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

INTRODUCTION

Magnesium-based bioresorbable scaffolds (Magmaris) are safe devices with good results in the long run like the BIOSOLVE II1 and BIOSOLVE III2 clinical trials show where no device thrombosis was seen at the long-term 12- to 24-month follow-up. Despite this fact, the device own limitations (ill-advised in cases of calcified complex coronary anatomy or in long lesions) have reduced its use significantly in the routine clinical practice to the point that only 224 procedures with bioresorbable devices were performed in Spain in 2019 (0.2% of the total number of devices implanted).3

As already mentioned, the good results reported in long-term follow-ups have turned the Magmaris (Biotronik, Germany) into the only bioresorbable metal scaffold to receive the CE marking (Conformité Européenne).4

The role Magmaris plays in the acute coronary syndrome setting is not widely known and further studies will be needed before its safety profile can be assessed. The objective of this work was to analyze—through an observational study in the routine clinical practice—the long-term (> 12 months) clinical safety of Magmaris scaffolds implanted in patients with acute coronary syndrome in the cath lab of a single center.

METHODS

Consecutive observational registry of patients diagnosed with acute coronary syndrome implanted with magnesium-based bioresorbable scaffolds between November 2016 and November 2018. The study was approved by the hospital ethics committee and all patients gave their signed written informed consent to participate in the study. The study primary endpoint was a composite of target vessel myocardial infarction, target lesion failure, and cardiovascular death. The study secondary endpoint included the device thrombosis. The PSP strategy (predilation, sizing, and postdilation) derived from the GHOSTEU registry was used in all the cases.5 In 100% of the patients the optical coherence tomography was used for the right characterization of the lesion and size of the vessel.

RESULTS

A total of 36 patients (29 males, 80%) were included with a median age of 59.61 ± 9.74 years. The follow-up period was 1001 days with an interquartile range of 342 days. Table 1 summarizes the baseline clinical characteristics of the sample as well as the main angiographic characteristics.

Table 1. Baseline clinical characteristics and angiographic parameters of the patients

A total of 100% of the patients received a Magmaris device in the target lesion causing the study acute coronary event. Drug-eluting stents were implanted at the discretion of the operator in 12 of the 36 patients (33.3%), and in 1 patient only (2.8%) the implantation of the stent and the Magmaris scaffold overlapped. However, in the remaining patients they were not implanted in the target vessel.

Only 1 Magmaris scaffold was used in 15 patients (41.7%), 2 in 12 cases (33.3%), 3 in 2 cases (5.6%), 4 in 3 cases (8.3%), 5 in 3 cases (8.3%), and a maximum of 6 Magmaris devices in 1 single patient (2.8%). In 20 patients (55.6%) the stent and the Magmaris device implantation overlapped.

Regarding the device-oriented composite endpoint, 0 cases of target vessel myocardial infarction occurred (0%). However, 2 cases of target lesion failure were confirmed (5.6%), and 1 noncardiovascular death (2.8%) was reported at the 36 months following Magmaris implantation. However, the cause remained elusive for the lack of an autopsy (figure 1). Regarding the secondary endpoints, no Magmaris thrombosis was reported at the follow-up (table 2).

Figure 1. Kaplan-Meier survival curve with respect to the study primary endpoint: a device-oriented composite endpoint of target vessel myocardial infarction, target lesion failure, and cardiovascular death. DOCE, device-oriented composite endpoint.

Table 2. Primary (device-oriented composite endpoint) and secondary clinical events of the patients at the follow-up (N = 36, 100%)

A total of 11 admissions were reported at the follow-up (30.6%). Among these, 8 were due to recurrent angina (22.2%), 2 to heart failure or de novo atrial fibrillation (5.6%), and 1 to atrioventricular block that required pacemaker implantation (2.8%).

The coronary angiography was repeated in 10 cases (27.8%), the absence of lesions was confirmed in 3 patients (8,3%), stent restenosis was reported in 1 patient 2.8%), Magmaris restenosis in 2 (5.6%), and de novo lesions in 4 patients (11.1%).

When the cases of Magmaris restenosis were studied across time it was found that all of these occurred after the 24-months follow-up (1 case after 737 days and the other after 1189 days). The cardiovascular death reported in 1 patient occurred 1084 days after implantation.

DISCUSSION

The magnesium-based bioresorbable scaffold (Magmaris) is a highly successful device when implanted following the recommendations made by the manufacturer6 including the right predilation and optimization of the lesions using intracoronary imaging modalities. A study proved that an optimal PSP technique was not associated with a lower rate of the device-oriented composite endpoint. However, patients with optimal PSP-3 had numerically fewer episodes compared to patients without optimal PSP-3 (0.5% vs 2.9%, P = .085, and 0.5% vs 1.8%, P = .248, respectively).7

The real-world 12-month follow-up results of a cohort registry with Magmaris have recently been published. These results have confirmed the Magmaris safety profile and its low rate of events (target lesion revascularization in 4.7%) and lack of thrombosis.8

Also, the use of magnesium-based bioresorbable scaffolds has been studied in a group of 50 patients with non-ST-segment elevation acute coronary syndrome. This device reached angiographic success in 100% of the cases. One case of failed target vessel revascularization was reported the day after the procedure that required the implantation of a bare-metal stent. No device-related events were reported at the 6-month follow-up.9

The Magmaris scaffold and the sirolimus-eluting stent were compared in a controlled, randomized, blinded, multicenter study of patients with ST-segment elevation acute coronary syndrome. This study proved that in 150 patients the primary endpoint of a greater vasomotor response to medication was better in the Magmaris group at the 1-year follow-up. However, the Magmaris scaffold was associated with a worse angiographic progression and a greater late luminal loss compared to the bare-metal stent. It was also associated with a higher rate of target lesion revascularization without a significantly higher number of thrombotic events being reported.10

In our registry, the immediate rate of successful device implantation was 100%. Device overlapping occurred in 55.6% of the cases with a high frequency of treatment of 2 and 3 vessels (55.4%). Despite the complexity of the lesions, device restenosis was only reported in 2 cases (5.6%) at the > 3-year follow-up. The rate of thrombosis at the follow-up was 0 cases and the rate of cardiovascular death—considering 1 case with the devices implanted 36 months beforehand (and without necropsy or previous clinical assessment)—was 2.8%. In our study of real-world clinical practice this confirms the device safety profile in the short and mid-term in the acute coronary syndrome setting. The results of the BIOSOLVE IV registry reported a target lesion failure rate of 4.3%,11 similar to the one seen in our registry—5.5%—despite our patients’ profile of higher ischemic risk (all of them with acute coronary syndrome and an average lesion length of 29.17 mm ± 13.39 mm with Magmaris overlapping in 55.6% of the cases).

