Optical coherence tomography for the diagnosis and management of stent thrombosis

INTRODUCTION

Acute myocardial infarction (AMI) is a medical emergency that requires a rapid response to minimize cardiac damage and improve patient survival. Initial recognition and early treatment based on the optimal reperfusion strategy are key to survival; however, implementing this protocol in rural and mountainous regions is a major challenge.1-4

Primary percutaneous coronary intervention (pPCI) is recommended in all cases provided it can be performed within 120 minutes (ideally in less than 90 minutes).4 If not contraindicated, fibrinolysis is the treatment of choice when this time frame cannot be guaranteed. Contraindications to fibrinolytic therapy may be classified as absolute or relative and should be evaluated on an individual basis. When fibrinolysis is contraindicated, primary angioplasty should be prioritized whenever feasible.1,4 The STEMI code in Catalonia was implemented as a regional health care network in June 2009 designed to organize the management of patients with suspected ST-segment elevation myocardial infarction (STEMI).5,6

Several authors have linked delays in reperfusion treatment to the type of infarction, the timing of symptom onset, and complications.7-9 Other studies suggest that a distance > 50 km to a PCI- capable center is associated with higher mortality rates vs early fibrinolysis.10,11 Other experiences, such as sharing patient data during prehospital care, including electrocardiograms (ECG) and the use of nighttime helicopter transfer to the PCI-capable center have been associated with shorter diagnosis-to-treatment times; however, a reduction in mortality has not been demonstrated.12 However, few studies have analyzed the factors causing delays in mountainous and hard-to-access geographic areas.

The main aim of this study was to determine the factors associated with delays in reperfusion treatment and those associated with mortality in patients treated under the STEMI code in a European mountainous area.

METHODS

Study design

We conducted an observational, retrospective, and quantitative study that included all STEMI code activations in the Alt Pirineu-Aran territory (Catalonia, Spain) from January 2015 through December 2020. The main sources of information were the STEMI code registry of the Department of Health of the Government of Catalonia5,6 and the database of the medical Emergency Medical Services (EMS) of Catalonia, which were cross-referenced to obtain a comprehensive overview. Because the data were derived from preexisting registries and analyzed anonymously, informed consent was deemed unnecessary. The study was approved by the Instituto Universitario de Investigación en Atención Primaria (IDIAP) Jordi Gol Ethics Committee, code CEIm 22/238-P. The SAGER guidelines were followed regarding potential sex and gender bias.

Study setting

Alt Pirineu-Aran is a mountainous region comprising 6 counties and represents 18% of Catalonia’s territory, yet it is home to less than 1% of its population. Population density is extremely low (12.6 inhabitants per km²), and most towns are located between 500 and 800 meters above sea level, far from a specialized hospital center.

This regional health care system faces several challenges. Prehospital care is provided by the EMS, a public service that operates 24 hours per day and provides coverage throughout the entire territory. Each county is served by 1 advanced life support unit, and the region has access to 1 medicalized helicopter, 1 of the 4 operating in Catalonia. Alt Pirineu–Aran includes 4 county hospitals, all of which are non–PCI-capable centers (figure 1).

Figure 1. Alt Pirineu-Aran Health Region. H03: Tremp medicalized helicopter. H: county hospitals. Unit call signs are identified with A for Alt Pirineu; 1st number indicates the type of unit (7, basic life support; 4, advanced life support + nurse; and 6, advanced life support + physician); 2nd and 3rd numbers indicate the location of the units on the map.

Hospital Universitario Arnay de Vilanova (Lleida, Spain) serves as the reference center for pPCI for Alt Pirineu-Aran, with the exception of the Cerdanya basic health area, where STEMI code patients are transferred to centers in the Barcelona metropolitan area (table S1).

Definitions and inclusion criteria

The definitions of “delay” used in the study were more than 10 minutes for fibrinolysis administration and more than 120 minutes for pPCI, measured from the time of ECG acquisition. These criteria were established on the basis of former studies and are consistent with current European clinical practice guideline recommendations.1-4

According to EMS protocols, a 90-minute transfer threshold—from ECG acquisition to arrival at the receiving hospital—is used to allow adequate time to perform pPCI and ensure compliance with the 120-minute target. To determine whether patients had a transfer time of less than 90 minutes to a PCI-capable center, a geographic analysis based on distance and estimate travel-time maps was performed.

Patients were included if the STEMI code was activated in Alt Pirineu–Aran and they were attended by EMS during the study period, as well as those who died after prior activation of the STEMI code.

Incomplete cases or those with coding errors were excluded, as were patients transferred to Toulouse (France) from Vall d’Aran.

Study variables

The variables analyzed included demographic, clinical, and logistical data. The primary time intervals assessed were symptom onset to first medical contact, time from first medical contact to ECG, and ECG to initiation of reperfusion treatment. The type of reperfusion strategy (fibrinolysis or pPCI) was recorded as well. Other relevant variables included the location of STEMI code activation, distance to the PCI-capable center, mode of transport to the PCI-capable center (ambulance or helicopter), and type of transfer (primary: direct care and transfer by a medicalized EMS ambulance; secondary: interhospital transfer; or delayed primary: initial assessment by a primary care physician or nurse-staffed ambulance followed by transfer to a medicalized ambulance or medical helicopter). Acute-phase complications and all-cause mortality at first medical contact, and at 24 and 48 hours, and at 15 days were also recorded.

Statistical analysis

The descriptive statistical measures used were absolute and relative frequencies for qualitative variables; mean and standard deviation for quantitative variables with normal distribution; and median and interquartile range for the remaining non-normally distributed quantitative variables, according to the Shapiro-Wilk test.

We analyzed a total of 4 binary outcome variables: use of fibrinolysis as the initial treatment, delays in fibrinolysis (> 10 minutes from ECG acquisition), delays in pPCI (> 120 minutes from ECG acquisition), and mortality. Furthermore, we evaluated associations between each outcome variable and patient- and care-related characteristics using the chi-square test for qualitative variables (or Fisher’s exact test when expected frequencies were < 5), the Mann-Whitney U test for non-normally distributed quantitative variables, and the Student t test otherwise. In addition, we analyzed the importance of variables for treatment delay and mortality using the Boruta algorithm for variable selection. Only variables not rejected by this algorithm were selected for subsequent multivariable analyses to reduce the risk of overfitting. A conditional inference classification tree was constructing using a Monte Carlo test with a minimum terminal node size of 3.

All statistical analyses were performed using R statistical software (R Foundation for Statistical Computing, Austria). P values < .05 were considered statistically significant.

RESULTS

During the study period, a total of 24 125 STEMI codes were activated across Catalonia. The study analyzed 225 cases occurring in Alt Pirineu-Aran, representing less than 1% of the total. Four patients were excluded for not meeting STEMI code criteria (1 pulmonary thromboembolism, 2 coding errors, and 1 duplicate case) (figure 2).

Figure 2. Flow diagram of STEMI codes. AMI, acute myocardial infarction; pPCI, primary percutaneous coronary intervention; EMS, Emergency Medical Services of Catalonia.

The mean age of the 221 included patients was 64.7 years (range, 27–96). Of these, 72.4% were men and 67.4% resided in the study area. All STEMI codes were activated after ECG acquisition at first medical contact, either at a county hospital (51.6%), by EMS at the patient’s home or in a public setting (28.9%), or at a primary care center (19.5%). The median time from first medical contact to ECG acquisition was 6 minutes, and from pain onset to ECG acquisition, 90 minutes (table 1).

Table 1. Clinical characteristics and care times of activated STEMI codes and comparison according to therapeutic decision

The incident location had a mean altitude of 838 meters and was located at distances ranging from 81 km to 257 km from the PCI-capable center (median, 131 km). Overall, 76.5% of patients were situated more than 90 minutes from the PCI-capable center (median estimate transfer time, 106 minutes). Air advanced life support was used in 52.5% of the transfers (table 1).

Differences were observed in the time from ECG acquisition to pPCI according to mode of transport (Kruskal-Wallis; P < .001). The median time was 183 minutes for ground ambulance, 138 minutes for helicopter transport, and 140 minutes for combined transport (table 1). Pairwise comparisons using the Mann–Whitney U test showed significant differences compared with ground transport after adjustment for the false discovery rate.

We observed marked variability in the annual frequency of STEMI code cases, with a particularly high number in 2019, and in the proportion of first-assistance fibrinolysis performed from a minimum of 10.5% in 2020 to a maximum of 34.6% in 2017. The number of cases attended in 2020 (the year of the COVID-19 pandemic) was slightly higher than in 2015–2017 (38 cases [17.2%]) but lower than in 2019, which recorded 57 cases (25.8%) (table 1).

Delays in treatment

In 91.5% of patients in whom the therapeutic decision was to perform fibrinolysis at first medical contact, the time between ECG acquisition and treatment exceeded the recommended threshold (> 10 minutes).

When the therapeutic decision was to perform pPCI, the time between ECG acquisition and pPCI exceeded the recommended threshold (> 120 minutes) in 79.6% of cases (table 2).

Table 2. Factors associated with delay in reperfusion treatment

Among patients located more than 90 minutes from a PCI-capable center who did not receive fibrinolysis at first medical contact, the reason for withholding treatment was not documented in 87 cases (68.5%). Although 76.5% of patients were situated more than 90 minutes from the PCI-capable center, a substantial underuse of fibrinolytic treatment was observed. Of note, patients with a longer time interval from symptom onset to ECG acquisition were more likely to receive fibrinolytic treatment earlier.

