Access to side branches with a sharply angulated origin: usefulness of a specific wire for chronic occlusions

INTRODUCTION

Drug-eluting stents (DES) remain the standard of treatment for patients undergoing percutaneous coronary intervention (PCI).1,2 However, DES are associated with a gradually and permanent increased risk of adverse events, particularly due to late stent thrombosis and in-stent restenosis, with a 2% incidence rate per year with no plateau observed.1 This risk is even higher when complex and long lesions are treated.3 In recent years, drug-coated balloons (DCB) have emerged as a potential alternative treatment option to DES. Following adequate lesion preparation, unlike traditional stents, DCBs can release an antiproliferative drug into the vessel wall without leaving behind a permanent metal scaffold. Notably, permanent scaffolding can distort and constrain the coronary vessel, thus impairing vasomotion and adaptive remodelling, while also promoting chronic inflammation.4 DCB-PCI is a well-established treatment for in-stent restenosis and small-vessel coronary artery disease (CAD).5,6 However, its role in de novo large vessel CAD remains controversial. In a recent randomized clinical trial (RCT) with patients undergoing de novo CAD revascularization, a strategy of DCB-PCI did not achieve non-inferiority vs DES in terms of device-oriented composite endpoint driven by higher rates of target lesion revascularization (TLR).7 Contrary to prior published research, our findings did not support similar clinical outcomes for DCB vs DES in patients with de novo large vessel CAD.8,9 A recent meta-analysis of 15 studies compared DCB-PCI or hybrid angioplasty vs DES-PCI in patients with vessels > 2.75 mm in diameter showing no significant differences in the clinical endpoints of TLR, cardiac death, and MI.10 However, 14 of the 15 included studies were non-RCT, and the recent previously reported RCT was not included. Nevertheless, individual non-inferiority studies often lack the statistical power needed to definitively compare these technologies, underscoring the need for a systematic appraisal of treatment effects and evidence quality. Therefore, we conducted a systematic review and meta-analysis of available RCT to provide a comprehensive and quantitative assessment of evidence on the efficacy of DCB vs the current-generation DES in de novo large vessel CAD in terms of adverse events at longest available follow-up.

METHODS

Search strategy and selection criteria

We conducted a meta-analysis of RCT according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 guidelines.11 Two reviewers independently identified the relevant studies through an electronic search across the MEDLINE and Embase databases (from inception to October 2024). In addition, we employed backward snowballing (eg, reference review from identified articles and pertinent reviews). No language, publication date or publication status restrictions were imposed. This study is registered with PROSPERO and the search strategy is available in the supplementary data.

Study selection

Two reviewers independently assessed trial eligibility based on titles, abstracts, and full-text reports. Discrepancies in study selection were discussed and resolved with a third investigator. Eligible studies needed to meet the following pre-specified criteria: a) RCT comparing PCI with DCB and PCI with DES; b) study population including patients with de novo large vessel CAD (eg, defined as vessel diameter ≥ 2.5 mm);12 c) availability of clinical outcome data (without restriction as to follow-up time). Exclusion criteria were a) lack of a randomized design; b) studies including patients undergoing treatment for in-stent restenosis; c) studies including patients with de novo small vessel CAD; d) lack of any clinical outcome data.

A reference vessel diameter ≥ 2.5 mm was established as the cut-off value to define large vessel based on a recent proposed standardized definition.12

Data extraction

Three investigators (J. Llau García, S. Huélamo Montoro and J. A. Sorolla Romero) independently assessed studies for possible inclusion, with the senior investigator (J. Sanz-Sánchez) resolving discrepancies. Non-relevant articles were excluded based on title and abstract. The same investigators independently extracted data on study design, measurements, patient characteristics, and outcomes using a standardized data-extraction form. Data extraction conflicts were discussed and resolved with the senior investigator.

Data on authors, year of publication, inclusion and exclusion criteria, sample size, patients’ baseline patients, endpoint definitions, effect estimates, and follow-up time were collected.

Endpoints

The prespecified primary endpoint was TLR. Secondary clinical endpoints were all-cause mortality, cardiac death, myocardial infarction (MI), target vessel revascularization (TVR) and major adverse cardiovascular events (MACE). Secondary angiographic endpoints were minimum lumen diameter (MLD) and late lumen loss (LLL). Each endpoint was assessed according to the definitions reported in the original study protocols, as summarized in table 1 of the supplementary data. All the endpoints were assessed at the maximum follow-up available.

Table 1. Main features of included studies

Risk of bias

The risk of bias in each study was assessed using the revised Cochrane risk of bias tool (RoB 2.0).11 Three investigators (J. Llau García, S. Huélamo Montoro and J. A. Sorolla Romero) independently assessed 5 domains of bias in RCT: a) randomization process, b) deviations from intended interventions, c) missing outcome data, d) outcome measurement, and e) selection of reported results (table 2 of the supplementary data).

