.15

Arguments for and against UFH pretreatment in STEMI

UFH is inexpensive, accessible, administered intravenously, and widely used in health care centers and ambulances. UFH is a necessary drug to prevent arterial and catheter thrombosis during PCI.

Beyond the potentially beneficial effects on open artery rates demonstrated in the meta-analysis, the use of UFH as pretreatment at the first medical contact does not seem to influence PCI per se. The rate of arterial puncture-related complications in anticoagulated patients is low when radial access is used; according to recent studies on the STEMI Code in Spain, 90% of angioplasties in STEMI patients are performed via radial access.4,5 There is still no information available on the potential impact of pretreatment on thrombus burden, no-reflow, ST-segment resolution, or infarct size, and no current studies have been designed to address these specific issues3 (table 4 of the supplementary data).

Clinical practice guidelines do not make definitive recommendations either due to the absence of adequately randomized trials evaluating the value of UFH pretreatment—not because there is evidence of no effect.1,3

In some patients misdiagnosed with STEMI (eg, those with aortic syndrome, pericarditis, myocarditis, NSTEMI, transient ST-segment elevation, Takotsubo syndrome, pulmonary embolism, pneumothorax, thoracic or esophageal disease, or musculoskeletal chest pain), pretreatment with UFH and antiplatelets may be harmful.

Notably, recent studies on the STEMI Code in Spain4-5 report that in 16.6% of all STEMI Code activations, the diagnosis of STEMI could not be confirmed, and in 3.6% of cases, no angioplasty was performed.

These misdiagnoses were not analyzed in the included meta-analyses. The design of the studies, most of which were retrospective, complicates the identification of risks associated with UFH use in these contexts. Theoretically, UFH pretreatment might be more beneficial in patients with recent thrombus formation, shorter times from symptom onset to first medical contact, and longer transfers to the PCI-capable center. However, in this meta-analysis, the review of study characteristics does not allow conclusions in this regard. There was no evident relationship between time metrics and the use of UFH pretreatment and the rates of open arteries or short-term mortality.

Need for randomized clinical trials

Clinical practice guidelines have become key reference documents for organizing health care delivery.1,2 These guidelines, developed by international experts who thoroughly review the scientific evidence to support their recommendations, are not always implemented in the routine clinical practice. One example, relevant to our field, is the use of antiplatelet pretreatment at the first medical contact. One year after the publication of the European Society of Cardiology guidelines on the management of acute coronary syndrome,1 which assigned a class IIb recommendation and level B evidence to dual antiplatelet therapy (DAPT) in STEMI, nearly all hospitals in Spain continued to administer DAPT at the first medical contact (table 1 of the supplementary data).

The current recommendation against antiplatelet pretreatment, similarly to the indication on pretreatment with UFH, is based on the absence of evidence demonstrating a benefit from DAPT and concerns on the potential bleeding risk associated with the use of long half-life antiplatelet agents in patients who may require emergency revascularization surgery.16-18 However, the need for emergency surgery is extremely rare in STEMI cases. Implementation of the clinical practice guidelines and reducing pretreatment to a single antiplatelet agent has been adopted in other European countries with preliminary positive results (EuroPCR 2024 presentation).19 In countries such as Denmark and Germany, and certain regions of Italy, STEMI care protocols include the administration of a single antiplatelet agent (acetylsalicylic acid) along with UFH.20 Despite the absence of a clear recommendation regarding UFH in the guidelines, it can be inferred that protocol developers trust in the theoretically beneficial effect of UFH, complementing antiplatelet therapy at the time of the first medical contact.

Study limitations

This study has inherent limitations related to its design. Observational studies, especially retrospective ones, are susceptible to various biases, including selection and confounding, as well as uncontrolled factors that may affect internal validity. However, several measures were taken to mitigate these biases and provide a robust interpretation of the findings, including a detailed sensitivity analysis to assess result consistency. Moreover, heterogeneity was explored using the Harbord test, which yielded high p-values for publication bias, indicating no significant evidence of such bias influencing our results. Despite this, heterogeneity remains an inherent challenge in meta-analyses that include observational studies with varying designs and quality. This variability was documented using measures such as τ² and considered in interpreting the findings.

Despite these limitations, the results remain valuable and should be interpreted with caution.

Another limitation is the heterogeneity in the number of patients included in the selected studies, the times for care and transfer, the doses of UFH administered, the definition of hemorrhagic complications, and the concomitant antiplatelet regimens used, all of which may have introduced bias.

CONCLUSIONS

The meta-analysis of retrospective studies and one clinical trial shows that pretreatment with UFH in patients with STEMI undergoing a primary angioplasty is associated with an increase in the initial TIMI grade 2-3 flow and a lower early mortality rate (figure 5).

Figura 5. Effect of unfractionated heparin pretreatment in patients with ST-segment elevation myocardial infarction (STEMI). Forest plot of the prevalence of TIMI grade 2-3 flow. References cited in this figure: Fabris et al.10, Emilsson et al.6, Bloom et al.7, McGinley et al.8, Karlsson et al.11, Giralt et al.9, and Zijlstra et al.12. 95% CI: 95% confidence interval, M-H: Mantel-Haenszel’s method, UFH: unfractionated heparin.

Specifically designed clinical trials are needed to establish the impact of early UFH administration, and current clinical practice guidelines should provide clearer recommendations on the optimal timing of UFH pretreatment in STEMI patients.

FUNDING

This work was funded by CIBERCV CB16/11/00385.

ETHICAL CONSIDERATIONS

Ethical considerations are not applicable to a meta-analysis, as no direct clinical data from individuals are collected and therefore ethics committee evaluation is deemed unnecessary. A subgroup analysis by sex was not performed because it would result in a loss of statistical power, and both women and men were represented. There is no prior evidence or data suggesting that men and women respond differently to IV heparin anticoagulant treatment.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

Artificial intelligence was not used.

AUTHORS’ CONTRIBUTIONS

M. Roldán Medina and A. Riquelme Pérez equally contributed to various phases of the study: study conception and design, data acquisition, analysis, and interpretation. Additionally, M. Roldán Medina contributed to drafting the original manuscript and editing and reviewing the final version, while A. Riquelme López was responsible for the final revision of the article.

R. López-Palop and P. Carrillo contributed to data acquisition, analysis, and interpretation, and to the final text review and editing. J. Lacunza participated in data acquisition, analysis, and interpretation. R. Valdesuso contributed to data acquisition, analysis, and interpretation.

J. García de Lara was involved in data acquisition, analysis, interpretation, and final text review and editing. J. Hurtado-Martínez contributed to data acquisition, analysis, and interpretation. J.M. Durán contributed to data acquisition, analysis, and interpretation. E. Pinar-Bermúdez participated in data acquisition, analysis, and interpretation. J.R. Gimeno and D. Pascual-Figal contributed to the study conception and design, data acquisition, analysis and interpretation, drafting, reviewing, editing, and approval of the final manuscript, as well as project administration.

CONFLICTS OF INTEREST

None declared.

ACKNOWLEDGMENTS

The authors would like to thank all colleagues from the Cardiology Department at Hospital Virgen de la Arrixaca, IMIB, and Universidad de Murcia whose collaboration made this study possible.

WHAT IS KNOWN ABOUT THE TOPIC?

• The early administration of unfractionated heparin (UFH) in ST-segment elevation myocardial infarction (STEMI) is controversial. Current clinical practice guidelines leave the timing of its administration before primary angioplasty to the physician’s discretion and do not provide clear recommendations on UFH pretreatment in STEMI patients prior to their arrival at the PCI-capable center.