Limitations

Our study main limitation is its small sample size, which shows the low penetration of resorbable scaffolds in our hospital setting. Another limitation is the registry observational nature with an inherent selection bias, without defined inclusion and exclusion criteria, and the use of second-generation drug-eluting stents in 33.3% of the patients outside de target vessel except for 1 case where the stent and the Magmaris device overlapped (2.8%).

Another limitation was the lack of an independent clinical event adjudication committee. However, 100% of the patients were followed-up (through electronic health records and phone calls) by the research working team.

CONCLUSIONS

In our registry of patients with acute coronary syndrome who received the Magmaris scaffold the primary endpoint of target lesion failure or target vessel myocardial infarction did not increase compared to registries previously published. No cases of scaffold definitive thrombosis were reported at the follow-up, and only 1 cardiovascular death was reported 36 months after implantation without knowing the definitive cause. Considering the aforementioned limitations, our results confirm that Magmaris scaffolds could have a favorable clinical profile in the complex setting of acute coronary syndrome.

FUNDING

No external funding has been received.

AUTHORS’ CONTRIBUTIONS

All authors contributed equally during the collection of clinical data and the performance of the interventional procedures including the follow-up of all of the patients.

CONFLICTS OF INTEREST

None reported.

REFERENCES

INTRODUCTION

The current estimates reveal the population gradual aging, which will be more evident in the coming years.1 Based on these estimates, by the year 2050, our country will become one of the oldest worldwide with more than 4 million people over 80 years of age. This means that the percentage of patients treated with primary angioplasty (PA) is on the rise in our setting.

Although old age is associated with worse prognoses, PA is still the best reperfusion strategy for these patients.2-5 This segment of the population has a high prevalence of comorbidities, is often recommended fewer treatments, and has a higher risk of complications during revascularization procedures. Also, these patients are often misrepresented in the clinical trials, meaning that there is little scientific evidence available on the clinical characteristics, results, and long-term prognosis after PA.6

The objectives of this study were to analyze the characteristics, results, mortality, and prognostic predictors of patients > 80 treated with PA in our center.

METHODS

Single-center, retrospective, and observational study. All patients > 80 treated with PA in our center from January 2013 through September 2019 were included. Different clinical and epidemiological variables like age, sex, cardiovascular risk factors, presence of comorbidities, and the total ischemic time were prospectively registered in the unit database. The Charlson Comorbidity was retrospectively obtained at admission to stratify the patients’ overall comorbidities.7,8 This study was approved by Hospital Universitario Fundación Alcorcón ethics committee and waiver of informed consent was accepted.

Catheterization and treatment

Most cases were treated with percutaneous coronary intervention using the standard technique via radial access. The contrast agents used in all the cases were iohexol (Omnipaque 350, and Omnipaque 300), and iodixanol (Visipaque 320). The number of main vessels damaged seen on the coronary angiography, the access route, the dose of contrast used, the x-ray image time, and the number and type of stent use were recorded. Angiographic success and the presence of complications during the procedure were recorded as well. The operator chose the type of stent he would use during the procedure, although the local protocol recommended the use of conventional stents preferably. Drug-eluting stents were spared for situations of high risk of restenosis.

Follow-up and endpoints

Follow-up data were obtained after reviewing our hospital electronic health records. Also, phone calls to the patient or his family were made followed by a standard survey when appropriate. The endpoints studied were in-hospital mortality and complications, cardiovascular events, and cardiac death at the long-term follow-up.

Definitions

Left ventricular systolic function was estimated on the echocardiogram. The presence of a left ventricular ejection fraction < 45% was considered moderate-to-severe left ventricular dysfunction. Cardiogenic shock was defined as systolic arterial pressure < 90 mmHg for, at least, 1 hour followed by tissue hypoperfusion that required inotropic support and/or intra-aortic balloon pump implantation. Cardiac deaths were due to acute coronary syndrome, heart failure or ventricular arrhythmia. Angiographic success was defined as the presence of TIMI grade ≥ 2 flow in the absence of residual stenosis > 50%. The glomerular filtration rate was estimated using the simplified modification of diet in renal disease (MDRD) equation.9 Chronic kidney disease was defined as a glomerular filtration rate < 60 mL/min/ 1.73 m2 at admission. Bleeding complications associated with vascular access were classified based on the Bleeding Academic Research Consortium (BARC) definitions.10 BARC type > 2 hemorrhages were considered major bleeding. Target lesion revascularization was defined as the need for a new revascularization procedure (whether percutaneous or surgical) of the coronary segment with stenting in the presence of angiographic restenosis (stenosis > 50%) and symptoms or signs of myocardial ischemia.

Statistical analysis

The statistical software package SPSS version 20 was used for the analysis of data. Quantitative variables were expressed as mean ± standard deviation. The categorical ones were expressed as absolute value and percentage.

Univariate and multivariate modified Poisson regression analyses were conducted to determine the independent prognostic factors of in-hospital mortality. The variables included in the multivariate analyses were those considered of the greatest clinical relevance: Killip Class > I at admission, age > 85, chronic kidney disease, Charlson Comorbidity index > 2, and presence of moderate-to-severe left ventricular dysfunction. Results were expressed as relative risks and their 95% confidence interval (95%CI).

Univariate and multivariate Cox regression analyses were conducted to determine the independent predictors of overall mortality at the long-term follow-up. The variables included in the multivariate analyses were those associated with a higher mortality rate in the univariate analysis and also those of the greatest clinical relevance: Killip Class > I at admission, age > 85, chronic kidney disease, Charlson Comorbidity index > 2, and presence of moderate-to-severe left ventricular dysfunction. Results were expressed as hazard ratios (HR) and their 95%CI. P values < .05 were considered statistically significant. The inter-group overall mortality-free survival rates based on the presence of chronic kidney disease and a Charlson comorbidity index > 2 were compared using the Kaplan-Meier Curves (log-rank test).

RESULTS

Clinical characteristics and of the interventional procedure

A total of 1269 PAs were performed in our center from January 2013 through September 2019. A total of 10.5% were ≥ 80 years old at admission. The study group included 133 patients (57 women [43%]) with a median age of 85.3 ± 3.8 years treated with PA. The study population had a high prevalence of cardiovascular risk factors. A total of 66.2% of the patients had chronic kidney disease. The anterior was the most common location of the infarction. A total of 16.6% of the patients were Killip Class III-IV. In 28.5% of the cases delays of more than 6 hours between the beginning of pain and reperfusion were reported. The mean Charlson Comorbidity index used to assess the comorbidities of the patients included in our series was 2.3 ± 1.6 (table 1).

Table 1. Clinical angiographic, and interventional procedure data

Regarding the angiographic and procedural data, the radial access was used in 80.5% of the patients of whom 47.4% had multivessel disease. Almost half of the patients were released from the hospital with incomplete angiographic revascularizations. Thrombus aspiration was performed in one fourth of the patients and drug-eluting stents were implanted in 30.8% of these patients (table 1).