Table 2. Baseline clinical characteristics of included patients

Statistical analysis

Odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using the DerSimonian and Laird random-effects model, with the estimate of heterogeneity being obtained from the Mantel-Haenszel method. The presence of heterogeneity among studies was evaluated with the Cochran Q chi-square test, with P ≤ .10 being considered of statistical significance, and using the I² test to evaluate inconsistency. A value of 0% indicates no observed heterogeneity, and values of ≤ 25%, ≤ 50%, > 50% indicate low, moderate, and high heterogeneity, respectively. Prediction intervals (95%) in addition to conventional 95%CI around ORs were calculated to assess residual uncertainty. Publication bias and the small study effect were assessed for all outcomes, using funnel plots. The presence of publication bias was investigated using Harbord and Egger tests and visual estimation with funnel plots. We performed a sensitivity analysis by removing one study at a time to confirm that the findings, when compared with DES, were not driven by any single study. To account for different lengths of follow-up across studies, another sensitivity analysis was performed using the Poisson regression model with random intervention effects to calculate inverse-variance weighted averages of study-specific log stratified incidence rate ratios (IRRs). Results were displayed as IRRs, which are exponential ratios of the regression model. Additionally, random-effect meta-regression analyses were performed to assess the impact of the following variables on treatment effect with respect to the primary endpoint: eg, percentage of patients with acute coronary syndrome (ACS), percentage of patients with diabetes mellitus, mean reference vessel diameter and follow-up duration. The statistical level of significance was 2-tailed P < .05. Stata version 18.0 (StataCorp LP, College Station, United States), was used for statistical analyses.

RESULTS

Search results

Figure 1 illustrates the PRISMA study search and selection process. A total of 7 RCT were identified and included in this analysis. The main features of included studies are shown in table 1.

Figure 1. Flow diagram of the search for studies included in the meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement.

All studies had a non-inferiority design. A clinical primary endpoint was selected in 1 study,7 and an invasive functional endpoint was selected in another trial,9 while angiographic primary endpoints were prespecified in the remaining studies.8,13-16 The mean clinical and angiographic follow-up were 21.5 months and 8.9 months respectively. A total of 4 studies were conducted in the context of ACS9,14-17 and 1 study in the context of chronic coronary syndrome (CCS).13 Finally, 2 studies enrolled both ACS and CCS patients.7,8 A total of 3 trials enrolled patients treated with second-generation DES (Firebird 2.0 [Microport, China], Xience Xpedition [Abbott Vascular, United States], Orsiro [Biotronik, Germany]),7,9,13 and 2 studies enrolled patients treated with third-generation DES (Biomine [Meril Life Sciences, India], Cordimax [Rientech, China]).14,15 One trial enrolled patients treated with second and third-generation DES (Xience Xpedition [Abbott Vascular, United States], Resolute Integrity, [Medtronic, United States], Firehawk, [MicroPort, China]).8 All studies included patients who underwent paclitaxel-DCB-PCI ([Pantera Lux, Biotronik, Germany],9,14 [SeQuent Please, B Braun, Germany],7,8,13,15 [Bingo DCB, Yinyi Biotech,China]),16 and none with sirolimus-DCB-PCI.

Baseline characteristics

A total of 2961 patients were included, 1476 of whom received DCB and 1485, DES for de novo large vessel CAD. The patients main baseline characteristics are shown in table 2.

Publication bias and asymmetry

Funnel-plot distributions of the pre-specified outcomes indicate absence of publication bias for all the outcomes (figures 1-8 of the supplementary data).

Risk of bias assessment

Table 2 of the supplementary data illustrates the results of the risk of bias assessment with the RoB 2.0 tool. One trial was considered at low overall risk of bias,7 5 raised some concerns8,9,13,14,16 and 1 presented a high overall risk of bias.15

Outcomes

Clinical outcomes

DCB use compared with DES was associated with a similar risk of TLR (OR, 1.21; 95%CI, 0.44-3.30; I² = 48%), all-cause mortality (OR, 1.56; 95%CI, 0.94- 2.57; I² = 0%), cardiac death (OR, 1.65; 95%CI, 0.90-3.05; I² = 0%), MI (OR, 0.97; 95%CI, 0.58-1.61; I² = 0%) and MACE (OR, 1.19; 95%CI, 0.74-1.90; I² = 13.5%). However, DCB was associated with a higher risk of TVR (OR, 2.47; 95%CI, 1.52- 4.03; I² = 0%) (figure 2, figure 3 and figures 9-10 of the supplementary data).