Interhospital transfers, incidents without participation of air advanced life support, and nighttime incidents located more than 90 minutes from the PCI-capable center showed greater delays in performing pPCI. Exclusive use of ground ambulance for transfer to the PCI-capable center was associated with a 96.9% rate of delay and emerged as the primary variable in the classification tree for delay between ECG acquisition and pPCI. Among helicopter transfers, delays were more frequent in interhospital transfers (85.4%). In primary or delayed primary transfers, delays were more common when the incident location was more than 90 minutes from the PCI-capable center (65.1%) compared with locations less than 90 minutes away (23.1%) (figure 3).

Figure 3. Classification tree for delay in primary percutaneous coronary intervention (pPCI). Three factors were significantly associated with delay: mode of transport (ambulance [A], helicopter [H], or combined use), type of activation (primary [P], delayed [D], or interhospital [S]), and estimated road travel time from the event location to the PCI-capable center in minutes (> 90 minutes < 90 minutes).

Mortality

A total of 18 patients (8.1%) died within the first 15 days. Mortality was significantly higher in patients who experienced a major event (asystole, intubation, shock, or ventricular fibrillation) within the first 24 hours. Age was significantly associated with mortality only at the 48-hour and 15-day follow-up. There were no significant differences in 15-day mortality between patients treated with fibrinolysis and those directly transferred for pPCI. Increased mortality was associated with treatment delays, particularly in the early mortality subgroup (< 24 hours); however, these differences did not reach statistical significance (table 3).

Table 3. Factors associated with mortality according to time from clinical course prior to death

DISCUSSION

In our study, only 20.4% of patients who underwent pPCI received treatment within 120 minutes. Only 4 of the 47 patients treated with fibrinolysis received therapy within 10 minutes.

Several studies, such as the STREAM,13 have shown that prehospital fibrinolysis followed by early pPCI may offer results similar to direct transfer for pPCI if patients are treated within the first 3 hours from symptom onset. In our analysis, we identified underuse of fibrinolytic therapy, along with insufficient documentation of the reasons for withholding treatment.

In contrast to the studies by Stopyra et al.9,14 conducted in North Carolina (United States) in which 60.5% of patients underwent pPCI within ≤ 90 minutes, only 20.4% of patients in our study achieved reperfusion within a broader threshold (< 120 minutes). These findings underscore longer treatment delays in our region and support more frequent consideration of fibrinolytic therapy.

Although Aboal et al.10,11 reported higher mortality rates associated with delayed pPCI, we did not observe a significant association in our study, despite a substantial lower proportion of patients undergoing pPCI within the target time (20.4% vs 42%). In addition, fibrinolysis was more frequently used in patients located more than 50 km from the PCI-capable center (66.7%), reflecting structural and logistical constraints specific to the Alt Pirineu-Aran region that influence treatment selection and reperfusion times.

In line with former evidence regarding mortality, the study results reinforce the clinical importance of time to care as a potential factor associated with worse prognosis, which is particularly relevant in early mortality (< 24 hours).

Compared with the study by Carol et al.,15 in which 58% of patients underwent pPCI after more than 120 minutes, our data show a substantial higher proportion (79.6%). Factors associated with delay, such as intubation, initial shock, and nighttime care, were consistent between the 2 studies; however, other variables, including left bundle branch block, were not. A notable finding of our study is that the care delivered by the EMS was associated with shorter treatment times compared with county hospitals.

Patient origin, geographic location, sex, number of resources involved, time required for therapeutic decision-making, and mode of transport influenced treatment times as well. Hakim et al.16 suggest that helicopter transport is less effective than ground transport, especially for distances of less than 50 km. In our study, 71% of patients transferred by helicopter (all located more than 50 km from the PCI-capable center) received pPCI after more than 120 minutes, which may be associated with the lack of a helipad at the reference PCI-capable center, requiring additional ground transfer, and service hours, mainly daytime during the study period. In constrast to other studies conducted during the COVID-19 pandemic,17,18 our series did not demonstrate a reduction in case volume or prolongation in alert time. However, 2020 was the year with the lowest use of fibrinolysis (4 cases, 10.5%).

Several studies indicate that delays in STEMI recognition and code activation have a direct impact on reperfusion time. One study highlights that training significantly improves these times,19 suggesting that lack of training or skills among professionals may generate delays in care and lower use of fibrinolysis. Our study shows appropriate timing in ECG acquisition and emergency recognition by teams. Delayed primary transfers included the highest percentages of patients with optimal reperfusion times (table 2).

Our findings underscore the need to review and optimize action protocols, particularly in non-PCI-capable centers and geographic areas with greater delays. It is essential to optimize professional response to suspected STEMI, improve therapeutic decision-making time, and explore innovative solutions such as triage systems and STEMI code detection with technological support, optimization of air transport, and greater coordination between PCI and non-PCI capable centers.

Limitations and strengths

This study has limitations due to the small population size in the rural areas studied, which required extending the study period to 6 years to obtain the collected sample. This extension implies that data underwent several changes in record systems (from paper to digitized format) and organizational modifications (implementation of triage in emergency departments and nighttime helicopter flights). The sample of 221 patients remains limited and may have affected the statistical power to detect significant differences between analyzed variables. Similarly, distances from the incident location and estimated average travel times under optimal conditions were used, without accounting for any potential delays due to traffic or other unforeseen factors.

CONCLUSIONS

The results of this study demonstrate the need to increase the use of fibrinolysis in areas distant from a PCI-capable center to reduce reperfusion delays. Documentation of the reasons for not performing fibrinolysis should be improved, as this limits interpretation regarding therapeutic appropriateness. Joint initial care by primary care and emergency teams, as well as delayed primary transfers, reduce reperfusion times and avoid interhospital transfers. Finally, the low number of deaths during the study period prevents multivariate analysis and only allows identification of the variables or characteristics associated with mortality described in the results.

Despite these limitations, the study provides a comprehensive analysis of variables and describes in detail how the investigated population is managed and transferred, something unprecedented in this context. In addition, cross-referencing and thorough review of 2 databases provide valuable information to assess treatment delays. Therefore, this study is a solid basis for future advances in improving STEMI code management in rural areas.

FUNDING

This study was funded by the Provincial Council of Lleida through “The strength of municipalities” project and by IRBLleida through project PP10851 of the Alt Pirineu-Aran Intramural Research Program (IREP).

ETHICAL CONSIDERATIONS

This study was approved by the IDIAP Jordi Gol Ethics Committee, code CEIm 22/238-P. The SAGER guidelines were followed regarding potential sex and gender bias.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

ChatGPT was used to improve the wording of some paragraphs of the article. After using this tool, the authors reviewed and edited the content as necessary and take full responsibility for the final version.

AUTHORS’ CONTRIBUTIONS

M. Navarra Llorens was responsible for study conception and design, overall supervision, and manuscript drafting. M. Martínez Alonso conducted the statistical analysis, interpreted the results, and critically reviewed the content. Y. Azeli was responsible for clinical analysis and critical review. S. Ferrandis Barrés collected data and contributed to the discussion and critical review. M. Canelles Seix collected data and reviewed the manuscript. L. Duch Grau participated in data collection, manuscript review, and final approval. A.M. Forradelles Rey collected data and performed critical review. M.A. Martínez Momblan supervised the project and critically reviewed the manuscript. X. Jiménez-Fàbrega supervised the project and provided intellectual contributions to the discussion. All authors approved the final text.

CONFLICTS OF INTEREST

None declared.

ACKNOWLEDGMENTS

We thank Mar Franch Casanovas and Francisco Iturbe Recasens for their collaboration in data collection, and Isidre Felip for his advice in drafting the manuscript.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

Coronary artery disease (CAD) is a significant national and global public health concern. In 2021, more than 254 million cases of CAD were diagnosed worldwide, with an incidence rate of 403.89 new cases per 100,000 people and a mortality rate of 113.94 deaths per 100,000. In Egypt, CAD is the most prevalent cardiovascular disease among men and women, with an overall prevalence of 4.27%.1 Key risk factors for CAD include smoking, gender, diabetes, hypertension, and dyslipidemia, with men experiencing a 2-fold higher rate than women.2 Computed tomography is the standard diagnostic imaging modality for stable CAD, while high sensitivity C-reactive protein is recommended for predicting stable CAD. Although regional wall motion abnormality (RWMA) is the gold standard echocardiographic marker for stable CAD, it is not effective in detecting subclinical myocardial damage.3

Two-dimensional (2D) speckle tracking echocardiography (STE) strain analysis measures myocardial deformation providing a more reliable evaluation of myocardial mechanics and addressing the limitation of RWMA in identifying subtle myocardial damage.4 Real-world evidence suggests that global (GLS) and regional longitudinal strain (RLS) offer better diagnostic accuracy and reproducibility in detecting stable CAD.5-7 GLS assesses ventricular shortening from base to apex to estimate overall strain in the left ventricle (LV), whereas RLS focuses on strain in specific LV segments. Other strain analysis methods include global radial strain (GRS), global circumferential strain (GCS), territorial longitudinal strain (TLS), regional radial strain (RRS), and regional circumferential strain (RCS), each measuring different aspects of myocardial strain.8 Our study aimed to evaluate the predictive role of TLS in stable CAD for identifying significant coronary artery lesions with ≥ 70% diameter stenosis.