Patient progression at the hospital setting

Regarding patient progression at the hospital setting, 63 patients (49%) developed heart failure and 24 patients (18%) died during admission. Two patients (1.5%) had stent thrombosis during their hospital stay. The cause of death of 21 of the dead patients (87.5%) was cardiovascular. There was a statistically significant higher in-hospital mortality rate in patients with Charlson comorbidity indices > 2 (28.9% vs 13.7%, P = .039), Killip Class > I (51.5% vs 7%; P < .001), and worse ventricular (26% vs 4.3%, P = .003) and renal functions (23.9% vs 6.7%; P = .031). The Killip Class-based mortality rate based was 7% for Killip Class I, 27.3% for Killip Class II, 57.1% for Killip Class III, and 66.7% for Killip Class IV (figure 1).

Figure 1. In-hospital mortality based on Killip Class.

In the multivariate modified Poisson regression analysis, the only independent prognostic factor of in-hospital mortality was the Killip Class at admission (relative risk, 6.5; 95%CI, 2.01-20.36; P = .001) (table 2).

Table 2. Factors associated with a higher in-hospital mortality rate. Univariate and multivariate modified Poisson regression analyses

Long-term follow-up

A long-term follow-up was conducted of the 109 survivors. The median clinical follow-up was 24.3 months (interquartile range, 6.9-49.4 months) with 3 patients (2.8%) lost to follow-up. The clin­ical events occurred at the follow-up are shown on table 3. The overall mortality rate at the long-term follow-up was 23% with 97.2% of deaths due to noncardiac deaths.

Table 3. Events at the long-term follow-up

In the univariate Cox regression analysis, the variables associated with a higher overall mortality rate were Killip Class > I (HR, 4.26; 95%CI, 2.38-7.62; P = .001), chronic kidney disease (HR, 7.24; 95%CI, 1.7-30.8; P = .007), and a Charlson Comorbidity index > 2 (HR, 2.74; 95%CI, 1.18-6.36; P = .019) (table 4). Patients with chronic kidney disease had a higher percentage of cases with Charlson Comorbidity indices > 2, but this difference was not statistically significant (19% vs 28,4%; P = .27).

Table 4. Factors associated with a higher mortality rate at the long-term follow-up. Univariate and multivariate Cox regression analyses

In the multivariate Cox regression analysis, the only independent predictors of overall mortality were chronic kidney disease (HR, 5.7; 95%CI, 1.29-25.5; P = .022), and a Charlson Comorbidity index > 2 (HR, 2.57; 95%CI, 1.07-6.18; P = .035) (table 4).

Patients with chronic kidney disease had lower survival rates at the long-term follow-up (56 ± 4.4 months vs 75 ± 3 months; P = .002) (figure 2). Patients with Charlson comorbidity indices > 2 also had lower survival rates at the long-term follow-up (45.5 ± 5.9 months vs 65.8 ± 3.3 months; P = .015) (figure 3).

Figure 2. Survival curves at the long-term follow-up stratified based on the presence of chronic kidney disease (log rank test, P = .002). ERC, chronic kidney disease.

Figure 3. Survival curves at the long-term follow-up stratified based on the presence of Charlson comorbidity indices > 2 (log rank test, P = .015).

DISCUSSION

Information on the results of PA in elderly patients and its long-term prognosis is scarce because this group of patients is often misrepresented in clinical trials.6 Our study emphasizes these patients’ high mortality rate (mainly due to cardiac causes)—both in-hospital and at the long-term follow-up—with a significant contribution from noncardiac mortality and comorbidities as prognostic predictors.

This segment of the population has special characteristics that pose an added risk. These are patients with a high prevalence of comorbidities and worse renal function.5 Diagnosis is not always easy because of the atypical symptoms reported and possible presence of previous changes on the EKG, factors that contribute to delaying reperfusion therapy.11 Finally, these are patients with a higher risk of bleeding and other complications during PA.12

Regarding the clinical profile of patients > 80 treated with PA in our center we should mention the higher percentage of women (43%) compared to other series from the general population, and the high prevalence of chronic kidney disease (66%), delays of more than 6 hours (29%), and advanced Killip Class (17%). All these characteristics are consistent with what has already been described by former studies in this population.5,13

Regarding the procedural aspects, the radial access was used in 80.5% of the cases. Elderly patients, especially women, have higher rates of failure with this access, but at the same time, these patients have the highest risk of bleeding with the femoral access. Rodríguez-Leor et al.14 reported on the possibility of achieving radial access in 95.1% in a population of patients > 75 treated with PA.

The in-hospital mortality seen in our study (18) is obviously higher to that of the general population, but not significantly different from that reported by other registries of elderly patients.12-17 In a group of 34 80-year-old patients treated with PA Sim et al.5 reported an in-hospital mortality rate of 18%. However, it went up to 37% in patients with ST-segment elevation acute coronary syndrome not treated with PA. In their prospective registry of 496 patients > 80 who received invasive treatment, Kvakkestad et al.12 reported an in-hospital mortality rate of 13%. In our series the main prognostic factor during admission was the patient’s hemodynamic situation measured using Killip Class. It is a well-known prognostic factor that has been widely described in PA studies.18

The mortality rate at the long-term follow-up was 23% with a striking contribution from noncardiac mortality, which is a differential factor with respect to series from the general population. This lower rate of adverse cardiovascular events in elderly patients who survive a myocardial infarction was found in other registries and may be due to the high early selection during the acute phase.13,17 In the aforementioned registry of Kvakkestad et al.12 the mortality rate at the 3-year follow-up was 29%. In the Swedish registry of 80-year-old patients treated with PA from 2001 to 2010, the annual mortality rate reported was 25%.17 In our series, the fact that mortality at the long-term follow-up was mostly noncardiac contributed to the fact that the main prognostic predictors at the long-term follow-up are extracardiac factors like renal function and the Charlson Comorbidity index. These factors may be understudied at the follow-up after PA.

The effect of comorbidities in the prognosis of patients is often quantified using the Charlson Comorbidity index.7,8 This index assigns a given score to a series of comorbidities based on the risk of mortality of every comorbidity. The overall score is associated with a given mortality risk. Over the last few years, interest has been growing on the analysis of comorbidities and other variables associated with age. However, data are still scarce on their prognostic influence on patients with infarction treated invasively. The existing growing heterogeneity among 80-year-old patients with infarction requires prognostic indices to stratify these patients into risk groups based on uniform criteria. Using a tool to guide us in the long-term prognosis of these patients may help us decide what the most suitable follow-up is. Several studies have proven the utility of the Charlson Comorbidity index in the acute coronary syndrome as a predictor of mortality. Núñez et al. determined the prognostic predictive value of this index in patients with myocardial infarction mostly treated conservatively.19 They found that the comorbidities present at admission were associated with higher rates of mortality or reinfarction at the 30-day and 1-year follow-up. In our series of invasive management, we found that a Charlson Comorbidity index > 2 was an independent predictor of mortality at the long-term follow-up. However, it is not a predictor of patient progression at the hospital setting where the most important thing is the patient’s hemodynamic situation. Therefore, in this population the Charlson Comorbidity index can help us plan their long-term follow-up.