WHAT DOES THIS STUDY ADD?

• Our meta-analysis and systematic review of studies on the safety and efficacy profile of UFH pretreatment in STEMI patients, compared with control patients who did not receive such pretreatment, demonstrates that pretreatment with UFH was associated with an increased TIMI grade 2-3 flow, a lower 30-day mortality rate, and fewer major bleeding events.

SUPPLEMENTARY DATA

REFERENCES

1. Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J Acute Cardiovasc Care. 2024;13:55-161. Erratum in:Eur Heart J Acute Cardiovasc Care. 2024;13:455

2. Lawton JS, Tamis-Holland JE, Sripal Bangalore, et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization.J Am Coll Cardiol. 2022;79:197-215.

3. Collet J, Zeitouni M. Heparin pretreatment in STEMI:is earlier always better?EuroIntervention. 2022;18:697-699.

4. Rodríguez-Leor O, Cid-Álvarez AB, Moreno R, et al. Regional differences in STEMI care in Spain. Data from the ACI-SEC Infarction Code Registry. REC Interv Cardiol. 2023;5:118-128.

5. Rodríguez-Leor O, Cid-Álvarez AB, Pérez de Prado A, et al. Analysis of the management of ST-segment elevation myocardial infarction in Spain. Results from the ACI-SEC Infarction Code Registry. Rev Esp Cardiol. 2022;75:669-680.

6. Emilsson O, Bergman S, Mohammad M, et al. Pretreatment with heparin in patients with ST-segment elevation myocardial infarction:a report from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). EuroIntervention. 2022;18:709-718.

7. Bloom J, Andrew E, Nehme Z, et al. Pre-hospital heparin use for ST-elevation myocardial infarction is safe and improves angiographic outcomes. Eur Heart J Acute Cardiovasc Care. 2021;10:1140-1147.

8. McGinley C, Mordi I, Kell P, et al. Prehospital Administration of Unfractionated Heparin in ST-Segment Elevation Myocardial Infarction Is Associated With Improved Long-Term Survival. J Cardiovasc Pharmacol. 2020;76:159-163.

9. Giralt T, Carrillo X, Rodriguez-Leor O, et al. Time-dependent effects of unfractionated heparin in patients with ST-elevation myocardial infarction transferred for primary angioplasty. Int J Cardiol. 2015;198:70,-74.

10. Fabris E, Menzio S, Gregorio C, et al. Effect of prehospital treatment in STEMI patients undergoing primary PCI. Catheter Cardiovasc Interv. 2022;99:1500-1508.

11. Karlsson S, Andell P, Mohammad M, et al. Editor's Choice —Heparin pre-treatment in patients with ST-segment elevation myocardial infarction and the risk of intracoronary thrombus and total vessel occlusion. Insights from the TASTE trial. Eur Heart J Acute Cardiovasc Care. 2019;8:15-23.

12. Zijlstra F, Ernst N, de BoerMJ, et al. Influence of prehospital administration of aspirin and heparin on initial patency of the infarct-related artery in patients with acute ST elevation myocardial infarction. J Am Coll Cardiol. 2002;39:1733-1737.

13. Mehran R, Rao S, Bhatt D, et al. Standardized bleeding definitions for cardiovascular clinical trials:a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123:2736-2747.

14. Costa G, Resende B, Oliveiros B, Gonçalves L, Teixeira R. Heparin pretreatment in ST segment elevation myocardial infarction:a systematic review and meta-analysis. Coron Artery Dis. 2025;36:28-38.

15. Ariza A, Ferreiro JL, Sánchez-Salado JC, Lorente V, Gómez-Hospital JA, Cequier A. Early Anticoagulation May Improve Preprocedural Patency of the Infarct-related Artery in Primary Percutaneous Coronary Intervention. Rev Esp Cardiol. 2013;66:148-150.

16. Koul S, Smith J, Götberg M, et al. No Benefit of Ticagrelor Pretreatment Compared With Treatment During Percutaneous Coronary Intervention in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. Circ Cardiovasc Interv. 2018;11:e005528.

17. Russo RG, Wikler D, Rahimi K, Danaei G. Self-Administration of Aspirin After Chest Pain for the Prevention of Premature Cardiovascular Mortality in the United States:A Population-Based Analysis. J Am Heart Assoc. 2024;13:e032778.

18. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction:randomised placebo-controlled trial. Lancet. 2005;366:1607-1621.

19. Siller J, Angiolillo D, De Luca L, Rymer J, Thim T, Zeymer U. Real-world practice adoption of latest guidelines for the acute management of ACS patients. En:Paris 2024. EuroPCR Course 2024. 35th edition;2024 May 21-24;Paris, France. Available at:https://www.pcronline.com/Courses/EuroPCR. Consulted 1 Mar 2025.

20. De Luca L, Maggioni A, Cavallini C, et al. Clinical profile and management of patients with acute myocardial infarction admitted to cardiac care units:The EYESHOT-2 registry. Int J Cardiol. 2025;418:132601.

* Corresponding author.

E-mail address: jgimeno@secardiologia.es (J.R. Gimeno).

INTRODUCTION

Severe tricuspid regurgitation (TR) is associated with a poor prognosis.1 Although the optimal timing for an isolated tricuspid valve procedure remains uncertain, in the late stages of the disease natural progression, patients already exhibit signs of right heart failure and respond poorly to diuretic treatment.2 In these advanced stages, any intervention may be futile.

Initial treatment involves diuretic drugs, with surgery being reserved only for selected cases. Furthermore, surgical outcomes are still modest, with high mortality rates associated with isolated tricuspid valve procedures.3 In this context, the European Society of Cardiology clinical practice guidelines on the management of cardiovascular diseases suggest that transcatheter techniques might play a role in the TR of selected patients.4

In recent years, there has been an exponential growth in transcatheter treatments for TR. The most widespread tricuspid repair techniques are percutaneous edge-to-edge repair and annuloplasty.5,6 In patients with complex tricuspid anatomies and those in more advanced stages of the disease, characterized by a severely dilated tricuspid annulus and large coaptation gaps, edge-to-edge repair and annuloplasty offer suboptimal results.7 For these patients, the alternative could be orthotopic transcatheter tricuspid valve replacement.

The EVOQUE transcatheter tricuspid valve replacement system (Edwards Lifesciences, United States) obtained the CE marking in 2023. The first implantation results of an EVOQUE tricuspid valve in Spain have recently been published.8

We present the first Spanish series of patients with severe symptomatic TR undergoing transcatheter implantation of the EVOQUE valve in the tricuspid position. The objective is to communicate our initial experience in terms of TR reduction, short-term follow-up, and postoperative complications, and provide scientific evidence on this innovative technology.

METHODS

We conducted a prospective, single-center observational study including 10 consecutive patients who underwent EVOQUE valve implantation to treat their symptomatic TR. Echocardiographic parameters and the 30-day clinical outcomes were evaluated. Transthoracic echocardiography was performed before discharge, and a follow-up computed tomography (CT) was performed 1 month following the procedure.

Patients had, at least, severe TR, quantified according to the Hahn and Zamorano classification:7 0, absent or minimal; 1, mild; 2, moderate; 3, severe; 4, massive; and 5, torrential. All patients showed signs or symptoms of TR or had been hospitalized for heart failure despite optimal medical therapy. In addition, all were eligible for valve replacement with the EVOQUE system. The indication for the intervention was established by the heart team, in full compliance with the European Society of Cardiology clinical practice guidelines on the management of valvular heart disease.4

Patients with severely depressed right ventricular systolic function, with anatomies that prevented correct device placement, and those with a life expectancies < 12 months were excluded. CT images were analyzed as part of the screening process by the operators and the Edwards EVOQUE team.

