Innovation in interventional cardiology

INTRODUCTION

Over the last 20 years, transcatheter aortic valve implantation (TAVI) has emerged as a successful therapeutic alternative strategy to surgery to treat aortic valve stenosis in patients of high, intermediate, and low surgical risk.1-6

Ischemic and bleeding complications are not rare after TAVI and can be life-threatening. Recently, the PARTNER 3 and Evolut Low Risk clinical trials have shown low, yet non-negligible, incidence rates of both stroke, and major bleeding within 30 days after TAVI.5,6

As of today, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is the most commonly used antithrombotic regimen after TAVI in patients without an indication for long-term oral anticoagulation enrolled in clinical studies. Indeed, the recommendations from different societal guidelines suggest 1 to 3, 3 to 6 or 6 months of therapy with clopidogrel plus low doses of aspirin. However, such recommendations have not been developed based on the results of large randomized clinical trials.7-10 Indeed, reports on course duration over the last decade have suggested a neutral or beneficial effect of single antiplatelet therapy (SAPT) compared to early DAPT followed by SAPT regarding vascular complications and major or life-threatening bleeding and no higher risk for myocardial infarction, and stroke.11-13 Recently, aspirin alone proved superior compared to a 3-month course of aspirin plus clopidogrel followed by aspirin in terms of bleeding alone and combined with thromboembolic complications at the 1-year follow-up.14

We conducted a meta-analysis of available randomized clinical studies to provide a comprehensive and quantitative assessment of the evidence available on the safety and efficacy profile of SAPT compared to DAPT after TAVI in patients with no indication for long-term oral anticoagulation.

METHODS

Search strategy and selection criteria

Randomized clinical trials (RCTs) including patients undergoing TAVI were evaluated to be included in this meta-analysis. Eligible studies had to meet the following prespecified inclusion criteria: a) RCTs comparing SAPT to DAPT after TAVI, and b) availability of clinical outcome data. The exclusion criteria were these: a) RCTs including patients requiring oral anticoagulation, b) lack of randomized design, c) lack of any clinical outcome data.

The search strategy, study selection, data extraction, and data analysis were performed based on The Cochrane Collaboration and the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.15

Back in August 31, 2020, we searched the PubMed and Embase databases. We also searched abstracts presented at relevant scientific meetings (American Heart Association, American College of Cardiology, European Society of Cardiology, EuroPCR, and Transcatheter Cardiovascular Therapeutics). We also used backward snowballing (ie, review of references from identified articles and pertinent reviews). The search strategy is available in the supplementary data.

Data extraction

Three investigators (J. Sanz-Sánchez, C. A. Pivato, and P. P. Leone) independently assessed studies with potential to be included. The senior investigator (G. G. Stefanini) resolved the discrepancies. Non-relevant articles were excluded based on title and abstract. The same investigators independently extracted data on the study design, measurements, patient characteristics, and outcomes, using a standardized data-extraction form. Data extraction conflicts were discussed and resolved with the senior investigator (G. G. Stefanini).

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

Outcomes of interest

The prespecified primary endpoint was life-threatening or major bleeding. The secondary clinical endpoints were all-cause mortality, myocardial infarction, stroke, and any bleeding. Each endpoint was assessed according to the definitions reported in the original study protocols as shown on table 1 of the supplementary data.

Table 1. Key study features

Risk of bias

The risk of bias in each study was assessed using the revised Cochrane risk-of-bias tool (RoB 2.0).16 Three investigators (J. Sanz- Sánchez, C. A. Pivato, and P. P. Leone) independently assessed 5 domains of bias in the RCTs: 1) randomization process, 2) deviations from intended interventions, 3) missing outcome data, 4) outcome measurements, and 5) selection of reported results (table 2 of the supplementary data).

Table 2. Baseline clinical characteristics of the patients included

Statistical analysis

The odds ratios (OR) and the 95% confidence intervals (CI) were calculated using the DerSimonian and Laird random-effects model with the estimate of heterogeneity being taken from the Mantel-Haenszel method. The number needed to treat (NNT) to prevent 1 event was calculated from weighted estimates of pooled ORs using the random-effects meta-analytic model. The presence of heterogeneity among the studies was evaluated using Cochran Q test based on a chi-square distribution with P values ≤ .10 considered statistically significant, and the I² test to evaluate inconsistencies. A value of 0% indicates no observed heterogeneity, and values of ≤ 25%, ≤ 50%, > 50% are indicative of low, moderate, and high heterogeneity, respectively. The presence of publication bias was investigated by visual estimation through funnel plots. We conducted a leave-one-out sensitivity analysis for the primary endpoint by iteratively removing 1 study at a time to confirm that our findings were not driven by any single study. Further sensitivity analyses were conducted by calculating the ORs with a 95%CI using a fixed-effects model with the Mantel and Haenszel method and the risk ratios with a 95%CI using both fixed-effects and random-effects models. The statistical level of significance was 2-tailed P values < .05. Statistical analyses were performed using the Stata software version 13.1 (StataCorp LP, College Station, United States).

RESULTS

Search results

Figure 1 shows the PRISMA study search and selection process. A total of 4 RCTs were identified and included in this analysis. The main features of the studies included are shown on table 1.

Figure 1. Flowchart of the study selection process.

A total of 541 patients treated with aspirin and 545 patients treated with DAPT after TAVI were included.

Baseline characteristics

The main baseline characteristics of the patients included are shown on table 2. Most patients underwent TAVI due to aortic stenosis. The Society of Thoracic Surgeons mean predicted risk of mortality was 4.4% and most of the procedures were performed via transfemoral access.

Publication bias and asymmetry

The funnel-plot distributions of the prespecified outcomes are indicative of lack of publication bias for all the outcomes (figures 1-5 of the supplementary data).

Outcomes

Compared to patients treated with DAPT, those treated with SAPT had a lower risk of life-threatening or major bleeding (OR, 0.44; 95%CI, 0.27-0.70; I² = 0%), and any bleeding (OR, 0.51; 95%CI, 0.36-0.71; I² = 0%) (figure 2). No differences were seen between patients treated with SAPT compared to those treated with DAPT in terms of all-cause mortality (OR, 1.01; 95%CI, 0.61-1.68; I² = 0%), myocardial infarction (OR, 0.50; 95%CI, 0.17-1.41; I² = 0%), and stroke (OR, 0.98; 95%CI, 0.54-1.77; I² = 0%) (figure 3). The NNT to prevent 1 life-threatening or major bleeding was 17 patients and the NNT to prevent any bleeding was 11 patients.

Figure 2. Bleeding outcomes in patients treated with SAPT compared to DAPT after TAVI. DAPT, dual antiplatelet therapy; SAPT, single antiplatelet therapy; TAVI, transcatheter aortic valve implantation.

Figure 3. All-cause mortality and efficacy outcomes in patients treated with SAPT compared to DAPT after TAVI. DAPT, dual antiplatelet therapy; SAPT, single antiplatelet therapy; TAVI, transcatheter aortic valve implantation.

Risk of bias assessment

Table 2 of the supplementary data shows the results of the risk of bias assessment using the RoB 2.0 tool. Two trials were considered at a low overall risk of bias11,14 and 2 presented some concerns.12,13

Sensitivity analyses

Findings remained consistent with the main analysis after calculating the ORs using a fixed effects model and risk ratios with both fixed and random-effects models (table 3 of the supplementary data).

The leave-one-out sensitivity analysis results remained consistent with the primary analysis (table 4 of the supplementary data).

DISCUSSION

The current meta-analysis evaluated available RCTs comparing SAPT with aspirin to DAPT in patients undergoing TAVI with no indication for long-term oral anticoagulation. The main findings were these:

Currently, the clinical practice guidelines recommend DAPT for 1 to 6 months after TAVI in patients with no indication for long-term oral anticoagulation.7-9 However, this regimen is not supported by actual evidence available. This practice is derived from the percutaneous coronary intervention field where the addition of a P2Y₁₂ inhibitor to aspirin compared to aspirin monotherapy proved to reduce the risk of ischemic complications especially stent thrombosis.17 The addition of clopidogrel to aspirin after TAVI has the theorical rationale of reducing the rate of ischemic cerebrovascular events, myocardial infarction, and valve thrombosis.

Ischemic stroke is one of the worst complications after TAVI. Its highest incidence rate occurs within the first 24 hours after the procedure. It seems to be mainly associated with embolized tissue waste during TAVI due to dilation of the calcified valve or navigation through the aortic arch.18-20 Instead, subacute stroke (between 1 to 30 days after the procedure)—representative of a quarter of the total number events at 2 years—4,21 are often associated with new-onset atrial fibrillation,22-24 against which DAPT is known to perform poorly.

Another motivation to prescribe DAPT after TAVI is to limit the rate of myocardial infarction. Nevertheless, the reported rate of myocardial infarction after TAVI is relatively low,4,21 and concomitant coronary artery disease is often treated percutaneously before TAVI. Therefore, the addition of a P2Y₁₂ inhibitor to aspirin after TAVI does not seem to offer any additional advantages compared to aspirin monotherapy regarding the reduction of the risk of myocardial infarction as our results showed.

Finally, while symptomatic valve thrombosis is a rare condition (< 1%), subclinical thrombosis has a higher incidence rate (from 10% to 40% according to different series).25-27 The clinical impact of this phenomenon is still unknown: it could not only impact valve durability due to pannus formation, but it also has been associated with a higher rate of transient ischemic attack.25,26 In this setting, the pathophysiology of thrombus formation after TAVI is also still under discussion as the relative weight of primary and secondary hemostasis is still to be established. On the one hand, the endothelial injury and high shear stress environment present all around the valve stent frame before re-endothelialization may favour platelet aggregation, thus leading to the formation of a platelet-rich thrombus. This is somehow similar to what happens during coronary stent thrombosis against which the most effective treatment has proven to be DAPT.17 On the other hand, the bioprosthetic sinus of the valve leaflets could favour a condition of low shear stress and flow turbulence, thus predisposing to the development of a thrombin-rich thrombus. DAPT seems to offer no benefit over SAPT in terms of reducing bioprosthetic valve thrombosis while oral anticoagulants have proven to both prevent and resolve this complication.25-27 However, so far the only trial to assess the role of anticoagulant therapy following TAVI in patients with no indication for long-term oral anticoagulation is the Global study comparing a rivaroxaban-based antithrombotic strategy to an antiplatelet-based strategy after transcatheter aortic valve replacement to optimize clinical outcomes (GALILEO). It was stopped following relevant safety issues seen on the interim analyses revealing higher rates of complications with low doses of rivaroxaban/aspirin compared to DAPT including hard endpoints like mortality (6.8% vs 3.3%).28

Overall, ischemic events post-TAVI seem to elude the antiplatelet action provided by thienopyridines added to aspirin. A current meta-analysis confirms that the addition of a P2Y₁₂ inhibitor does not reduce the risk of ischemic events (ie, myocardial infarction, and stroke), but most importantly predisposes patients to a higher risk of life-threatening or major bleeding. The bleeding risk reduction seen with SAPT compared to DAPT shown by this meta-analysis is of great clinical relevance, with a NNT of only 11 patients to prevent any bleeding and a NNT of 17 patients to prevent 1 life-threatening or major bleeding. Moreover, since most of the bleeding events occur within 30 days after the procedure, likely due to periprocedural antithrombotic therapy and access site bleeding complications,1-4,29 even a short-term DAPT course raises safety issues in term of bleeding events.