METHODS

Study design

We conducted a 24-month cross-sectional, open-label, single-cohort, single-center study was at the cath lab of a tertiary care teaching hospital. Investigators were not blinded to the study group. Prior to conducting the study, its design and protocol were reviewed, approved, and registered with Ain Shams University Hospital Human Ethics Committee on 1 July 2021 under trial registration No. Md 110/2021.

Written informed consents was obtained from all human research subjects and study participants. Participant privacy rights were strictly protected, data were anonymized, and study procedures were conducted in accordance with the Egyptian National Commission for Bioethics statement on ethical conduct in human research. Furthermore, the study adhered to the SAGER guidelines to address potential sex- and gender-related bias.

Study participants

Patients with typical or atypical anginal chest pain evaluated at the outpatient clinic and cath lab of a single tertiary care center between August 2021 and August 2023 were included in the study. Patients with acute coronary syndrome, myocardial infarction, non-sinus rhythm, normal coronary angiography (CAG), prior percutaneous coronary intervention or coronary artery bypass grafting, inadequate echocardiographic window, or valvular or myocardial disease were excluded.

Study procedures

A total of 738 patients were enrolled and undewent history taking and data collection for gender, age, diabetes mellitus, hypertension, smoking, dyslipidemia, chronic kidney disease, peripheral arterial disease, stroke, sedentary lifestyle, myocardial infarction, and family history of CAD. Furthermore, patients undewent blood pressure measurements and comprehensive cardiac examination, including assessment for abnormal auscultatory findings, prior cardiac surgery, cardiomegaly, and heart failure. Moreover, all patients underwent 12-lead electrocardiogram, 2D echocardiography and 2D STE using an IE 33 ultrasound system (Philips, The Netherlands) with an X5-1 phased-array transducer; CAG with digital image acquisition and storage, complete blood count; lipid profile; liver and kidney function tests; coagulation studies (prothrombin time, activated partial thromboplastin time, and international normalized ratio); and serial cardiac enzyme measurements. The 2D echocardiography was conducted before the CAG and the 2D STE after the CAG. The cardiologists performing 2D echocardiography and 2D STE were specialized in echocardiography, held level III competency according to the European Society of Cardiology Core Curriculum, and were blinded to the coronary angiographic data.9 Furthermore, the interventional cardiologists, who analyzed the CAGs were blinded to the results of the echocardiographic evaluation. Data documented with CAG included the severity of coronary artery stenosis according to the Coronary Artery Disease-Reporting and Data System and the regional distribution of the area supplied with the epicardial coronary artery according to the 17 LV segment model. A coronary lesion of ≥ 70% diameter stenosis was considered significant, and such patients were classified as having severe stable CAD.10 A consecutive sample of 199 eligible participants with severe stable CAD was selected, assigned, and allocated to a single group (figure 1). Operators performing 2D echocardiography and 2D STE were blinded to the coronary angiographic data. Data documented with 2D echocardiography and 2D STE included RWMA, wall motion score index (WMSI), and strain analysis. RWMA was categorized into normal with an assigned score of 1, hypokinetic with an assigned score of 2, akinetic with an assigned score of 3, and dyskinetic with an assigned score of 4. The WMSI represents the average RWMA of the 17 analyzed segments in a 17 LV segment model.11 Myocardial function by strain imaging was evaluated on a frame-by-frame basis by automatic tracking of acoustic markers (speckles) throughout the cardiac cycle in a 17 LV segment model, and GLS was obtained by averaging the myocardial function of all 17 segments. The endocardial borders were traced in the end-systolic frame of the 2D images from the 3 apical views for analyses of longitudinal strains. RCS analysis was obtained from the 3 parasternal short-axis views. RRS analysis from the 3 apical views was conducted manually by tracking the average peak systolic radial excursion for each segment between 2 points (endocardial and epicardial) of 3 levels for each of the 17 segments. Peak systolic strains were obtained for 17 longitudinal, 17 radial, and 16 circumferential LV segments. All segmental values were averaged to GLS and GCS for each study participant and automatically displayed in a bull’s-eye plot. TLS measured the number of impaired territories based on the cutoff results of the RLS analysis from the segments supplied with the corresponding coronary arteries in a 17 segment LV model as follows: 7 segments for the left anterior descending coronary artery (LAD), 5 for the right coronary artery (RCA), and 5 for the left circumflex artery (LCx).12

Figure 1. Flow chart of stable coronary artery disease cohort selection. CAG, coronary angiography; STE, speckle tracking echocardiography.

Endpoints

The endpoint of the study was the predictive role of TLS in stable CAD for identifying the location and severity of significant coronary artery lesion with ≥ 70% diameter stenosis.

Statistical analysis

Our study was a cross-sectional, open-label, single cohort, single center study. The echocardiographic assessment outcomes were coded, and data were analyzed with the SPSS v29 software package (IBM, United States). Shapiro-Wilks test was used to assess normality of data. Qualitative data was expressed as frequencies (number of cases) and relative frequencies (percentages), and quantitative data as means, standard deviations, medians, and interquartile ranges. Comparisons of parametrically distributed quantitative variables were performed using the Student t test or analysis of variance (ANOVA), whereas nonparametrically distributed quantitative variables were compared using the Mann-Whitney test, and between qualitative variables using the chi-square test or Fishers exact test, as appropriate.13,14 Inter- and intra-observer variability was assessed by reanalyzing the data of 18 randomly selected study participants and reported as intraclass correlation coefficient (ICC), whose scale ranges from 0 to 1 where 1 represents perfect reliability with no measurement error and 0, no reliability. An ICC value < 0.5 indicates poor reliability; 0.5-0.75, moderate reliability; 0.75-0.9, good reliability; and > 0.90, excellent reliability.15 The area under the curve (AUC) was constructed to detect the cutoff for optimal sensitivity and specificity of regional strains. Receiver operating characteristic (ROC) curve comparison was performed using MedCalc version 10.3.1.0 (MedCalc Software, United States). Confidence interval was set to 95% and the accepted margin of error at 5%. 01. A P value <05 was considered statistically significant, and a P value < .01 was considered highly significant. Final analyses were conducted according to the per-protocol approach.

RESULTS

Baseline characteristics and sociodemographic features

The baseline characteristics and sociodemographic features of the study cohort are shown in table 1. Male predominance was the pivotal sociodemographic characteristic of the enrolled participants (56.5%), and the mean age was 60.4 ± 9.9years. Baseline risk factors and comorbidities of the study cohort included hypertension in 68.5%, diabetes mellitus in 70%, dyslipidemia in 66%, and smoking in 47%, respectively. There were no withdrawals, and all participants completed the study.

Table 1. Baseline characteristics and sociodemographic features of stable coronary artery disease cohort

Coronary angiographic characteristics of stable coronary artery disease cohort

The location and severity of significant coronary lesions with ≥ 70% diameter stenosis is shown in table 2. Most study participants had single-vessel disease (68%). Among significant lesions, 63 (22%) were located in the LCx, 121 (43%) in the LAD, and 98 (35%) in the RCA.

Table 2. Coronary angiographic characteristics of stable coronary artery disease cohort

Strain analysis of stable coronary artery disease cohort

The global strain analysis showed a GLS range of -26% to -8%, with a mean value of -16.4 ± 3.6%, and a GCS range of -35% to -10%, with a mean value of -18.4 ± 4.9%. The regional strain analysis (RSA) of 3383 segments showed RWMA in 3378 segments (99.8%), a mean WMSI of 1.3 ± 0.2 with sensitivity and specificity rates of 88% and 61%, respectively, GLS in 3365 segments (99.5%), GCS in 3184 segments (100%), global radial strain in 3352 segments (99%), significant hypoperfusion (coronary lesions with ≥ 70% diameter stenosis) in 1472 segments (43%), and normal perfusion to mild-to-moderate hypoperfusion (coronary lesions with < 70% diameter stenosis) in 1911 segments (57%). The medians and the interquartile ranges of the regional strain parameters for coronary lesions with ≥ 70% diameter stenosis demonstrated significant differences vs the corresponding pa­rameters for coronary lesions with < 70% diameter stenosis. The median RLS was -20% (IQR, -23% to -17%) for lesions < 70% diameter stenosis vs -12% (IQR, -14% to -9%) for lesions ≥ 70% diameter stenosis (P < .001). The median RRS was 40% (IQR, 38%-43%) for lesions < 70% diameter stenosis vs 33% (IQR, 21%-39%) for lesions ≥ 70% diameter stenosis (P < .001) (figure 2). The median RCS was -19% (IQR, -24% to -14%) for lesions < 70% diameter stenosis vs -17% (IQR, -22% to -12%) for lesions ≥ 70% diameter stenosis (P < .001). RWMA were detected in 38% of the segments supplied by significant coronary lesions with ≥ 70% diameter stenosis compared with 6% of the segments supplied by non-significant coronary lesions with < 70% diameter stenosis (P < .001).

Figure 2. Regional radial strain analysis of a study participant with stable coronary artery disease showing 42% strain of the mid inferoseptal segment.

Feasibility and reproducibility of stable coronary artery disease cohort

The ICC for inter- and intra-observer variability of segmental strains were measured in 21 of the 199 patients study cohort (11%). The results of the ICC for inter- and intra-observer variability of segmental strains were 0.91 and 0.96 for GLS, 0.94 and 0.97 for GCS, and 0.86 and 0.92 for GRS.