Glomerular filtration rate impairment is a powerful predictor of mortality in different conditions including myocardial infarction.20 Same as it happens with the Charlson Comorbidity index, in our series of patients, renal function impairment was also an independent predictor of long-term mortality. This confirms that a more comprehensive assessment of 80-year-old survivors of a PA including an accurate assessment of comorbidities and renal function can optimize the management of this population after hospital discharge.

Risk stratification and decision-making are especially complex in 80-year-old patients with myocardial infarction because these a highly heterogeneous patients in whom chronological age may not reflect their actual biological situation. In view of our study findings we believe that in elderly patients it is important to include the measurement of the glomerular filtration rate and, above all, the assessment of comorbidities in the decision-making process at the long-term follow-up after PA. The close follow-up of these patients with several comorbidities can help diagnose potential decompensations (both cardiac and noncardiac) to prevent new hospitalizations. On the other hand, comorbidities determine a high use of drugs which favors the appearance of adverse events, interactions, and therapeutic compliance mistakes. The best thing to do would be to maximize compliance in this population, specify the benefits expected, and minimize the risks associated with the therapy used. Also, optimizing the management of noncardiac diseases can be the key to stabilize coronary artery disease. For all this, keeping a close collaboration with geriatric units after the hospital discharge of 80-year-old patients treated with PA improves their prognosis.

Limitations and strengths

Although the demographic, clinical, and angiographic data were collected prospectively, this was a retrospective analysis with the corresponding limitations of this type of studies. The size of the sample may have limited the statistical power of our study to detect the statistical significance of some associations. Also, the low number of events may have limited the reliability of the multivariate analysis regarding in-hospital mortality and mortality at the long-term follow-up since it included 5 variables in each of these 2 analyses. Since this was a single-center study, results may not be generalizable to other settings.

One of the strengths of the study is that results are based on a thorough and consecutive registry of patients from our setting who were hospitalized after a PA. Also, that a great deal of clinical, analytical, and angiographic information was obtained during their hospital stay and several evolutionary variables were registered at the very long follow-up.

CONCLUSIONS

Patients over 80 treated with PA have a high in-hospital mortality rate (18% in our series). The only independent predictor of in-hospital mortality was Killip Class. Over the next 2 years, mortality is still very high (23%), but is basically associated with noncardiac problems. The independent predictors of overall mortality at the long-term follow-up were chronic kidney disease and a Charlson Comorbidity index > 2

FUNDING

None.

AUTHORS’ CONTRIBUTIONS

L. Hernando Marrupe and J. Botas Rodríguez had the study idea. L. Hernando Marrupe, J. Botas Rodríguez, C. Marco Quirós, and R. Gayoso Gayo designed the study. L. Hernando Marrupe, C. Marco Quirós, R. Gayoso Gayo, V. Espejo Bares, V. Artiaga de la Barrera, C. Jiménez Martínez, R. Del Castillo Medina, and A. Núñez García collaborated in the study data mining. L. Hernando Marrupe, and E. Pérez Fernández conducted the statistical analysis. L. Hernando Marrupe, C. Marco Quirós, and R. Gayoso Gayo interpreted the results and wrote the manuscript first draft. L. Hernando wrote the manuscript final version, and J. Botas conducted the manuscript critical review.

CONFLICTS OF INTEREST

None reported.

REFERENCES

INTRODUCTION

Physiological assessment using the fractional flow reserve (FFR) or the instantaneous wave-free ratio (iFR) is strongly recommended by the European guidelines to the guide percutaneous coronary intervention (PCI) decision-making process to treat intermediate coronary stenosis (indication I, level of evidence A) and multivessel disease (indication IIa, level of evidence B).1-7

The established cut-off values based on landmark trials to safely postpone treatment of a coronary lesion are FFRs > 0.80 and iFRs > 0.89.2-7 Unlike the FFR, the new iFR resting index allows us to analyze the physiological significance of each segment in the presence of coronary arteries with several lesions. Syncvision is a new software that analyzes the specific contribution of each coronary segment allowing us to predict physiological improvement after percutaneous treatment.8,9 It’s not necessary to use any vasodilators either, thus reducing any potential side effects.3,4

However, the evidence supporting the use of coronary physiology assessment with both indices and the use of the Syncvision software in other type of lesions and other clinical scenarios is scarce.8-10 For this reason, it is not quite clear whether the same cut-off value established in the landmark trials should be used; or if safety, utility, and efficacy will be the same.

The objective of this study is to describe our experience with coronary physiology assessment using the iFR (and/or the Syncvision- guided iFR-pullback study) in all-comer patients undergoing invasive coronary angiography.

METHODS

We performed a single-center retrospective study including all patients who underwent functional assessments (using the iFR) and/or the Syncvision software at our center between January 2017 and December 2019 on a PCI decision-making process. The cut-off value to consider the need for revascularization was the same one established by the landmark clinical trials (iFR ≤ 0.89).3,4 The pressure guidewires used for the functional assessment were the Volcano Verrata, and the Volcano Verrata Plus (Philips Volcano, Belgium). The use of the Syncvision software to guide the iFR study as well as the lesions assessed were left to the operator’s discretion.

All subjects included in the study gave their informed consent to undergo the procedure and for data analysis and publication. Additionally, the study received the proper ethical oversight and was approved by our center ethics committee.

Inclusion and exclusion criteria

Patients with the following criteria were included: a) consecutive patients in whom an invasive coronary angiography was performed due to stable or unstable symptoms or silent ischemia; b) presence of, at least, a lesion or vessel physiologically assessed with the iFR during the index procedure. The following exclusion criteria were stablished: a) impossibility to understand the informed consent during the index procedure; b) written informed consent to use data for research purposes not provided.

Lesion classification

The lesions physiologically assessed were classified based on their angiographic characteristics and/or clinical setting: a) intermediate lesions: lesions with a 40% to 80% angiographic stenosis as seen on the quantitative coronary angiography (QCA); b) sequential or diffuse coronary lesions: presence of, at least, 2 sequential lesions or a coronary segment with diffuse disease (coronary vessel with multiple plaques in most of the epicardial territory) with a total length of 25 mm; c) bifurcation lesions: presence of a coronary stenosis at bifurcation level with a side branch size large enough to be protected; d) in-stent restenosis: presence of focal or diffuse in-stent restenosis with a a 40% to 80% angiographic stenosis as seen on the QCA; e) coronary bypass lesion, defined as, at least, a lesion in the coronary artery bypass grafting or native vessel presenting with proximal total occlusion.