Based on the evidence published so far and the results of this research, in patients with no indication for long-term anticoagulation undergoing TAVI, aspirin monotherapy should be preferred over DAPT. However, larger trials are still needed to determine whether antiplatelet strategies should be tailored and based on the valve implanted (balloon-expandable vs self-expandable) or on the particular valve-in-valve implantation setting; also, to elucidate the role of alternative antiplatelet regimens (ie, P2Y₁₂i monotherapy), and oral anticoagulants.

Limitations

The results of our study should be interpreted considering some limitations. First, this was a study-level meta-analysis that provided average treatment effects. Also, the lack of patient-level data from the studies included data prevents us from assessing the impact baseline clinical and procedural characteristics had on treatment effects. Secondly, minor differences in the definition used were present in the ischemic endpoints, thus limiting the reliability of the effect estimates. However, in terms of the bleeding endpoints, the VARC definition was used in all the studies included, which adds to the robustness of our findings. Finally, the limited number of studies and patients as well as the small event rate for certain endpoints such as myocardial infarction may have reduced the statistical power to detect any significant inter-group differences.

Additional evidence will be provided by ongoing randomized trials: the Antithrombotic strategy after trans-aortic valve implantation for aortic stenosis (ATLANTIS, NCT02664649) trial will evaluate the benefit of apixaban therapy (standard dose) vs standard of care; the Anticoagulant versus dual antiplatelet therapy for preventing leaflet thrombosis and cerebral embolization after transcatheter aortic valve replacement (ADAPT-TAVR, NCT03284827) trial will compare edoxaban (standard dose) vs DAPT. Finally, the Dual antiplatelet therapy versus oral anticoagulation for a short time to prevent cerebral embolism after TAVI (AUREA, NCT01642134) trial will study a strategy of vitamin K antagonist vs a 3-month course of DAPT.

CONCLUSIONS

In patients without an indication for long-term anticoagulation undergoing TAVI, monotherapy with aspirin compared to DAPT is associated with a lower risk of life-threatening or major bleeding, and a comparable risk of all-cause mortality, myocardial infarction, and stroke.

FUNDING

None.

AUTHORS’ CONTRIBUTIONS

J. Sanz-Sánchez, C. A. Pivato, P. P. Leone, and M. Chiarito con­- tributed to the design, analysis, and writing of this manuscript. D. Regazzoli, and G. Petriello contributed to the design, and writing of this manuscript too. B. Reimers, G. Condorelli, and G. G. Stefanini contributed to the study design, writing, and supervision.

CONFLICTS OF INTEREST

G. G. Stefanini reported a research grant from Boston Scientific, and speaker/consulting fees from B. Braun, Biosensors, and Boston Scientific. D. Regazzoli reported speaker fees from Amgen, and Boehringer. The remaining authors declared no conflicts of interest whatsoever.

SUPLEMENTARY DATA

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

Aortic stenosis (AS) is the most commonly treated valvular heart disease in Western countries.1 In a relatively small but growing proportion of patients (from 3.5% to 12%), AS may present as cardiogenic shock (CS) with an estimated short-term mortality as high as 70% if definitive surgical or percutaneous treatment is not provided.2 CS is characterized by an inadequate tissue perfusion as a result of a decompensated cardiac disease that translates into a low-output state. Early management is directed toward keeping a steady hemodynamic profile and ensuring tissue oxygenation through medication or advanced support.3 However, specific therapies are required to ensure a complete resolution, yet conventional surgical aortic valve replacement (SAVR) is often associated with a very high risk of mortality.2

Several trials have shown that transcatheter valve implantation (TAVI) is a safe alternative to SAVR in low-to-high risk patients in stable situations and it is currently considered the preferred alternative in those of high prohibitive surgical risk.4-7 Nevertheless, the risk scores for the main studies that settled the evidence for TAVI procedures were estimated after excluding patients with CS. As a consequence, the main outcomes in this challenging scenario have not been randomly compared to surgery. Actually, such a comparison is unlikely to be performed due to the highly variable baseline profile and differential availability of resources such as mechanic circulatory assist devices. In addition, the different outcomes in emergency TAVIs and planned interventions have been scarcely researched; still, they are key to improve results in what stands as the worst possible clinical scenario. We aimed to assess the current outcomes of emergency/urgent TAVI and the main factors conditioning its prognosis through a systematic review and meta-analysis.

METHODS

Literature search strategy

A systematic review of all published articles in PubMed and Google Scholar databases between January 2014 and January 2020 regarding emergency/urgent versus elective TAVI in severe AS was independently performed by 2 of the authors (A. Aparisi and M. Carrasco-Moraleja). Searched terms were “emergency” and/or “urgent”, “elective”, AND “transcatheter valve replacement” or “TAVR” (transcatheter aortic valve replacement) or “heart failure” and/or “cardiogenic shock”. Definition of emergency/urgent procedures was variable, but the consensus reached for this article was to include patients who required an unscheduled TAVI procedure to treat their refractory heart failure or CS to correct this condition within the next 72 hours after admission. A total of 7 studies8-14 were chosen, and the inclusion criteria established by our group were: a) the study population included patients with aortic stenosis who underwent TAVI; b) only cohort studies that compared emergency or urgent to elective TAVI were included; c) only full English peer-reviewed papers with enough data of outcomes were chosen. The selected exclusion criteria were: a) abstracts; b) case reports; c) editorials; d) experts’ opinions; and e) repetitive studies. Discrepancies between reviewers were resolved through discussion, and consensus was reached. Flowchart is shown on figure 1 and the main features of the studies included are shown on table 1 of the supplementary data.

Figure 1. Flowchart showing search results and selection of the studies included in the meta-analysis.

Table 1. Baseline clinical and echocardiographic characteristics of patients undergoing elective or emergency TAVIs

Primary endpoints

Primary endpoints were short-term mortality and procedural success. Secondary outcomes were perioperative complications. Complications were mostly reported by using the definitions established by the Valve Academic Research Consortium-2.15

Statistical analysis

Qualitative variables were expressed as absolute frequency and percentage. Continuous variables were expressed as mean ± standard deviation unless specified otherwise. To compare the demographic variables and the risk factors between thew groups, the chi-square test or Fisher’s exact test were used for the categorical variables. The Student t test was used for the continuous variables, when applicable.

As a measure of the combined effect, the studies included the odds ratio (OR), a 95% confidence interval, and statistical significance. The homogeneity among the studies was compared using the QH statistic. With regard to the low sensitivity of this test, P values < .10 were considered significant. To somehow overcome this limitation, the I2 statistic was estimated as well, which measures the percentage of the overall variation of the studies explained by the heterogeneity and its 95%CI. A random effects model was used for cases in which the I2 statistic was > 50% and a fixed effects model was used for the opposite cases. The potential publication bias was assessed using a funnel plot, Egger’s test, and Begg and Mazumdar rank correlation test. In the presence of publication bias, the trim-and-fill method was used to reassess the pooled OR. Sensitivity analyses sequentially eliminating dissimilar studies were also conducted.

All P values were 2-tailed. Statistical analyses were conducted using the R software, version 3.6.1 (R Project for Statistical Computing) and Review Manager 5.3.

RESULTS

Patient distribution and baseline characteristics

Seven studies were selected including a total of 84 427 patients who underwent TAVIs, with 70 186 elective procedures (83.1%) and 14 241 emergency ones (16.9%). The main baseline characteristics according to the elective or emergency character of the intervention are shown on table 1 and sensitivity and asymmetry analyses are shown on table 2 of the supplementary data and figure 1 of the supplementary data. Asymmetry was detected for acute kidney injury and, therefore, the trim-and-fill method had to be used to reassess the odds ratio. The percentage of men who underwent elective procedures (52.1%) was higher compared to emergency interventions (50.27%, P < .001). Overall, patients treated urgently showed more comorbidities as summarized by the logistic EuroSCORE (65.9% ± 21% vs 29.4% ± 18%, P < .001) and the Society of Thoracic Surgeons Risk Score (STS) (29.4 ± 27.4 vs 13.7 ± 11.6, P < .001). However, the classical cardiovascular risk factors did not differ among groups (hypertension and diabetes mellitus) and the rates of myocardial infarction and percutaneous coronary intervention were similar. On the contrary, those treated urgently more often had undergone a previous aortic valve replacement. Regarding the main echocardiographic characteristics, emergency procedures were performed in patients with left ventricular (LV) function deterioration (39.5% ± 17.8% vs 52.5% ± 12.8%; P < .001), larger LV end-diastolic diameters (55 ± 9 vs 48 ± 7; P < .001), but similar aortic valve areas (0.66 ± 0.21 vs 0.70 ± 0.23; P = .308), and transaortic mean gradients (40.3 ± 18.3 vs 43.9 ± 16.3; P = .061).

Table 2. Procedural characteristics of patients undergoing elective or emergency/urgent TAVIs

Perioperative characteristics

Procedural results from the studies included are shown on table 2. Transfemoral access (79.3% vs 76.8%; P = .177) and use of general anesthesia (84.5% vs 85.4%; P = .17) were the preferred approaches in both groups. Elective TAVIs showed a higher procedural success rate (93.6% vs 92.5%; P = .007) and a lower need for mechanical circulatory support (1.96% vs 3.56 %; P < .001). Other procedural outcomes were comparable between both cohorts.

Postoperative outcomes

The main postoperative outcomes are shown on table 3 and figure 2. The ORs for perioperative myocardial infarction, life-threatening bleedings, need for permanent pacemaker implantation, and stroke were similar regardless of the planned or emergency setting. On the contrary, the elective cohort showed a smaller rate of acute kidney injury (9.6% vs 22.4%; OR = 2.26; 95%CI, 1.84-2.76; P < .001), and need for dialysis (1.1% vs 2.8%; OR = 2.37; 95%CI, 2.09-2.68; P < .001). Overall, this translated into shorter hospital stays for elective cases, lower in-hospital (3.3% vs 5.75%; OR = 1.32; 95%CI, 1.32-2.83; P < .001), 30-day (4.43% vs 8.84%; OR = 3.13; 95%CI, 1.68-5.80; P < .001), and 1-year mortality rates (19.7% vs 34.47%; OR = 2.87; 95%CI, 1.67-4.94; P = .0001) for elective TAVI (figure 3).