Preoperative analysis

Preoperative CT was performed to assess the feasibility of valve implantation. The patients’ treatment rejection rate was 17%.

The EVOQUE valve

The EVOQUE valve is a self-expanding nitinol tri-leaflet bovine pericardial valve with an anchoring system that can extend between the chordae tendineae of the subvalvular apparatus to capture the free edge of the native tricuspid leaflets (septal, anterior, and posterior) with an intra-annular skirt. The 28-Fr delivery system outer diameter has been designed for transfemoral venous access, and includes a primary flexion handle, a secondary flexion handle, and a depth handle to facilitate alignment and positioning of the device inside the native valve. There are 3 sizes are available, with outer diameters of 44 mm, 48 mm, 52 mm, and 56 mm.9

Implantation procedure

The procedure is monitored with fluoroscopy and intraoperative transesophageal echocardiography, relying heavily on live 3D imaging to ensure correct valve position and trajectory. A pre-shaped support guidewire (Safari type, Boston Scientific, United States) is placed inside a deflectable sheath (9-14-Fr) in the right ventricle, across the tricuspid annulus. The device is advanced through the delivery catheter and positioned across the tricuspid annulus, where it is deployed from the ventricular side, while placing the anchors underneath the tricuspid leaflets and above the papillary muscles. Since, at this point, the delivery system is still recapturable, a comprehensive assessment of anatomy and position can be performed. During device deployment, the 9 anchors are identified, ensuring that the leaflets are above them in systole and the papillary muscle heads are below.

Afterwards, leaflet “capture” occurs, which is monitored by 3D transesophageal echocardiography, while making the necessary trajectory and height adjustments. Continuous retraction of the system results in shortening of the valve ventricular portion. After confirming satisfactory leaflet capture, the valve ventricular portion is fully expanded, and the valve atrial portion is released from the system. Minimal changes in device position upon release may be due to further device shortening, tension release, and anchor coupling with annular tissue. After releasing the valve, the device stability, residual central and paravalvular regurgitation, valve orifice area, diastolic gradients, and hemodynamics are all confirmed by echocardiography and fluoroscopy.

Regarding antithrombotic regimen, the established protocol was to maintain the patient’s pre-existing anticoagulation (all patients except for 1 had an indication for chronic anticoagulation), without antiplatelet therapy. The only patient without baseline anticoagulation received acetylsalicylic acid.

Statistical analysis

Statistical analysis for descriptive studies was performed using Student’s t-test for mean comparison. The Wilcoxon signed-rank test was used for TR comparison before the procedure and after EVOQUE valve implantation. SPSS version 22.0 was used for the analysis.

Ethical aspects

The study protocol fully complies with the principles set forth in the Declaration of Helsinki and was approved by the hospital local ethics committee.

RESULTS

The patients’ baseline clinical characteristics are shown in table 1. Their mean age was 77.2 years, and 60% were women (n = 6). The severity of TR was categorized as severe in 30% of cases, massive in 30%, and torrential in 40%. The patients’ mean TRISCORE score was 4.6, indicating low-to-moderate risk. According to the 4A classification10 (asthenia, anorexia, ascites, and edema), most patients fell within the A1 and A3 categories. Regarding baseline rhythm, 80% of patients were in atrial fibrillation. One patient had a pre-existing right bundle branch block and developed complete atrioventricular block (AVB) after valve implantation, requiring permanent pacemaker implantation in the coronary sinus. A total of 40% of the patients were pacemaker carriers, which added complexity to the procedures, while 30% had previous hospitalizations for right heart failure symptoms. The mean B-type natriuretic peptide value of the patients was 221 pg/mL.

Table 1. Baseline clinical characteristics of the patients (n = 10)

Right heart catheterization for baseline pressure measurement was performed in 70% of the patients. Significant pulmonary hypertension was present in 5 of the 7 patients who underwent the procedure (71%). Pulmonary hypertension was post-capillary in all cases, with elevated pulmonary capillary wedge pressure.

The baseline echocardiography categorized the TR as severe, massive, or torrential in all patients, based on standard severity parameters. Regarding the assessment of right ventricular function, the usual estimation difficulties were observed, and tricuspid annular plane systolic excursion, right ventricular strain, and ejection fraction by 3D echocardiography were evaluated. Information is shown in table 1. No baseline cardiac magnetic resonance imaging was performed.

Requiring no transseptal puncture, the implantation procedure is performed under general anesthesia with transesophageal echocardiography guidance. The median duration of the procedures was 129.5 minutes. Figure 1 illustrates different moments of the intervention.

Figure 1. EVOQUE valve implantation (Edwards Lifesciences, United States). A: each anchor and its capture position with the leaflet can be assessed using 3D echocardiography. B: optimal final results.

Results, in terms of TR reduction, were excellent in all patients, with residual TR being at most mild and without paravalvular leaks (figure 2). The rate of procedural success was 100% according to the Tricuspid Valve Academic Research Consortium criteria.11 Transprosthetic gradient was 4.8 mmHg in the worst-case scenario, with a mean transtricuspid gradient in the 10 patients of 2.5 mmHg.

Figure 2. Near-complete reduction of tricuspid regurgitation (TR) after EVOQUE valve (Edwards Lifesciences, United States) implantation, immediately and at the follow-up. The Wilcoxon signed-rank test was performed for paired data (baseline vs post-implantation TR).

Early (30-day) complications after the intervention are shown in table 2. As notable complications and data, patient #1 exhibited severe functional mitral regurgitation 5 days after the EVOQUE valve implantation in the tricuspid position (previously had mild-to-moderate functional mitral regurgitation), which resolved by returning to baseline after the administration of levosimendan and IV diuretic treatment. Patient #3 (with a pre-existing right bundle branch block) developed complete AVB 3 days after the procedure, requiring implantation of a single-chamber pacemaker with a lead in the coronary sinus, which turned out to be uneventful. Patients #3 and #4 both exhibited transient right ventricular failure requiring dobutamine and close monitoring, and both resolved with optimal medical therapy within a few days. The CT scan of patient #8 performed 1 month after discharge revealed the presence of prosthetic valve thrombosis as confirmed by transesophageal echocardiography (figure 3); this complication was not present on the pre-discharge echocardiography. Prosthetic valve thrombosis was also detected in patient #10 on the follow-up CT 1 month after the procedure, also confirmed by echocardiography. In the 2 cases, thrombosis was asymptomatic, and both patients remain on unfractionated heparin.

Table 2. Early complications and initial progression

Figure 3. Anterior leaflet thrombosis of the EVOQUE valve (Edwards Lifesciences, United States).