Endpoints

The primary endpoint of the study was the rate of major adverse cardiovascular events (MACE) at the follow-up. The MACE were defined as a composite of cardiac death, myocardial infarction (MI), definitive or probable stent thrombosis, and new target lesion revascularization (TLR). All deaths were considered cardiovascular unless unequivocal non-cardiac causes would be established. Myocardial infarction included spontaneous ST-segment elevation MI or non-ST-segment elevation acute myocardial infarction. The TLR was defined as a new revascularization of a baseline physiologically negative lesion at the follow-up or as a repeat revascularization of a baseline physiologically positive lesion percutaneously treated during the index procedure.

The secondary endpoints established were: a) analysis of the primary endpoint components separately; b) rate of MACE based on the clinical setting (stable angina or acute coronary syndrome), non-ST-segment elevation acute myocardial infarction (NSTEMI), and ST segment elevation myocardial infarction (STEMI); c) rate of MACE based on the baseline iFR; d) to determine the type of lesions where the Syncvision software was used for the iFR-pullback study.

Follow-up

The patients’ follow-up was performed through phone calls, hospital record reviews or outpatient visits.

Quantitative coronary measurements

Quantitative coronary measurements were performed using a validated system (CAAS system, Pied Medica Imaging, The Netherlands). These were the measurements analyzed: reference vessel diameter, minimum lumen diameter, percent diameter stenosis, and lesion length. All measurements were performed at baseline and after the PCI.

Statistical analysis

Continuous variables were expressed as mean ± standard deviation, and the Student t test was used to establish comparisons. The categorical variables were expressed as frequency and percentage, and compared using the chi-square test. The univariate analysis was performed with the following covariates: age, male sex, current smoking status, dyslipidemia, left ventricular ejection fraction, acute coronary syndrome, multivessel disease, clopidogrel, ticagrelor, right coronary artery as the study vessel, other vessels analyzed, and baseline iFRs ≤ 0.89. Results were reported using odds ratios (OR), and two-sided 95% confidence intervals. In all the cases, P values < .05 were considered statistically significant. The statistical analysis was performed using the IBM-SPSS statistical software package (version 24.0 for Macintosh, SPSS Corp., United States).

RESULTS

The study flowchart is shown on figure 1. During the study period, a total of 2951 patients underwent coronary angiography at our center. The iFR-based physiological assessment was performed in 277 patients (9.4%) with 433 lesions. The baseline clinical data are shown on table 1. The mean age was 65 ± 10 years, and 74% of the patients (204) were men. The prevalence of comorbidities was high (diabetes mellitus, 41%; previous MI, 32%; peripheral arterial disease, 4%; cerebrovascular disease, 6%; chronic kidney disease, 13%). The clinical presentation included stable angina in 160 patients (58%), NSTEMI in 91 patients (33%), and STEMI in 26 patients (9%).

Table 1. Baseline clinical data

Angiographic and procedural data

Angiographic and procedural data are shown on table 2. Radial access was the access of choice in most of the cases (392 lesions, 91%). A total of 186 patients (67%) showed angiographic multivessel disease. Regarding the angiographic Syntax I score, 232 patients (84%) had Syntax scores < 22, 41 patients (15%) between 22 and 32, and only 4 patients (1%) > 32 without any differences being reported between stable and unstable patients. The vessel most frequently analyzed was the left anterior descending coronary artery (180, 42%) followed by the right coronary artery (99, 23%). The left main coronary artery was evaluated in 23 patients (5%).

Table 2. Angiographic and procedural data

The mean reference diameter was 3.3 mm ± 3 mm with a mean vessel stenosis of 49% ± 16%, and a mean lesion length of 21 mm ± 12 mm. The mean diameter of the stent implanted was 2.8 ± 0.4. All the stents implanted were drug-eluting stents (100%). Intracoronary imaging was used in 14 patients (3%).

The instantaneous wave-free ratio was obtained in 433 lesions, with a baseline value of 0.89 ± 0.12. The physiological assessment results after the PCI were obtained in 129 lesions (29.8%) with a final iFR of 0.93 ± 0.04.

The lesions physiologically assessed are shown on table 2. The most common type of lesions undergoing physiological assessment were angiographically moderate lesions (244, 56.4%) followed by sequential and diffuse lesions (118, 27.3%). Physiological assessment was used in 51 bifurcation lesions (11.8%) basically to guide the intervention over the side branch while using a provisional stenting strategy.

The Syncvision software for the iFR-pullback study was used in 155 lesions to guide the decision-making process (35.8%). Sequential and diffuse coronary lesions were the most common lesions analyzed by the iFR-pullback study (91 vessels, 58.7%, figure 2) followed by angiographically moderate lesions (52 vessels, 33.5%). This software was used in 5 bifurcation lesions (3.2%) to establish a baseline physiological classification or confirm an optimal physiological result after the PCI in both branches. The remaining lesions assessed by the iFR-pullback study were 6 focal or diffuse in-stent restenoses (3.9%) and 1 saphenous vein bypass graft with diffuse disease (0.6%).

Figure 2. Images of iFR-coregistration with the Syncvision software from a left circumflex artery with diffuse disease in its middle segment (48 mm of lesion length). The baseline distal iFR was 0.69. The Syncvision-guided iFR-pullback study demonstrated physiological significance only in the proximal segment. Direct implantation of a 2.5 mm × 15 mm DES was performed with a final iFR of 0.92. The stent length reduction regarding the angiographic lesion was 33 mm.

Follow-up

Follow-up data were available for 274 out of 277 patients (99%). After a mean 18 ± 10-month follow-up, 17 patients (6.1 %) presented with a major adverse cardiovascular events (table 3), 7 patients (2.5 %) with TLR, 2 of them over a lesion treated during the index procedure (0.7%) and 5 (1.8%) due to disease progression of a baseline physiologically negative lesion; 6 patients (2.2 %) suffered from acute myocardial infarction (1 patient due to acute stent thrombosis, another to a new lesion not evaluated at the index procedure, another to a baseline physiologically non-significant lesion, and the remaining 3 patients due to failed previously revascularized lesions); also, 4 patients (1.4%) presented with unclear or cardiac death. There were no differences regarding MACE between baseline physiologically negative and positive lesions (table 3).

Table 3. Rate of major adverse cardiovascular events at the follow-up based on the clinical presentation

Based on their clinical signs, patients who presented with ACS had an increased rate of new myocardial infarction at the follow-up (5.3% vs 0.6%; P < .05), although no differences were found regarding unclear or cardiac death (0.9% vs 1.8%; P = .9) and the overall MACE (8.5% vs 4.4%; OR, 2.056, 0.759-5.572; P = .156 (table 3).