Figure 2. Forest plot reporting trial-specific and summary ORs with 95%CIs for the endpoint of A) target lesion revascularization; B) all-cause mortality; C) myocardial infarction; D) MACE. 95%CI, 95% confidence interval; DCB, drug-coated balloon; DES, drug-eluting stents; MACE, major adverse cardiovascular events; OR, odds ratio. References: REC-Cagefree I.,7 Nishiyama et al.,13 Xue Yu et al.,8 REVELATION,9 Hao et al.,16 Wang et al.,14 and Gobic et al.15

Figure 3. Central Illustration. DCB, drug-coated balloon; DES, drug-eluting stent; RCT, randomized clinical trial; TVR, target vessel revascularization. References: REC-Cagefree I.,7 Nishiyama et al.,13 Xue Yu et al.,8 REVELATION,9 Hao et al.,16 and Wang et al.14

Angiographic outcomes

Compared with DES, DCB use yielded significant smaller MLD (SMD, −0.36; 95%CI, −0.56 to −0.15; I² = 34.5%) and similar risk of LLL (SMD, −0.35; 95%CI, −0.74 to 0.04; I² = 81.4%) at follow-up (figure 4).

Figure 4. Forest plot reporting trial-specific and summary ORs with 95%CIs for the endpoint of A: minimum lumen diameter, and B: late-lumen loss. 95%CI, 95% confidence interval; DCB, drug-coated balloon; DES, drug-eluting stents; MACE, major adverse cardiovascular events; MLD, minimum lumen diameter; SMD, standardized mean difference; OR, odds ratio. References: Nishiyama et al.,13 Xue Yu et al.,8 REVELATION,9 Gobic et al.,15 Hao et al.,16 and Wang et al.14.

Prediction intervals were consistent with CI for all the outcomes except for TVR and MLD, which included the value of no difference.

Sensitivity analysis

A leave-one-out pooled analysis by iteratively removing one study at a time was performed for all endpoints. Treatment effects were consistent with the main analysis for TLR, all-cause mortality, cardiac death, MI and MLD. The risk of TVR was no longer significantly higher among patients undergoing DCB when removing the CAGEFREE I trial,7 and the risk of LLL was significantly lower among patients undergoing DCB-PCI when removing the REVELATION trial.9 However, an increased risk of MACE was observed among patients undergoing DCB-PCI when removing the study by Xue Yu et al.18 (tables 3-10 of the supplementary data). A sensitivity analysis using estimated IRRs was performed to account for varying follow-up lengths, confirming that our main analysis findings remained unchanged (table 11 of the supplementary data).

Random effect meta-regression analysis found no significant impact of the proportion of patients presenting with ACS (P = .882), diabetes mellitus (P = .641), mean reference vessel diameter (P = .985) and follow-up duration (P = .951) on treatment effect with respect to the primary endpoint.

DISCUSSION

This meta-analysis provides a comprehensive and updated quantitative analysis of available evidence on the comparison of DCB vs DES in de novo large vessel CAD, including data from 2961 patients enrolled in 7 RCT. The main findings of the study are:

a) The use of DCB was associated with a similar risk of clinical events vs DES except for TVR. However, data for this outcome was only available in 3 of the 7 included studies and the increased risk in patients undergoing DCB-PCI was not significant when the CAGEFREE I trial was removed. In addition, prediction intervals were not consistent with the CI. Therefore, the results of this outcome should be interpreted with caution.

b) The effect of DCB on the risk of TLR was not affected by the proportion of patients presenting with ACS or diabetes, as well as the mean reference vessel diameter or follow-up duration as assessed by meta-regression analysis.

c) DCB was associated with lower MLD at angiographic follow-up, but with similar LLL vs DES.

DES are the standard of treatment for patients undergoing PCI. However, complications such as stent thrombosis and in-stent restenosis still occur with rates estimated at 0.7-1% and 5-10% at the 10-year follow-up respectively.19,20 Therefore, in recent years there has been a growing concern for developing strategies to reduce stent-related adverse events. In this context, DCBs have emerged as a potential treatment alternative based on a “leaving nothing behind” strategy. Nevertheless, data of patients presenting with de novo large CAD is scarce and conflicting. The CAGEFREE I is the only available clinically powered RCT that included 2272 patients undergoing de novo non-complex CAD revascularization across 40 centers in China. A strategy of DCB-PCI did not achieve non-inferiority vs DES in terms of device-oriented composite endpoint driven by higher rates of TLR in the DCB-PCI group (3.1% vs 1.2%, P = .002). On the other hand, in single-center RCT conducted by Nishiyama et al. with 60 patients with CCS undergoing elective PCI a trend toward lower rates of TLR in the DCB-PCI group (0% vs 6.1%, P = .193) was shown at the 8-mont follow-up.13 Similarly, in a RCT including 170 patients undergoing PCI for de novo large CAD lower rates of TLR at the 12-month follow-up were found in patients undergoing DCB-PCI (1.6% vs 3.4%, P = .306).14 In our analysis when pooling data from all available RCT, the risk of TLR was similar among patients undergoing DCB-PCI or DES-PCI. Notably, since this result was obtained with a moderate heterogeneity (I² ≈ 50%), it should be interpreted with caution regarding its general applicability. These findings remained unvaried at the leave-one-out analysis. In addition, prediction intervals were consistent with CI around ORs showing lack of residual uncertainty. Previous studies have shown that in-stent restenosis after DES is not a benign phenomenon, presenting as an ACS in about 70% of the cases, with 5-10% of these resulting in MI.21 We could speculate that the lack of permanent scaffold with DCB vs DES may predispose to a less aggressive pattern of restenosis and not increase the risk of thrombotic vessel closure beyond 3 months when vessel healing after DCB-PCI has occurred.22