Table 3. Main postoperative outcomes of patients undergoing elective or emergency/urgent TAVIs

Figure 2. Forest plot showing the main postoperative complications of patients included in the meta-analysis.* * Vertical line represents “no difference” point between the emergency and the elective TAVI groups. Horizontal lines represent the 95%CI. Squares represent the OR for each study (the size of each square shows the amount of information given by each study). Diamonds represent pooled OR from all studies.

Figure 3. Forest plot showing the in-hospital to 1-year mortality rates of patients included in the meta-analysis.* * Vertical line represents “no difference” point between the emergency and the elective TAVI groups. Horizontal lines represent the 95%CI. Squares represent OR for each study (the size of each square shows the amount of information given by each study). Diamonds represent pooled OR from all studies.

DISCUSSION

When patients with AS present with severe acute heart failure (HF) or CS the 5-year all-cause mortality is above 60% despite the implementation of therapies to treat valvular heart disease, which poorly compares to this rate in patients free of HF (~20%) or with chronic HF symptoms (~30%) in this setting (16). Determining the factors that condition such a high mortality rate is the key to improve the management of this growing group of patients. The main findings of this study are: a) patients who required emergency TAVIs had a higher baseline risk compared to planned procedures, not only due to the emergency setting, but also to a high burden of comorbidities and deterioration of LV function; b) although procedural success rate was significantly higher in planned cases, this difference was small (93.6% vs 92.5%; P = .007) suggestive that the higher short- and mid-term mortality rates seen in emergency cases were mainly due to postoperative complications, not to the intervention per se; c) need for mechanical circulatory support and dialysis was higher after emergency cases. The early identification of patients at risk who may require these therapies might be useful for a better indication of TAVI in emergency settings.

Baseline characteristics and predicted mortality

In our study, emergency/urgent TAVI patients had a more significant number of comorbid conditions compared to those who underwent elective procedures. We should mention that the Society of Thoracic Surgeons (STS) score has been widely used to assess mortality risk in SAVR patients.17 Nevertheless, the score developed by the Transcatheter Valve Therapy (TVT) group to evaluate in-hospital and 30-day mortality rates18 may be more accurate. According to that score, the prognosis is strongly influenced by the presence of chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and need for emergency TAVI. Of note, AS with concomitant CKD has been linked to higher all-cause and cardiovascular mortality rates compared to patients with AS and without this condition; indeed, the increase of all-cause mortality exponentially correlates with a decline in the glomerular filtration rate.19 In addition, the higher rate of anemia20 and increased bleeding risk in CKD patients is well-known, which conditions a higher need for red blood cell transfusion21 parallel to a deterioration of renal function and survival rate.

The LV function is a well-known prognostic factor of valvular heart disease and its deterioration conditions surgical or transcatheter aortic valve treatment even in asymptomatic patients.22 We should mention that the similar transaortic gradient, despite a reduced LV function in the emerging baseline cases, suggests a more severe valve disease, probable more calcified and degenerated native valves, as also suggested by the higher rate of aortic regurgitation of this cohort. Therefore, the multidisciplinary and multi-imaging approach might be particularly useful for procedural planning and outcome improvement.23

Procedural complications and mortality

Most procedural complications were similar in elective and emergency TAVIs. Although this may be partially explained by the growing operators’ experience worldwide and the lack of differences in the rate of transfemoral approach,24 the greater use of mechanical circulatory support devices may have been particularly relevant in emergency/urgent cohorts. Indeed, the more limited LV contractile reserve of this group of patients can lead to rapid deterioration in the presence of complications like periannular shunts, severe aortic regurgitation or coronary obstruction. Therefore, the presence of risk factors for these complications may suggest the need for circulatory support devices in certain cases before valve implantation as a potential strategy to avoid dreadful prognoses if they occur in the emergency setting.25-27 Prior experience with the Impella device and extracorporeal membrane oxygenation is shown on table 3 of the supplementary data; however, whether there are mortality differences between those with and without mechanical support requires further research. Since procedural success was similar to that of the standard setting, the clinical translation of this is that, even if these cases can be performed successfully in all centers by implanting TAVI, this profile of patients should only be treated in centers with mechanical circulatory support devices available (particularly ECMO), which would exclude low volume or non-surgical centers.

In the present meta-analysis, the cases treated with isolated balloon aortic valvuloplasty were not included. This strategy bears a class IIb-C level of evidence in the last iteration of the guidelines, but it is often used as a bridging therapy to definitive TAVI in hemodynamically unstable patients.28,29 A single-center retrospective study found that TAVI may be superior to a stand-alone balloon aortic valvuloplasty and medical therapy in patients with severe AS and CS, since the isolated balloon aortic valvuloplasty is not free of complications (~25%) and has higher mortality rates.30 Despite of this, large randomized controlled trials exploring this scenario with TAVI are lacking.

Postoperative complications associated with a higher mortality rate

In this systematic review and meta-analysis, we found that emergency/urgent TAVIs had a significantly higher rate of AKI, hemodialysis, and mortality. This is consistent with previous reports that found that patients with post-TAVI AKI were more likely to die. Besides, AKI is a predictor of sepsis, which is also an independent predictor of mortality. The main factors increasing the risk of AKI include CKD, peripheral artery disease, diabetes mellitus, and deterioration of LV function.31,32 A prophylactic strategy may vary from simple hydration with a normal saline solution to forced diuresis with early supportive measures;33 indeed, the use of prophylactic dialysis has been explored in TAVI patients with a high risk of AKI and may be particularly useful in the emergency setting.

Study limitations

There are several limitations related to this systematic review and meta-analysis. First, the studies included were observational since no multicenter randomized studies specifically addressing this topic could be found. Secondly, the definition of emergency/urgent procedures was variable in the studies although an inclusive definition was reached by the study team. Finally, the results may not be generalizable and should be interpreted with caution due to the high heterogenicity reported, which may relate to variability in the study samples and designs.

CONCLUSIONS

In conclusion, the association between emergency/urgent TAVIs and a higher short-to-mid-term mortality rate is mainly due to a high-risk baseline profile, advanced stage of the cardiac disease, and higher rate of acute renal failure. The early identification and referral of patients at high risk for circulatory collapse or AKI need to be properly identified to reduce the TAVI related mortality rate. Further research is needed to elucidate the role of TAVI in emergency or urgent scenarios.

FUNDING

No funding to declare.

CONFLICTS OF INTEREST

Dr. Amat-Santos is a proctor for Boston Scientific.

MATERIAL ADICIONAL

REFERENCES

INTRODUCTION

Percutaneous left atrial appendage closure (LAAC) has been extensively studied in clinical trials. Despite the excellent results of efficacy and safety regarding the LAAC from randomized clinical trials,1 these studies are limited by their design, which is still not applicable to our routine clinical practice. Maybe this is the reason why in our setting, the LAAC program is still far from reaching its full potential.2 Without detriment to the current level and grade of clinical recommendation for the LAAC,3 the medical community will only gain confidence in this procedure when further studies are presented assessing its performance in our routine clinical practice.

The LAAC is a solid structural procedure that in Spain is only second to transcatheter aortic valve implantation (TAVI).4 The experience gained with the LAAC has moved the focus of attention from the early aspects of success and safety towards other issues still not properly addressed such the performance of LAAC reducing long-term cardiovascular events or its lingering benefits over time.

To this day, there are very few papers gathering the long-term experience gained with the LAAC with a median follow-up of 2.5 years.1,5-9 It is only from this long-term perspective that we will understand the value of a procedure largely based on the prophylaxis of the thromboembolic complications occurred during the patient’s life.

The objective of this study was to present our own experience in the follow-up of the population treated with LAAC from the beginning of this program to assess its overall performance and, especially, the reduction of long and very long-term thromboembolic and bleeding events.

METHODS

Our study is a retrospective analysis of the LAAC activity developed consecutively in a teaching hospital from March 2011 through February 2020. This procedure was indicated by different large volume hospital units including the internal medicine, neurology, and cardiology units. Our unit has included the LAAC as a strategic program within our structural heart procedures.

Left atrial appendage closure: the procedure and the device implanted

All procedures were performed in an identical working setting (facilities and personnel). However, 3 different modalities were used: on the one hand, general anesthesia and conscious sedation, both with transesophageal ultrasound guidance, and a third modality with fluoroscopy guidance only while the patient remained awake.

Although at the beginning of our experience only general anesthesia was used, 2.5 years later the possibility of conscious sedation administered by our personnel started to become a reality; the criterion to choose between general anesthesia or conscious sedation was logistical due to the discretional participation of the anesthesiology unit in structural heart procedures. In both modalities, the type of probe used for the transesophageal ultrasound was the exact same one.

The protocol of conscious sedation consisted of sedoanalgesia through the IV administration of 50 mg of pethidine followed by a bolus of 0.5 mg/kg of propofol with slow infusion in 3 min. with continuous monitorization of saturation and hemodynamics. After the introduction of the transesophageal probe several boluses of 10 mg of IV propofol were administered on demand based on the patient’s discomfort or rejection.

The procedure guided by fluoroscopy only was spared for cases with absolute or relative contraindication for transesophageal ultrasound use (in our unit we do not have intracavitary ultrasound) and for patients considered very frail for anesthetic induction; however, it became a reality 4 years after we started our experience. In these patients, a coronary computed tomography angiography was recommended to assess the left atrial appendage and discard the presence of an inner thrombus; in any case, an angiography was performed via transseptal access through a pigtail catheter from the left atrial appendage ostium without selective cannulation to discard the presence of thrombus. After catheterizing the left atrial appendage, a 180º rotational acquisition was performed through the injection of contrast at a flow rate of 8 mL/s with a total of 48 mL; by doing this a 3D image of the left atrial appendage was obtained (software i-Pilot, Siemens, Germany) that fused with the real fluoroscopy.

The 2 most popular devices in the market today were used: the WATCHMAN device in its WATCHMAN 2.5 and WATCHMAN Flex versions; Boston Scientific, United States) and the AMPLATZER ACP/Amulet device (Abbott, United States); the LAmbre device (Lifetech Scientific, China) was implanted anecdotically. The selection of one or the other did not follow any clinical or anatomical criteria and the alternate use of both devices was well-balanced. Only in fluoroscopy-guided procedures the AMPLATZER Amulet device was preferential since its delivery criteria are basically fluoroscopic.

Performance of left atrial appendage closure and follow-up

The definitions were based on the Munich consensus document regarding the LAAC.10 Successful LAACs were defined as successful devices (successful implantation of the first device selected) and successful procedures (uneventful final successful implantation within the first 24 hours). The device was released after confirming the suitability of ultrasound and fluoroscopic parameters. In cases performed under fluoroscopy guidance, position and stability were assessed over the fusion imaging as well as the lack of uncovered lobes in the angiography.

