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

INTRODUCTION

By the end of December 2019, The People’s Republic of China reported the World Health Organization on the first cases detected of an unknown pneumonia caused by a new type of coronavirus in the City of Wuhan, China.1,2 Since then, the disease caused by this virus has spread rapidly bringing the healthcare systems of several countries to the point of collapse ultimately triggering dramatic preventive measures by the health authorities.

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a tremendous social, economic, and health impact across the world. Again and again, the healthcare setting has sustained several organizational and care changes that have triggered significant variations in the management therapeutic approach of the remaining diseases.3-5 Some studies have reported a lower number of admissions due to cardiovascular diseases, which has had a significant impact on morbidity and mortality alike.6-8

Pressure to the healthcare system due to COVID-19, the lockdown, and the lower demand for assistance are some of the reasons that may account for these changes. The objective of this study is to assess the rate of acute coronary syndrome (ACS) across the different stages of the pandemic in Spain, as well as the impact it has had on morbidity, mortality, and therapeutic management.

METHODS

Retrospective, observational, and multicenter study including data from patients admitted to 4 tertiary care centers of our country from 3 autonomous communities due to ACS from February 14, 2020 through June 24, 2020. Patients with ST-segment elevation acute coronary syndrome (STEACS), and non-ST-segment elevation acute coronary syndrome and were included. Patients with acute myocardial infarction and without significant lesions in coronary arteries were excluded. Patients were categorized into 3 groups based on the length of hospital stay: group A, from February 14 through March 14, 2020 (1 month before the lockdown); group B, from March 15 through May 24, 2020 (during the lockdown), and group C, from May 25 through June 24, 2020 (1 month after the stay-at-home lockdown). The patients’ baseline characteristics, acute complications, and cardiovascular events reported at the follow-up like all-cause mortality, cardiac death, stroke, reinfarction, stent thrombosis, and need for rehospitalization were recorded. In patients with STEACS the times elapsed between symptom onset and the first medical contact (FMC), and between electrocardiographic diagnosis until reperfusion were recorded. Clinical follow-up was completed back in July 25, 2020. Data curation was approved by the local ethics committee of each participant center.

The study primary endpoint was to assess the differences reported in all-cause mortality after 30 days since the onset of the acute coronary event among the 3 study groups. The study secondary endpoint was to analyze the differences reported in a composite of cardiac death, stroke, admission due to new ACS, stent thrombosis, and need for new revascularization. Complications reported after infarction at the follow-up, a high left ventricular ejection fraction, and revascularization times (from symptom onset until the first medical contact, and from diagnosis until reperfusion) were also studied in a secondary analysis and compared among the 3 groups.

Statistical analysis

Categorical variables were expressed as number and percentage using brackets and compared using the chi-square test or Fisher’s exact test, when appropriate. Continuous variables were expressed as mean and standard deviation or median and interquartile range in cases without a normal distribution. The Shapiro-Wilk test was used to assess the normal distribution of continuous variables that were compared using the analysis of variance (ANOVA) for independent samples or Kruskall-Wallis H test based on their normal distribution looking for differences among the 3 groups. Survival was studied using the Kaplan-Meier curves, and differences were assessed using the log-rank test. Cox proportional hazards regression analysis was used to assess the impact of group B (lockdown period) in the overall mortality of the patients. All estimates were performed using the statistical software package STATA version 15.1. P values < .05 were considered statistically significant.

RESULTS

A total of 634 patients were included from February 14, 2020 through June 24, 2020. Of these, 205 were patients from group A, 303 from group B, and 126 from group C with a median follow-up of 98 days (63-137 days). The number of admissions due to ACS was 120, 138, and 151 within the first, second, and third months since the state of alarm declared. This lowered the rate of admissions due to ACS by 41%, 33%, and 26%, respectively compared to the rates reported 1 month before the lockdown for the same 30-day period (figure 1).

Figure 1. Absolute number of patients admitted due to acute coronary syndrome, expressed in weeks and categorized into group A, B, and C.

A total of 356 (56.2%) from the overall number of patients were admitted due to STEACS, and 278 (43.8%) due to non-ST-segment elevation acute coronary syndrome. The cohort baseline characteristics are shown on table 1. Patients admitted during the lockdown (group B) were younger (P = .012) and had lower levels of hypertension and dyslipidemia. On the other hand, these patients’ past medical history showed less ischemic heart disease, and coronary revascularization (P < .001).

Table 1. Baseline characteristics, diagnosis at admission, and treatment

A diagnostic coronary angiography was performed on 97.1% of the cohort without any differences being reported regarding percutaneous coronary intervention throughout the different periods studied (P = .652); however, a significant reduction in the number of surgical coronary revascularizations performed during the lockdown was reported (group A, 5.4%; group B, 2.7%; group C, 8.1%; P = .045) including the subgroup of patients with left main coronary artery disease or 3-vessel disease (P = .003) (table 1).

A total of 36 deaths were reported, 22 of which were due to cardiovascular causes. No statistically significant differences were reported in the all-cause mortality rate after 30 days among the 3 groups (P = .327). According to a Cox regression analysis, being in the lockdown group (group B) was not associated with a higher all-cause mortality rate (P = .60). No survival differences were reported either among the 3 groups (figure 2).

Figure 2. Kaplan-Meier survival curves for all-cause mortality in groups A (February 14-March 14), B (March 15-May 24), and C (May 25-June 24).

No significant differences were reported at the follow-up in a composite of cardiac death, stroke, readmission due to new ACS, stent thrombosis, and new revascularization (P = .120). The remaining clinical events at the follow-up are shown on table 2 and the in-hospital events on table 3.

Table 2. Clinical events at the follow-up

Table 3. In-hospital events

Regarding delay times, significant differences were reported among the different groups with longer times elapsed between symptom onset and the first medical contact during (group B) and after lockdown (group C) compared to the previous period (group A): group A, 66 min (45-180), group B, 120 min (60-240), group C, 120 min (60-240); P = .007). The time elapsed between symptom onset until the first medical contact was similar in groups B and C (P = .7102). Finally, the time elapsed between diagnosis and reperfusion was shorter in patients from group C (P = .025) compared to the remaining cohort (table 4).