Notably, 5 of the 7 studies included in this meta-analysis enrolled patients presenting with ACS. A total of 34% of the patients included in the CAGEFREE study presented with ACS, with 16% being STEMI cases.7 Four other studies only included STEMI patients.7,9,14-16 Although the performance of DCB in the STEMI scenario is unknown, its use in clinical practice is increasing.23 Culprit lesion plaques in STEMI patients are usually soft and adequate plaque modification can be easily achieved through DCB-PCI (< 30% residual stenosis and low grade of dissection).23 Moreover, the ruptured lipid rich plaque can potentially be an ideal reservoir for effective paclitaxel uptake.24 On the other hand, DCBs carry specific risks for STEMI patients, such as acute recoil and culprit lesion closure, because they don’t provide vessel scaffolding.

In our study, the proportion of patients presenting with ACS had no impact on treatment effects on the meta-regression analysis. Nevertheless, further RCT with adequate sample size are needed to obtain more solid evidence in this field. Of note, complex lesions (eg, severe calcification and bifurcations with planned two-stent technique) were excluded from the studies that included patients presenting with CCS.7,8 Therefore, our findings might not be generalized to this population.

The better angiographic surrogate outcomes with DES-PCI vs DCB-PCI found in our meta-analysis after pooling data from 6 studies can be explained by the absence of a metal scaffold to expand the vessel lumen and the acute recoil following balloon angioplasty. This justifies the lower MLD achieved after DCB-PCI vs DES-PCI. While our analysis did not show significant differences regarding LLL during follow-up, the value of LLL was lower among patients undergoing DCB-PCI when excluding the REVELATION trial.9,17 This study showed extremely low LLL in both DCB and DES groups vs other available evidence from RCT.15,16 The presence of positive vessel remodeling with a late lumen enlargement after the use of DCB evaluated by intracoronary imaging modalities has been evidenced in multiple studies, and seems to be associated with small vessel disease, fibrous and layered plaques and a post-PCI medial dissection arc > 90°.25,26,27 However, evidence of this phenomenon in patients with large vessel CAD is less known.22 It should, therefore, be noted that all studies in this meta-analysis used paclitaxel-DCB. While the evidence comparing sirolimus and paclitaxel-DCB is scarce, 2 recent RCT have shown better angiographic results with the lipophilic component. In the first one, with 121 patients with the novo small vessel CAD, sirolimus-DCB failed to achieve non-inferiority for net-lumen gain at 6 months.28 In the second study, with 70 patients, the 2 devices showed similar results of LLL at 6 months, although patients treated with paclitaxel-DCB had more frequent late luminal enlargement.29 Due to the small sample size and although there is not enough evidence to evaluate differences across clinical endpoints, we cannot assume that there is a class effect across all DCBs. There are larger ongoing RCT to evaluate the outcomes of sirolimus DCB vs DES in large vessels that will provide evidence in this field.30,31

Limitations

The results of our investigation should be interpreted in light of some limitations. First, this is a study-level meta-analysis providing average treatment effects. The lack of patient-level data from the included studies prevents us from assessing the impact of baseline clinical, angiographic and procedural characteristics on treatment effects. Second, minor differences in definition were present for some endpoints (eg, MACE), limiting the reliability of effect estimates. Third, one study which accounted for approximately 75% of all patients included did not included angiographic follow-up,7 thus limiting the evaluation of DCB and DES on angiographic outcomes. Fourth, the clinical follow-up varied from 6 to 24 months. Ideally, outcomes such as TLR should be compared at uniform follow-up across studies (eg, at 1 year), which was not consistently possible in the current analysis. Nonetheless, these differences in follow-up duration were accounted with the IRRs, as detailed in the Methods section. However, longer follow-ups are needed to establish the safety and efficacy profile of DCB vs DES throughout time. Fifth, the definition of large vessel is inconsistent across trials, which might be a source of bias. Finally, the limited number of studies and patients, and the small event rate for some endpoints, such as all-cause mortality may reduce the power for detecting significant differences across groups.

CONCLUSIONS

This meta-analysis provides the most updated quantitative evidence on the use of DCB vs DES for the treatment of de novo large vessel CAD in both CCS and ACS. DCB-PCI is associated with similar TLR and LLL at mid-term follow-up representing an appealing treatment option for patients with large vessel CAD.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

Ethics approval was deemed unnecesary for this meta-analysis as all data were collected and synthesized from previous studies. Additionally, no informed consent was required as there were no patients involved in our work. The meta-analysis of RCT was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 guidelines. We confirm that sex/gender biases have been taken into consideration.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence has been used in the preparation of this article.