Regarding treatment after the implant, there was no pre-specified criterion and the patient’s bleeding risk was adjusted. All patients were assessed using a thoracic ultrasound within the first 24 hours prior to hospital discharge. Adherence to the transesophageal ultrasound control 1.5 months after the procedure was very irregular.

Follow-up was conducted back in February 2020 by reviewing the Andalusian (Diraya) electronic health record system. The appearance and dates of the following events were registered: death and causes, ischemic stroke/systemic embolism, major bleeding (incapacitating and major hemorrhages), and medical therapy at the follow-up. The futility of the LAAC was defined as mortality rate due to non-cardiac causes reported within the first year.

The performance of the LAAC at the follow-up was assessed using the risk reduction rate of thromboembolic (ischemic stroke/systemic embolism) or bleeding events (major bleeding) while taking into account the risk estimates from the CHA₂DS₂-VASc11 and HASBLED scores,12 respectively.

A 4-year follow-up limit has been established to start taking about «very long evolution» since this was the follow-up period of the Protect AF clinical trial1 that confirmed the superiority regarding mortality of LAAC over anticoagulation.

Statistical analysis

The estimates were obtained using IBM SPSS v26.0 and Epidat 4.2 statistical software. Initially, a descriptive analysis of data was conducted by generating means and standard deviations of numerical variables, and frequency and percentage distributions of qualitative variables.

The comparison between the demographic and clinical quantitative variables was conducted using the ANOVA test after verifying the hypotheses of normality using the Shapiro-Wilks test; when significant differences were seen, multiple comparisons were conducted using the Bonferroni correction.

The comparison among the different qualitative variables was conducted using contingency tables and the chi-square test.

The comparison between event incidence rates was conducted using the Rothman index score and 95% confidence intervals (95%CI) were estimated using Rosner’s method.

Finally, Kaplan-Meier curves were generated and then compared using the log rank test.

RESULTS

Population

The population studied included 260 patients with nonvalvular atrial fibrillation aged between 42 and 92 years old. The clinical characteristics of the population are shown on table 1.

Table 1. Clinical characteristics of the population

The most common indication for LAAC was the absolute contraindication for anticoagulant therapy due to hemorrhagic events in 229 cases (88.1%) or high-risk (2 patients with brain tumors and 1 patient with an aortic dissection; 1.1%). In 28 patients (10.8%) indication was due to the inability to take oral anticoagulants due to different bleeding risks: in 13 due to rejection to anticoagulant therapy, in 6 due to previous psychiatric history that did not recommend it, in 3 due to higher risk of falling, in 3 due to poor control of the international normalized ratio, and in other 3 due to cardioembolic stroke yet despite the proper anticoagulant therapy.

When the LAAC was indicated, therapy was mostly anticoagulation (68.8% of the patients): vitamin K antagonists (83 cases, 31.9%), direct anticoagulants (71 cases, 27.3%) or dual therapy (anticoagulation and single antiplatelet therapy, 25 cases, 9.6%). Regarding patients who were not on anticoagulant therapy prior to the LAAC, 48 of them (18.5%) were on antiplatelet therapy and 33 (12.7%) did not use any antiplatelet/anticoagulant drugs.

While follow-up was being conducted (February 2020 or prior to the patient’s death), our population was being treated with absence of antiplatelet/anticoagulant therapy (51 patients, 19,9%), single antiplatelet therapy with acetylsalicylic acid (135 patients, 52.5%), single antiplatelet therapy with clopidogrel (51 patients, 19,9%), dual antiplatelet therapy (14 patients, 5.4%) or anticoagulation (6 patients, 3%) (figure 1).

Figure 1. Evolution of antithrombotic therapy prior to the left atrial appendage closure (LAAC) until the final follow-up (%).

Procedural characteristics

Procedures were performed mostly under general anesthesia and monitored under transesophageal ultrasound guidance (59.6%). Conscious sedation, also monitored under transesophageal ultrasound guidance, was performed in 27.3% of all procedures. Only 13.1% of all procedures were performed under fluoroscopy guidance only.

The most commonly used device was the WATCHMAN (142 patients, 54.6%) followed by the AMPLATZER ACP/Amulet (116 patients, 44.6%), and occasionally the LAmbre (2 patients, 0.8%). Given the extension of the follow-up period, 2 models of the WATCHMAN (generation 2.5 in 125 patients and WATCHMAN Flex in 17 patients) and 2 models of the AMPLATZER device (ACP in 16 patients and Amulet in 100 patients) were used.

The device success rate was 98.5% (failed in 4 patients). Failed cases were due to the device not meeting the sealing criteria for the left atrial appendage so it had to be recaptured; after choosing a different device (different size, and in 1 case, also a different model), the procedure ended satisfactorily.

Procedural success was 98.8%; 1 oropharyngeal hemorrhage due to traumatic intubation and 2 tamponades were the reason for the lack of success. Tamponades (0.77%) were due, in the first case, to a perforation of the left atrial appendage in the recapture maneuver of the WATCHMAN device; the second case, after 24 hours, was due to the perforation of the left pulmonary artery possibly eroded by the LAmbre device. These 2 patients had a good clinical progression, the first one after pericardiocentesis and the second one after surgery with pericardial patch interposition between the pulmonary artery and the left atrial appendage. No deaths, strokes, or systemic embolisms were reported during the procedure or within the first 24 hours.

The number of serious adverse events reported within the first week was 6 (2.3%) as shown on table 2.

Table 2. Serious adverse events within the first 7 days after the implant

The comparative analysis between the results of the first 50 LAACs and the remaining ones give us a glimpse of the existence of a learning curve that can be seen in the procedural variables that assess the operator’s technical skills (significant reduction of fluoroscopy time and radiation dose from the first 50 procedures): 13.6 ± 5.5 min vs 18.7 ± 18.2 min and 18 413 µGym ± 11 622 µGym vs 24 798 µGym ± 18 802 µGym,2 respectively with P values = .03). However, no differences were found in the procedural success rate (98% for the first 50 cases and 99% for the remaining ones).

The procedural characteristics of the left atrial appendage closure are shown on table 3.

Table 3. Procedural characteristics

Follow-up and events

With a median follow-up of 2.5 years ± 1.9 years (median, 1.4 years; 95%CI, 1.1 to 1.9 years) our series included 637.9 patients-year.

A total of 58 deaths were reported at the follow-up (22.3% of the sample, 9.1% patients-year). Half of them were due to cardiac causes (4.6% patients-year). A total of 6 deaths were due to noncardiac causes within the first year, which means that LAAC futility rate was 2.3%.

Events such as ischemic strokes/systemic embolisms were reported in 9 patients (1.4% patients-year, 95%CI. 0.6-2.7); compared to the estimated risk of 5.7% patients-year, the reduction of relative risk was 75.2% (P < .001). A total of 19 major hemorrhages were reported (3.0% patients-year. 95%CI. 1.8-4.7), which is a 58.5% reduction of relative risk compared to the estimated risk of 7.2% patients-year (P < .001)

The assessment of the protective capacity of LAAC to avoid long-term thromboembolic phenomena and major hemorrhages is very relevant. Events were compared in patients with follow-ups of up to 4 years (n = 206; 346.7 patients-year) and in patients beyond this 4-year follow-up mark (n = 54; 291.3 patients-year). It was confirmed that, over time, protection against thromboembolic and hemorrhagic events still remains, and there is even a decreasing tendency: annual rate per 100 patients-year for ischemic stroke/embolism of 2.0 vs 0.7 (P = 0.17) and for major hemorrhages of 4.0 vs 1.7 (P = .09) in patients with up to 4-year follow-ups and longer follow-ups, respectively. The comparison of event-free survival rates for thromboembolism and major bleeding between the different populations based on the duration of the follow-up did not show any significant results (log rank with P = .10 for thromboembolisms and P = .54 for hemorrhages) (figure 2).

Figure 2. Thromboembolic event-free (A) and major bleeding-free (B) survival curves of patients with < 4 year (green) and > 4-year follow-up (gray). The curve comparison does not show any significant differences for either one of the events.

Follow-up based on the type of device implanted

A comparative analysis of the event-free survival rate in patients treated with the WATCHMAN and AMPLATZER devices found no significant differences between the 2 regarding their protective capabilities against ischemic strokes/systemic embolisms (log rank P = .86); however, the WATCHMAN showed a major hemorrhage-free cumulative incidence rate superior to the AMPLATZER device (log rank P = .01) (figure 3).

Figure 3. Thromboembolic event-free (A) and major bleeding-free (B) survival curves of patients with the AMPLATZER (green) and the WATCHMAN device (gray). No differences were seen in the devices used for thromboembolic events, but there were differences regarding major bleeding with a higher event-free survival rate in patients treated with the WATCHMAN device.

DISCUSSION

This real-world single-center registry shows our experience performing left atrial appendage closure in 260 consecutive patients with nonvalvular atrial fibrillation over the last 9 years. Results have been exposed in an attempt to answer the following questions: what were the results of LAAC in our population? what is the actual performance of LAAC reducing thromboembolic or hemorrhagic events compared to the estimated risk rates? and finally, is this this event reduction maintained at the follow-up?

The clinical characteristics of our population are consistent with those of the LAAC target population in the routine clinical practice. Thus, our population showed clinical characteristics of thromboembolic risk that were similar to those published in large registries: the CHA₂DS₂-VASc score of 4.3 was intermediate between the AMPLATZER Amulet registry13 with a CHA₂DS₂-VASc score of 4.2 and the NCDR registry14 with a CHA₂DS₂-VASc score of 4.6. Regarding the risk of bleeding, in our population the mean HAS-BLED score was 3.8, slightly higher compared to the numbers already published, and situated between the EWOLUTION registry with a HAS-BLED score of 2.315,16 and the AMPLATZER Amulet registry with a HAS-BLED score of 3.3.13

This high risk of bleeding of our population may be explained by the fact that the indication for LAAC for almost 90% of the patients was a past medical history of bleeding (mostly gastrointestinal followed by cerebral); for the remaining 10%, the indication for LAAC was the «inability to take oral anticoagulants due to different risks of bleeding»,10 that is, by a number of reasons that forced the patient (5% of the population) or the doctor to make the decision of choosing mechanical local therapy over the anticoagulant therapy. Although in our case the volume of elective decisions regarding the LAAC is far from the volume reported in the German registry LAARGE,17 where patient selection was essential to propose the indication in a fourth of the population, a reflection can be made on to what extent information brought to the patient is decisive to generalize this therapy.