DISCUSSION

The initial experience in Spain with the transcatheter implantation of the EVOQUE tricuspid valve shows excellent results in terms of TR reduction, well beyond the transcatheter treatments available so far for tricuspid valve repair. However, it is important to compare these data with those of the TRISCEND12 and TRISCEND II13 clinical trials. The former12 analyzed 176 patients with, at least, moderate TR treated with the EVOQUE valve. Significant and sustained TR reduction, increased cardiac output, and improved survival were reported, with low readmission rates and clinical and quality of life improvement. More recently, the results of the TRISCEND II trial13,14 have been published on 392 patients randomized to receive the EVOQUE valve plus optimal medical therapy or optimal medical therapy alone. TR reduction was notable in all cases. In our series, the clinical outcomes of all patients were mild or less residual TR following implantation, without significant paravalvular leaks. Similarly, the TRISCEND II study13 also showed a significant and sustained TR reduction, indicating that the EVOQUE valve is effective. Regarding valve-induced atrioventricular conduction disturbances, in our series, 1 patient (10%) with pre-existing right bundle branch block developed complete AVB requiring the implantation of a single-chamber pacemaker with coronary sinus pacing. In the TRISCEND II study,13 17.4% of patients from the intervention group also required permanent pacing after implantation. This finding highlights the need for prolonged monitoring, as clear predictors of AVB development have not been identified. One patient from our series had severe mitral regurgitation after implantation, which resolved with levosimendan. This type of complication was not specifically reported in the TRISCEND II, suggesting that it may be a rare finding. Mitral regurgitation is a dynamic condition which depends on each patient’s hemodynamic status. The patient who presented it had moderate mitral regurgitation prior to the procedure. Patients with severe mitral regurgitation were excluded from the TRISCEND study.13

Comprehensive assessment of right ventricular function prior to implantation is essential. In our series, 2 patients (20%) presented transient right ventricular failure, which resolved with optimal medical therapy. Acute right ventricular failure is not specifically mentioned in the TRISCEND II trial,13 which excluded patients with pre-existing severe right ventricular failure and severe pulmonary hypertension.

Another relevant aspect is antithrombotic treatment after valve implantation. In our series, 1 patient presented EVOQUE valve thrombosis on the control CT performed 1 month after the procedure; no thrombus was visualized on the pre-discharge echocardiography, and the transprosthetic gradient was normal (2 mmHg). This patient was discharged on rivaroxaban 20 mg, which she was already on. The other patient with prosthetic valve thrombosis was on acenocoumarol due to a mechanical heart valve, with an INR (International Normalized Ratio) between 2.5 and 3.5. In the 2 cases, anticoagulation therapy with low molecular weight heparin was prescribed. In the first case, thrombosis persisted on the transesophageal echocardiography performed 1 week later; the second case is still pending follow-up echocardiography. Of note, the TRISCEND II study13 recommended anticoagulation with warfarin (INR, 2.5-3.5) or a different anticoagulant, and antiplatelet therapy with acetylsalicylic acid for 6 months. In our center, the protocol requires maintaining only the patient’s pre-existing anticoagulation (all of whom had an indication for chronic anticoagulation), without antiplatelet therapy. The only patient without baseline anticoagulation received acetylsalicylic acid. On the other hand, in our center, the 2 cases of prosthetic valve thrombosis were diagnosed by CT, which was not performed following the TRISCEND II study protocol criteria13, meaning subclinical thrombosis could not be ruled out. Whether this has any relevance at the follow-up in terms of early valve degeneration is something that will have to be studied in the future. It is considered necessary to perform a CT in these patients undergoing novel transcatheter treatments to anatomically assess the results more accurately and rule out any complications that may go unnoticed with other imaging modalities.

The trade-off of antithrombotic treatment is an increased risk of bleeding. The TRISCEND II study13 reported a rate of major bleeding of 15.4% in the intervention group; in our series, it was 10%, as only 1 patient exhibited overt hematuria requiring transfusion, who was on acenocoumarol without antiplatelet therapy. Although the rate of major bleeding was slightly lower in our series than in the TRISCEND II study,13 we did have 1 case of prosthetic valve thrombosis. Therefore, more evidence is needed to make solid recommendations on the antithrombotic regimen that optimizes the risk/benefit ratio.

Hemodynamic result after valve implantation was optimal in terms of TR reduction. In our series, the maximum transprosthetic gradient was 4.8 mmHg, which is consistent with the low values reported in the TRISCEND II,13 indicating adequate hemodynamic valvular function in the 2 cohorts, which supports the ability of the EVOQUE valve to provide efficient valvular performance with low flow resistance. Of note, in the case of prosthetic valve thrombosis diagnosed by CT, the transtricuspid gradient by echocardiography was 2 mmHg, which highlights the utility of CT in these patients’ initial follow-up, as subclinical thrombosis could otherwise go unnoticed.

The TRISCEND II trial13 observed a reduction in hospital readmission rates and an improvement in clinical parameters. Although quality of life was not directly measured in our series, the significant reduction in TR suggests a relevant clinical benefit that could be reflected in future follow-ups.

CONCLUSIONS

EVOQUE valve implantation is effective in reducing TR and offers an acceptable safety profile in patients with severe TR. Careful patient selection and close monitoring are essential, particularly in those with pre-existing cardiac rhythm disturbances or compromised right ventricular function. Further real-world studies are needed to confirm the long-term safety and efficacy profile of this valve.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

This work has been approved by >Hospital Ramón y Cajal Ethics Committee. Informed consent was obtained from all the patients. Possible sex and gender variables have been taken into consideration in full compliance with the SAGER guidelines.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

Artificial intelligence was not used.

AUTHORS’ CONTRIBUTIONS

A. Sánchez-Recalde conceived and designed this work and supervised the drafting of the manuscript. A. Pardo Sanz was responsible for manuscript drafting, data management, and image design. A. González and A. García were involved in the study of patients and clinical outcomes, and manuscript revision. L.M. Domínguez and J. Alfredo Salinas assisted with image and table design. L. Salido collaborated drafting and revising the manuscript. C. Fernández-Golfín and J.L. Zamorano were responsible for supervising the entire process and final version of the article.

CONFLICTS OF INTEREST

None declared.

REFERENCES

INTRODUCTION

Assessment and treatment of intermediate coronary lesions (those where percent diameter stenosis accounts for 30%-90% of the vessel lumen) remains a clinical challenge.1 Over the past 10 years this field has undergone significant changes, primarily due to theoretical and technological advances in physiological evaluation techniques.2,3

Prior to the existence of these techniques, the assessment of intermediate lesions was based on the degree of relative narrowing of the vessel lumen vs healthy segments, being this reduction subjectively determined by the operator, without knowledge of its physiological repercussion.2 The development of pressure guidewire methods, along with their validation and proven prognostic significance (particularly in the context of chronic coronary syndrome) from the late 1990s to the early 2000s,4 has led to substantial progress in intermediate lesions evaluation, which has enabled a more accurate classification based on their clinical relevance.5

The initial method developed, and still considered the gold standard, is fractional flow reserve (FFR).5 This technique estimates blood flow across a coronary lesion by measuring pressure differences.6 To make this estimation between pressure and flow, maximal coronary vessel hyperemia, primarily achieved through adenosine infusion, is necessary.6 FFR is defined as significant if flow difference across the lesion is > 20% (FFR ≤ 0.80).6 Beyond merely identifying which lesions benefit from revascularization, FFR has shown improved survival vs revascularization based on relative narrowing assessment. Furthermore, it has allowed lesion exclusion where revascularization is deemed unnecessary, thus reducing stent implantation rates and any potential complications associated with both this procedure and antiplatelet therapy.7

Despite the clear benefits of using intracoronary physiology, the need for invasive pressure guidewires, IV adenosine (with its potential complications), the time required, and even the outright rejection by interventional cardiologist may have led to a lower than expected adoption.8 These limitations triggered the appearance of non-adenosine-based methods, such as quantitative flow ratio (QFR) or resting full-cycle ratio, appeared.9,10 This methods use a specific moment of the cardiac cycle (for example the instantaneous wave-free ratio uses the diastolic free-wave period) where microvascular resistances are minimal, allowing correlation between pressures and flow without the use of adenosine.11,12 However, despite eliminating this limitation, the use of pressure guidewires is still a barrier.8

Simultaneously with the development of these adenosine-free techniques, angiography-derived physiological assessment techniques (ADPAT) emerged, enabling the physiological evaluation of coronary lesions without the need for a guidewire or adenosine. These techniques, initially derived from those used in coronary lesion assessment in computational tomography,13 are based on the computational evaluation of lesions through fluid dynamics in coronary angiography. Since then, multiple options have emerged including QFR, ultrasonic flow ratio (uFR), vessel fractional flow reserve (vFRR), fractional flow reserve derived from routine coronary angiography (FFRangio) and coronary angiography-derived fractional flow reserve (CaFFR). All of them have been validated and compared with the gold standard FFR in prospective direct comparative studies of diagnostic accuracy.14-20

The aim of this article was to provide a review of the different validation studies of ADPAT vs FFR and offer a meta-analysis on the accuracy of each option, both collectively and individually.