Finally, we performed a univariate analysis and found no risk or protective factors for MACE in this cohort of patients (table 4).

Table 4. Univariate analysis of the different variables with potential impact in the rate of major adverse cardiovascular events between groups

DISCUSSION

This study tried to describe our experience using the physiological assessment and the Syncvision software in all-comer patients who underwent percutaneous coronary evaluations. The main findings of our study are: a) the use of the iFR in lesions of all-comer patients with the same cut-off values than established in the main trials showed a low percentage of MACE at the mid-term follow-up (6.1%); b) patients who presented with acute coronary syndrome showed an increased rate of myocardial infarction at the mid-term follow-up, and a trend towards a higher rate of MACE (OR, 2.056, 0.759-5.572; P = .156); c) The Syncvision-guided iFR-pullback study provided additional information to guide the PCI decision-making process, especially in complex lesions like sequential lesions and diffuse coronary artery disease.

The fractional flow reserve was the first physiological index that demonstrated its utility, safety, and efficacy guiding the revascularization decision-making process.2,5-7 To obtain it, the use of a hyperemic agent to reduce vascular resistance is mandatory. Adenosine is the most commonly used drug, but it presents a series of side effects and contraindications.3,4,11,12 The more recent resting index (the instantaneous wave-free ratio) has demonstrated similar utility, safety, and efficacy to the FFR.3,4 Furthermore, it has 2 main advantages: first, it is not necessary to use vasodilators, thus reducing side effects, contraindications for use, and procedural time; secondly, it allows us to assess the contribution of each lesion when the vessel presents several lesions, with the specific Syncvision-guided iFR-pullback study.8,9

For these reasons, the coronary physiology assessment is already the routine practice at the cath lab for the assessment of intermediate lesions,2-5 and multivessel disease.6,7 The main clinical setting included in these studies was stable angina. Patients with NSTEMI could be included if the lesion evaluated was identified as a non-culprit lesion. However, patients with STEMI, left main coronary artery lesions, and coronary artery bypass grafting lesions were not represented in the trials; also, the percentage of bifurcation lesions and sequential or diffuse coronary lesions is tiny. The cut-off value for the FFR and the iFR is well defined in those trials, being safe to postpone a lesion with a FFR > 0.80 or an iFR > 0.89. However, information is scarce on the utility and efficacy of physiological assessment and the same cut-off values in other types of lesions and clinical presentations.13 A multicenter registry that used the iFR to guide revascularization in patients with left main coronary artery stenosis has just been published. Using a cut-off value of 0.89, the authors conclude that postponing a left main coronary artery lesion with a iFR > 0.89 seems to be safe.10

Our study results suggest that the use of physiological assessment and the Syncvision software to guide the PCI decision-making process in all-comer patients with the same cut-off values as established by the landmark trials seems useful and safe regardless of the lesion and clinical presentation undergoing evaluation. Also, the MACE rates are similar to those reported by the landmark trials with selected lesions and patients.3,4 The iFR was the index used more often. The reasons are the faster and more comfortable use,3,4 and the possibility of lesion assessment with the Syncvision software.8,9

An important point of the study was to evaluate the rate of MACE based on the clinical presentation. Although no significant differences in the overall rate of MACE were found, patients who presented with acute coronary syndrome showed a significantly higher rate of MI at the follow-up, and a trend towards a higher rate of overall MACE. We think that this absence of statistical significance could be associated with a lack of statistical power.

A type of lesion included in the study was bifurcation lesions. Physiological assessment was used mainly to guide the side branch results during a provisional stenting strategy, thus keeping the pressure wire jailed as previously described.14,15 However, another interesting use of the iFR-pullback study with the Syncvision software was to stablish the baseline physiological contribution of every segment included in the most accepted classification.16

Finally, the Syncvision-guided iFR-pullback study was used in 155 lesions (36%). The main type of lesions where this software was used were diffuse and tandem lesions. This software can predict the physiological contribution of each lesion or coronary segment, which is why we believe that it is a very useful tool to avoid treating lesions without any physiological contribution and probably without clinical benefits. That is why this software seems to reduce the total stent length implanted regarding angiographically-guided revascularization with potential benefits at long-term follow-up.17,18 A clinical trial is currently in the recruitment phase to demonstrate the efficacy of this software reducing the length of the stent implanted in this type of lesions without detriment to the adverse events.19

In our experience, the key aspects to properly perform this technique are: a) a perfect aortic pressure curve allows the accurate detection of diastole through the software; b) passing the pressure sensor as distally as possible; c) finding a projection where the artery can be seen completely and with the least foreshortening possible; d) withdrawing the pressure guidewire very slowly so that the software can perfectly recognize the length of each arterial segment; e) checking that there is not drift when the pressure guidewire reaches the coronary ostium (iFR different to 1 ± 0.02) to avoid erroneous results; f) performing the coronary angiography in the same position as the guidewire withdrawal without any modifications to the height of the table or the C-arm, and with a higher flow and volume of contrast to facilitate the software recognition of all the lesions. The main problem when using this technique is the presence of lesions with complicated wiring. The pressure wire has a hydrophilic non-polymeric coating that is useful in most lesions. However, it may be very challenging to reach the distal part of the artery in very complex lesions (calcified, angled lesions…), and our experience with previous normalization, wire disconnection, the microcatheter exchange technique, and reconnection is very limited, but still there is a significant level of drift.

Limitations

The study presents several limitations. It is a retrospective, single-center analysis with a low number of patients and lesions. Therefore, the results should be interpreted with caution, although it could be a hypothesis-generating study for future larger scale randomized clinical trials.

CONCLUSIONS

The use of coronary physiology assessment using the iFR and the Syncvision-guided iFR-pullback study in the routine daily practice and in all-comer patients seems safe with a low percentage of MACE at the mid-term follow-up. The Syncvision-guided iFR-pullback study provides additional information to guide the PCI decision-making process.

FUNDING

The study has not had funding.

AUTHORS’ CONTRIBUTION

F.J. Hidalgo-Lesmes prepared the main draft of the manuscript. S. Ojeda-Pineda participated in the drafting of the manuscript. C. Pericet-Rodríguez, R. González-Manzanares, A. Fernández-Ruiz, and M.G. Flores-Vergara all contributed to the analysis and interpretation of data. A. Luque-Moreno, J. Suárez de Lezo, and F. Mazuelos-Bellido participated in the conception and design of the study. M.A. Romero-Moreno, and J.M. Segura Saint-Gerons revised the manuscript critically for important intellectual content. M. Pan Álvarez-Ossorio approved the final version of the manuscript.