The LAAC is a procedure with high device and procedural success rates in most of the series already published. In our series the device success rate in the implant was 98.5%; 1.5% of failed procedures were due to an erroneous selection of the size of the device. However, the left atrial appendages of all the patients from the series were eventually sealed, which contrasts with up to 7% of the procedures cancelled due to inaccessible left atrial appendage anatomies;14 this may have to do with our capacity to approach this procedure using different modalities (general anesthesia, conscious sedation, and fluoroscopy without ultrasound guidance) and different types of occluder devices (yet the device had to be changed for a different one only in 1 patient in order to finish the procedure). Our procedural success rate was 98.8%, which is higher compared to the rate reported in other registries with similar populations regarding their baseline clinical characteristics.14 Regarding procedural safety, our adverse event rate within the first 7 days after the procedure was 2.3%, which is consistent with the rate reported by large registries.13-16 Overall, this speaks of the progressive decline seen in the rate of adverse events reported during the early stage after the procedure.

In the consecutive analysis of procedural results like the left atrial appendage closure, right from the beginning of our experience and until today, the presence of a learning curve may be anticipated. However, beyond procedural variables like the radiation duration and dose, no differences were reported regarding the procedural success rate between the early period and the rest of the experience. Standardizing procedures and training the operators may be the reasons of the high success rate reported in left atrial appendage closure despite the poor early experience reported.18

Our registry, with a median follow-up of 2.5 years and a fifth of the patients with follow-up periods > 4 years allows us to assess the efficacy of the LAAC with a certain perspective. In the first place, mortality rate is surprisingly high since 22.3% of the patients included died at the follow-up. This is an annual mortality rate of 9.1%, 3 times higher compared to the 4-year follow-up of the Protect AF,1 but it is nearly identical as other registries with a similar risk population compared to ours.9 The highest mortality risk seen at the follow-up has been associated with factors such as age, male sex, history of stroke or intracranial hemorrhage, low ejection fraction, and chronic kidney disease;8,9 in any case, this high mortality rate seen at the follow-up shows how frail this diseased population really is, which would justify an interesting debate on the futility of the LAAC in some patients19 (2.3% in our series).

The primary endpoint of LAAC is to reduce the risk of cardiac embolism in a population with nonanticoagulated atrial fibrillation. In our case, the annual rate of ischemic stroke and embolism was 1.4%, which was a significant reduction of the relative risk of 75%, which is consistent with the best data reported in the medical literature.20 Regarding major bleeding, in a population with an estimated rate of bleeding > 7%, our rate was 3.0%, that is, half the rate reported by other authors.9

To this day, very few studies have been conducted on the long-term efficacy profile of the left atrial appendag-e closure. In the Ibérico II registry,8 the rate of thromboembolic events remained low while the rate of major bleeding was lower compared to the early rates at the 2-year follow-up. In our population, the analysis of patients with very long clinical courses (implantation times > 4 years) revealed that the efficacy of the LAAC still remains. Also, that thromboembolic and bleeding events showed a tendency towards a lower incidence rate compared to the earliest stage.

Limitations

This study has some limitations. In the first place, no systematic antithrombotic pattern was followed after implantation. Instead, it was left to the operator’s discretion, which may have impacted the short-term bleeding rate. On the other hand, no systematic imaging follow-up was arranged 45 days to 3 months after implantation, which means that an important piece of information was lost: the rate of thrombosis associated with the device, lack of residual sealing…

CONCLUSIONS

In our setting, left atrial appendage closure is an effective therapy for patients with nonvalvular atrial fibrillation and coagulation issues. It significantly reduces the rates of thromboembolic and hemorrhagic events that remain consistent in the very long term.

FUNDING

No funding related for this work.

AUTHORS' CONTRIBUTION

R.J. Ruiz-Salmerón: author of the manuscript; M. Ronquillo-Japón, C. Robles-Pérez, M. Iglesias-Blanco, C. Rubio-Iglesias,R. García de la Borbolla, C. Carrascosa-Rosillo, S. Rodríguez de Leiras, M. Vizcaíno-Arellano, and I. Méndez-Santos: critical review and J. Polo-Padillo: statistical analysis.

CONFLICTS OF INTEREST

None reported.

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

INTRODUCTION

Severe aortic stenosis is a common disease in our setting and has high morbidity and mortality rate. Its basic treatment is valve replacement.1 Over the last 2 decades, transcatheter aortic valve implantation (TAVI) has joined the traditional surgical aortic valve replacement (SAVR).2

Data are clear on the association between results and certain characteristics of the centers. The fact that has been most described in the medical literature is that, regarding mortality and complications, better results are obtained in those centers that reach the activity threshold (per center and per operator) for certain processes and procedures,3^-7 including coronary artery bypass graft (CABG)5,8 and primary angioplasty.9^-11 Regarding TAVI, the association between volume and results has been reported in hospitals in the United States.12^-14 In Germany, this association is less obvious.15 In Spain, the association between volume and results has also been reported for CABG.16

There are fewer studies that analyze the structural characteristics of the centers and their association with the characteristics of the healthcare systems of every country and the results obtained. In Spain, Bertomeu et al.17 found a lower mortality rate in patients with acute myocardial infarction (AMI) in high-volume centers with higher complexity. Worner et al.18 described a lower mortality rate in the management of AMI in hospitals with cardiac surgery and intensive care unit (CICU) capabilities. Rodríguez-Padial et al.19 found better results in the management of AMI in hospitals serving large communities. The association between CICU availability and better results has also been reported in our setting for the management of cardiogenic shock due to ST-segment elevation myocardial infarction.20

Our objective was to analyze the structural variables of the treating centers (availability of CICU), the volume of procedures performed and their association with results obtained after aortic valve replacement (whether through TAVI or SAVR).

METHODS

Population and sources of data

This is an observational and retrospective study of all the patients discharged from the hospitals of the Spanish National Healthcare System who underwent a SAVR o a TAVI procedure. The source of data was the minimum basic dataset (MBD) of the Spanish National Healthcare System of 2014 and 2015 (the only years available with a specific code for TAVI in the MBD). The clinical results of the patients transferred were assigned to the centers from which they were eventually discharged. Whenever the same episode was treated through TAVI and SAVR, it was considered as a TAVI treated episode and SAVR as a TAVI related complication. The main result variables were in-hospital mortality, length of the hospital stay, and in-hospital complications. The codes used for the complications seen are shown on table 1 of the supplementary data.

Table 1. Differences in the profile of patients and in the results of transcatheter aortic valve implantation based on the structural characteristics of each center (2014-2015)

Hospital structural variables

To analyze the possible correlation between the hospital structural variables and the results of aortic valve implantation both the volume of procedures performed and the cardiovascular resources available were studied. Hospitals were classified based on the availability of cardiology related resources and according to the RECALCAR criteria21 (table 2 of the supplementary data). Regarding this study, to analyze the inter-hospital differences, only those with cath lab capabilities without (type 3) and with cardiac surgery (type 4) were included. The availability of CICU based on a survey previously conducted by the Spanish Society of Cardiology was also included.22 The characteristics to consider the presence of a CICU were: a) a comprehensive capacity to manage patients in critical condition including invasive mechanical ventilation, and b) the administrative adhesion of the CICU to the cardiology unit.

Table 2. Differences in the profile of patients and in the results of surgical aortic valve replacement based on the structural characteristics of each center (2014-2015)

Statistical analysis

The risk adjustment models were specified based on the Centers for Medicare and Medicaid Services (CMS) methodology. Regarding CABG, the variables included in the 30-day mortality model were considered as independent variables.23 Also, certain variables anticipated by the Society of Thoracic Surgeons score for aortic valve replacement—and that can be identified in the MBD24—were included too. Finally, the CMS model was adjusted to the data structure of the MBD after gathering secondary diagnoses based on clinical categories.25 The multilevel logistics regression models were also adjusted.26,27 Only statistically significant comorbidities and odds ratio (OR) > 1.0 were considered for the adjustment model.

Based on specified models the risk-adjusted standardized mortality ratio (RA-SMR) was estimated.28 To adjust the length of the hospital stay, the Poisson regression model was used including the year of hospital discharge, the sex of the patient, and the degree of severity of groups related by refined diagnosis as risk factors. The expected length of the hospital stay was obtained from the individual predictions of the adjusted model. Also, the risk-adjusted length of stay ratio (RA-LOSR) was estimated as the coefficient between the length of the stay observed and the length of the stay expected.

To distinguish between high and low-volume hospitals (based on the number of episodes treated), a group clustering algorithm was used. To that end, the mathematical model used was developed with two thirds of the database and validated with the remaining third. The algorithm ranked as high-volume centers for TAVI those that performed ≥ 46 procedures, and as high-volume centers for SAVR those that performed ≥ 240 procedures during the study 2 year-period (2014-2015).

Quantitative variables were expressed as means ± standard deviations and the qualitative ones as frequencies and percentages. The correlation among the quantitative variables was analyzed using Pearson correlation coefficient. For comparison purposes, the Student t test for 2 samples and the analysis of variance (ANOVA) were used with correction of the level of significance using the Bonferroni method for ≥ 3 groups. Comparisons among the different categorical variables were conducted using the chi-square test or Fisher’s exact test.

All comparisons were bilateral, and differences were considered statistically significant with P values < .05. Statistical analyses were conducted using the STATA 13 and SPSS v21.0 software package.

RESULTS

A total of 2055 TAVIs and 15146 SAVRs were performed. Back in 2014 a total of 812 TAVIs were performed in 47 centers and in 2015 the number went up to 1243 in 53 centers.

The differences seen in the profile of the patients who underwent TAVI and SAVR are shown on table 1 and table 2, respectively, based on the type of hospital where procedures were performed. No statistically significant differences regarding age and sex were seen in patients who underwent TAVI in any of the 4 groups. Still, comorbidity was significantly higher (higher Charlson index and higher incidence of heart failure) in patients treated in type 3 non-CICU hospitals.

Regarding patients who underwent SAVR, by definition in type 4 hospitals, no statistically significant differences were seen regarding age, sex or presence of comorbidities among patients treated with and without CICU except for a higher prevalence of cardiogenic shock and previous percutaneous coronary interventions in non-CICU hospitals (2.0% vs 1.3%, P < .001; and 4.9% vs 3.9%, P = .004, respectively) (table 2).

The in-hospital mortality adjustment model for surgical aortic valve replacement showed good discrimination capabilities (area under the ROC curve, 0.84; 95% confidence interval [95%CI], 0.82-0.85) and calibration (P < .001). The model median odds ratio was 1.73, indicative of a high inter-hospital variability.

The SAVR specific in-hospital mortality adjustment model also showed excellent discrimination and calibration capabilities too (area under the ROC curve, 0.84; 95%CI, 0.83-0.84; calibration, P < .001) that were slightly lower for the TAVI specific adjustment model (area under the ROC curve, 0.79; 95%CI, 0.74-0.84; calibration, P < .001).