AUTHORS’ CONTRIBUTIONS

J. Llau García, S. Huelamo Montoro and J.A. Sorolla Romero participated in literature research and study selection. J.A. Sorolla Romero, L. Novelli and J. Sanz Sánchez contributed to the conception, design, drafting and revision of the article. P. Rubio, J.L. Díez Gil, L. Martínez-Dolz, I.J. Amat Santos, B. Cortese, F. Alfonso, and H.M. Garcia-Garcia contributed to the critical revision of the intellectual content of the article.

CONFLICTS OF INTEREST

F. Alfonso is an associate editor of REC: Interventional Cardiology; the journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. The authors declared no relevant relationships with the contents of this paper.

SUPPLEMENTARY DATA

REFERENCES

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: (J.R. Gimeno).

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 the instantaneous wave-free ratio (iFR) or resting full-cycle ratio.9,10 These methods use a specific moment of the cardiac cycle (for example the iFR uses the diastolic wave-free 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, Murray law-based quantitative 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, Murray law-based quantitative flow reserve; 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

Patients’ baseline characteristics (n = 4818)
Characteristics (cohorts where this data is available)	(± 95%CI) or %
Mean age (26)	66.4 ± 1.3
Male (26)	3318 (68.9%)
Mean BMI (kg/m2) (17)	26 ± 0.8
Hypertension (25)	3189 (66.2%)
Diabetes (25)	1263 (26.2%)
Dyslipidemia (21)	2438 (50.6%)
Mean LVEF (%) (10)	59.6 ± 3.3
Prior or current smoker (23)	1406 (29.2%)
Prior MI (20)	566 (11.7%)
Prior PCI (20)	1314 (27.3%)
Prior CABG (13)	47 (1%)
BMI, body mass index; CABG, coronary artery bypass grafting; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention. Data are expressed as mean value and standard deviation across the studies.

Table 2. Indications for cardiac catheterization

Indication for cardiac catheterization	(%)
Silent isquemia	323 (6.8)
Stable angina	2483 (51.5)
Acute coronary syndrome	1475 (30.6)
Unstable angina	1142 (23.7)
AMI	333 (6.9)
NSTEMI	204 (4.2)
STEMI	13 (0.3)
MI subtype not specified	116 (2.4)
Others	127 (2.6)
AMI, acute myocardial infarction; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

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, Murray law-based quantitative flow reserve; 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, Murray law-based quantitative flow reserve; 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

Vessel characteristics (n = 5440)	(%)
Left main coronary artery	89 (1.7)
Left anterior descending coronary artery	2921 (53.7)
Diagonal branch	52 (1)
Ramus intermedius	54 (1)
Left circumflex artery	772 (14.2)
Obtuse marginal branch	108 (2)
Right coronary artery	1075 (19.8)
Posterolateral branch	7 (0.1)
Interventricular branch	8 (0.15)

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 has been beneficiary of Río Hortega CM22/00168 and Miguel Servet CP24/00128 grants from Instituto de Salud Carlos III. This work has been partially funded by Gerencia Regional de Salud de Castilla y León with grant number GRS 3157/A1/2024.

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

The optimal strategy and timing of complete revascularization in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease remains unclear, and current recommendations are controversial.1 According to 2023 European Society of Cardiology (ESC) guidelines, complete revascularization, based solely on angiographic severity, is recommended in “stable” STEMI patients.2 Conversely, the 2023 Asia-Pacific Expert Consensus Document suggested a treatment strategy of non-culprit lesions (NCL) based on angiographic severity and invasive physiological assessment with fractional flow reserve (FFR) or non-hyperemic pressure ratios for patients with STEMI.3

FFR and non-hyperemic pressure ratios may be inaccurate in acute coronary syndrome (ACS), as hyperemic flow may be reduced due to microcirculatory dysfunction, while the resting flow may be higher due to neurohumoral compensatory mechanisms.4

Angiography-derived indices are additional physiological tools. They need ≥ 1 angiographic projections plus frame count analysis and/or aortic pressure that may also be different in the acute setting.

Furthermore, drugs such as hypolipidemic agents may promote plaque regression, potentially impacting the results of physiological assessment after a few months into therapy.5

Our main objective was to evaluate the changes in invasive physiological measurements of NCL between the acute and staged phases of ACS.

Secondly, we aimed to evaluate the effects of different therapies on physiological measurements.

METHODS

Eligibility criteria

We included studies that evaluated the physiology of NCL during acute and staged interventions for ACS. Studies conducted on assessments following percutaneous coronary interventions of non-culprit vessels, or with patients with chronic coronary syndrome were excluded.