ROC curve and area under the curve analysis in patients with stable coronary artery disease

AUC was constructed to detect the cutoff for optimal sensitivity and specificity of regional strains (table 3). The AUC for RLS was 0.947 (P < .001) which detected a cutoff of ≥ -16% for optimal sensitivity and specificity of RLS. ROC curve comparison showed that RLS exhibited the highest predictive value for identifying significantly hypoperfused segments (with ≥ 70% diameter stenosis) at a cutoff of ≥ -16% vs the RRS (AUC difference, 0.149; 95%CI, 0.132-0.167; P ≤ .0001), RWMA (AUC difference, 0.277; 95%CI, 0.262-0.293; P ≤ .0001), and RCS (AUC differ- ence, 0.348; 95%CI, 0.327-0.368; P ≤ .0001), respectively (figure 3).

Table 3. Area under curve for detection of cutoff for optimal sensitivity and specificity of the regional strains

Figure 3. Receiving operating characteristic curve comparison of stable coronary artery disease cohort comparing regional longitudinal strain, regional radial strain, regional circumferential strain, and regional wall motion abnormalities in predicting significant ≥ 70% diameter stenosis. RCS, regional circumferential strain; RLS, regional longitudinal strain; RRS, regional radial strain; RWMA, regional wall motion abnormality.

ROC curve analysis of regional longitudinal strain in patients with stable coronary artery disease

Guided by the detected cutoff of ≥ -16% for the optimal sensitivity and specificity of RLS, the predictive role of TLS in stable CAD for identifying the location and severity of significant coronary artery lesions with ≥ 70% diameter stenosis was explored (table 4). The ROC curve analysis of the RLS at a cutoff of ≥ -16% demonstrated that the optimal number of impaired segments that could predict the location and severity of significant coronary lesions with ≥ 70% diameter stenosis was ≥ 3 impaired segments out of the 7 territorial segments of LAD to predict proximal or significant lesion in the mid-LAD and ≥ 3 impaired segments among the 5 territorial segments of either the LCx or RCA to predict proximal significant lesion in the LCx or RCA (figure 4).

Table 4. Receiving operating characteristic curve analysis of regional longitudinal strain

Figure 4. Territorial longitudinal strain of study participants with stable coronary artery disease. Top row: representative study participant with significant proximal left anterior descending coronary artery lesion (≥ 70% diameter stenosis; red arrow). Global longitudinal (L) strain was -18.7%. Seven segments within the left anterior descending coronary artery territory (anteroseptal, anterior regions, and apex) demonstrated impaired strain (≥ -16%), consistent with a true-positive finding, whereas left circumflex and right coronary artery territories showed preserved strain (< -16%), consistent with true-negative findings. Bottom row: representative of a study participant with a significant proximal right coronary artery lesion (≥ 70% diameter stenosis; blue arrow). Global longitudinal strain was -23.3%. Four segments within the right coronary artery territory (mid, basal inferior, and inferoseptal) demonstrated impaired strain (≥ -16%), consistent with a true-positive finding, whereas left anterior descending artery and left circumflex artery territories showed preserved strain (< -16%), consistent with true-negative findings.

DISCUSSION

Despite being the gold standard echocardiographic marker for stable CAD, RWMA is ineffective at detecting subclinical myocardial damage.3 Our study aimed to evaluate the predictive capability of TLS in identifying the location and severity of significant coronary lesions with ≥ 70% diameter stenosis.

Participants in our study had a mean age of 60.4 ± 9.9 years (range, 38-81 years), with 112 men (56.5%). Most participants had single-vessel disease (68%); 45 (23%), 2-vessel disease; and 19 (10%), 3-vessel disease. Significant coronary lesions with ≥ 70% diameter stenosis were located in the LCx, LAD, and RCA in 63 (22%), 121 (43%), and 98 cases (35%), respectively. Similarly, Koulaouzidis et al. found that 57% of their participants had single-vessel disease with ≥ 50% diameter stenosis.16 Observational studies suggest that most single-vessel coronary occlusions occur in the proximal LAD.17,18

In our cross-sectional study, GLS ranged from -26% to -8%, averaging -16.4 ± 3.6%, while RLS for lesions < 70% diameter stenosis was -20% (IQR, -23% to -17%) vs -12% (IQR, -14% to -9%) for lesions ≥ 70% diameter stenosis (P < .001). Norum et al. concluded that a GLS cutoff of -17.4% to -20.3% could predict CAD in patients with chest pain, with sensitivity rates between 51% and 81% and specificity rates between 58% and 81%.19 There is limited real-world data on RSA in stable CAD. Montgomery et al. found that summed LAD segmental strain demonstrated a sensitivity and specificity of 66% at a cutoff of -20.3% for predicting LAD lesions ≥ 50% diameter stenosis.20 Shimoni et al. demonstrated that segmental analysis using the least 10-percentile peak systolic strain (PSS) outperformed global PSS and GLS.21 Biering-Sørensen et al. observed that significant left main stenosis (≥ 70%) affected apical longitudinal strain (ALS) more than significant lesions did in the LAD or LCx, despite similar GLS results.22 Carstensen et al. studied asymptomatic CAD in patients with aortic stenosis using an 18-segment LV model, finding that only ALS and mid-longitudinal strain were significant independent predictors of asymptomatic CAD, which is consistent with other studies indicating that proximal lesions impact all defined regions.23-25 Liu et al. showed that a cutoff of ≥ -23.5% for endocardial RLS and GLS of the LAD was higher in identifying significant LAD stenosis (≥ 50%) vs strain values from other layers.26

Our findings indicate that at a cutoff of ≥ -16%, TLS can predict the location and severity of significant coronary lesions with ≥ 70% diameter stenosis. Specifically, impairment of ≥ 3 of 7 in the LAD predicted significant proximal or mid lesions, whereas impairment of ≥ 3 of 5 segments in either the LCx or RCA predicted significant proximal lesions. TLS has not been extensively studied in stable CAD. Eek et al. found that at a cutoff of ≥ -14%, impaired blood supply in ≥ 4 segments predicted acute coronary occlusion with improved sensitivity (85%) and specificity (70%) vs the left ventricular ejection fraction.12 Sarvari et al. noted that although TLS, GLS, and GCS were affected in patients with non-ST-segment elevation myocardial infarction, the differences between GLS and TLS were not statistically significant.24 Caspar et al. demonstrated that TLS has high predictive value for significant lesions with ≥ 50% diameter stenosis across the 3 major coronary territories.25

The takeaway from our study is that TLS enhances the diagnostic capacity of RLS, accurately predicting both the location and severity of significant coronary lesions with ≥ 70% diameter stenosis. While several non-invasive methods show acceptable sensitivity and specificity,27 they usually face limitations regarding availability and cost. Echocardiography is widely accessible, and strain analysis can be performed offline, making it beneficial for patients with chest pain, allowing for assessment prior to invasive procedures or costly imaging modalities. Further studies are needed to clarify the diagnostic and prognostic significance of TLS in patients with chest pain.

Strengths and limitations

Our study was conducted on a well-balanced cohort with regards to the risk factors and baseline characteristics and did not have missing data allowing robust per protocol analysis, the interventional cardiologists who analyzed the CAGs were blinded to the results of the echocardiographic evaluation, whereas the investigators who performed the 2D echocardiography and the 2D STE were blinded to the coronary angiographic data, hence observer bias was minimized. Despite its strengths, the limitations of the study require consideration. It was a single centre cross-sectional study which didn’t allow us to investigate the chronological relationship between the echocardiographic and the coronary angiographic data in stable patients with CAD. There was no invasive functional assessment of the coronary blood flow with fractional flow reserve, RRS was assessed manually, and 36 study participants (18%) with impaired myocardial function (left ventricular ejection fraction ≤ 50%) were selected for the study. Patients with stable CAD patients and coronary microvascular disease (microvascular angina) and normal CAG and patients with stable CAD and abnormal CAG with coronary lesions with < 70% diameter stenosis were excluded from the study cohort overestimating the RLS of the study cohort. Inclusion of patints with stable CAD and abnormal CAG with coronary lesions with ≥ 70% diameter stenosis could only limit the generalizability of the study results to the population with stable CAD. Ultimately, ROC curve analysis of RLS in stable CAD, used to explore the role of TLS in predicting the location and severity of significant ≥ 70% diameter stenosis relied on clinically limited metrics, namely sensitivity and specificity. As a result, the high RLS performance estimate (0.947) may be biased, and the cutoff of ≥ -16% potentially misleading. Consequently, WMSI was not included in the analyss, and no incremental diagnostic value for RLS over WMSI could be established.

CONCLUSIONS

RLS indicated potential clinical relevance in the diagnosis of stable CAD and TLS demonstrated a significant ability to predict the site and level of significant coronary lesion with ≥ 70% diameter stenosis in patients with stable CAD.

DATA AVAILABILITY

Data are available from the corresponding author upon request.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

The study design and protocol were approved by the human ethics committee of the Ain Shams University Hospital before study initiation on 1 July, 2021. The study was registered and assigned trial registration No. Md 110 / 2021. Written informed consent was obtained from all human research subjects and study participants, including consent for publication. Participant privacy was strictly protected, and all data were anonymized, informed consents were signed by study participants for publication, and the study procedures were conducted in full compliance with the Egyptian National Commission for Bioethics statement on ethical conduct in human research, and SAGER guidelines have been followed with respect to possible sex/gender bias.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

The authors declare that they have not used any type of generative artificial intelligence for the drafting of this manuscript, nor for the creation of images, graphics, tables, or their corresponding captions.