Characteristics of the treating center and TAVI results

Type 4 hospitals had a significantly lower RA-SMR compared to type 3 hospitals (4.04 ± 0.98 vs 4.47 ± 0.79). No statistically significant differences were seen on the RA-LOSR (0.99 ± 0.81 vs 1.07 ± 0.81; P = .278). The presence of a CICU was associated with a slightly lower, but sill statistically significant, RA-SMR (4.03 ± 0.87 vs 4.1 ± 1.07; P < .001). The correlation between CICU and a lower RA-SMR was also found in type 4 (4.03 ± 0.88 vs 4.05 ± 1.08; P < .001) and type 3 hospitals (4.09 ± 0.06 vs 4.59 ± 0.87; P < .001) (table 3).

Table 3. Differences in the results of transcatheter aortic valve implantation based on the characteristics each center (2014-2015)

CICU capable type 4 hospitals had a higher incidence of postoperative shock (1.8% vs 0.6%; P = .017), the same incidence of sepsis (0.8% vs 0.8%; P < .819), and a lower RA-SMR (4.03 ± 0.88 vs 4.05 ± 1.08; P < .001) compared to non-CICU hospitals.

Regarding the volume of procedures performed by the hospitals, the median of TAVI per year was 11 [2-36 for low-volume centers and 33 [9-67] for high-volume hospitals. The RA-SMR was lower in high-volume hospitals (3.95 ± 1.08 vs 4.26 ± 0.72; P < .001) (table 4 and figure 1). The mean adjusted stay did not show any differences between CICU capable and non-CICU hospitals (1.00 ± 0.85 vs 0.98 ± 0.77; P = .581). In general, regarding the crude complication rates, TAVI did not show any statistically significant differences between high and low-volume hospitals (table 4).

Table 4. Differences in the results of transcatheter aortic valve implantation based on the volume of cases of each center (2014-2015)

Figure 1. In-hospital mortality adjusted comparison for transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR). Note that, regarding SAVR, in low-volume centers with CICU only 1 center was excluded. CICU, cardiac surgery and intensive care unit; RA-LOSR, risk-adjusted length of stay ratio; RA-SMR, risk-adjusted standardized mortality ratio.

Characteristics of the treating center and SAVR results

The presence of a CICU turned out to be a protective factor for in-hospital mortality in these patients (OR, 0.79; 95%CI, 0.67-0.93; P = .005). However, the different RA-SMRs seen among various centers with and without CICU capabilities did not show statistically significant differences (5.91 ± 1.49 with CICU vs 5.94 ± 1.72 without it; P = .335) (figure 1). The same thing happened with the RA-LOSR. CICU capable type 4 hospitals had a higher incidence of postoperative shock (2.2% vs 1.3%; P = .024) but a lower incidence of sepsis (1.1% vs 2.3%; P < .001) (table 5).

Table 5. Differences in the results of surgical aortic valve replacement based on the characteristics of each center (2014-2015)

In relation to the volume of procedures performed, the RA-SMR was lower in high-volume hospitals (5.89 ± 1.54 vs 6.27 ± 2.02; P < .001) (table 6) without any statistically significant differences with respect to the RA-LOSR (0.99 ± 0.73 vs 1.06 ± 0.75; P = .463). No statistically significant differences were seen between high and low-volume hospitals in the crude complication rates (table 6).

Table 6. Differences in the results of surgical aortic valve replacement based on the volume of cases of each center (2014-2015)

Association between TAVI and SAVR results

In type 4 hospitals, no statistically significant linear correlations were found between the RA-SMRs of TAVI and those of SAVR (r = 0.21; P = .14). Similarly, the SAVR high-volume variable had a non-statistically significant protective effect when it was introduced in the risk-adjustment model of TAVI related in-hospital mortality (OR, 0.73; 95%CI, 0.33-1.62). The 17 hospitals (1134 episodes identified) that shared the TAVI and SAVR high-volume feature had a TAVI related RA-SMR that was significantly lower compared to centers with the TAVI and SAVR low-volume feature (4 ± 1.1 vs 4.5 ± 0.7; P < .001). A single center (80 episodes) with a high-volume of TAVI and a low-volume of SAVR had the lowest TAVI related RA-SMR of all (2.8 ± 0.3; P < .001 with respect to a high-volume of TAVI and SAVR performed).

DISCUSSION

This study findings that included real-world data in our country, show a consistent correlation between the hospital structural characteristics and the results obtained in aortic valve replacement procedures, both surgical and transcatheter (figure 1). High-volume hospitals with cardiac surgery and intensive care units (CICU) have lower risk-adjusted mortality rates in both procedures.

In relation to the association between volume and results, our study also shows TAVI results that are consistent to those described by the medical literature,10^-14 with mortality rates that are similar to those seen in other countries in the study period (2014-2015) and higher to those published for 2015-2017.14 In Spain, the mortality rate differences seen after adjusting for high and low-volume centers are lower to the ones reported, which may be explained because, actually in those years in Spain, low-volume centers were being compared to very low-volume centers. Therefore, 52 out of the 53 center that performed TAVIs in Spain from 2014 through 2015 were within the range of the 2 lower quartiles (5-54 procedures per year), per volume of procedures performed, in the study conducted by Vemulapalli et al.14. Only 7 of those centers were above the range of the lower tercile in the study conducted by Kaier et al.15.

These data should be interpreted in the context of the learning curve of this technique in our country.29

The correlation between a higher volume and a lower RA-SMR was also found for SAVR. Again in this case, low-volume centers were being compared since only 12 and 10 out of the 42 centers, in 2014 and 2015 respectively, performed > 200 SAVRs, and over 70% of the centers were within the 2 lower quartiles of SAVR volume according to the study conducted by Hirji et al.30.

In this study, TAVI and SAVR high-volume centers had a lower TAVI-adjusted mortality rate compared to low-volume centers for both procedures, which is consistent with the findings reported by Mao et al.31. However, the only hospital identified as a high-volume center for TAVI and a low-volume center for SAVR had excellent TAVI results; since it was a single center with limited number of cases (4% of all TAVIs performed), this finding, suggestive that specific experience is more relevant than global experience in aortic valve replacement procedures, should be studied in the future. However, this is reasonable because it shows that here experience accumulates per processes or specific dedicated teams rather than centers in general.

Since no references were found in the medical literature, the newest finding of this study was the association between the presence of a CICU and the lower mortality rate reported for both techniques. This correlation is even more solid and clinically significant for TAVI rather than SAVR, which seems somehow intuitive, since patients treated with SAVR are often referred to general intensive care units.

The association between CICU availability and optimal results in the management of cardiogenic shock in the AMI setting20 had been described by the Spanish National Healthcare System. However, this association had not been reported in surgical procedures. Medical literature describes a virtuous relation between the volume of SAVRs performed and TAVI results, which is probably associated with the greater experience of the heart team.29,31 The presence of a CICU can be a variable that includes both the cardiologists’ greater experience and higher participation in the management of patients in critical cardiac condition and the experience of the hospital, cardiology unit, and cardiac surgery unit. In both cases, the CICU contributes to a better management of patients treated with interventional procedures (TAVI and SAVR) across the entire healthcare process.

Therefore, the results described may me important to plan healthcare and allocate resources such as teaching and training in the 2 aforementioned procedures.

Limitations

This study is a retrospective analysis of administrative data. However, even with its inherent limitations, the validity of its design has been compared to clinical registries.26,32 Such reliability allows us to compare the results of multiple hospitals33 and has been used specifically to analyze TAVI results.11-13,29,30 However, we should mention that data from the MBD should be interpreted with caution because they were not audited. Finally, this study shows the early experience with TAVI, probably still within the learning curve of this technique in the centers studied, which is why findings should be compared to more recent and larger series.

CONCLUSIONS

There is a correlation between the structural characteristics of the treating centers and the results obtained in aortic valve replacement, both surgical and endovascular, with great heterogeneity among the various centers. Large volume hospitals with cardiac surgery units and CICU capabilities have a lower risk-adjusted mortality rate in both procedures.

FUNDING

This study has been funded by an unconditional grant from the Interhospital Foundation for Cardiovascular Research.

AUTHORS' CONTRIBUTIONS

I. J. Núñez-Gil: conceptualization, drafting of the manuscript and analysis; J. Elola and M. García-Márquez: conceptualization, data collection and analysis, drafting and critical review of the manuscript; J. L. Bernal and C. Fernández: data collection and analysis and critical review of the manuscript; A. Íñiguez, L. Nombela Franco, P. Jiménez-Quevedo, J. Escaned and C. Macaya: elaboration and critical review of the manuscript; and A. Fernández-Ortiz: conceptualization, data analysis, preparation and critical review of the manuscript.

CONFLICTS OF INTEREST

None reported.

ACKNOWLEDGEMENTS

We wish to thank the Health Information Institute of the Spanish National Healthcare System at the Spanish Ministry of Health, Consumer Affairs and Social Welfare for partially disclosing the MBD database.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

The STENTYS Xposition S (STENTYS S.A., Paris, France) is a sirolimus-eluting self-expanding nitinol stent designed to adapt its size to the vessel diameter and facilitate its complete apposition when exerting chronic strength towards the outside. It has long been confirmed that one of the most important factors of stent thrombosis is the incorrect apposition of the stent.1 The characteristics of this stent make it especially useful to revascularize acute coronary syndromes (ACS), especially ST-segment elevation acute coronary syndromes with lesions with high thrombotic load. Also, a potential benefit in ectatic coronary vessels and lesions with great proximal and the distal diameter mismatch has been confirmed, bifurcations (left main coronary artery [LMCA] included), and venous grafts.

The objective of this study was to assess the benefit of this stent in the routine clinical practice by analyzing the type of lesions this stent is used with and the immediate angiographic results and at the clinical follow-up.

METHODS

A cohort of consecutive patients treated with the STENTYS Xposition S stent was analyzed from January 2018 through October 2019 in a tertiary hospital where over 1000 percutaneous coronary interventions are performed each year. All coronary lesions were quantified using a quantitative coronary angiography. Lesions in vessels with changes in size (ectasia or proximal-distal diameter mismatch of the lesion), in a bifurcation, in the presence of a high thrombotic load or in a venous graft were analyzed. The interventional strategy to be followed, imaging modalities included, was left to the operator’s criterion. The clinical and follow-up data were obtained from the electronical clinical records of the healthcare system of our autonomous community. All events were defined in a standard way according to the Academic Research Consortium-2 (ARC-2) consensus document.2

Patients' informed consent was obtained to the interventional procedure and, subsequently, verbal informed consent was given during the follow-up.

The data analysis was conducted using the IBM SPSS 20.0 statistical software package. Continuous variables were expressed as mean ± standard deviation or median with interquartile range depending on whether they followed a normal distribution or not, respectively. Qualitative variables were expressed as relative percentage. The cumulative incidence of events at the follow-up was estimated.