METHODS

Literature search strategy

We conducted a systematic review of comparative research on FFR and ADPAT from January through February 2024. The PubMed database was used to search for articles on concordance, agreement, and diagnostic accuracy. Multiple searches were conducted using the following algorithm: FFR/FFR permuted with each mainly commercialized tool (QFR, uFR, vFRR, FFRangio and CaFFR) while trying to avoid CT and articles developed mainly in acute coronary syndrome through the commands “NOT (CT) NOT (“acute coronary syndrome”)”. Date range was limited from January 2012 through December 2023. PRISMA statement guidelines were followed, and the review was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) with registration No. CRD420251042828.

Eligible criteria

A total of 4580 terms were identified through the entire search process. These terms and their combinations were carefully selected by 2 different operators to refine the search for articles comparing the main ADPAT from the main commercial vs FFR. Articles involving coronary computed tomography angiography and those where comparisons were mainly drawn within the context of acute coronary syndrome were also excluded by the operators. Based on these criteria, an initial pool of studies was established.

A total of 15 studies were subsequently excluded based on prespecified criteria, including those that specified the presence of patients with concurrent or treated aortic stenosis, had more than 25% of patients diagnosed with atrial fibrillation, or involved angiography- derived physiological assessments for coronary lesions conducted within the first 29 days of acute myocardial infarction (either on the culprit lesion or non-culprit lesions).

In cases where the time elapsed from myocardial infarction to angiography-derived evaluation was nonspecific; articles were also excluded if more than 30% of patients had undergone coronary angiography due to acute myocardial infarction.

Furthermore, studies specifying the presence of 10% or more patients with prior surgical revascularization were excluded, as were those where the comparison between angiography-based physiological assessment methods and FFR was conducted on mammary artery grafts, radial artery grafts, or saphenous vein grafts.

After applying the selection criteria, a total of 29 articles were initially chosen for analysis. However, 2 articles (FAST [virtual FFR])21 and Ai et al.22 were subsequently excluded because they did not provide or calculate sensitivity and specificity data from their analyses. Consequently, the final analysis included 27 articles.

Two articles were divided and included as different items in the analysis as they showed 2 different analyzed cohorts on their studies: Smit et al.,23 where QFR was compared with the FFR in 2 cohorts: 1 with diabetes mellitus and the other without the disease; Zuo et al.24 divided patients in 2 cohorts based on whether the vessel was severely calcified or not. The uFR was compared with the FFR in each group. Each cohort was included in our analysis. Finally, the study by Emori et al.25 “Diagnostic accuracy of quantitative flow ratio for assessing myocardial ischemia in prior myocardial infarction,” presented 2 distinct cohorts based on the presence of prior myocardial infarction (≥ 30 days from coronary angiography). Although one cohort depicted an acute coronary syndrome scenario, it fulfilled our inclusion criteria, leading to the inclusion of both cohorts in the final analysis.

Statistical and methodologic analysis

The homogeneity across studies was contrasted using the QH statistic. Regarding the low sensitivity of this test, P < .10 values were considered significant. To overcome this limitation, the I2 statistic was estimated as well, which measures the proportion of the total variation of the studies, explained by the heterogeneity and its 95% confidence interval (95%CI). A random effects model was used for all cases using the pooled method of DerSimonian Laird. If heterogeneity was present, meta-regression analyses were conducted to explore the sources of heterogeneity (figure 1 of the supplementary data). The presence of publication bias was tested using the Deek funnelplot (figure 2 of the supplementary data).

Figure 1. Selected articles flowchart and exclusion criteria. ADPAT, angiography-derived physiological assessment techniques; AMI, acute myocardial infarction.

Figure 2. Summary receiver operating characteristic (SROC) curves and Q* index for subgroup analyses of software-derived coronary angiography-derived fractional flow reserve (caFFR); FFR, fractional flow reserve; QFR, quantitative flow ratio; uFR, ultrasonic flow ratio; VFAI, vessel fractional anatomy index; vFFR, vessel fractional flow reserve.

From the reported values of sensitivity, specificity, negative predictive value, positive predictive value, accuracy, and the number of vessels assessed, all 2 × 2 tables for the 0.8 cutoff point of the tests were constructed. Subsequently, pooled estimates for sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio were derived from these data.26

The confidence intervals of sensitivity and specificity were calculated using the F distribution method to compute the exact confidence limits for the binomial proportion (x/n). The summary receive operator curve (SROC) was also calculated from which we drew all the points of sensitivity and 1-specificity and adjusted the weighted regression curve using Moses’ Model. Spearman correlation coefficient between sensitivity and specificity was used to assessed constant diagnostic odds ratio (positive likelihood ratio and negative likelihood ratio) employing a symmetric SROC.27 The area under curve (AUC) was computed by numeric integration of the curve equation using the trapezoidal method. Additionally, we applied the bootstrap methods for estimated AUC of multiple SROC. We provided the resultant bootstrap P values and 95%CI of the AUC for pairwise comparisons of the different methods (table 1 of the supplementary data). Furthermore, we provided an influence diagnostic method based on the AUC by performing leave-one-study-out analyses (table 2 of the supplementary data). Pearson correlation coefficients were transformed into Fisher’s z-values to calculate variance and we performed a meta-analysis and calculated the 95%CI (figure 3 of the supplementary data). Fagan’s Nomogram (figure 4 of the supplementary data) was used to graphically estimate how the result from a diagnostic test altered the probability of a patient having a disease. We assessed applicability and risk of bias based on the modified version of the QUADAS-2 tool28 (figure 5A,B of the supplementary data). All analyses were conducted using R Statistical Software (v4.2.0; R Core Team 2022) and performed using dmetatools R package (1.1.1; Noma H 2023), mada R package (0.5.11; Sousa-Pinto 2022) and TeachingDemos R package (2.13; Greg Snow 2024).

Table 1. Patients’ baseline characteristics

Table 2. Indications for cardiac catheterization

Figure 3. Forest plots and summary statistics for sensitivity and specificity estimates from a meta-analysis of FFR across different indices, using a random-effects model. 95%CI, 95% confidence interval; caFFR, coronary angiography–derived fractional flow reserve; FFR, fractional flow reserve; QFR, quantitative flow ratio; uFR, ultrasonic flow ratio; VFAI, vessel fractional anatomy index; vFFR, vessel fractional flow reserve. Xu et al.,16 2017; Fearon et al.,36 2019; Yuasa et al.,33 2023; Morris et al.,39 2013; Westra et al.,29 2018; Echavarría-Pinto et al.,31 2022; Stähli et al.,34 2019; Omori et al.,35 2019; Westra et al.,17 2018; Li et al.,18 2020; Pellicano et al.,14 2017; Emori et al.,25 2018; Tu et al.,15 2014; Zuo et al.,24 2024; Tu et al.,19 2021; Omori et al.,42 2023; Hrakesh et al.,32 2020; Kornowski et al.,37 2016; Masdjedi et al.,20 2022; Tröbs et al.,38 2016; Yazaki et al.,30 2017; Smit et al.23 2019; Daemen et al.,43 2022; and Papafaklis et al.,41 2014.