AUTHORS’ CONTRIBUTIONS

The study was designed by A. Rezq and H. Shaalan, the data was collected, analyzed, and interpreted by M.A. Hashem and A.E. Nayel, the manuscript was drafted by M.A. Hashem and critically reviewed by A. Rezq, A.K. Araquib, A.E. Nayel, and H. Shaalan, and A. Rezq, A.E. Nayel, A.K. Araquib, and H. Shaalan approved the final manuscript. The authors take full responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

CONFLICTS OF INTEREST

None declared.

REFERENCES

INTRODUCTION

Transcatheter aortic valve implantation (TAVI) is one of the treatments that has been shown to improve prognosis and reduce mortality in patients with symptomatic severe aortic stenosis.1 Currently, according to the clinical practice guidelines outlined by the European Society of Cardiology (ESC),2 TAVI is the treatment of choice in patients aged ≥ 70 years, while the American Heart Association and the American College of Cardiology (AHA/ACC) clinical practice guidelines indicate that it may be considered from the age of 65 years.3,4.

Although TAVI is considered a safe procedure, complications may occur;5 however, their incidence has declined over the years owing, among other factors, to advances in preoperative cardiac imaging, the development of improved models of transcatheter heart valves and delivery sheaths, and the increasing experience of the teams performing the procedure.6 However, not all complications are directly associated with valve implantation, and some are due to auxiliary devices used perioperatively. One example is the temporary transvenous pacemaker traditionally used for rapid right ventricular (RV) pacing, which requires an additional puncture (generally in the femoral, jugular, subclavian, or brachial vein) and the insertion of a catheter into the RV.

A meta-analysis published in 2019 reported that, even today, despite the availability of imaging modalities that facilitate implantation, transvenous temporary pacing remains associated with complications in 22.9% of patients.7 Many of these complications could be avoided by performing left ventricular (LV) pacing using the pre-shaped guidewire during TAVI, which eliminates the need for any additional vascular accesses or specific devices.8 In 2019, the randomized clinical trial EASY TAVI compared both techniques showing a similar safety and efficacy profile, resulting in lower costs and shorter procedural and fluoroscopy times with LV pacing.9 Although the utility of the SAFARI 2 (Boston Scientific, United States), Confida (Medtronic, United States), Lunderquist (Cook Medical Inc., United States), Amplatz Extra-Stiff (Cook Medical Inc.), Amplatz Super Stiff (Boston Scientific), and SavvyWire (OpSens Inc., Canada) guidewires has already been demonstrated10,11, there are no studies on the Circulo guidewire (Abbott, United States).12

The aim of this study was to evaluate the performance of the pre-shaped Circulo guidewire for LV pacing during TAVI (figure 1A).

Figure 1. A: pre-shaped Circulo guidewire. B: grounding for left ventricular pacing through the skin. C: grounding for left ventricular pacing through a guidewire.

METHODS

We conducted an observational, prospective, multicenter study. The primary endpoint was to demonstrate the efficacy of rapid LV pacing, defined as a decrease in systemic systolic pressure < 60 mmHg. Secondary endpoints included pacing threshold, the need for conversion to RV pacing, and safety.

The Circulo guidewire

Circulo is a 275-cm–long polytetrafluoroethylene–coated guidewire. It features a double curve at its distal end, with a circular configuration slightly different from that of other guidewires, which reduces ventricular compression. This characteristic is particularly notable in the smaller curve.

Study population

The study protocol was approved by Hospital Clínic de Barcelona Ethics Committee (Barcelona, Spain) in full compliance with the ethical principles outlined in the Declaration of Helsinki. A total of 50 consecutive patients with severe aortic stenosis or regurgitation undergoing TAVI in 8 Spanish centers with the pre-shaped Circulo guidewire for LV pacing were prospectively included. Patients were excluded if, in the investigators’ judgment, they required RV pacing, lacked femoral access, or underwent TAVI without the need for rapid pacing.

Baseline characteristics were collected, including sex, age, weight, height, surgical risk, history of pacemaker implantation, atrial fibrillation, ischemic heart disease, or bundle branch block. Echocardiographic characteristics included LV size, LV ejection fraction, and the presence of severe valvular heart disease.

TAVI with left ventricular pacing

TAVI was performed according to the clinical practice of each center. The grounding configuration for LV pacing and the type of TAVI were decided by each center based on patient characteristics (figure 1B-C). During LV pacing, systemic blood pressure and pacing threshold were measured. To determine the LV pacing threshold, pacemaker output was initially increased to the maximum and then gradually reduced until loss of capture was observed. The lowest voltage capable of capturing the ventricle on all beats was selected. Systemic blood pressure was measured using an arterial catheter.

Procedural characteristics were recorded, including venous access, grounding configuration for LV pacing, LV pacing threshold, systemic blood pressure during rapid LV pacing, conversion to pacing using a different LV guidewire or RV pacing, type and size of the transcatheter heart valve, need for balloon pre- or postdilatation, and complications according to the Valve Academic Research Consortium-3 (VARC-3) criteria, including vascular and access-related complications, hemorrhages, neurological events, new conduction disturbances and arrhythmias, acute kidney injury, structural heart complications, length of stay, and mortality.5

Follow-up

Follow-up was conducted 30 days after TAVI, either by telephone or in person. Complications were adjudicated according to VARC-3 criteria.5

Statistical analysis

Quantitative variables are expressed as mean and standard deviation or median and interquartile range (IQR), depending on whether distribution was normal, as previously assessed using the Kolmogorov–Smirnov test. The qualitative ones are expressed as total number and percentage. Statistical analyses were performed using IBM SPSS Statistics (version 27) and RStudio (version 4.5.1). Depending on the variable, Fisher’s exact test, the Kruskal–Wallis test, or ANOVA was applied.

RESULTS

Baseline characteristics

Baseline characteristics are shown in table 1. A total of 50 patients were included in the study, 31 (62%) women and 19 (38%) men. The mean age of the cohort was 80.56 ± 6.26 years. In terms of past medical history, the mean body mass index was 27.38 ± 4.6 kg/m²; 17 patients (34%) had ischemic heart disease; 12 (24%), atrial fibrillation; 3 (6%), a previously implanted pacemaker; 4 (11.8%), first-degree atrioventricular block (AVB); and 6 (12%), bundle branch block (4 patients had left bundle branch block and 2, right bundle branch block). The PR interval ranged from 140 ms to 240 ms, with a median of 170 ms (IQR, 158-190), and QRS duration ranged from 72 ms to 170 ms, with a median of 90 ms (IQR, 80-110). Median surgical risk, assessed using the EuroSCORE II, was 2.06% (IQR, 1.62-3.36).

Table 1. Baseline characteristics of the patients

Baseline echocardiographic evaluation demonstrated a mean LV end-diastolic diameter of 45.28 ± 7.83 mm, a mean LV ejection fraction of 58.48 ± 8.63%, and a mean transaortic gradient of 47.24 ± 19.25 mmHg. Severe aortic regurgitation was present in 6 patients (12%) and was the primary valvular heart disease in 2 cases (4%). There were no patients with severe tricuspid regurgitation.

Procedural characteristics and performance of the pre-shaped guidewire

LV pacing avoided venous access in nearly half of the patients (n = 24; 48%). Among those requiring venous access, the femoral vein was the most widely used site (n = 20; 77%), followed by the brachial (n = 4; 15%) and jugular veins (n = 2; 8%). Grounding methods for LV pacing varied, with skin grounding being the one most frequently used (n = 22; 44%), followed by grounding to a guidewire via venous access (n = 19; 38%), and needle-based grounding methods (n = 9; 18%) (table 2).

Table 2. Procedural characteristics and perioperative complications and 30-day follow-up

The Navitor valve (Abbott, United States) was the most frequently used transcatheter heart valve (n = 28; 56%), followed by the SAPIEN (Edwards Lifesciences, United States) and the Myval (Meril Life Sciences, India) valves (n = 6; 12%). The least frequently used ones were the Evolut (Medtronic, United States) and the ACURATE (Boston Scientific, United States) (n = 5; 10%). Self-expanding valves accounted for 76% of all implanted transcatheter heart valves. Valve sizes ranged from 23 mm to 34 mm, with a median of 25 mm (IQR, 23-27). Predilatation was performed in most patients (n = 41; 82%), whereas postdilatation was required in only 20% (n = 10) (table 2). The mean LV pacing threshold was 7 ± 3.48 mV, and in 100% of patients (n = 50), a decrease in systolic blood pressure < 60 mmHg was achieved without loss of capture during rapid LV pacing. Comparative data across the different guidewires are presented in table 3. No patient required conversion to an alternative LV pacing guidewire, and only 3 (6%) required RV pacing, all due to AVB following balloon predilatation or during advancement of the valve into the LV. No guidewire exchange was required to advance the TAVI delivery system (table 2).