Case reports, conference abstracts, commentaries, editorials, and reviews were excluded as well. An initial protocol was registered in PROSPERO with registration No. CRD42024574683.

Search strategy, and study selection

We conducted the search across ClinicalTrials.gov, Embase (via Ovid), Google Scholar, PubMed, and Web of Science from inception through 26 April 2024 (initial search). We used the “Review articles” filter in Google Scholar and the “Topic” field in Web of Science. No language restrictions were applied.

Duplicates were removed using Deduplicator (SR-Accelerator) software. Title/abstract and full text screening was conducted independently by 2 authors using Rayyan software.

Back in July, 2 authors conducted a backward and forward citation analysis of the included articles using Citationchaser software.

The search strings were repeated in 6 December 2024 (in Embase, sources with invalid date limits were excluded). Simultaneously, we looked into any online conference news on imaging modalities and physiological measurements.6 Additionally, we looked into the “Slide Library” section using the “2024” filter on another web page.7

Finally, we manually reviewed the references of the articles included after the initial search.

All discrepancies were resolved by consensus.

Selection process was recorded in sufficient detail to complete a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram.8

Data extraction

The following data were extracted from each article: a) study characteristics; b) population characteristics; c) type of physiological index(es); d) follow-up duration; e) primary endpoint.

The primary endpoint was the variation between acute and staged indices regarding statistical significance, mean difference (MD), and disagreement on revascularization decision.

One author extracted the data, and another one checked it independently. We contacted the authors of eligible studies when clarifications were needed.

Risk of bias assessment

Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools,9-11 as appropriate.

Two authors independently assessed the risk of bias for each study. We used red for high, yellow for moderate, and green for low risk of bias based on positive answers being ≤ 49%, 50%-69%, or ≥ 70%.

Data synthesis

We conducted a descriptive synthesis of the evidence. Results from data extraction were shown in separate tables based on risk of bias, or bubble charts. Some data were rounded to the nearest integer (age, diameter of stenosis of NCL, and follow-up) or 2 decimal places (MD).

Unless otherwise specified, P values < .05 were considered statistically significant. When MDs were unreported, they were estimated by calculating the difference between staged and acute mean values. When required, a formula for estimating the means was applied.12

In bubble charts, the size of the bubbles represents the number of patients or lesions if the former was not reported. Acute−/staged+ disagreement indicates an acute value above the threshold, with the staged value below the revascularization cut-off. Acute+/staged− disagreement represents the opposite.

RESULTS

Characteristics of the articles, participants, and indices

Results of the search and selection processes are shown in figure 1. Extracted data are shown in table 1 and table 2.

Figure 1. PRISMA flow diagram. PRISMA, preferred reporting items for systematic reviews and meta-analyses.

Table 1. Extracted data of studies with low risk of bias

A total of 20 articles were included13-32 (1 article in the form of a conference presentation).19 Publication years went from 2010 through 2024. The total number of reported patients was 4379.

In every publication, the patients are predominantly men and non-diabetic. The main clinical presentation was STEMI, except for 3 studies.19,29,31

The following methods were assessed: a) angiography-derived: Murray law-based quantitative flow ratio (muQFR), quantitative flow ratio (QFR), vessel FFR (vFFR); b) hyperemic (FFR); and c) non-hyperemic indices: instantaneous wave-free ratio (iFR), resting distal-to-aortic coronary pressure ratio (P_d/P_a). When reported, the FFR was obtained using adenosine.

Reported patients for each index are as follows: 2340 (muQFR), 1187 (QFR), 710 (FFR), 243 (iFR), 92 (vFFR), and 73 (resting P_d/P_a).

Risk of bias

The studies mainly used an observational (cohort) design. Cohort studies on angiography-derived methods were retrospective, except for 1 article on QFR.28 Those on FFR and non-hyperemic indices were prospective, except for 2 substudies.22,26

QFR was also evaluated by 1 quasi-experimental study27 and 1 randomized controlled trial.13

Finally, the FFR was assessed by 2 randomized controlled trials, in samples with predominance of non-ST-segment elevation myocardial infarction (NSTEMI).19,31,33

Results are shown in table 1 of the supplementary data, table 2 of the supplementary data, and table 3 of the supplementary data. There were no studies with high risk of bias.

Table 2. Data drawn from studies with moderate risk of bias

Primary endpoint

Statistical significance

There were no articles on relevant changes in muQFR,16,30 resting P_d/P_a,25 and vFFR17 at the follow-up.