CONFLICTS OF INTEREST

F.J. Hidalgo-Lesmes received minor fees from Philips Volcano Europe unrelated to the manuscript; S. Ojeda-Pineda received minor fees from Terumo and Philips Volcano Europe unrelated to the manuscript; M. Pan Álvarez-Ossorio received minor fees from Terumo, Abbott Vascular, and Philips Volcano Europe unrelated to the manuscript. The remaining authors declared no conflicts of interest.

REFERENCES

INTRODUCTION

The limitations of an accurate assessment of the hemodynamic significance of coronary artery lesions through angiographic guidance alone are well-known.1 Instead, the fractional flow reserve (FFR) has proven to be a useful technique to address the coronary physiology and the hemodynamic significance of coronary segments before and after performing an intervention.2-4 Also, measuring FFR post-stenting has proven to be a strong and independent predictor of major adverse cardiovascular events at the 2-year follow-up.3-5

While FFR primarily takes into account the relative luminal narrowing and the amount of viable myocardium perfused by a specific vessel, several factors have been shown to impact the FFR values prior to performing a percutaneous coronary intervention (PCI). Therefore, longer lesion length, high syntax scores, calcifications, and tortuosity are associated with significantly lower FFR values. Conversely, the presence of microvascular dysfunction, chronic kidney disease and female gender have been associated with higher FFR values.6-11

At the present time, there is lack of data on independent predictors of post-PCI FFR. Therefore, the objective of the present study was to assess the patient and procedural characteristics associated with low post-PCI FFR in an all-comer patient population.

METHODS

The FFR-SEARCH study is a prospective single-center registry that assessed the routine distal pressure divided by the aortic pressure (Pd/Pa) and FFR values of all consecutive patients after an angiographically successful PCI. The primary endpoint was to study the impact of post-PCI FFR on the rate of major adverse cardiovascular event at the 2-year follow-up. Accordingly, no further actions were taken to improve post-PCI FFR. The study was performed in full compliance with the Declaration of Helsinki. The study protocol was approved by the local ethics committee. All patients gave their written informed consent to undergo the procedure. Also, anonymous datasets for research purposes were used in compliance with the Dutch Medical Research Act. A total of 1512 patients treated between March 2016 and May 2017 at the Erasmus Medical Center were eligible to enter our study. A total of 504 of these patients were excluded due to hemodynamic instability (156), a rather small distal outflow (129), the operator’s decision not to proceed with post-PCI hemodynamic assessment (148) or other reasons (79). A total of 1000 patients were included in the study. The microcatheter could not cross the treated lesion in 28 patients, technical issues with the catheter prevented post-PCI assessments in 11 patients, and in 2 patients the post-PCI FFR measurements had to be aborted prematurely due to adenosine intolerance. This left 959 patients whose post-PCI FFR values were measured in at least 1 angiographically successfully treated lesion.

Quantitative coronary angiography

The preprocedural lesion type was defined according to the ACC/AHA guidelines12 and divided into 4 categories: A, B1, B2, and C. Comprehensive quantitative coronary angiography analyses were performed pre- and post-stent implantation in all the treated lesions. An angiographic view with minimal foreshortening of the lesion and minimal overlapping with other vessels was selected. Similar angiographic views were used pre- and post-stent implantation. Measurements included pre- and postprocedural percent diameter stenosis, reference vessel diameter, lesion length, and minimum luminal diameter (MLD). In case of a total occlusion in patients presenting with ST-segment elevation myocardial infarction (STEMI) or chronic total coronary occlusion (CTO), the MLD was considered zero and the percent diameter stenosis, 100%. The reference vessel diameter and the lesion length were measured from the first angiographic view with restored flow. All measurements were taken using CAAS for Windows, version 2.11.2 (Pie Medical Imaging, The Netherlands).

Fractional flow reserve measurements

All FFR measurements were acquired using the Navvus RXi system (ACIST Medical Systems, United States), a dedicated FFR microcatheter with optical pressure sensor technology.13,14 Measurements were performed after an intracoronary bolus of nitrates (200 µg). The catheter was advanced while mounted over the previously used guidewire approximately 20 mm distal to the most distal border of the stent. The FFR was defined as the mean distal coronary artery pressure divided by the mean aortic pressure during maximum hyperemia achieved by the continuous IV infusion of adenosine at a rate of 140 µg/kg/min via the antecubital vein. In this study no vessels were assessed using intracoronary adenosine.

Statistical analysis

At baseline, the categorical variables were expressed as counts (percentage) and the continuous ones as mean ± standard deviation. To assess the independent predictors of post-PCI FFR, all the patient and vessel characteristics were primarily assessed through an univariate test using a mixed effects model (LME-model) with a random effect for the patients and a fixed effect for the post-PCI FFR. All variables were subsequently inserted in a multivariate LME-model using the enter method that resulted in all the significant independent predictors of post-PCI FFR values. A forest plot was developed to depict all variables with the corresponding 95% confidence intervals (95%CI). Beta (β) values show the average increase or decrease of the FFR values in the case of dichotomous variables or the increment per unit increase in the case of continuous variables. Statistical analyses were performed using the statistical software package R (version 3.5.1, packages: Hmisc, lme4 and nlme, RStudio Team, United States).

RESULTS

Demographic characteristics

The mean age was 64.6 ± 11.8 years and 72.5% were males. In 959 patients, at least, 1 lesion was measured with an overall 1165 successfully treated and measured lesions. The patient demographics and baseline characteristics are shown on table 1. Up to 70% of the patients presented with an acute coronary syndrome, and 18% had confirmed thrombus as seen on the angiography. Intravascular imaging modalities were used in 9.6% of the patients to guide the procedure. Overall, 1.4 ± 0.6 lesions were treated per patient and in 1.2 ± 0.5 lesions per patient the post-PCI FFR was successfully assessed. The average overall stent length per vessel was 29 mm ± 17 mm with an average stent diameter of 3.2 mm ± 0.5 mm.

Table 1. Baseline patient and vessel characteristics

The mean post-PCI FFR was 0.91 ± 0.07 and 7.7% of vessels had a post-PCI FFR ≤ 0.80. In the LME-model and after adjusting for independent predictors of post-PCI FFR, the left anterior descending coronary artery (LAD) as the measured vessel was the strongest predictor of post-PCI FFR (adjusted β = -0.063; 95%CI, -0.070 to -0.056; P < .0001) followed by the postprocedural MLD (adjusted β = 0.039; 95%CI, 0.015-0.065]; P = .002). Additionally, male sex, in-stent restenosis, CTO, and pre- and post-dilatation were negatively correlated with postprocedural FFR. Conversely, type A lesions, thrombus-containing lesions, postprocedural percent diameter stenosis, and stent diameter were positively correlated with postprocedural FFR. The R2 for the entire model was 53%. Figure 1 shows all significant and non-significant adjusted predictors included in the LME-model. Table 2 shows all adjusted and unadjusted predictors with corresponding β values and 95%CI. The most important predictors are shown on figure 2.