Figure 4. Forest plots and summary statistics for positive predictive value (PPV) and negative predictive value (NPV) estimates from a meta-analysis of FFR across different indices, using a random-effects model. 95%CI, 95% confidence interval; caFFR, coronary angiography–derived fractional flow reserve; FFR, fractional flow reserve; QFR, quantitative flow ratio; uFR, ultrasonic flow ratio; VFAI, vessel fractional anatomy index; vFFR, vessel fractional flow reserve. Xu et al.,16 2017; Fearon et al.,36 2019; Yuasa et al.,33 2023; Morris et al.,39 2013; Westra et al.,29 2018; Echavarría-Pinto et al.,31 2022; Stähli et al.,34 2019; Omori et al.,35 2019; Westra et al.,17 2018; Li et al.,18 2020; Pellicano et al.,14 2017; Emori et al.,25 2018; Tu et al.,15 2014; Zuo et al.,24 2024; Tu et al.,19 2021; Omori et al.,42 2023; Hrakesh et al.,32 2020; Kornowski et al.,37 2016; Masdjedi et al.,20 2022; Tröbs et al.,38 2016; Yazaki et al.,30 2017; Smit et al.,23 2019; Daemen et al.,43 2022; and Papafaklis et al.,41 2014.

RESULTS

Finally, a total of 27 articles were suitable for inclusion, as illustrated in figure 1. From these articles, a total of 4818 patients and 5440 vessels were added to the analysis. The population characteristics and mean cardiovascular risk factors are detailed in table 1 highlighting the existence of 3189 (66.18%) patients with hypertension, 2438 (50.6%) with dyslipidemia, and 1263 (26.2%) with diabetes. Notably, most patients included in the study were men (68.86% of the sample).

Thirteen of the selected articles were prospective in design. The most extensively studied vessel was the left anterior descending coronary artery (2921; 53.69%), followed by the right coronary artery (1075; 19.61%) and the left circumflex artery (772; 14.2%). Additionally, 89 left main coronary arteries were analyzed, accounting for 1.6% of all vessels. Angiography was primarily performed for stable angina (2483; 51.53%). Of note, while 1475 (30.61%) angiographies were prompted by acute coronary syndrome, only 333 (6.9% of the total) were performed in the context of acute myocardial infarction with or without ST-segment elevation, and the remaining 1142 in the context of unstable angina. Indications for cardiac catheterization are shown in table 2. The left anterior descending coronary artery was the most frequently studied vessel, accounting for 2921 patients (53.7% of the total studies). Proportions for other vessels are available in table 3.

Table 3. Number of studies per vessel performed across the different studies

The QFR15-17,23,25,29-34 (QAngio XA 3D QFR, Medis Medical Imaging System; The Netherlands) was the most widely used software with a total of 13 patient cohorts from 11 articles, comprising 1987 patients and 2315 vessels, which accounts for 41.2% and 42.6% of the total, respectively. The correlation between QFR and FFR was excellent, showing an r = 0.82 (95%CI, 0.77-0.877). The overall sensitivity rate of QFR was 84% (95%CI, 80-88) with a specificity rate of 90% (95%CI, 87-93). The positive predictive value was 81% (95%CI, 77-84) with a total negative predictive value of 92% (95%CI, 90-94). The AUC for this technique was 0.937.

The second most analyzed technique, with a total of 5 articles, was FFRangio14,35-38 (Cathworks FFRangio, Israel), where this technology was employed in 696 patients and 841 vessels (14.4% and 15.45% of the total, respectively). The overall sensitivity rate of FFRangio was 90% (95%CI, 83-94) with a specificity rate of 95% (95%CI, 91-97). The positive predictive value was 90% (95%CI, 85-93) with a total negative predictive value of 94% (95%CI, 91-96).

vFFR (Pie Medical Imaging, The Netherlands) on the other hand, had an excellent correlation with FFR across the 3 included studies,20,39,40 contributing 647 patients and 663 vessels to the analysis (representing 13.42% of patients and 11.96% of vessels). The mean sensitivity and specificity rates were 82% (95%CI, 72-89) and 0.94% (95%CI, 89-97), respectively. The summary positive predictive value was 89% (95%CI, 82-93), and the summary negative predictive value, 91% (95%CI, 86-94).

Following its recent validation in 2022, the uFR (AngioPlus, Pulse Medical Imaging Technology, China) is supported by only 2 articles,19,24 one of which includes 2 cohorts based on vessel calcification. The uFR had a sensitivity rate of 80% (95%CI, 69-87) and a specificity rate of 0.94 (95%CI, 89-97). The summary positive predictive value was 85% (95%CI, 79-90), and the summary negative predictive value, 91% (95%CI, 87-94).

Only 1 article of CaFFR (Flashangio, Rainmed Ltd., China) was included.18

The analysis included 2 non-commercialized tools, VFAI41 and AngioFFR,42 which were not individually evaluated. Both were compared to FFR only once.

Overall, a strong correlation between the different ADPAT and FFR was observed (r = 0.83, 95%CI, 0.80-0.85), with a mean ADPAT value of 0.82 (95%CI, 0.81-0.83) (all the ADPAT set a value ≤ 0.80 for lesion significance) and a mean FFR of 0.83 (95%CI, 0.82-0.85).

The summary AUC for predicting significant FFR (≤ 0.80) was excellent at 0.947. The SROC for the different ADPAT is shown in figure 2.

The overall sensitivity rate was 85% (95%CI, 81-87) with a specificity rate of 93% (95%CI, 91-94). The positive predictive value was 86% (95%CI, 83-88) with a total negative predictive value of 92% (95%CI, 91-94). The main commercially available ADPAT values of sensibility, specificity, positive predictive value and negative predictive value are shown in figure 3 and figure 4.

DISCUSSION

Key findings

Our key findings were: a) ADPAT emerge as a reliable and practical method for assessing the physiological significance of intermediate coronary lesions, which is consistent with previous literature.44-46 ADPAT consistently demonstrates agreement with the current gold standard (FFR) regarding mean values and lesion classification, without vasodilator medication or pressure guidance; b) By summarizing the diagnostic capabilities of each ADPAT from the included studies, we were able to perform the first direct comparison of various angiography-based methods for evaluating coronary lesions. We presented the main commercially available options and their respective diagnostic accuracies relative to FFR. Additionally, an overview of these techniques was provided; c) We also included innovative methods, such as uFR, based on Murray’s Law, while offering a unique approach by using a single projection to estimate lesion significance, potentially overcoming a significant limitation of current techniques, which often require specific projections and a certain quality image.

The overall results confirmed that different ADPAT serve as an appropriate method for evaluating intermediate coronary lesions, as they demonstrated a strong correlation with FFR. This correlation extended to sensitivity, specificity, and predictive values as illustrated in figure 4. Notably, the studies exhibited homogeneity without significant discrepancies in their weighting within the analysis, as observed through the resampling techniques employed.

In comparative analysis, while ADPAT exhibit adequate sensitivity and positive predictive values regarding lesion significance, their specificity and negative predictive value exceed 90%. This high specificity allows ADPAT to more accurately identify physiologically non-significant lesions, thereby avoiding unnecessary revascularization.