Table 4. Times between symptom onset and the first medical contact, and between electrocardiographic diagnosis and reperfusion (guidewire passage), in minutes, in the cohort of patients with ST-segment elevation acute coronary syndrome

DISCUSSION

The main findings from this study were a lower number of admissions due to ACS within the first few months of lockdown, and longer periods of time elapsed between symptom onset and the first medical contact in patients with STEACS that did not translate into higher morbidity and mortality rates.

Lower rate of acute coronary syndrome

Former studies have reported less activity at the cath lab due to fewer admissions due to ACS during the pandemic, especially in the STEACS setting.7,9-11 Our findings confirm this trend with a significant 41% drop within the first 30 days compared to the previous month. This reduction was kept in the remaining time during and after lockdown; however, as the isolation measures were being lifted and the rate of cases of COVID-19 dropped, a gradual increase in the number of admissions due to ACS was confirmed. One of the contributing factors may have been the intense pressure put to the healthcare system within the first few months of lockdown with the corresponding underdiagnosis of ACS and fewer admissions reported.12 Another hypothesis that may justified the lower rate of ACS during this time is the higher number of out-of-hospital sudden deaths reported. Although reported by other authors in the past, this was not cause for analysis in our study.13-16

Times elapsed among symptom onset, the first medical contact, and revascularization in patients with ST-segment elevation myocardial infarction, and association with adverse events

During the lockdown (group B) patients with STEACS were admitted more often (P = .003). The time elapsed between symptom onset and the first medical contact was significantly longer during this time compared to other times, which is consistent with the peak number of cases reported (similar findings to those reported by former studies);17 however, this delay did not increase the rates of mechanical complications or mortality. This can be explained because patients admitted during the lockdown (group B) were younger and had fewer comorbidities.18,19 Data suggests that elderly patients with more serious past medical histories and associated comorbidities may have delayed or even postponed indefinitely their access to the healthcare system over fears of getting infected.20,21

Rodríguez-Leor et al.22 reported time delays between symptom onset and the first medical contact, and similar times between diagnosis and reperfusion. This delay was associated with a higher mortality rate during the pandemic (7.5% vs 5.1%), which contradicts our findings. The lack of a direct association between time delays until diagnosis and the appearance of adverse events is not easy to explain. However, a plausible hypothesis can be the higher number of out-of-hospital sudden deaths reported due to mechanical complications or malignant arrhythmias followed by the corresponding selection bias since this study included hospitalized patients only.

Therapeutic strategies: percutaneous coronary intervention and surgical revascularization

No differences were found regarding the percutaneous invasive management of patients with ACS before, during or after lockdown. This data is consistent with most studies published on the management of ACS during the pandemic.12,22

However, we should mention the significant decrease of myocardial revascularization procedures despite the non-negligible number of patients with left main coronary artery disease or 3-vessel disease. A total of 17.7% of these patients were treated with myocardial revascularization 1 month before the lockdown, only 5.5% during the lockdown, and 34.5% the following month. Although some registries confirm the lower number of coronary artery bypass grafts performed,23 this tendency has not been confirmed in other studies.18,23

The fact that fewer myocardial revascularization procedures were performed during the lockdown can be explained by the overall tendency to delay any surgical acts as much as possible during these months, something already hypothesized in other studies.24

Limitations

This study has some limitations associated with the analysis of multicenter and observational data. Also, the study short follow-up period may have prevented the finding of potential consequences or differential events among the study groups. The lack of information on cases of ACS treated during the pandemic that never really made it to tertiary care centers also casts a shadow over the conclusions that can be drawn.

CONCLUSIONS

Significantly fewer admissions due to ACS were reported during the lockdown. Also, although time between symptom onset and the first medical contact was longer during this period in patients with STEACS, the mortality rate was similar among the 3 study groups.

FUNDING

None reported.

AUTHORS’ CONTRIBUTIONS

J. Echarte-Morales: clinical data mining, manuscript drafting, project design, and management of the study. C. Minguito-Carazo: data analysis, manuscript drafting and revision process. PL Cepas-Guillén, V. Vallejo García, ID. Poveda Pinedo, A. Salazar Rodríguez, E. Arbas Redondo, J. Guzmán Bofarull, and D. Tebar Márquez: data mining and manuscript revision process. E. Sánchez Muñoz: data mining. E. Martínez Gómez: data mining, manuscript drafting and revision process. T. Benito-González: statistical counselling, and manuscript revision process. M. López Benito, A. Viana Tejedor, I. Cruz-González, PL Sánchez Fernández, M. Sabaté, and F. Fernández-Vázquez: project organization. Authors submitting this manuscript accept full responsibility for its content as defined by the International Committee of Medical Journal Editors (ICMJE).

CONFLICTS OF INTEREST

None whatsoever.

REFERENCES

INTRODUCTION

Coronary artery disease and mental health disorders frequently coexist and have a bidirectional relationship.1,2 Patients with mental health disorders have an increased risk of coronary artery disease and, inversely, it is not rare for patients to experience symptoms of depression or anxiety after a cardiac event.3 Moreover, depression in patients with CHD is associated with a poor adherence to treatment, unhealthy lifestyle habits, and a poor prognosis.4-8

Selective serotonin reuptake inhibitors (SSRIs) are often prescribed as first-line agents to treat depression and anxiety,9,10 but have a potential for increased bleeding risk due to the concomitant inhibitory effect on the platelet serotonin reuptake transporter (5-HTT).11 Platelet 5-HTT inhibition has been associated with a reduced platelet activation and aggregation, and with a prolonged bleeding time.12,13 On the other hand, some studies have linked SSRI-related bleeding risk to older age, comorbidities or polypharmacy.14,15

Bleeding risk due to antithrombotic therapy is a major concern following percutaneous coronary intervention (PCI) as hemorrhagic events are prognostically unfavorable as recurrent ischemic events.16,17 While bleeding risk depends on multiple clinical and laboratory features,18,19 the identification of potential modifiable factors is key to optimize the balance between ischemic and bleeding risk.20 Prior studies have evaluated the bleeding risk of patients with a concomitant treatment of SSRIs and dual antiplatelet therapy (DAPT) plus aspirin and clopidogrel with contradictory results.21-23 However, the impact of SSRIs plus therapy with more potent P2Y₁₂ inhibitors (eg, ticagrelor or prasugrel) or triple antithrombotic therapy with DAPT plus an oral anticoagulant (OAC) has never been explored. In this study we tried to compare the 1-year risk of bleeding after PCI and concomitant guideline-recommended antithrombotic therapy (including clopidogrel, ticagrelor or prasugrel-based DAPT and triple antithrombotic therapy) in patients with or without prescribed SSRIs.