Figure 1. Forest plot of independent predictors of post-PCI FFR. Adjusted beta values with 95% confidence intervals. Triangles indicate significant predictors while circles are indicative of non-significant predictors in the multivariate generalized mixed model to predict post-PCI FFR. ACS, acute coronary syndrome; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; LAD, left anterior descending coronary artery; CTO, chronic total coronary occlusion; MLD, minimum lumen diameter.

Table 2. Predictors for post-PCI FFR

Figure 2. Forest plot of most important predictors of post-PCI FFR. Adjusted beta values with 95% confidence intervals. The figure includes all significant predictors from the multivariate generalized mixed model predicting post-PCI FFR except for categorical variables with beta values < 0.02. LAD, left anterior descending coronary artery; CTO, chronic total coronary occlusion; MLD, minimum lumen diameter.

DISCUSSION

This study is the largest report to this day of predictors of post-PCI FFR. Based on data derived from the FFR-SEARCH registry, we could identify several patient and procedural predictors of post-PCI FFR. These predictors will bring more in-depth interpretations of post-PCI FFR values to be able to identify correctly which vessels are prone to future events. At first, male gender appeared to be negatively correlated with postprocedural FFR. This finding is consistent with the findings of former studies that focused on the impact of gender on pre-PCI FFR measurements.6,11,15,16 Compared to females, males are known to have a lower prevalence of microvascular dysfunction.8,17 The concept of FFR is based on drug-induced maximal hyperemia to minimize microvascular resistance. Microvascular dysfunction may hamper this vasodilator response and consequently result in a dampened flow response and high FFR.15 Subsequently, on average, males have larger myocardial masses and myocardial perfusion territories compared to females.18,19 The importance of the latter is illustrated by the second and strongest predictor of post-PCI FFR in this study, the FFR measurements in the LAD. FFR values are associated with the myocardial mass and the outflow territory of the measured vessel. As such, the LAD—the vessel with the largest perfusion area—has previously been associated with lower pre- and postprocedural FFR values.20-22

The diameters of the stents implanted in the RCA are larger, on average, but the outflow territory of the LAD is even larger.23 This discrepancy between luminal dimensions and myocardial mass may explain why the optimal improvement of the FFR measurements in the LAD is difficult to achieve.23

Thirdly, larger stent diameters and larger post-PCI MLDs were associated with higher post-PCI FFR values. However, higher postprocedural percent stenosis was also associated with higher post-PCI FFR values. While these findings may seem contradictory, post procedural percent stenosis was not associated with post-PCI physiology in the DEFINE PCI study either.24

In the intravascular ultrasound substudy of the FFR-SEARCH registry, van Zandvoort et al. showed that evident signs of residual luminal narrowing including focal lesions, underexpansion, and malapposition were present in a significant amount of vessels with post-PCI FFR values ≤ 0.85. These findings were not readily apparent on the comprehensive quantitative coronary angiography.25 Percent diameter stenosis was 20% in the cohort of patients with post-PCI FFR values ≤ 0.85 and > 0.85.26

Together with the latter predictors of post-PCI FFR we identified several others. A dedicated analysis of 26 CTOs recently showed that postprocedural FFR values are typically low initially; however they seem to increase at the 4-month follow-up. The initially low post-PCI FFR values is thought to be due to the microvascular dysfunction of the recently opened vessel, a phenomenon that improves after several months.27 In-stent restenosis and pre- and postdilatation were associated with lower post-PCI FFR values. A finding that is consistent with former studies that showed that, in general, complex lesions are associated with lower post-PCI FFR values.20,21,26,28

Also, it was interesting to see the impact of clinical presentation on post-PCI FFR values in the study population in which most patients presented with acute coronary syndrome. Contrary to former studies that questioned the validity of invasive hyperemic physiological indices in patients with acute coronary syndrome, we could not confirm the impact of clinical presentation on post-PCI FFR values. However, the identification of a thrombus, that often occurs after a ruptured plaque in patients with acute coronary syndrome, was associated with significantly higher FFR values. Despite the restoration of epicardial flow by the PCI, a relatively large number of patients with STEMI have abnormal myocardial perfusion at the end of the procedure.29 This phenomenon is thought to be related to microvascular obstruction due to distal embolization (reperfusion injury) and tissue inflammation due to myocyte necrosis.30,31 The latter may explain the significantly higher post-PCI FFR values reported in patients presenting with thrombus-containing lesions compared to those without such lesions. Conversely, our findings also show that in patients without thrombus-containing lesions the post-PCI FFR may be a valuable diagnostic tool for the identification of patients at a high risk of future adverse cardiac events.

Limitations

This study was conducted with the Navvus microcatheter, a dedicated rapid exchange microcatheter with a mean diameter of 0.022 in that proved its utility in a slight but significant underestimation of the FFR compared to conventional 0.014 in pressure guidewires.32 That is why we cannot directly extrapolate the current findings to wire-based FFR devices.14 Based on the study protocol, no further action was taken in the presence of low post-PCI FFR values. The Target FFR and FFR REACT studies (NCT03259815 and NTR6711) will provide further information on post-PCI FFR and the potential of further actions to improve post-PCI FFR and clinical outcomes.33,34 These studies should also focus on the trade-off of potential benefits and harm when performing additional interventions in order to improve the final FFR values.

CONCLUSIONS

In this substudy of the FFR-SEARCH registry, the largest real-world post-PCI FFR registry conducted to this day, we identified sex, LAD vessels, postprocedural MLD, and several other independent predictors of postprocedural FFR.

FUNDING

The FFR SEARCH study was conducted with institutional support from ACIST Medical Inc.

AUTHORS' CONTRIBUTION

Conception and design: L.J.C. van Zandvoort, N.M. van Mieghem, and J. Daemen. Data aquisition: L.J.C. van Zandvoort, K. Masdjedi, J. Wilschut, W. Den Dekker, R. Diletti, F. Zijlstra, N.M. van Mieghem, and J. Daemen. Statistical analysis and manuscript writing: L.J.C. van Zandvoort and J. Daemen. Providing criticial feedback to the manuscript and approving the final content: L.J.C. van Zandvoort, K. Masdjedi, T. Neleman, M.N Tovar Forero, J. Wilschut, W. Den Dekker, R. Diletti, F. Zijlstra, N.M. van Mieghem, and J. Daemen.

CONFLICTS OF INTEREST

L.J.C. van Zandvoort received institutional research support from Acist medical Inc. J. Daemen received institutional research support from Pie Medical, ACIST Medical Inc., PulseCath, Medtronic, Boston Scientific, Abbott Vascular, Pie Medical and speaker and consultancy fees from PulseCath, Medtronic, ReCor Medical, ACIST Medical Inc. and Pie Medical. The remaining authors declared no conflicts of interest.

REFERENCES