From a technical standpoint, it was notable that these results were primarily obtained from assessments of the left anterior descending coronary artery (53.6%), with only 1 dedicated study on the left main coronary artery. Despite this, left main coronary arteries contributed a significant proportion (1.66%) to the overall analysis, showcasing proficient classification of significant lesions (AUC = 0.82) and indicating the feasibility of applying tools in this context.

QFR was the most frequently included tool in the analysis, representing 13 out of 27 cohorts. Despite multiple validations vs the FFR in diverse contexts, most studies align closely, demonstrating a correlation between QFR and FFR.

Comparing results across different tools, minimal differences were observed, with FFRangio and CaFFR showing slightly superior overall results vs other methods. However, it’s important to note that the results of the CaFFR are based solely on validation articles, and when considering only validation studies, results among tools are very similar.

Although QFR is frequently studied, its results might require more robust validation because there are limited articles on FFRangio, especially on chronic coronary syndrome in patient groups like those with left main disease or diabetes.

While ADPAT have been validated vs the FFR in various clinical scenarios, such as severe aortic stenosis, atrial fibrillation, or non-culprit coronary lesions in acute coronary syndrome, the inclusion of these scenarios in our analysis could potentially bias the results due to variations in study characteristics and the unique features of each disease affecting lesion assessment.

The limitation of this study stems from including a large proportion of pivotal studies for each analyzed tool, which were not performed under real-world clinical conditions. Consequently, the applicability of their results may be restricted, as demonstrated by a recent study from independent laboratories comparing the 5 main non-hyperemic indices with FFR under real-life conditions.47

Although the study demonstrated a good correlation between the indices and FFR, the levels of diagnostic accuracy reported in the pivotal studies were not achieved.

In this regard, QFR has been recently evaluated vs the FFR in the FAVOR III Europe trial,1 which included 2000 patients who were randomized (1:1) to QFR-guided or FFR-guided treatment of intermediate lesions. The results showed that the QFR-guided group had higher rates of mortality, myocardial infarction, and unplanned revascularization at 12 months.

Although these findings may initially seem discouraging, they do not contradict the results of our study, in which non-hyperemic indices demonstrated superior performance over conventional angiography in the functional classification of lesions. Therefore, their use remains valuable in clinical scenarios where invasive assessment with a pressure guidewire or the use of adenosine is not feasible or contraindicated.

Of note, while QFR is currently the most widely used non-hyperemic index, it is the only one that has been evaluated in clinical trials with hard clinical endpoints vs FFR. Other tools with promising results are still to be investigated in this context.

CONCLUSIONS

Substantial correlations and concordances have been demonstrated between ADPAT and FFR. These techniques have also shown accurate categorization of lesions deemed significant by the current gold standard (FFR). However, the results of the FAVOR III Europe study1 indicate that QFR–guided revascularization, compared with FFR-guided revascularization, is associated with higher rates of mortality, myocardial infarction, and unplanned revascularization. Therefore, the current role of ADPAT requires re-evaluation.

In this context, the use of QFR may be most appropriate when invasive assessment using a pressure guidewire is not feasible or when adenosine is contraindicated. Additionally, due to the unique characteristics of other clinical scenarios, further reviews are warranted to evaluate the diagnostic accuracy of this index.

FUNDING

C. Cortés-Villar is beneficiary of a Contrato Río Hortega grant from Instituto de Salud Carlos III with code CM22/00168.

ETHICAL CONSIDERATIONS

The present study was conducted in full compliance with the clinical practice guidelines set forth in the Declaration of Helsinki for clinical research and was approved by the ethics committees of the reference hospital (Hospital Clínico Universitario de Valladolid) and other participant centers. Possible sex- and gender-related biases were also taken into consideration according to the SAGER recommendations.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence was used in the writing of this text.

AUTHORS’ CONTRIBUTIONS

J. Ruiz-Ruiz and C. Cortés-Villar participated in the study design, data analysis, manuscript drafting, and critical revision. C. Fernández-Cordón and M. García-Gómez contributed to data collection and results analysis. A. Lozano-Ibáñez and D. Carnicero-Martínez contributed to data gathering. S. Blasco-Turrión and M. Carrasco-Moraleja contributed to the statistical analysis. J.A. San Román-Calvar and I.J. Amat-Santos performed the final review and approved the version for publication.

CONFLICTS OF INTEREST

None declared.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

Coronary artery disease is the leading cause of mortality worldwide.1 Despite the safety involved in deferring invasive treatment in patients with stable coronary artery disease without functionally significant lesions,2 a percentage of patients experience cardiovascular events at the long-term follow-up.3 It has been reported that cardiovascular events not only depend on the degree of coronary obstruction assessed by intracoronary physiology4-5 but also on the global atherosclerotic burden and its vulnerability assessed by intracoronary imaging modalities.6-8

The new era of coronary physiology is based on predicting fractional flow reserve by reconstructing the coronary tree using angiography and computational fluid dynamics.9-10 Estimating quantitative flow ratio (QFR) is the most validated method of the ones currently available.

QFR—which predicts fractional flow reserve^10-11—has proven to be a better tool than angiography alone to guide the need for lesion revascularization12 and shown long-term prognostic value13. Furthermore, it provides quantitative information out of the 3D reconstruction of the coronary tree, including minimum diameter and area, reference diameters, luminal volume, and atherosclerotic plaque volume in the studied vessel. However, the prognostic value of this quantitative analysis has not been sufficiently studied.

The main aim of this study was to determine the prognostic value of global plaque volume (GPV) in patients with stable coronary artery disease without functionally significant lesions at a 5-year follow-up.

METHODS

We conducted a retrospective observational study on a cohort of patients from 6 tertiary referral centers.

Study population

Patients who underwent coronary angiography from January through December 2015 for suspected stable coronary artery disease were included. Each participant center retrospectively enrolled all patients who underwent coronary angiography for suspected stable coronary artery disease and met the inclusion criteria. Patients with chronic total coronary occlusions, prior coronary artery bypass graft surgery, or inadequate angiographic quality for analysis were excluded. Additionally, patients whose angiographic analysis revealed a positive QFR study (< 0.80) in any coronary territory were excluded. The principal investigator conducted a retrospective follow-up at each center within the next 5 years following the index procedure. Baseline and procedural characteristics, and events at the follow-up were collected by local investigators. The study fully complied the good clinical practice principles and regulations set forth in the Declaration of Helsinki for research with human subjects. The study protocol was approved by the ethics committee of the reference hospital (Hospital Clínico Universitario de Valladolid) and the institutional review boards, including informed consent obtained from participants or, alternatively, approval for retrospective data analysis under ethical committee supervision.

Angiographic analysis

A blinded angiographic analysis of diagnostic coronary angiograms was performed by trained analysts at a centralized imaging unit (Icicorelab, Valladolid) using specialized software (QAngio XA 3D QFR, Medis Medical Imaging System, The Netherlands). A 3D reconstruction of the 3 major coronary vessels was performed using 2 different projections with > 25° of separation. For the right and left circumflex coronary arteries, the proximal marker was manually placed at the vessel ostium, while for the left anterior descending coronary artery, it was placed at the left main coronary artery ostium. The distal marker was placed at the end of the coronary artery. Plaque volume was estimated by calculating the difference between the theoretical reference vessel volume in the absence of atherosclerotic disease and the estimated vessel volume in angiography using QFR software via quantitative analysis. Reference diameters, minimum diameter, and minimum area were obtained for each vessel. Considering contrast flow through the coronary tree, QFR was calculated according to FAVOR II standards for the physiological significance of coronary lesions. Patients with functionally significant disease (QFR < 0.80) were excluded.