METHODS

Study design and setting

Retrospective study including all consecutive patients discharged after PCI performed at a single center during 2018. Those treated with SSRIs were propensity score-matched (PSM) to a control group to compare bleeding outcomes at the 1-year follow-up. Antithrombotic treatment was decided by the clinical cardiologist in accordance with the current clinical practice guidelines.24 This study was conducted according to the Declaration of Helsinki and was approved by the local clinical research ethics committee. Written informed consent was obtained from all patients before the PCI.

Population

All patients discharged after the PCI performed during the study period were eligible. Those treated at discharge with single antiplatelet therapy, DAPT were excluded—not including acetylsalicylic acid—as well as those anticoagulated with low-molecular-weight heparin for other reasons. Patients with missing information at the follow-up were also excluded. Clinical and procedural data, treatment at discharge, and outcomes during the first year were reviewed through electronic health records. Patients were treated with SSRIs if their list of prescriptions at discharge included one of the following: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine or sertraline.

Endpoints

The primary safety endpoint was major bleeding at the 1-year follow-up. Secondary endpoints were a composite of major or non-major clinically relevant bleeding, and a composite of major adverse cardiovascular events (MACE). Major bleeding was defined as a bleeding event type 3 or 5 according to the Bleeding Academic Research Consortium (BARC). Major/non-major clinically relevant bleeding was defined as BARC type 2, 3 or 5 bleeding event.25 MACE was defined as a composite outcome of cardiovascular death, non-fatal myocardial infarction or unplanned revascularization. Events were independently adjudicated by 2 cardiologists who were unaware of the SSRIs group.

Statistical analysis

Categorical variables were expressed as counts (percentages), and the continuous ones as mean ± standard deviation or median [interquartile range] according to their distribution assessed using the Shapiro-Wilk test. P values were obtained using the chi-square test or the Mann-Whitney U test, as appropriate. PSM was conducted to account for the confounding biases.26 Logistic regression was used to determine the probability of being treated with SSRIs and included the following confounding variables potentially associated with SSRIs treatment and the primary endpoint:27 age, sex, prior relevant bleeding, hypertension, cancer, past medical history of hematologic disease or anemia, liver disease, creatinine clearance, treatment with potent P2Y₁₂ inhibitors or concomitant OAC. The nearest neighbor matching method with no replacement, and a caliper width of 0.1 were used in the PSM on a 1:1 ratio. Propensity score histograms and standardized mean differences before and after the PSM were used to evaluate the balance of the groups regarding the covariates.28 Time-to-event analyses were conducted using the Kaplan-Meier and Cox proportional hazards methods. To determine major bleeding predictors in the unmatched cohort, a multivariate Cox regression model was conducted that used a purposeful selection model and prioritized parsimony. Clinical meaningful variables and those showing P values < 0.2 in the univariate analysis were included. Statistical analyses were performed using SPSS software (version 24; IBM Corp., United States) and R software (version 4.0.3; R Foundation for Statistical Computing, Austria). Matching was performed using the MatchIt R package (Ho, Imai, King, & Stuart, 2011) while covariate balance was assessed using the Cobalt R package (Greifer, 2021).

RESULTS

Baseline clinical characteristics

A total of 1063 patients were treated with PCI during the study period, 1002 of whom met the selection criteria and were included in the analysis. A total of 139 patients (13.9%) were treated with SSRIs at discharge (figure 1). Median age was 66 years (58-75), and 745 patients (74.4%) were male with a median PRECISE-DAPT score of 13 [9-22]. Regarding antithrombotic therapy, 684 patients (68.3%) were treated with potent P2Y₁₂ inhibitors and 102 (10.2%) were concomitantly treated with OAC. The baseline clinical characteristics of the overall population and the unmatched groups are shown on table 1. Patients from the SSRIs group were more likely to be women. They also had a more extensive past medical history of hypertension, diabetes mellitus, cancer, significant bleeding, and hematologic disease or anemia. Both the HAS-BLED and the PRECISE-DAPT bleeding risk scores were higher in the SSRIs group.

Figure 1. Patient flowchart. PCI, percutaneous coronary intervention; SSRIs, selective serotonin reuptake inhibitors.

Table 1. Baseline clinical characteristics of the overall population, and SSRIs/non-SSRIs users before matching

Unmatched analysis

In the overall population there were a total of 19 major bleeding events at the 1-year follow-up: 4 (2.9%) in the SSRIs group, and 15 (1.7%) in the unmatched non-SSRIs group (P = .350). Of these, 4 (21.1%) were fatal, 10 (52.6%) GI bleedings, 4 (21.1%) intracranial bleedings while the remaining ones occurred in other locations.

The multivariable Cox model identified the following independent predictors for the primary endpoint of major bleeding: PRECISE-DAPT score ≥ 25, and concomitant anticoagulation. Table 2 shows the univariable and multivariable Cox predictors for the primary endpoint.

Table 2. Univariable and multivariable Cox predictors for major bleeding

The major/non-major clinically relevant bleeding endpoint occurred in 4 patients (2.9%) from the SSRIs group, and in 43 patients (4.9%) from the unmatched no-SSRIs group (P = .290). The rate of MACE was similar in both groups: 11 events (7.9%) in the SSRIs group and 50 events (5.8%) in the non-SSRIs group.