A significant difference in FFR, iFR, and QFR was found in 3, 2, and 1 article(s),14,22-26 respectively. In 1 study, the difference in QFR was non-significant, with a significance threshold of .001.28

These variations were seen in cohorts of STEMI patients.14,22-26 Studies including non-ST-segment elevation acute coronary syndrome (NSTEACS) did not show any relevant differences regarding the QFR15 or the FFR.19,21,29,31

A total of 4 articles20,22,25,26 evaluated > 1 method. The iFR and FFR were both stable in the study by Musto et al.,20 while the iFR was more stable than the FFR in a different article.25 The QFR was compared to both the FFR26 and the iFR.22 Unlike these indices, the QFR did not show any significant changes in staged phases.22,26

Mean differences

The most valued indices showed varying results. muQFR had MD values close to 0 in both studies.16,30

QFR variations were observed at both lower22,26,28 and higher values.14,15,18 Conversely, the FFR and the iFR varied towards smaller and greater values, respectively.22-26,29,31 Their MDs ranged from − 0.02 to + 0.06 (QFR), − 0.03 to 0.00 (FFR), and 0.00 to + 0.03 (iFR).14,19-21,24,25,28 MD values of 0.01 were observed more often.

In STEMI patients, the MDs of the FFR, the iFR, and the QFR were close to 0 only in studies with mean follow-ups of < 1 week.20,32 In studies including NSTEACS, the FFR MDs were close to 0 after longer mean follow-ups (> 1 month).19,21 Furthermore, Ntalianis et al. showed a greater stability of FFR in patients with NSTEMI (MD, 0.00) vs those with STEMI (MD, − 0.02).21

Disagreement

Disagreement in the indication for revascularization is shown in figure 2. MDs of 0.01 resulted in variable disagreements: 5%-18%.15,18,23,25

Figure 2. Disagreement between acute and staged values in the indication for PCI. B, Barauskas; C, Cortés; E, Erbay; FFR, fractional flow reserve; H, Huang; iFR, instantaneous wave-free ratio; K, Kirigaya; L, Li; muQFR, Murray law-based QFR; N, Ntalianis; PCI, percutaneous coronary intervention; QFR, quantitative flow ratio; SE, Sejr-Hansen; SH, Shukla; SP, Spitaleri; T, Thim; V, van der Hoeven; vFFR, vessel fractional flow reserve.

Unlike the QFR, the FFR and the iFR consistently showed a higher frequency of one type of disagreement: acute−/staged+ for FFR,21,23,25 and acute+/staged− for iFR.24,25

Secondary endpoint

A total of 4 studies compared the effects of different drugs on the physiological parameters.13,19,27,31

Ticagrelor (which can increase the levels of adenosine) was compared to clopidogrel and no significant differences were found in the FFR of non-culprit vessels after 6 months of treatment.31

Another 3 studies compared a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (eg, alirocumab or evolocumab) plus high-intensity statin (HIST) (eg, rosuvastatin 20 mg/day) vs statin-only therapy.13,19,27

In a nonrandomized study, the QFR values were significantly higher in the evolucumab group at 12 months.27 However, in 2 randomized studies, no significant differences were observed across the 2 treatment groups in the QFR at 12 months or in the FFR at 3 months, respectively.13,19

DISCUSSION

The main findings of this systematic review are these: firstly, in STEMI patients, the muQFR, resting P_d/P_a, and vFFR indices remained relatively stable in retrospective and/or small studies. The FFR, iFR, and QFR showed variability between acute and staged phases. Secondly, the FFR did not change significantly in prospective cohorts or randomized controlled trials including NSTEACS. Thirdly, the QFR was more stable than both the FFR and the iFR in direct comparisons, although only the FFR and the iFR exhibited consistent directions of change. Fourthly, PCSK9 inhibitors added to HIST did not influence physiological measurements compared with HIST in randomized controlled trials.

The muQFR demonstrated stability in a large sample of patients. This index is based on a single angiographic view, unlike other angiography-based methods that require 2 angiographic projections. This characteristic might reduce observer variability and enhance reliability. Future prospective and comparative studies are needed to confirm the validity of this method.

Although low variations for FFR, iFR, and QFR were observed in cohorts of STEMI patients,20,32 these studies were limited by short-term follow-ups. Thim et al. found a non-significant change in the iFR with 5-day follow-ups, whereas there were significant changes with ≥ 5 day follow-ups.24 Therefore, physiological disarrangements initiated at the acute moment of STEMI might still exist if a staged procedure is conducted close to the index event.24,25

Angiographic, hemodynamic, and microcirculatory variables may alter acute physiologic assessment and account for the higher reliability of the FFR in NSTEACS vs STEMI.

In patients with microvascular dysfunction, epicardial blood flow cannot increase sufficiently during maximal hyperemia, thus causing a reduced pressure gradient across the stenotic lesion,29 and higher FFR values.

In STEMI patients, microcirculatory indices (coronary flow reserve and index of microcirculatory resistance) were significantly worse during the acute phase, along with a higher FFR.25 Conversely, studies including NSTEACS did not show any significant differences in the coronary flow reserve and/or index of microcirculatory resistance at the follow-up.21,29,31

Furthermore, STEMI patients showed greater acute angiographic severity, along with lower QFR or iFR values,14,22 which may be attributed to vasoconstriction typically occurring during the acute phase.