Statistical analysis

Categorical variables are expressed as totals and percentages, and continuous ones as means and standard deviations. GPV was estimated as the sum of plaque volume across 3 coronary territories.

The primary endpoint—major adverse cardiovascular events (MACE)—was a composite of cardiac death, acute myocardial infarction, or all-cause unplanned hospital admission.

An optimal GPV cutoff as a predictor of MACE was determined using the receiver operating characteristic (ROC) curve as the value with the maximum Youden index. Multivariate logistic regression models were used to calculate the odds ratio and 95% confidence interval as independent predictors for MACE. Variables with P < .20 in the univariate analysis were included in the multivariate model as covariates.

Event-free survival was compared using Kaplan-Meier and Mantel-Haenszel analyses. All probability values were two-tailed, and P < .05 was considered statistically significant. Statistical analysis was performed using Stata (16.1, StataCorp, College Station, United States).

RESULTS

Descriptive population analysis

A total of 803 patients were evaluated for inclusion in the registry, 122 of whom (15.2%) were excluded due to chronic occlusions in ≥ 1 coronary territory, 17 (2.12%) due to previous surgical myocardial revascularization, and 159 (19.2%) due to inadequate angiographic analysis in, at least, 1 coronary territory. Among the remaining patients, 228 (45.1%) had significant coronary artery disease (QFR < 0.80) in, at least, 1 coronary territory, which left a final cohort of 277 patients. Patient flowchart is shown in figure 1.

Figure 1. Flowchart of the patient selection process for inclusion in the study. CABG, coronary artery bypass graft; CTO, chronic total coronary occlusion; QFR, quantitative flow ratio.

The mean age of the population was 65.8 years (most were hypertensive [74.4%] men [66.1%]). Table 1 illustrates the baseline characteristics of the population. The median follow-up was 69 months, during which time 5 patients were lost to follow-up.

Table 1. Baseline characteristics of the included population

Angiographic analysis

Mean plaque volume in the study population was 170.5 mm³ (± 16.5); mean QFR was 0.95. Table 2 illustrates the overall means from the angiographic analysis according to the coronary territory studied. Plaque volume was independently analyzed for each coronary territory and was significantly higher in the right (243 mm³) vs the left anterior descending (161.4 mm³) and left circumflex coronary arteries (172.9 mm³). Data on this analysis by coronary territories are shown in table 1 and figure 1 of the supplementary data.

Table 2. Characteristics of the angiographic analysis performed in the 3 coronary territories using quantitative flow ratio

Prognostic value of global plaque volume

The primary event (MACE) occurred in 116 patients, which amounts to 42.7% of the cohort at the follow-up. Among these patients, 11% died, 2.6% suffered an acute myocardial infarction, and 38.1% required unplanned hospitalization. Patients who developed MACE had a significantly higher GPV (231.6 vs 111.8 mm³; P < .001), as well as those with a higher mortality rate (255.2 mm³ vs 154.3 mm³; P = .04) or unplanned hospitalizations (235.0 mm³ vs 125.4 mm³; P < .001). However, there were no significant differences in patients who experienced acute myocardial infarction (235.1 mm³ vs 169.3 mm³; P = .51).

The optimal GPV cutoff to predict events was set at 44 mm³ based on ROC curve analysis (sensitivity, 64%; specificity, 65.8%; LR⁺, 1.9; LR^–, 0.6).

Table 3 illustrates the study of the main determinants of the primary event. Variables with a significance level of P < .10 were included in the multivariate analysis. In the final model, age and GPV were independent predictors. A GPV > 44 mm³ was associated with a 2.8-fold higher risk of events at the follow-up (figure 2).

Table 3. Uni- and multivariate analysis of determinants of the main event

Figure 2. Kaplan-Meier curve showing the patients’ event-free survival based on their global plaque volume.

DISCUSSION

The main finding of this study is that GPV quantification emerged as an independent prognostic factor in patients without functionally significant coronary artery disease, which demonstrated that those with a higher GPV experienced more events at the follow-up. The optimal GPV cutoff for event prediction was set at 44 mm³. This study emphasizes the importance of anatomically characterizing coronary arteries without significant lesions.

Despite the absence of significant coronary artery obstructions, some patients still experience events during follow-up.14 In patients with a negative QFR functional study, it has been reported that the 5-year rate of events—cardiac death, target vessel myocardial infarction—is 11.6%,3 similar to our findings, where mortality rate was 11% and acute myocardial infarction occurred in 2.6% of patients. Determining the difference between the actual vessel diameter and the estimated diameter obtained through 3D reconstruction from QFR-based angiography has been used in other studies.15 This estimation—previously derived from coronary computed tomography16-17—has demonstrated the prognostic significance of plaque volume differences between normal and non-obstructive coronary arteries. These differences have also been confirmed using invasive imaging modalities such as intravascular ultrasound.18 Although angiography-derived percent luminal stenosis shows poor concordance with myocardial ischemia,19 a greater degree of coronary stenosis (percent diameter stenosis > 50%) is associated with a higher event rate at the 2-year follow-up in patients without functionally significant coronary lesions.20 The present study takes a step further into the minimally invasive characterization of atherosclerotic burden using easy-to-implement 3D coronary tree reconstruction technology as an independent prognostic factor in patients without functionally significant coronary lesions. In this regard, this study is consistent with recent studies which demonstrated that subclinical atherosclerosis burden—measured by vascular ultrasound for carotid plaque quantification and computed tomography for coronary calcium scoring—in asymptomatic individuals is independently associated with all-cause mortality.21

Based on these findings, GPV measurement enables the identification of patients who, despite having no significant coronary lesions, are at risk of developing events within the next 5 years, allowing for intensified treatment and cardiovascular risk factor control. However, this study has limitations, including its retrospective design for patient inclusion and recruitment, the use of indirect methods—such as QFR—to estimate plaque volume, and the inability of this method to describe plaque characteristics, or potential lipid plaque vulnerability. Of note, the estimated plaque volume in each coronary artery was not specifically correlated with events in that territory but rather with overall adverse cardiovascular events. Therefore, further studies are needed to confirm or refute this hypothesis.

CONCLUSIONS

Plaque volume, calculated by 3D coronary tree reconstruction, is an independent predictor of events in patients with suspected stable ischemic heart disease without significant coronary artery disease. The optimal GPV cutoff for event prediction is 44 mm³.

FUNDING

C. Cortés received funding through the Río Hortega contract CM22/00168 and Miguel Servet CP24/00128 from Instituto de Salud Carlos III (Madrid, Spain).

ETHICAL CONSIDERATIONS

The present study was conducted in full compliance with clinical practice guidelines set forth in the Declaration of Helsinki for clinical research and was approved by the ethics committees of the reference hospital (Hospital Clínico Universitario de Valladolid) and other participant centers. Possible sex- and gender-related biases were also considered.

DECLARATION ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence was used in the writing of this text.

AUTHORS’ CONTRIBUTIONS

C. Cortés and J. Ruiz-Ruiz participated in study design, data analysis, manuscript drafting, and critical review. C. Fernández and M. García participated in data collection and result analysis. F. Rivero and R. López-Palop assisted in data collection. S. Blasco and A. Freites contributed to statistical analysis. L. Scorpiglione and M. Rosario Ortas Nadal collaborated in data interpretation. O. Jiménez participated in manuscript preparation and initial review. J.A. San Román Calvar and I.J. Amat-Santos conducted the final review and approved the version for publication.

CONFLICTS OF INTEREST

None declared.

SUPPLEMENTARY DATA

REFERENCES