The Kaplan-Meier curves and the associated risk tables for each endpoint of the unmatched cohorts are shown on figure 2.

Figure 2. Kaplan-Meier curves for the primary bleeding outcome (A), the secondary composite bleeding (B), and the ischemic outcomes (C). Unmatched cohort. SSRIs, selective serotonin reuptake inhibitors.

Propensity score matching analysis

The variables used in the PSM, the standardized mean differences, and the Propensity score distributions of the unmatched and matched samples are shown on figure 3. PSM resulted in an excellent balance of covariates with standardized mean differences ≤ 10% in all variables included in the Propensity score. There was also a very good balance across the other baseline characteristics and bleeding risk scores except for diabetes mellitus and hyperlipemia that were more prevalent in the SSRIs group (table 3).

Figure 3. Variables used in the propensity score matching analysis and their standardized differences (A), and the propensity score distributions (B) of the unmatched and matched samples. OAC, oral anticoagulant.

Table 3. Baseline clinical characteristics of SSRIs/non-SSRIs users after matching

The rate of major bleeding at the 1-year follow-up was 2.9% for both patients on SSRIs and the matched SSRIs non-users (HR, 1.01; 95%CI, 0.25-4.03; P = .991). There were no non-major clinically relevant bleedings in the SSRIs group and 6 (4.3%) among SSRIs non-users (HR, 0.39; 95%CI, 0.16-1.27; P = .120). No differences in MACE were reported between the SSRI and the non-SSRIs groups (HR, 1.01; 95%CI, 0.44-2.33; P = .979) (figure 4).

Figure 4. Kaplan-Meier curves for the primary bleeding outcome (A), the secondary composite bleeding (B), and the ischemic outcomes (C). Matched cohorts. SSRIs, selective serotonin reuptake inhibitors.

DISCUSSION

The main findings of this study can be summarized as follows: a) the use of SSRIs was frequent among patients undergoing PCI; b) patients prescribed with SSRIs had a higher baseline bleeding risk; c) despite the imbalance reported in the baseline characteristics, after adjustment SSRIs users were not associated with a significant excess of major or clinically relevant bleeding at the 1-year follow-up.

There is a strict correlation between coronary artery disease and mental health disorders. In our study up to 13.9% of patients treated with PCI were prescribed SSRIs. This group has more comorbidities and bleeding risk factors with the potential to complicate the clinical decision-making process regarding antithrombotic therapy selection. Importantly, whether SSRIs trigger a higher bleeding risk through a biological effect on platelet 5-HTT receptors or are a marker of a higher bleeding risk through concomitant comorbidities has been the matter of discussion in prior studies.

Labos et al.21 reported an increased risk of bleeding in patients taking both SSRIs and acetylsalicylic acid or clopidogrel-based DAPT after myocardial infarction. On the contrary, Lasella et al.22 assessed the impact of SSRI therapy on patients on DAPT after PCI finding no excessive bleedings in patients on SSRIs. Interestingly, they reported a lower risk of MACE in patients on SSRIs compared to those on mirtazapine, but a higher risk compared to patients on either one of the 2 antidepressants. This may be explained by a protective effect of SSRIs on MACE29 that could be exceeded by the unfavorable effect of mental health disorders on cardiovascular events.30 Another interpretation could be associated with the pharmacokinetics of clopidogrel since it is a prodrug that requires enzymatic conversion into its active metabolite by cytochrome P450 (CYP).31 Bykov et al.23 reported an increased risk of ischemic events in patients on clopidogrel and a CYP2C19-inhibiting SSRI compared to those on noninhibiting SSRIs. No differences were found regarding major bleeding. The study did not include a group of patients without SSRI treatment.

We should mention that none of the aforementioned studies included patients treated with potent P2Y₁₂ inhibitors, which is currently the standard of care of patients with ACS. To our knowledge, this is the first study to assess the impact of SSRIs on a cohort of patients treated with potent P2Y₁₂ inhibitors prasugrel or ticagrelor. In our population, two thirds of the patients were treated with potent P2Y₁₂ inhibitors, which is more consistent with the antiplatelet strategies recommended by the current clinical practice guidelines.32,33 In this clinical setting, despite the imbalances reported in the baseline bleeding risk in an unadjusted analysis, we found no differences regarding major or clinically relevant bleeding events among patients on SSRIs and the matched group without a SSRI prescription. Hence, while the prescription of SSRIs can be a marker of a higher risk population with more comorbidities and risk factors, this may not translate into an independent predictor of bleeding events after accounting for the potential confounders. This is consistent with prior evidence in the medical literature. In the study conducted by Labos et al.21 patients on SSRI had a more significant past medical history of hypertension, renal failure, anemia or other hematologic disease, and non-GI bleeding. Lasella et al.22 reported that SSRIs users were more likely to have diabetes, hypertension, dyslipidemia, COPD, and chronic kidney disease.

Our findings are clinically relevant for different reasons. Although SSRIs have been associated with a potential for an increased bleeding risk, a direct translation into an excess of adverse events has not been confirmed yet. Our data provide reassurance on the relative safety profile of potent antithrombotic therapies in association with SSRIs, which did not substantially increase the risk of bleeding during the first year after PCI when the treatment decision-making process is based on a thorough evaluation of the features of bleeding and ischemic risk.