Consequently, the FFR seems more reliable in NSTEACS vs STEMI due to reduced acute microcirculatory impairment and/or vasoconstriction.

Literature trials support the use of the FFR in NCL of NSTEMI during the acute phase (eg, within the index hospitalization).34,35 In contrast, acute FFR-guided complete revascularization did not show any significant benefits in terms of death or myocardial infarction in STEMI patients.36-39

The higher stability of QFR when directly compared to the FFR or the iFR was limited to a small number of patients in post-hoc substudies.22,26 A MD of 0.01 sometimes led to non-trivial disagreement on revascularization decision,25 likely due to baseline values being near the cut-off. Therefore, it is essential to have an index which remains stable or demonstrates consistent changes, such as the FFR and the iFR. Similarly, these indices demonstrated a greater frequency of a specific type of disagreement (methodological variations–wire positioning–may explain the less frequent cases of disagreement).24

Therefore, the FFR and the iFR could be considered in the acute STEMI as an alternative to delayed assessments,25 considering that the FFR tends to decrease and the iFR tends to increase. The FFR could guide the revascularization of positive lesions (FFR ≤ 0.80).25 In patients with a FFR > 0.80, acute iFR assessment can be used to delay the revascularization of negative NCL (iFR > 0.89).24 In the remaining cases (iFR ≤ 0.89), some authors suggested a staged reevaluation.24 At least 5 days after the index procedure should go by. This was the minimum time needed to observe the initial resolution of acute physiological disturbances.24

Finally, when plaques are correctly identified as functionally negative, they may still be vulnerable and associated with adverse events. NCL exhibiting thin-cap fibroatheromas as defined by optical coherence tomography, and having a muQFR ≤ 0.80, showed the highest event rate,40 which suggests that imaging can offer additional prognostic information.

PCSK9 inhibitors have shown minimal impact on coronary physiology, despite greatly reducing low-density lipoprotein-cholesterol (LDL-C) levels. A large treatment effect on HIST only,19 minor flow limitation at baseline, and microvascular compensation may account for this finding.13

However, combining alirocumab with HIST resulted in a greater increase in cap thickness of fibroatheromas vs statin monotherapy as assessed by optical coherence tomography.41 Moreover, lower LDL-C levels after an ACS are associated with the occurrence of fewer cardiovascular events.2 Therefore, PCSK9 inhibitor treatment is recommended in patients who do not reach their LDL-C target despite maximum tolerated statin and ezetimibe therapy.2

Limitations

The wide variety of indices to assess coronary physiology has led to a lack of evidence on some of them; similarly, few studies made direct comparisons among such indices.

Our evaluations are mainly based on observational studies with a very different follow-ups.

Angiography-based methods frequently exhibited bias due to their retrospective analysis. Some patients were excluded because of the poor quality of angiographies or anatomic issues, such as ostial lesion or severe vascular tortuosity. Some angiographies were not obtained optimally according to the specific acquisition guide.

CONCLUSIONS

The assessment of functional indices for NCL during the initial procedure for STEMI is not absolutely reliable. This evidence is due to potential variability of the FFR, the iFR, and the QFR outside the acute phase. Although variation was not significant for muQFR, resting Pd/Pa, and vFFR, retrospective and/or limited data limit the generalizability of these findings.

Both the FFR and the iFR showed consistent directions of change. Therefore, during an acute STEMI, the FFR can guide the revascularization of positive NCL, while the iFR can help defer revascularization of negative NCL. A negative FFR with a positive iFR should be reevaluated.

The FFR shows robust data supporting its use in NLC of NSTEMI during the acute phase, meaning that it is a more reliable index for initial ACS procedures.

DATA AVAILABILITY

Search string for Google Scholar: “acute coronary syndrome”|”myocardial infarction” “fractional flow reserve”|FFR| “hyperemic ind”|”resting ind”|iFR|”instantaneous wave-free ratio”| “angiography-based ind”|”angiography-derived ind”|QFR|”quantitative flow ratio”|OFR staged|repeated|later. The remaining search strings are available upon request.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

Ethical committee and patient’s informed consent: not applicable. We followed the SAGER guidelines with respect to possible sex/gender bias.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

Microsoft Copilot was used to help edit the English version of the text.

AUTHORS’ CONTRIBUTIONS

F. Vergni designed the work. F. Vergni, S. Buscarini, L. Ciurlanti, and F.L. Gurgoglione contributed to data acquisition (screening, and/or extraction). F. Vergni, and L. Ciurlanti conducted the critical appraisal. F. Vergni, and S. Buscarini contributed to data interpretation. F. Vergni, and F.L. Gurgoglione drafted, edited and reviewed the work. F. Vergni, S. Buscarini, L. Ciurlanti, F.L. Gurgoglione, F. Pellone, and M. Luzi approved the final version for publication.

CONFLICTS OF INTEREST

None declared.

SUPPLEMENTARY DATA

REFERENCES