Table 3. Performance of the preformed left ventricular pacing guidewire

Complications

The overall rate of complications was 14% (n = 7), with conduction disturbances being the most frequent. Perioperative AVB requiring temporary pacemaker implantation occurred in 6 patients (12%), 4 of whom (8%) exhibited postoperative persistent complete AVB and eventually required permanent pacemaker implantation. One patient experienced a minor vascular complication in the form of vascular occlusion, which was successfully treated by transcatheter procedure and resolved without sequelae. There were no strokes or other major adverse events. The median length of stay from TAVI to discharge was 3 days (IQR, 2-5). The in-hospital survival rate was 100%, and no readmissions or deaths were recorded at the 1-month follow-up. Perioperative complications and those occurring within 1 month after the procedure are shown in table 2.

DISCUSSION

The main findings of the study were these: a) LV pacing using the pre-shaped Circulo guidewire was effective, achieving a reduction in systolic blood pressure < 60 mmHg in 100% of patients; b) no patient required switching to an alternative LV pacing guidewire; c) only 3 patients required conversion to RV pacing, all due to AVB following predilatation; d) the procedural success rate of TAVI was 100%; and e) there were no complications related to the Circulo guidewire. These results demonstrate the safety and efficacy profile of LV pacing using the Circulo guidewire and support its usefulness during transfemoral TAVI.

In this study, the success rate of LV pacing with the Circulo guidewire was comparable to that reported in former studies using other guidewires.8-11,13,14 Only 4% of patients presented right bundle branch block on baseline electrocardiography, indicating a cohort with a low risk of developing conduction disturbances. No patient required switching to an alternative LV pacing guidewire, and only 3 (6%) required conversion to RV pacing due to the onset of AVB after balloon predilatation or during valve advancement into the LV. In 2 of these 3 cases, LV pacing had been effective, with adequate pacing thresholds of 2.5 mV and 3.0 mV; however, although the procedure could have been continued using LV pacing, the operators decided to implant a transvenous temporary pacemaker before valve implantation, anticipating the need for pacing support after the procedure. In the third case, LV pacing was attempted, but due to the absence of adequate capture, conversion to RV pacing with implantation of a transvenous temporary pacemaker was performed. These patients did not present notable clinical differences, and aside from predilatation, no additional predictive factors were identified. The pacing thresholds recorded were slightly higher than those observed in former studies (7 mV vs 3.36 mV-7.5 mV);10 however, these discrepancies were not clinically relevant and are plausibly explained by inter-operator variability inherent to the technique.

Because transvenous temporary pacemaker implantation was only required in patients who developed AVB during or after the procedure, LV pacing with the Circulo guidewire avoided the implantation of 44 temporary pacemakers among 50 cases (88%). In former studies, this approach has been shown to reduce both procedural and fluoroscopy times.9,15,16 Therefore, although LV pacing can be performed in all patients, it is most beneficial in those at low risk of AVB and subsequent pacing requirements. In such cases, transvenous temporary pacemaker implantation can be avoided, a procedure associated with potential complications, such as inadvertent arterial puncture (0.3%), major hemorrhage (2.7%), deep vein thrombosis (0.3%), pulmonary thromboembolism (0.1%), pneumothorax (0.1%), cardiac perforation (0.7%), lead dislodgement (3.4%), pacing failure (7.7%), and the need for multiple placement attempts (0.9%).7

Although it is evident that LV pacing reduces most complications associated with transvenous RV temporary pacemaker implantation, the main concerns regarding LV pacing have focused on the risk of aortic bioprosthesis embolization due to loss of capture and the risk of perforation related to advancing the guidewire inside the LV during pacing. However, multiple studies have shown no significant differences in valve embolization rates between the 2 techniques, with some reporting a trend toward a lower risk of cardiac tamponade with LV pacing, likely attributable to the greater myocardial thickness of the LV vs the RV.9,14,15 In our study, there were no cases of device embolization or cardiac tamponade or LV pacing-related complications.

Study limitations

One limitation of the present study is that guidewire selection was left to the operator’s discretion, which may have introduced selection bias. In the cohort presented, only 4% of patients exhibited right bundle branch block on baseline electrocardiography, which is representative of a population at a low risk of developing arrhythmic complications. However, the operator-dependent choice of guidewire enhances the external validity of the results, as it more accurately reflects real-world clinical decision-making. Another limitation is the absence of a comparison group undergoing RV or LV pacing with other guidewires, which limits the ability to directly compare outcomes between techniques. Instead, results were compared with those of previously published studies.

CONCLUSIONS

The use of the Circulo guidewire for LV pacing during TAVI proved to be safe and effective, with a low overall rate of TAVI-related complications and no guidewire-related complications. This approach avoids the need for transvenous temporary pacemaker implantation in most patients at low risk of arrhythmic complications, thus potentially reducing procedural risks and simplifying perioperative management.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

The study protocol was approved by Hospital Clínic de Barcelona Clinical Research Ethics Committee in full compliance with the ethical principles outlined in the Declaration of Helsinki. All participants signed informed consent prior to inclusion in the study. No sex-based subgroup analysis was performed, as this could compromise the statistical power of the study and both sexes were adequately represented in the cohort; furthermore, there is no prior evidence suggesting sex-related differences in response to LV pacing using a pre-shaped guidewire.

DECLARATION ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence was used in the development of this article.

AUTHORS’ CONTRIBUTIONS

A. Regueiro designed the protocol, database, and study framework, and coordinated statistical analysis, data interpretation, and manuscript drafting. I. Anduaga contributed to protocol design, database development, and study framework, performed statistical analysis and data interpretation, and drafted the manuscript. A. Ruberti, V. Vilalta, I.J. Amat-Santos, F. Díez-Delhoyo, L.L. Gheorghe, J.A. Baz, J.F. Díaz Fernández, L. Gutiérrez-Alonso, and X. Carrillo participated in data collection and critically reviewed the manuscript. All authors approved the final published version.

CONFLICTS OF INTEREST

A. Regueiro is a consultant for Abbott, Edwards, Haemonetics, Medtronic, and Meril. J.F. Díaz Fernández is a consultant for Abbott, Boston Scientific, and Medtronic. I.J. Amat-Santos is a proctor for Boston Scientific, Medtronic, Meril, and MicroPort. The remaining authors declared no conflicts of interest whatsoever.

REFERENCES

INTRODUCTION

Multivessel coronary artery disease is defined as the presence of ≥ 70% luminal stenosis in at least 2 major epicardial coronary arteries due to atherosclerotic plaque. Approximately 40% of patients with ST-segment elevation myocardial infarction (STEMI) exhibit multivessel coronary disease, which is associated with an increased risk of recurrent myocardial infarction and mortality.1-3 Evidence from randomized controlled trials has underscored the advantages of comprehensive revascularization with multivessel percutaneous coronary intervention (PCI) over culprit-lesion-only PCI, notably reducing the risks of cardiac death, myocardial infarction, and ischemia-driven revascularization at 1 year.4-6 There are 2 strategies to approach non-culprit lesions: immediate PCI which involves the revascularization of both culprit and non-culprit lesions during the index procedure, and staged PCI, where the treatment of non-culprit lesions is deferred to a later stage.

The 2021 clinical practice guidelines outlined by the American College of Cardiology/American Heart Association (ACC/AHA) acknowledge non-culprit vessel revascularization as a class IIb recommendation for patients with STEMI.7 However, determining the optimal timing for revascularization of non-culprit lesions remains a clinical challenge7,8 While PCI for non-culprit lesions has demonstrated superiority over a strategy of treating the culprit lesion alone,4-6 the timing of intervention, whether immediate or staged, lacks conclusive evidence.8,9

The objective of this meta-analysis was to compare staged vs immediate PCI for non-culprit lesions in hemodynamically stable patients with STEMI and multivessel disease. We hypothesize that both the staged and immediate PCI targeting non-culprit vessels will demonstrate comparable levels of safety, efficacy, and rate of complications.

METHODS

We conducted the present study following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.10 All steps were conducted in full compliance with the Cochrane Handbook of Systematic Reviews and Meta-analysis of Interventions (version 6.3).11 This meta-analysis protocol was registered on PROSPERO on 4 December, 2023, under protocol ID: CRD42023485163.l. During the peer-review process, the literature search was updated using the same search strategy, databases, and eligibility criteria described in supplementary data S1 to identify newly published randomized evidence.

Criteria of the included studies

We evaluated randomized controlled trials comparing immediate vs staged PCI for non-culprit lesions in adults with STEMI and multivessel coronary artery disease. Eligible studies were required to report extractable numerical data for at least 1 prespecified outcome of interest, as defined below. Trials reporting outcomes exclusively as Kaplan-Meier curves without corresponding event counts or effect estimates or reporting outcomes only as composite endpoints without separate data, were excluded from quantitative synthesis. No publication time limit was applied; however, the search was restricted to studies published in Spanish, English, or German. Case-control and cross-sectional studies, systematic reviews, meta-analyses, case reports, basic science research, conference abstracts, and letters to the editor were excluded.

Literature search strategy

We conducted a comprehensive and systematic search across 3 databases (PubMed, EMBASE, and COCHRANE) from their inception until 28 September, 2025. Keywords used for the search included “coronary artery disease”, “immediate multivessel percutaneous coronary intervention”, “staged multivessel percutaneous coronary intervention”, “acute coronary syndrome”, “multivessel disease”, “myocardial infarction”, “major adverse cardiovascular events”, “ST-segment elevation myocardial infarction”. These keywords were combined using Boolean operators AND and OR. The search details for each database are available in the supplementary data S1.