Our study also included a proportion of patients treated with concomitant antiplatelet and OAC therapy (~10%), which is consistent with the current standard practice.34 The impact of SSRIs on bleeding outcomes in patients with AF treated with OAC has also been examined in the past. Various authors have reported a higher risk of major bleeding in patients concurrently treated with SSRIs and warfarin.35,36 On the contrary, Quinn et al.37 did not find a significantly increased risk of bleeding among patients from the ROCKET AF trial assigned to warfarin or rivaroxaban who were also on SSRIs. However, there was a modest but non-statistically significant higher risk of major bleeding in the warfarin group. Since SSRIs are CYP2C9 inhibitors, an increase of warfarin plasma concentrations could explain these findings.38 This reaffirms the importance of non-vitamin k antagonists to reduce the risk of bleeding also in this population given the need for multiple antithrombotic agents after the PCI and the higher baseline bleeding risk reported.39

Limitations

The current study has several limitations. First, its retrospective observational design, and the relatively small size of the sample limits our ability to provide definitive conclusions due to the residual possibility of type-2 errors. Secondly, despite the PSM resulted in a good balance between the selected potential confounders and the other baseline characteristics, the presence of residual confounding factors cannot be completely ruled out. For example, some variables associated with bleeding like the presence of diabetes mellitus or peripheral arterial disease were not included in the propensity score model. Yet similar findings were observed in the adjusted and unadjusted analyses. Thirdly, the classification of SSRI users was based on treatment at discharge without accounting for treatment adherence or discontinuation.

CONCLUSIONS

In this real-world study, a combination of SSRIs and potent antithrombotic therapies was frequently prescribed after PCI. Although the prescription of SSRIs was associated with a higher baseline bleeding risk in the unadjusted analysis this was not the case with an excess of major or clinically relevant bleeding reported at the follow-up.

FUNDING

None reported.

AUTHORS’ CONTRIBUTIONS

R. González-Manzanares, and S. Ojeda conceived and designed the study. R. González-Manzanares, M. Ruiz-Moreno, C. Fernández-Avilés, L. Carmona-Artime, G. Flores-Vergara, and F. Costa collected analyzed data and interpreted the results. R. González-Manzanares, M. Ruiz-Moreno, S. Ojeda, and F. Hidalgo drafted the manuscript and completed the critical revisions. S. Ojeda, F. Hidalgo, G. Flores-Vergara, F. Costa, J. Suárez de Lezo, and M. Pan reviewed and revised the manuscript, and approved its final version before submission. All authors gave their final approval to the version that would eventually be published.

CONFLICTS OF INTEREST

S. Ojeda is an associate editor of REC: Interventional Cardiology. The journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. S. Ojeda, and M. Pan declared having received honoraria for lectures given for Abbott, Boston, World Medical, and Terumo. J Suárez de Lezo declared having received honoraria for lectures given for Abbott. The remaining authors declared no conflicts of interest whatsoever.

REFERENCES

INTRODUCTION

The most widely used strategy to treat coronary artery disease (CAD) is percutaneous coronary intervention (PCI) with stent implantation, particularly with the current generation of drug-eluting coronary stents (DES), since their distinctive features improve the clinical outcomes of PCI.1 However, the treatment of long and diffused coronary lesions remains challenging, especially in long lesions in tapered coronary arteries where variations in vessel diameter may require the implantation of > 1 stent per lesion.2,3

The use of either multiple stents or a single long stent are the most common treatment strategies for long and diffused lesions in tapered arteries. Both approaches may be associated with clinical failure due to the potential risk of mechanical mismatch of the stent size.1,4,5 Multiple short overlapping stents with variable diameters are often implanted to adequately match the size of long tapered lesions. Because of potential discrepancies regarding diameters when using long nontapered stents, a proximal optimization technique may be used to reconstruct the vessel natural geometry. However, this solution does not come without problems such as stent fracture due to vessel rigidity, restenosis due to a higher vascular injury, delayed healing, very late stent thrombosis (ST), vessel aneurysm, side branch jailing, higher treatment cost, overuse of antirestenotic drugs, and increased exposure to radiation and contrast media, and death or myocardial infarction.6,7

A single long BioMime (Meril Life Sciences Pvt. Ltd., India), an ultrathin biodegradable polymer coated sirolimus-eluting coronary stent (SES) system, is often enough to treat long and diffused lesions. Thus, the local arterial walls can be saved from overexposure to drug/metal avoiding any potential associated adverse events at the follow-up like delayed healing, perioperative myocardial infarction (MI), risk of target lesion revascularization, and very late ST. The aim of this study was to evaluate the safety and level of performance of the long nontapered BioMime SES system (37 mm, 40 mm, 44 mm, 48 mm) in consecutive real-world patients with long and diffused de novo coronary lesions.

METHODS

Study design and population

This was a prospective, non-randomized, multicentre study that included a total of 696 consecutive patients (aged ≥ 18 years) from 14 clinical centers across Spain. All the study investigators are listed in the appendix of this article.

All consecutive patients included had been treated of long and diffuse de novo coronary lesions through the implantation of, at least, 1 long nontapered BioMime system (37 mm, 40 mm, 44 mm, 48 mm). The study was conducted in observance of the privacy policy of each research center including its rules and regulations for the appropriate use of data in patient-oriented research. This study was also conducted in observance of the Declaration of Helsinki, and approved by the ethics committee. Written informed consents were obtained from all the participants before the procedure.

Study device and procedure

The BioMime is a biodegradable polymer coated SES system with different lengths available to treat long and diffused coronary lesions. It uses an ultra-thin strut (65 µm), and a cobalt-chromium platform that has a unique hybrid design of open and closed cells with uniformly thin coating (2 µm) of bioabsorbable polymers, PLLA (poly-L-lactic acid), and PLGA (poly-lactic-co-glycolic acid). The stent elutes sirolimus (1.25 µg/mm²) between 30 and 40 days after implantation. The currently available long lengths of BioMime are 37 mm, 40 mm, 44 mm, and 48 mm. The device is CE marked.

The PCI was performed according to the standard treatment guidelines and followed by each participant center. Predilatation and postdilatation were left to the operator’s discretion though postdilatation was recommended per protocol.

Preoperatively, a 300 mg loading dose of aspirin plus a second anti-platelet agent (clopidogrel, ticagrelor, or prasugrel according to the clinical settings and operator’s preference) were administered in all the consecutive patients included.

Postoperatively, all patients were administered a 12-month course of dual antiplatelet therapy plus aspirin (75 mg to 100 mg once a day) indefinitely beyond the first year. A 1.6- and 12-month clinical follow-up was conducted after the index procedure, as required, and based on symptoms.