RESULTS

From January 2018 through September 2019, 1692 percutaneous coronary interventions with stent implantation were performed. The STENTYS Xposition S stent was used in 50 patients (62 lesions). The patients’ median age was 66 years [49-92]. Eighty-eight per cent of the patients were males. Table 1 shows the clinical characteristic of patients and coronary lesions. The most common clinical presentation was ST-segment elevation acute coronary syndrome in 23 patients (46%) followed by non-ST-segment elevation acute coronary syndrome in 22 patients (44%), and stable angina in 5 patients (10%). According to the classification established by the American College of Cardiology/American Heart Association the most common type of lesion was B1 lesion (38.7%). The right coronary artery was the most frequently treated vessel in 33 patients (53.2%).

Table 1 Clinical characteristics of patients and angiographic characteristics of the lesions

Ectasia and great proximal-distal diameter mistmatch at the lesion were the main indication for the use of this stent, in 72.6% of the lesions, with a mean vessel reference diameter of 4.1 mm ± 0.8 mm. A certain size was required to use this type of stent. The percutaneous coronary interventional on a bifurcation was the second most common indication, in 27.4% of the patients (2 of them on the LMCA). The most common type of bifurcation according to the Medina classification was 1-1-0, in 9 cases (52.9%). The secondary branch was damaged in 17% of the patients. The provisional stenting technique was the most widely used in 15 cases (88.2% of bifurcations) re-crossing to the secondary branch in 9 of them (60%). The dilatation of the secondary branch only occurred in 7 patients and only in the other 2 stents were implanted: one in a 0-1-1 bifurcation according to the Medina classification (minicrash technique) and the other in a 1-1-1 bifurcation according to this classification (TAP technique [T-and protrusion technique]). In both cases the STENTYS Xposition S stent was implanted in the main vessel and a non-self-apposing stent in the secondary branch (figure 1).

Figure 1. A: lesion with significant thrombotic load in the mid right coronary artery, which remains after thrombus aspiration. B: 3.5-4.5 mm × 27 mm Xposition S direct stent implantation. C: final angiographic result. D: significant stenosis in distal left main coronary artery. E: 3-3.5 mm × 27 mm Xposition S stent implantation from the proximal left main coronary artery to the left anterior descending coronary artery. F: angiographic result after postdilatation.

A high thrombotic load (Thrombolysis in Myocardial Infarction flow grade 4-5) was seen in 8 lesions. All of them in ectatic coronary vessels or with proximal-distal caliber mismatch. No case of venous graft treated with STENTYS was reported.

Predilatation occurred in 32 lesions (51.6%) and postdilatation in 37 (59.7%). The criterion used for postdilatation was angiography guided visual underexpansion. Intravascular ultrasound was performed in 15 patients (30%) before the implant. It was also used in 2 patients to optimize the percutaneous coronary intervention given the persistent stent underexpansion seen on the angiography. In both cases the minimum lumen area was > 5.5 mm2 with stent expansion > 80% and lack of incomplete apposition (defined as a strut separation of > 0.4 mm axial and 1 mm longitudinal) (figure 2). The optical coherence tomography was performed in a patient with ST-segment elevation acute coronary syndrome before and after the implant. It revealed a high thrombotic load with lack of immediate stent malapposition.

Figure 2. A: acute thrombotic occlusion in left circumflex artery with Thrombolysis in Myocardial Infarction flow grade 0. B: the intravascular ultrasound shows a great deal of thrombus in the lesions despite thrombus aspiration. C: implantation of 2 3.5-4.5 mm × 27 mm Xposition S overlapping stents. D: the intravascular ultrasound performed after stent implantation confirms the good angiographic results and lack of stent malapposition.

Angiographic success was achieved (with the stent properly implanted, a residual lesion ≤ 10%, and Thrombolysis in Myocardial Infarction flow grade 3) in all patients but 1, in whom stent implantation failed in a severely calcified LMCA lesion. In this case, predilatation was first attempted using a conventional balloon and then a cutting balloon on the LMCA severe distal lesion. A 3.3-4.5 mm × 22 mm STENTYS Xposition S stent was implanted with stent loss during retrieval, which remained braced to the guide catheter. Afterwards, a balloon-expandable drug-eluting stent was successfully implanted. The un-crimped stent was retrieved by crossing a guidewire from the femoral access through the stent distal struts. It was finally captured with a snare.

The median score obtained in the PRECISE-DAPT risk calculator (Predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy) was 16.5 (7-25), and the median score obtained in the DAPT index (Dual antiplatelet therapy) was 1.15 (−2-4). Ticagrelor was the most commonly used P2Y₁₂ inhibitor (58.1%). A 12-month course of dual antiplatelet therapy was prescribed in 48 patients (96%).

After a median follow-up of 373 days (256-439), 1 patient had an acute myocardial infarction 3 months after the intervention. However, the coronary angiography did not reveal coronary artery disease progression but confirmed the good results of the previous intervention. An 84-year-old woman died at admission due to heart failure. Three patients died of non-cardiac causes: 1 due to septic shock at admission, the other patient died 6 months after the percutaneous coronary intervention due to high-grade lymphoma, and the third one 4 months after the percutaneous coronary intervention due to lung cancer. No cases of definitive stent thrombosis or revascularization of the treated lesion were reported. No bleeding was seen either at the follow-up.

DISCUSSION

This type of stent is not widely used in our setting and we believe 2 are the reasons why. The first one is the need for a learning curve to know how to handle this implant. In former iterations of the device, the delivery system had some technical limitations like the jumping phenomenon that could occur right when the sheath was being released due to the elastic properties of nitinol. Unlike its predecessor (STENTYS sirolimus DES), the stent of the new STENTYS Xposition S system, is mounted over a semicompliant balloon and covered by a 0.0032 in-thick sheath. The reason for balloon inflation is not to dilate the stent, but to rupture the external sheath from the distal to the proximal border to allow a proper vessel-wall stent apposition. This has reduced the complexity of the release mechanism.3 However, we should remember that after the implant, the retrieval of both the balloon and the device sheath should be conducted with care by separating the guide catheter from the ostium to avoid deep intubation. The other reason that may explain why this stent is still not widely used can the augmented profile of the device and its rigidity, which both reduce its navigational and crossing capabilities compared to balloon-expandable stents.

Due to the characteristics of the stent and the experienced gained using it, the clinical settings where it can be useful are: ectatic vessel, since the stent reaches 6.5 mm of diameter with the device L size; proximal and distal diameter mismatch due to its adaptative capabilities to the vessel caliber; lesions with high thrombotic load, since this stent self-expanding capabilities facilitate its expansion until it reaches the vessel wall if thrombus reabsorption occurs, which avoids late stent malapposition; and bifurcations with ostial damage and 30º to 70° angles. The stent z-shaped mesh and the presence of small interconnectors facilitate re-crossing the lateral branch and disconnecting the struts without having to use the final kissing balloon technique. Thanks to its self-expanding capabilities, the unconnected struts cover the lateral branch ostium making the double stent technique unnecessary on many occasions.

In the studies published on former iterations of the device, the self-expanding stent proved superior to the balloon-expandable stent regarding better apposition. The randomized APOSSITION II clinical trial,4 conducted among patients with acute myocardial infarction, showed a lower rate of stent malapposition (defined as > 5% of struts per patient as seen on the optical coherence tomography) 3 days after the primary percutaneous coronary intervention. The APOSSITION IV clinical trial,5 also conducted among patients with acute myocardial infarction, showed a significantly lower percentage of stent malapposition at the 4-month follow-up in patients treated with self-expanding stents compared to patients treated with balloon-expandable stents (0.07% vs 1.16%; P = .002). However, no inter-group differences were found at the 9-month follow-up (0.43% vs 0.28%; P = .55) or in the rate of major adverse cardiovascular events (MACE). The clinical repercussions of this improvement in the early apposition of the stent has not been studied thoroughly. The APOSSITTION III trial6 showed that the use of STENTYS BMS in the percutaneous coronary intervention setting was associated with acceptable cardiovascular results at the 2-year follow-up, an overall rate of MACE of 11.2%, and a rate of stent thrombosis of 3.3%. We should mention that this study revealed a significant reduction of adverse events after the systematic implementation of a standard protocol (predilatation, implantation, postdilatation). The data available support the hypothesis of the need for mild postdilatation to avoid early complications probably because the stent does not have enough radial strength to achieve a proper expansion in rigid often calcified lesions, especially when predilatation is not fully effective. Therefore, postdilatation would avoid the incomplete expansion of the stent, which may increase the risk of stent thrombosis.7

Our study with the STENTYS Xposition S stent reached angiographic success in 98.4% of the cases, although we should remember that, from the anatomical point of view, they were not complex lesions (only 30% were type C lesion). Stent implantation failed in 1 severely calcified LMCA lesion; it is precisely in this type of lesions where its use is ill-advised, especially if predilatation is not effective.8

Regarding its use in bifurcations the studies published to this day have also discussed a former iteration of this device with good results. In the observational, multicenter, and prospective OPEN II trial,9 the rate of MACE at the 12-month follow-up was 13% (10.1% at 6 months). This rate of events was basically due to the need for revascularization of the treated lesion, while the rate of stent thrombosis at the 12-month follow-up was 1%. We should also mention that the kissing balloon technique was only used in 21.7% of the patients. Also, there were no significant differences in the rate of MACE between patients in whom the kissing balloon technique was used and those in whom it was not used.9

To this day, the only study published on the new STENTYS Xposition S model is the TRUNC, a prospective and multicenter study that assessed the efficacy and safety profile of this type of stent in the LMCA. Angiographic success was achieved in 96.6% of the patients and the overall rate of MACE was 8.3% at the 12-month follow-up, basically due to revascularization of the lesion treated in 5.4%.10 Here we should mention the preliminary results reported by the SIZING (Worldwide every-day practice registry assessing the Xposition S self-apposing stent in challenging lesions with vessel diameter variance) and WIN (World-wide registry to assess the STENTYS Xposition S for revascularization of coronary arteries in routine clinical practice) registries. Both registries confirm the safety and efficacy profile of the current iteration of the stent in the routine clinical practice.

Limitations

Our study has several limitations. Because of its retrospective, single-center nature and the limited number of cases involved, we cannot draw definitive conclusions on the device safety and efficacy profile. No intracoronary imaging modality was performed systematically to guide the implant, which may have been useful, especially the optical coherence tomography. However, we believe that this study is relevant due to the scarce evidence available on the last iteration of this stent.

CONCLUSIONS

In our series of lesions located in ectatic vessels or with proximal-distal diameter mismatch and in bifurcations, the STENTYS Xposition S stent is a good therapeutic alternative that achieves good immediate angiographic results and good mid-term clinical results.

FUNDING

No funding to declare.