Screening of literature search results

All duplicates were removed using Zotero reference manager software. Records were initially screened by title and abstract by one author (E. Andrade-Arbaiza), followed by full-text assessment when potentially eligible. Two independent authors (D. Paulino-González, and L.H. García-Mena) reviewed full-text articles for inclusion and methodological quality, with disagreements being resolved by consensus or third-party adjudication (D. A. Navarro-Martínez). Studies were excluded at the full-text stage if they lacked extractable numerical data for prespecified outcomes or did not report outcomes separately, precluding quantitative synthesis. A detailed list of excluded studies with reasons for exclusion is provided in table S1. References cited in included studies were also manually screened for eligibility.

Data extraction

Data extraction was performed using standardized Excel spreadsheets to collect baseline population characteristics, key study features, outcome measures expressed as risk ratios, and domains for quality assessment. Outcome data were included only when numerical information was directly available or could be reliably derived without reconstruction from survival curves.

Assessing the risk of bias

The risk of bias of included randomized controlled trials was assessed usingvVersion 2 of the Cochrane risk-of-bias tool for randomized trials (ROB 2), in accordance with the Cochrane Handbook of Systematic Reviews of Interventions.11

Endpoints

The prespecified endpoints of this meta-analysis were cardiac death, all-cause mortality, stroke, reinfarction, and acute kidney injury (AKI). Given minor variations in endpoint definitions across trials, detailed outcome definitions as reported by each study are summarized in table S2. Outcomes were analyzed as dichotomous variables using event counts and percentages, and risk ratios with 95% confidence intervals (95%CI) were calculated.

Data analysis

Dichotomous outcomes were analyzed using pooled event data from the included studies and are reported as risk ratios with 95%CI. P values < .05 were considered statistically significant. Associations between outcomes and immediate vs staged PCI were evaluated using a random-effects model (DerSimonian–Laird method) to account for between-study heterogeneity.12 Statistical analyses and forest plots were generated using RevMan version 5.4.1 (Cochrane Collaboration) for MacOs.

Statistical analysis

Pooled risk ratios (RR) and incidence rate ratios (IRR) were estimated using random-effects models with appropriate adjustments, and heterogeneity was assessed using the I² statistic. Sensitivity analyses, trial sequential analysis, and meta-regression were performed to evaluate the robustness of findings and explore potential effect modifiers. Detailed methodological procedures are shown in the supplementary data S2.

Assessment of heterogeneity

Heterogeneity was assessed using Cochran’s Q test (P < .10) and quantified with the I² statistic, with values > 50% indicating substantial heterogeneity.

RESULTS

A total of 6 studies13-18 met the predefined inclusion criteria and were included in the analysis. The study selection process is summarized in the PRISMA flow diagram shown in figure 1. All included studies evaluated staged or immediate PCI in non-culprit arteries of patients with STEMI and multivessel disease.

Figure 1. PRISMA flow diagram. The diagram reflects the initial search and the updated search performed during peer review using the same strategy and eligibility criteria (supplementary data S1). NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

In the staged strategy, PCI of nonculprit lesions was performed a mean of 18.6 days (IQR, 7-34) after the index procedure. The total patient population included in our meta-analysis was 4267 patients, of whom 2479 underwent immediate PCI and 1788, staged PCI. Summary and baseline characteristics are shown in table 1. The characteristics of the included studies are summarized in table 2.

Table 1. Baseline characteristics and treatment of the included studies’ populations

Table 2. Summary of included studies.

Cardiac death

There were no significant difference between staged and immediate PCI regarding the risk of cardiac death (RR, 1.26; 95%CI, 0.89-1.79; P = .19). No heterogeneity was observed among the included studies (I² = 0%). These findings are shown in figure 2A.

Figure 2. Risk Ratios of cardiac death and all-cause mortality. A: cardiac death: risk ratio (RR) across the included trials are represented by solid squares, with horizontal lines indicating 95% confidence intervals (95%CI). B: all-cause mortality: RR across trials are shown by solid squares, with 95%CI indicated by horizontal lines. The bibliographical references cited in this figure correspond to the following studies: Politi et al.14 (2010), Maamoun et al.16 (2011), Wood et al.17 (2019), Park et al.15 (2023), Stähli et al.13 (2023), and Kim et al.18 (2025).

All-cause mortality

There were no significant differences in the risk of all-cause mortality between patients undergoing staged PCI and those treated with immediate PCI (RR, 1.18; 95%CI, 0.93-1.50; P = .17), with no heterogeneity detected among studies (I² = 0%) (figure 2B).

Reinfarction

The analysis demonstrated a statistically significant lower risk of reinfarction with immediate vs staged PCI (RR, 0.63; 95%CI, 0.40-0.98; P = .04), which amounts to an approximately 37% relative risk reduction with the former. There was no heterogeneity across trials (I² = 0%). These findings are shown in figure 3A.

Figure 3. Risk ratios for reinfarction and acute kidney injury. A: reinfarction: risk ratio (RR) across the included trials are represented by solid squares, with horizontal lines indicating 95% confidence intervals (95%CI). B: acute kidney injury: RR across trials are shown by solid squares, with 95%CI indicated by horizontal lines. The bibliographical references cited in this figure correspond to the following studies: Politi et al.14 (2010), Maamoun et al.16 (2011), Wood et al.17 (2019), Park et al.15 (2023), Stähli et al.13 (2023), and Kim et al.18 (2025).

Acute kidney injury

There were no significant differences between the 2 strategies (RR, 0.91; 95%CI, 0.64-1.31; P = .62), indicating no clear association between the revascularization strategy and the risk of AKI. There was no heterogeneity among the included studies (I² = 0%). These results are shown in figure 3B.

Stroke

Stroke was reported in only 3 of the studies included, and our analysis showed no significant differences between staged and immediate PCI for this outcome (RR, 1.17; 95%CI, 0.66-2.05; P = .59). There was no heterogeneity among the included studies (I² = 0%). These results are shown in figure S1.

Publication bias was assessed using funnel plots, Egger’s regression, and trim-and-fill analyses for reinfarction, cardiac death, and all-cause mortality. There was no visual evidence of funnel-plot asymmetry (figure S2). For reinfarction, trim-and-fill imputed 1 potentially missing study, with the pooled effect remained statistically significant (IRR, 0.59; 95%CI, 0.38-0.90). For cardiac death and all-cause mortality, 2 studies were imputed in each analysis; however, pooled effects remained non-significant, with no heterogeneity detected (I² = 0%). Overall, these results suggest no substantial publication bias, although the limited number of included trials reduces the power of formal tests for funnel plot asymmetry.

Sensitivity analyses

Leave-one-out sensitivity analyses confirmed the robustness of the pooled estimates across all primary endpoints (figure S3). For all-cause mortality and cardiac death, exclusion of individual studies did not materially alter the results, with pooled RRs remaining within the confidence intervals of the main models and I² = 0% in all scenarios. For reinfarction, estimates consistently favored immediate PCI (RR range, 0.46-0.75), with I² = 0% supporting the internal consistency of the findings.

Incidence rate ratios

At the 1-year follow-up, IRR analysis showed that immediate PCI was associated with a lower rate of reinfarction vs staged PCI. Under the random-effects model, the pooled IRR was 0.60 (95%CI, 0.39-0.94; I² = 0%), which is consistent with the common-effect model (IRR, 0.59; 95%CI, 0.38-0.92), supporting the robustness of this finding (figure S4). In contrast, there were no significant differences between the strategies regarding cardiac death (IRR, 1.26; 95%CI, 0.90-1.77; I² = 0%) or all-cause mortality (IRR, 1.17; 95%CI, 0.84-1.64; I² = 0%), indicating stable estimates with negligible heterogeneity across studies (figures S5, S6).

Trial sequential analyses

Trial sequential analysis were conducted for cardiac death, all-cause mortality, and reinfarction (figure 4A-C). For cardiac death and all-cause mortality, the accrued sample represented 33% and 58% of the required information size, respectively; in both analysis, the cumulative Z-curves remained within nonsignificant boundaries, indicating insufficient evidence to confirm or exclude a 30% relative risk reduction. For reinfarction, only 3.4% of the required information size was reached, and the Z-curve remained well within the futility zone, showing a non-significant trend favoring immediate PCI. Collectively, these results demonstrate that current data remain underpowered to establish definitive conclusions across outcomes, despite a consistent numerical pattern supporting immediate revascularization.

Figure 4. Trial sequential analysis. Trial sequential analysis for (A) cardiac death, (B) all-cause mortality, and (C) reinfarction. In all panels, the cumulative Z-curve is shown in blue, trial sequential monitoring boundaries in red, and conventional significance thresholds as horizontal magenta lines. PCI, percutaneous coronary intervention. The bibliographical references cited in this figure correspond to the following studies: Politi et al.14 (2010), Maamoun et al.16 (2011), Wood et al.17 (2019), Park et al.15 (2023), Stähli et al.13 (2023), and Kim et al.18 (2025).