Endpoints and definitions

The safety endpoints were the occurrence of major adverse cardiovascular events (MACE) at the 1-, 6-, and 12-month follow-up after the index procedure. MACE was defined as a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, ST, and major bleeding.

MI was defined as the development of new pathological Q waves on the electrocardiogram or elevated creatinine kinase (CK) levels ≥ 2 times the upper limit of normal with elevated CK-MB levels in the absence of new pathological Q waves or new ischemic symptoms (eg, chest pain or shortness of breath).8 Cardiac death was defined as any deaths resulting from AMI, sudden cardiac death, heart failure mortality or stroke. Clinically driven target lesion revascularization was defined as a new PCI performed on the target lesion or coronary artery bypass graft of the lesion in the previously treated segment or within the 5 mm proximal or distal to the stent site or edge of DES inflation. ST was classified based on the definitions established by the Academic Research Consortium.9 Moderate-to-severe bleeding events were defined according to the GUSTO (Global Use of Strategies to Open Occluded Arteries) criteria. Procedural success was defined as a successful PCI without in-hospital major clinical complications including death, MI, and clinically driven target lesion revascularization. Device success was defined as the deployment of the study stent at the intended target lesion attaining final residual stenosis < 30% of the target lesion estimated both angiographically and through visual estimation.

Statistical analysis

Since there is no intervention, to study this cohort of patients we thought that the best method was to perform a descriptive analysis for an objective, comprehensive, and informative study of data. A a descriptive statistical analysis of the relevant variables was performed after collecting data. All statistical analyses were performed using the SPSS statistical software platform. Measures of central tendency such as means summarize the level of performance of a group of scores while measures of variability describe the spread of scores among the participants. Both are important to understand the behavior of this cohort. One provides information on the level of performance, and the other tells us how consistent that performance is. Categorical data were expressed as frequency and percentages. No further models were conducted as the idea of this paper was to describe a group of patients, not to compare groups or search for significant inter-group differences.

RESULTS

Baseline demographic and clinical characteristics

The data of 696 consecutive patients (742 BioMime stents implanted, 157 different stents) were collected in the study that mostly included males (80.1%). The baseline demographic and clinical characteristics of patients are shown on table 1. The patients’ mean age was 64.6 ± 14 years. Conventional risk factors for CAD in the study population were diabetes mellitus (39%), hypertension (67.2%), dyslipidemia (64.8%), and active smoking (26.44%). The clinical status at admission is shown on table 1. Most patients (63.39%) had acute coronary syndrome.

Table 1. Baseline demographic and clinical characteristics

Lesion and procedural characteristics

Out of a total of 899 lesions identified in 696 consecutive patients, 742 long and diffused de novo type C coronary lesions (1.07 lesions per patient) were successfully treated with long BioMime stents. No other stents were needed to treat the lesion initially handled with a long BioMime device. A total of 157 other lesions were treated with 157 different stents. Therefore, no overlapping was needed in any of the lesions treated with a long BioMime device. A total of 40% of the patients had 1-vessel disease, 37% 2-vessel disease and 23% of the patients had 3-vessel disease. The left anterior descending coronary artery followed by the right coronary artery were the main arteries treated. In 3.8% of the cases BioMime implantation involved the left main coronary artery. The mean length of the implanted BioMime SES system was 43.8 mm along with an average diameter of 3.1 mm. The immediate procedural and device success rates were 99.7% and 100%, respectively. The procedural variables are shown on table 2 and table 3.

Table 2. Lesion and procedural characteristics

Table 3. BioMime sirolimus-eluting stent system characteristics

Clinical outcomes at follow-up

Clinical follow-up was completed in 96.12% of the patients included at the 12-month follow-up. A total of 3.88% out of 696 patients were lost to follow-up after 12 months.

The cumulative incidence of MACE at the 1-, 6-, and 12-month follow-up was 2.2%, 6.6%, and 8.1%, respectively. The individual MACE at the follow-up are shown on table 4. The rates of cardiac death were 0.59% and 2.09% after 1 month and 1 year, respectively.

Table 4. MACE at the follow-up

DISCUSSION

In the current study, the long nontapered BioMime SES system proved its safety and level of performance in consecutive real-world patients with long and diffused de novo coronary lesions. Despite the all-comers inclusion criteria defining a high-risk population, and the anatomical need for a long stent, procedural (99.7%) and device (100%) success were achieved and the clinical follow-up was quite favorable.

Studies have shown that the dimensions of coronary arteries taper naturally along with their length. They observed that 23% of the arteries had ≥ 1 mm taper and 19% arteries a 0.5 mm to 0.99 mm taper.10 Stent sizing is critical for a successful PCI regarding the treatment of long tapered lesions. Stent oversizing (stents that are larger in diameter compared to the healthy artery) may induce pathological stress on the arterial wall, aneurysm formation, late ST, and even late perforations. Stent undersizing, on the other hand, (stents that are smaller in diameter compared to the healthy artery) may lead to ST due to stent malapposition.11 Consistent with this, tapered stents were developed to potentially minimize clinical failure and maximize clinical benefits in these patients. This fact may be due to the specific design of the BioMime stents.

Ultrathin struts facilitate navegability, flexibility, and conformability of the vessel geometry while maintaining an excellent radial force. In addition, the open cell design throughout the entire body of the stent favors a less stiff device that follows more closely the tapered contour of the artery resulting in less arterial wall stress. Compliant stents should be considered for tapered artery applications, perhaps even to avoid the need for tapered stents, at least up to 48 mm length, as shown in our data.12-16

The use of long coronary stents (≥ 30 mm), but not as long as the lesions treated in this registry, to treat long and diffuse native vessel disease, saphenous vein graft disease, and long coronary dissections is associated with a reasonable procedural success rate and acceptable early and intermediate-term clinical outcomes.17 The treatment of very long CAD showed similar target lesion faliure at the 2-year follow-up for single DESs compared to overlapped DESs.18 Our results suggest that both strategies are reasonable therapeutic options for patients with diffuse CAD. However, DES overlap occurs in > 10% of the patients treated with PCI in the routine clinical practice, and has been associated with impaired angiographic and long-term clinical outcomes including death or myocardial infarction.19 In addition, the development of risk areas for malapposition with a single stent is significantly lower compared to overlapping stents. In cases where stent overlap cannot be avoided, deployment strategies should be optimized or new stent designs considered to reduce the risk of restenosis.20 A single stent strategy is often more cost-effectiveness, and involves the administration of fewer contrast and fewer balloons. New designs of very long stents allow us not only to treat increasingly complex lesions, but also to simplify the procedure, and reduce the number of stents used with very favorable results, at least, similar to those obtained with overlapping stents.21 Former studies have confirmed the safety and level of performance of the BioMime Morph, a very long tapered stent (60 mm) that can be considered the treatment of choice for very long and diffused tapered de novo coronary lesions in the routine clinical practice.22 However, in long lesions treated with single stents of up to 48 mm in length, our results suggest that nontapered stents give very good clinical results.