AUTHORS' CONTRIBUTIONS

Data collection: A. Pérez Guerrero, I. Caballero Jambrina. Data analysis: A. Pérez Guerrero, G. Fuertes Ferré, I. Caballero Jambrina, G. Galache Osuna, M.C. Gracia Ferrer. Analysis and interpretation of data: A. Pérez Guerrero, G. Fuertes Ferré, J. Sánchez-Rubio, G. Galache Osuna, M.C. Gracia Ferrer. Critical review of manuscript: J.A. Diarte de Miguel, M.R. Ortas Nadal.

CONFLICTS OF INTEREST

None declared.

REFERENCES

INTRODUCTION

The physiological assessment of coronary lesions is a routine practice in contemporary cath labs and is strongly recommended by the European guidelines to guide the percutaneous coronary intervention (PCI) decision-making process.1 Unlike fractional flow reserve, the new instantaneous wave-free ratio (iFR) index allows us to analyze the physiological significance of each lesion and each coronary segment.2-5 This has led to the creation of the new and specific SyncVision software package (SyncVision version 4.1.0.5, Philips Volcano, Belgium), that shows the functional compromise of each lesion and predicts the expected iFR improvement after percutaneous treatment.3,4

Few observational studies published have analyzed the reduction in the length of the stent implanted compared to angiography-guided revascularization in long and diffuse coronary lesions.4,5 However, this reduction could be detrimental to the complete coverage of the plaque in this type of lesions, which has proven to be a predictor of major adverse cardiovascular events at the follow-up.6

The objective of our study is to analyze the utility of the iFR and SyncVision software to guide the PCI decision-making process in long, sequential, and diffuse coronary lesions.

METHODS

We have designed a multicenter, randomized, controlled, and open-label trial to compare SyncVision/iFR-guided revascularization to angiography-guided revascularization in patients with long, sequential or diffuse significant angiographic coronary lesions (ClinicalTrials.gov identifier: NCT04283734). All the variables that will be analyzed during the study are shown on table 1.

Table 1. Variables that will be analyzed during the study

Additionally, the study has received the proper ethical oversight and has been approved by the Ethical Comitee of Córdoba.

Inclusion and exclusion criteria

Patients with the following criteria are being included: a) patients > 18 years old who require percutaneous coronary treatment due to ischemia (silent, stable angina or acute coronary syndrome); b) presence of a vessel with sequential lesions separated by < 10 mm from each other with a total lesion length > 25 mm and a percent diameter stenosis > 60% (as seen on the quantitative coronary angiography assessment) in, at least, 1 segment; or a coronary segment > 30 mm with diffuse disease, and a percent diameter stenosis > 60% (as seen on the quantitative coronary angiography assessment) in, at least, 1 region; c) baseline iFR ≤ 0.89 distal to a potentially randomizable lesion.

We have stablished the following exclusion criteria: a) patients with acute coronary syndrome with non-optimal results in the culprit vessel (final Thrombolysis in Myocardial Infarction (TIMI) flow grade < III, non-reflow phenomenon during treatment, residual coronary dissection, lost or compromise of a major side branch); b) patients with acute coronary syndrome and left ventricular ejection fraction < 45%; c) life expectancy < 12 months; d) patients with severe aortic stenosis; e) contraindication for dual antiplatelet therapy for at least 12 months; f) presence of significant thrombocytopenia (< 10 x 109/L); g) patients with an indication for bypass surgery according to the heart team; h) pregnancy; i) inability to understand the informed consent.

Endpoints

The study primary endpoint is the reduction of the average length of the stent implanted in the SyncVision-guided group measured in millimeters (mm) compared to the angiography-guided group. The study secondary endpoint is a composite of cardiac death, myocardial infarction, definitive or probable stent thrombosis, new target lesion revascularization or new target lesion failure (major adverse cardiovascular events [MACE]); and the assessment of residual ischemia through single-photon emission computed tomography at the 6-month follow-up.

Procedure

After the diagnostic phase, the use of intracoronary vasodilators is mandatory to exclude possible coronary spasms. Lesions will be assessed by 2 expert operators (prior to randomization) to determine the coronary segment to treat when the revascularization is angiography-guided based on current routine clinical practice. Afterwards, the iFR will be determined at baseline. If the obtained iFR is ≤ 0.89, patients will be randomized to the angiography-guided revascularization group (the control group) or to the iFR pullback-guided revascularization group using the SyncVision software (figure 1). Intracoronary imaging can be used in both groups based on the operator’s criteria to optimize the angiographic result.

Figure 1. Summary of randomization, treatment targets, and follow-up of the iLARDI study. iFR, instantaneous wave-free ratio; MACE, major adverse cardiovascular events; PCI, percutaneous coronary intervention.

In the intervention group, a pressure wire (Verrata pressure guidewire, Philips Volcano, Belgium) will be inserted trough a guide catheter towards the vessel ostium to normalize the pressure between the aortic and the vessel ostium. Secondly, the pressure wire will be advanced distally to the lesion. Under stable hemodynamic conditions (without the administration of vasodilators), we will determine the baseline iFR. Afterwards, the wire will be removed under continuous fluoroscopy, and in the same projection. If the iFR at the vessel ostium is 1 ± 0.02, the absence of drift will be confirmed and an angiogram in the same angiographic position will be performed. The SyncVision software can recognize the vessel analyzed and identify the physiological contribution of every lesion and every segment, predicting the improvement of the iFR after treatment. The iFR improvement is depicted as yellow dots. Each yellow dot represents an iFR improvement of 0.01 if that zone was percutaneously treated. The accumulation of many yellow dots suggests that the contribution of that lesion to physiological compromise is high. After performing the physiological assessment of each lesion, the operator would have to treat the minimum segment needed to achieve an iFR of 0.90. Cases without an accumulation of dots have been considered as physiological diffuse disease (defined as the presence of < 20% of the total number of dots) in the coronary segment physiologically assessed. Those cases will be medically treated due to the theoretical absence of benefit of the percutaneous treatment (figure 2 and figure 3).

Figure 2. Flowchart of technical treatment details of patients randomized to the intervention group.

* We consider as optimization the postdilatation of the previous stented area if an in-stent accumulation of yellow dots is seen; or the percutaneous treatment of a new segment with physiological compromise not seen in the baseline iFR-pullback study. iFR, instantaneous wave-free ratio.

Figure 3. Image of iFR co-registration using the SyncVision software in a patient included in the study and randomized to the intervention group with a diffuse lesion in the left anterior descending coronary artery, and the physiological contribution of every segment. The estimated length of the stent to achieve an iFR > 0.89 is 50.6 mm.

Follow-up

Patients will be followed either through phone calls or physical examination at the 3, 6 and 12-month follow-up. At the 6-month follow-up a stress single-photon emission computed tomography (physiological or pharmacological) will be performed in all patients. The composite of cardiovascular death, definitive or probably stent thrombosis, new target lesion failure or new target lesion revascularization will be considered as MACE.

Quantitative coronary measurements

Quantitative coronary measurements will be performed using a validated system (CAAS system, Pie Medica Imaging, Netherlands). The measurements analyzed will be the vessel reference diameter, the vessel minimal lumen diameter, and the percentage of stenosis. All measurements will be taken at baseline and after the PCI.

Statistical analysis

Regarding the statistical analysis, quantitative variables will be expressed as mean ± standard deviation and qualitative variables as absolute numbers and percentages. To determine the relationship among quantitative variables, we will be using the paired Student t test for paired data. To determine the relationship among the qualitative ones, we will use the chi-squared test. In all cases, differences will be considered significant with P values < .05. We will be using the IBM SPSS Statistics software package (version 24.0 for Macintosh, SPSS Corp., United States). To calculate the sample size, we have performed a retrospective analysis of the last 20 patients who were treated at our centre and showed a sequential or diffuse lesion in the coronary vessel analyzed from the iFR-pullback study. The mean length of the stent implanted was 43 ± 9 mm and the reduction of stent length was 12 ± 8 mm on the angiographic analysis. With these data, we have stablished an expected length reduction of 15 mm. The calculated sample size to achieve the primary endpoint with an 80% confidence level and a 5% margin of error was 100 patients.

RESULTS

The recruitment of patients started back in February 2020. After 1 month, we have included the first 7 patients. We expect to complete the recruitment by February 2021 and the follow-up by February 2022.

DISCUSSION

To our knowledge, this randomized study is, the first one to assess the potential benefits of using the SyncVision software in long, sequential or diffuse coronary lesions. Currently, the study is in the recruitment phase and the first patients have already been recruited.

The iFR has proven to be useful in the PCI guide decision-making process.7,8 However, the evidence supporting the use of SyncVision is scarce and controversial in long, sequential or diffuse lesions. On the one hand, the software allows us to know the coronary segments with the highest physiological compromise. This allows us to revascularize only those segments that immediately improve the physiological result with a potential reduction of the length of the stent implanted, which happens to be a predictor of MACE at the follow-up.9 On the other hand, it’s possible that even if we obtain a good immediate physiological result and a reduction of the stent length implanted we won’t be fully covering the plaque in some lesions or coronary segments, which has also proven to be a predictor of MACE.6

A limitation of the study is the sample size, enough to achieve the primary endpoint, but probably inadequate to see differences in MACE. However, we think that it can provide an early insight on the utility of iFR pullback study to guide the PCI decision-making process in this type of lesion. Also, it can be a hypothesis-generator study for future larger-scale studies to show benefits in terms of clinical events reduction.

For these reasons, we believe that the iLARDI is an interesting study that will shows us the potential benefit of SyncVision to guide the PCI decision-making process in long, sequential or diffuse coronary lesions. We intend to complete the results by February 2022.

CONCLUSIONS

The iLARDI study is the first randomized trial to assess the potential utility of SyncVision-guided revascularization in long, sequential and diffuse coronary lesions.

FUNDING

Funds from the Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI) have been used to pay for the liability insurance associated with clinical research.

AUTHORS' CONTRIBUTION

All the authors have participated in the study and in the manuscript:

F. Hidalgo has participated has mainly drafted of the manuscript and has participated in the conception and design of the study. R. González has also participated in the conception and design of the study, and in the analysis and interpretation of data. S. Ojeda has mainly participated in the conception, design of the study and revision of the manuscript. C. Pericet has participated in the conception and design of the study. A. Lostalo has also collaborated in the analysis and interpretation of data. J. Segura has also revised it critically for important intellectual content. N. Paredes and J.C. Elizalde have also contributed in the analysis and interpretation of data. A. Luque has participated in the draft of the manuscript. F. Mazuelos has also contributed in the analysis and interpretation of data. J. Suárez de Lezo and M. Romero have revised it critically for important intellectual content. M. Pan has done the final approval of the manuscript submitted.

CONFLICTS OF INTEREST

F. Hidalgo, S. Ojeda, and J. Segura received personal fees from Philips Volcano. M. Pan received minor fees from Abbott, Philips Volcano, and Terumo. The remaining authors declared no conflicts of interest whatsoever.

REFERENCES