Meta-regression

Exploratory meta-regression analyses were conducted to assess whether procedural timing or baseline comorbidities influenced reinfarction outcomes. The association between time to staged PCI and reinfarction risk showed a negative but non-significant slope (β = –0.016 per day; 95%CI, –0.042-0.010; P = .22), with no residual heterogeneity (I² = 0%), indicating consistent effects across studies (figure S7). Similarly, diabetes prevalence (β = 0.021 per 1% increase; 95%CI, –0.017 to 0.058; P = .22) and hypertension prevalence (β = –0.064 per 1% increase; 95%CI, –0.214 to 0.085; P = .40) were not significantly associated with reinfarction risk, with no evidence of residual heterogeneity (I² = 0% for both) (figures S8-S9). Collectively, these findings suggest that neither procedural timing nor comorbidity burden materially modified the comparative risk of reinfarction between immediate and staged PCI; however, given the study-level and exploratory design of these analyses, results should be interpreted with caution.

Risk of bias assessment

Risk of bias assessment was assessed using version 2 of the Cochrane risk-of-bias tool for randomized trials (ROB 2), as outlined in the Cochrane Handbook of Systematic Reviews of Interventions.11 Four clinical trials were judged to have a low overall risk of bias, whereas the study by Maamoun et al.16 was rated as the only clinical trial having some concerns (table 3).

Table 3. Risk of bias summary for randomized studies (RoB 2)

DISCUSSION

The present meta-analysis provides a focused comparison of immediate vs staged PCI in patients with STEMI and multivessel disease. By integrating randomized evidence using complementary analytical approaches, our findings offer an updated and clinically relevant synthesis of the safety and efficacy profile of these 2 revascularization strategies in a well-defined population.

Although cardiac death and all-cause mortality are clinically relevant, they are relatively rare outcomes in contemporary STEMI populations undergoing multivessel revascularization. In the present analysis, there were no statistically significant differences between immediate and staged PCI for either endpoint. These neutral findings should be interpreted in the context of limited statistical power, as reflected by the low cumulative incidence of events and trial sequential analysis indicating that the required information size has not yet been reached.19,20 Additional IRR analyses yielded consistent results, further supporting the absence of a clinically meaningful survival difference between strategies. Accordingly, mortality outcomes do not appear to discriminate between immediate and staged PCI, and treatment selection should instead be guided by patient-specific clinical stability and procedural considerations rather than isolated mortality endpoints alone.

Regarding reinfarction risk, immediate PCI was consistently associated with a significantly lower rate of reinfarction vs staged PCI. Exploratory meta-regression analyses did not identify procedural timing, diabetes, or hypertension prevalence as significant modifiers of this association. Trial sequential and sensitivity analyses showed consistent results across the models, with no evidence of heterogeneity. Although the required information size was not fully reached, the consistency of findings across multiple analytical approaches supports a robust association between immediate PCI and reduced recurrent ischemic events.

Regarding AKI, there were no significant differences between immediate and staged PCI, with low event rates and no heterogeneity across trials. The limited number of events precluded meaningful trial sequential analysis, highlighting insufficient power to detect small differences. Although post-PCI AKI is influenced by multiple factors, including contrast exposure and procedural complexity,21 current evidence does not support the assumption that staged PCI reduces renal risk by distributing contrast load.22 None of the included trials were specifically powered for renal outcomes, and AKI definitions varied across studies. Therefore, until adequately powered trials with standardized definitions become available, PCI timing decisions should remain individualized, taking into account baseline renal function and overall procedural risk.23

There were no significant differences in the rates of stroke between staged and immediate PCI, with few events being reported across trials, limiting statistical power. Available evidence suggests that stroke risk after PCI in STEMI is more closely related to procedural factors than to the timing of non-culprit revascularization.15 Accordingly, stroke does not appear to represent a clinically discriminative endpoint when comparing immediate and staged revascularization strategies in this population.

Historically, international clinical practice guidelines favored a staged approach to complete revascularization in STEMI with multivessel disease, largely due to concerns regarding procedural complexity, contrast exposure, and hemodynamic instability during the index intervention. However, cumulative randomized evidence has challenged this paradigm, showing that immediate complete PCI can be performed safely in hemodynamically stable patients, with outcomes comparable or superior to staged strategies.13,17,24,25 Notably, most prior trials primarily enrolled clinically stable patients following successful reperfusion, which may limit the generalizability of their findings to higher-risk STEMI populations. In this context, the OPTION-STEMI trial extends the available evidence by including patients with transient or mild hemodynamic instability, thereby providing contemporary data that better reflect real-world clinical complexity.18

Consistent with our primary findings, immediate and staged PCI did not differ in cardiac death or all-cause mortality at 1 year, while immediate PCI was associated with a lower risk of reinfarction. Beyond clinical outcomes, immediate complete revascularization may offer economic advantages by reducing the length of stay, avoiding repeat cardiac catheterizations, and optimizing resource utilization. In contrast, staged PCI often requires a second procedure and hospitalization, increasing cumulative costs by up to 50% in some analyses,26,27 and mirroring the additional expenses associated with unplanned readmissions for recurrent ischemia. In this context, a single-session revascularization strategy may provide both clinical and economic value, particularly in health care systems with constrained resources, where contemporary PCI costs remain substantial.28

From a safety and efficacy perspective, both staged and immediate PCI represent acceptable revascularization strategies in appropriately selected patients with STEMI and multivessel disease. In the present analysis, immediate PCI was primarily associated with a reduction in recurrent ischemic events, while major adverse cardiovascular events, including cardiac death and all-cause mortality did not differ significantly across strategies. Accordingly, the choice between immediate and staged PCI may increasingly be guided by patient-specific clinical characteristics and logistical considerations rather than concerns regarding procedural safety.

Although not directly assessed in this meta-analysis, emerging evidence suggests that systemic biological factors—such as inflammation, hypercoagulability, and sympathetic activation—may influence recurrent ischemic risk beyond angiographic severity alone.29,30 In addition, features of plaque vulnerability have been associated with future ischemic events in non-culprit lesions, even when angiographically mild.31 Integrating biological risk markers and clinical stability into revascularization decision-making, therefore, represents a relevant direction for future research aimed at refining individualized strategies in patients with STEMI and multivessel disease.

Limitations

Several limitations should be acknowledged. First, only 6 randomized controlled trials were included, resulting in limited statistical power, particularly for rare outcomes. Second, this analysis was restricted to patients with STEMI and multivessel disease; therefore, the findings should not be extrapolated to other acute coronary syndrome populations, and the limited number of trials reporting all prespecified outcomes may reduce the robustness of certain estimates. Third, the use of aggregate study-level data precluded adjustment for individual patient characteristics and limited the assessment of patient-level effect modification; accordingly, meta-regression analyses were exploratory and should be interpreted with caution given the small number of included studies and the potential for ecological bias. Finally, variability in the timing of staged PCI across trials may have introduced residual clinical heterogeneity, and formal assessments of publication bias were underpowered due to the limited number of studies.

CONCLUSIONS

This meta-analysis, integrating additional analytical approaches, provides a focused comparison of immediate vs staged PCI in patients with STEMI and multivessel disease. Immediate PCI was consistently associated with a lower risk of reinfarction, without significant differences being reported in cardiac death or all-cause mortality, stroke, or renal injury. Although the cumulative evidence remains below the required information size for certain hard endpoints, the consistency of findings across multiple analyses supports the robustness of the observed reduction in reinfarction events. From a clinical perspective, these results suggest that immediate complete revascularization can be performed safely in appropriately selected patients and may reduce the burden of reinfarction. Accordingly, the choice between immediate and staged strategies should increasingly be guided by patient-specific clinical stability and practical considerations rather than by concerns regarding procedural safety alone. Future research incorporating biological risk markers may further refine individualized revascularization strategies in this population.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

This meta-analysis was based exclusively on data from previously published studies and involved secondary analyses of publicly available information. Therefore, approval by an Ethics Committee or institutional review board was deemed unnecessary. As no individual patient data or case reports were included, informed consent was not applicable. All the studies included were conducted in full compliance with the ethical standards of the respective institutions at the time of their original publication.

In line with the SAGER guidelines, we assessed sex and gender reporting in the included randomized trials. While sex was generally reported at baseline, sex-disaggregated outcome data and gender-related variables were rarely available, precluding analyses by sex or gender. This limitation should be considered when interpreting the results.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

During the preparation of this work the authors used ChatGPT 5.2 to review the syntaxis and grammar of this document. After using this tool/service, the authors reviewed and edited the content as needed and took full responsibility for the content of the published article.

AUTHORS’ CONTRIBUTIONS

D. Paulino-González: conceptualization, formal analysis, drafting – review and editing. L.H. García-Mena: formal analysis, investigation, drafting – review and editing. E. Andrade-Arbaiza: methodology, investigation, drafting – review and editing. D.A. Navarro-Martínez: methodology, formal analysis; J.L. Maldonado-García: formal analysis, drafting – review and editing; S.A. Xiloj-López: investigation. C.J. Palomino-Ojeda: investigation, drafting – review and editing, R.M. Arellano-Sánchez: data curating, formal analysis. N.E. Antonio-Villa: data curating, formal analysis, drafting – review and editing. A. Ricalde-Alcocer: drafting – review and editing, supervision. D. Araiza-Garaygordobil: drafting – review and editing, supervision.

CONFLICTS OF INTEREST

None declared.

ACKNOWLEDGEMENTS

The authors respectfully honor, in memory, a beloved family member of one of the coauthors, and gratefully acknowledge the support of Dr. Pavel Pichardo-Rojas.

SUPPLEMENTARY DATA

REFERENCES