Limitations

One limitation may be the follow-up period that may not be enough to determine the long-term safety and level of performance of long BioMime SES system in patients with long and diffused de novo coronary lesions.

CONCLUSIONS

This study confirmed the favorable procedural and device success, and the optimal safety outcomes reported at the follow up, of the long nontapered BioMime SES system, up to 48 mm length, in real-world patients with long and diffused de novo coronary lesions.

FUNDING

The current study was partially funded by Palex Medical, and Meril (data collection, web design, and ethical committee).

AUTHORS’ CONTRIBUTIONS

E. Domingo contributed to the study design, database completion, clinical follow-up, data analysis, and manuscript writing. J. Guindo contributed to the study design. R. Calviño Santos, J. Antoni Gomez, X. Carrillo, J. Sánchez, L. Andraka, A. Torres, J. Casanova-Sandoval, R. Ocaranza Sanchez, J. León Jiménez, J.F. Muñoz, R. Trillo Nouche, and M. Fuertes contributed to the database completion, and clinical follow-up. I. Otaegui contributed to the database completion, data analysis, and clinical follow-up. B. García del Balnco contributed to the study design, data analysis, and manuscript writing.

CONFLICTS OF INTEREST

None reported.

APPENDIX 1: STUDY INVESTIGATORS

REFERENCES

INTRODUCTION

The first descriptions of a coronary aneurysm were reported by Morgagni back in 1761, and the first series of 21 patients were reported in 1929.1-4 Since then, a variable incidence rate—between 0.3% and 12%—has been reported in several series following the implementation of imaging modalities and coronary angiography.5 The overall incidence rate reported in a cohort of over 436 000 contemporary coronary angiographies from an international registry is 0.35%.5 Same as it happens with the clinical presentation and profile, treatment varies significantly.5,6 Still, revascularization is often required here.6 Over the last few years, some of the alternatives available propose the use of stent-grafts for the exclusion of coronary aneurysms.5-14

These devices—initially developed for other indications15 such as coronary perforations—have proven useful and safe in the short-term, and in cases and series previously published.7-10,12

The main goal of this paper is to describe the frequency of use of this type of stents for the management of coronary aneurysms and characterize its long-term results using patients with drug-eluting stents as the control group since they have had good results in this context.5

METHODS

This paper uses data curated from the International Coronary Artery Aneurysm Registry (CAAR) (NCT-02563626).16 Using a methodology already published, this ambispective registry included data from adult patients (≥ 18 years) who underwent a coronary angiography for whatever reason in 32 hospitals from 9 different countries.5 Coronary aneurysm was defined as a focal dilatation (< 1/3 of the vessel) 1.5 times larger compared to the vessel diameter in a healthy adjacent segment; the giant aneurysm was defined as a dilatation 4 times larger compared to the reference diameter.16 Investigators were advised to collect a consecutive case series in specific closed periods of time. Both the clinical and the procedural variables were collected, as well as the events occurred during the index hospital stay considered as that moment when it was first reported that the patient had, at least, 1 coronary aneurysm. Then, after validating which patients were eligible, the clinical follow-up was performed with information from the health records collected via medical consultations or phone calls. As stated in former reports, the protocol was initially approved by the coordinating center ethics committee and then by the centers that required it. Data were collected anonymously, and patients gave their informed consent to all the study procedures. Clinical decisions were always made by the treating physician of every patient without any influence from the study protocol whatsoever. The analysis of this study only included patients who received a stent-grafts or drug-eluting stents in an aneurysmal area.

The study primary endpoint was to describe the real-life use of stent-grafts to treat coronary aneurysms. Secondary endpoints were to determine the occurrence of events at the long-term follow-up. Similarly, another secondary endpoint was to conduct a comparison with patients who received drug-eluting stents in the aneurysmal area. If both types of stents were implanted, the patient from the stent-graft group was considered. Similarly, the analyses were conducted individually in each patient.

Statistical analysis

The statistical package SPSS v24.0 (IBM-SPSS, United States) was used to conduct the statistical analysis. Data are expressed as mean ± standard deviation or as median and interquartile range, when appropriate. Categorical variables were expressed as percentages. Inter-group comparisons were made using the chi-square test with qualitative variables. On the other hand, the Student t test, Mann-Whitney U test or Wilcoxon test were used, when appropriate, with continuous variables. The long-term event-free survival curves for the different analyses and groups were obtained using the Kaplan-Meier method. In them, the inter-group comparisons were performed using the log-rank test.

Based on the principle of parsimony, multivariable models were used in which, to avoid ann excess of variables in the analysis, only those with P values ≤ .10 were included in the univariate study that will be further explained later. Both the hazard ratio (HR) and the confidence intervals were estimated at 95% (95%CI) based on a Cox logistic regression model with backward elimination (Wald). Two-tailed P values < .05 were considered statistically significant.

RESULTS

Out of a total of 1565 patients eventually considered in the global registry, 250 were referred for coronary artery surgery and 829 to receive some type of percutaneous revascularization.5 A total of 17 of these patients received, at least, 1 stent-graft to treat their coronary aneurysm. Also, 196 patients received a drug-eluting stent in the aneurysmal area. Therefore, the 17 and 196 patients mentioned before were included in the subsequent analyses of this study. Figure 1 shows the flow of patients.

Figure 1. Flow of the registry patients. The devices encircled in an oval were analyzed in this study. In the stent-graft group it was studied whether patients received a device of this type regardless of other devices.

Approximately, 8% of the patients specifically treated in the aneurysmal area received a stent-graft. Table 1 shows the clinical and angiographic characteristics, and the long-term events of both patients who received stent-grafts and those who received drug-eluting stents. Males were predominant and often showed signs of dyslipidemia, previous coronary arteriopathy, coronary artery disease with previous revascularization, and giant aneurysms in the cohort implanted with stent-grafts. The frequency and type of complications reported at the long-term follow-up with an overall median follow-up of 38 months are shown on table 1. No statistically significant differences were seen at the follow-up regarding the clinical events. A composite event rate of major adverse cardiovascular events (MACE) of 29.6% was reported in patients treated with drug-eluting stents compared to 23.5% in those treated with stent-grafts. Individually, the most common event reported in the group implanted with stent-grafts was unstable angina (11.8%). In the group treated with drug-eluting stents, the most common event was unstable angina (10.2%) and death (10.2%). Every individual event is shown on table 1.

Table 1. Overall characteristics of patients treated with stent-grafts compared to those treated with drug-eluting stents as first-line therapy for the management of coronary aneurysms

Coronary angiographies at the follow-up became available for 69 patients (32.4%). Eight of them were performed in the group with stent-grafts and only 1 confirmed failed stent implantation due to in-stent restenosis. In the group treated with drug-eluting stents, the aneurysm grew bigger or new aneurysms appeared in over 15% of the patients with follow-up coronary angiographies available. The rate of thrombosis in this selected group reached 9.8%. Table 2 provides an overall comparison between patients with the composite endpoint of MACE and those without it.

Table 2. Clinical and angiographic characteristics of patients depending on whether they showed, at least, 1 major adverse cardiovascular event at the follow-up^a

The multivariate analysis on the occurrence of MACE included in the model the use of stent-grafts. On the other hand, the univariate analysis included variables with P values ≤ .10. All of them are shown on table 2 including the presence or not, of peripheral vasculopathy (on therapy), previous diagnosis of aneurysm (in a territory different from the coronary one), diagnosed connective tissue disease, left ventricular ejection fraction, use of intracoronary imaging modalities (optical coherence tomography or intravascular ultrasound), and acute indication to perform index catheterization.

It was confirmed that the following variables remain in the model as independent predictors of the development of the composite endpoint: the existence of connective tissue disease (HR, 5.94; 95%CI, 1.82-19.37), left ventricular dysfunction—below 55%—(HR, 1.84; 95%CI, 1.09-3.1), and the acute indication for index catheterization (HR, 2.98; 95%CI, 1.39-6.3) (figure 2). The use of intracoronary imaging modalities—more common in the cohort implanted with stent-grafts—reached differences that were not statistically significant in the multivariate analysis. It was not a discriminator either regardless of the use of stent-grafts or drug-eluting stents (table 1, table 2, and figure 2).

Figure 2. Kaplan Meier survival curves free of the composite MACE event. A: on the use, or not of the stent-graft for the management of the aneurysm. B: based on whether the indication for index catheterization was acute (acute coronary syndrome, heart failure, etc.). C: regarding the use, during the angioplasty, of any of these intracoronary imaging modalities (intravascular ultrasound, optical coherence tomography or both), D: stratification based on the left ventricular ejection fraction (LVEF) when the angioplasty was performed.

DISCUSSION

This analysis is one of the largest series of coronary aneurysms published including data from real-life patients. It compares 2 of the most widely used therapeutic strategies in this context,5 and its main findings are:

a) The most widely used revascularization method in patients with coronary aneurysms was percutaneous.

b) The exclusion technique, that is, the use of stent-grafts, was used in a relatively lower number of cases (8%).

c) The clinical profile of patients treated with drug-eluting stents was similar compared to patients treated with stent-grafts. However, the presence of giant aneurysms is more common in the latter group. Also, it is probably one of the factors that operators pay most attention to when choosing one stent over the other.

d) An acute indication for the index catheterization and the presence of ventricular dysfunction, at that particular moment, are independent factors of poor prognosis in the study cohort.

e) In the long-term, a similar safety and efficacy profile can be seen in both arms of treatment making stent-grafts a reasonable alternative in selected cases with coronary aneurysms.

The specific treatment of patients with coronary aneurysms has not been well-defined yet to the point that it is not even quoted by the international clinical guidelines on revascularization.5 Over the last few years, several series and registries have been published trying to shed light on this issue.5,6,8,11 Generally speaking, coronary aneurysm is a rare coronary comorbidity. Nonetheless, the average interventional cardiologist sees 1 or several cases each year in his cath lab.7,16 As a matter of fact, in our own experience its estimated that its incidence rate is around 0.35% according to over 430 000 coronary angiographies performed,5 and around 1% according to a recent Chinese series of a little over 11 000 coronary angiographies.17 For this reason, it is important to have clinical data available to guide the management of this entity.7

Also, the coronary aneurysm is a clear marker of anatomic complexity and in adult patients it is suggestive of extensive coronary artery disease, and possibly, poor prognosis compared to milder forms of coronary arteriopathy.7 In previous analyses, the use of drug-eluting stents in patients with coronary aneurysms has been proposed as a therapeutic option clearly superior to conventional stents.5 That is why—as it happens with the rest of patients with ischemic heart disease—this type of platforms is widely recommended for patients with coronary aneurysms. Similarly, the use of an intense and thorough antithrombotic therapy is probably associated with fewer evolutionary complications, which is really reasonable considering the already mentioned high ischemic risk of these patients.11,18

The use of stent-grafts has been proposed as an alternative that can restore the anatomy of the blood vessel. Although the early design of these stents originally served other purposes, the data supporting the feasibility of their use with a high rate of success are extensive.8 In our series, the stent most widely used was the classically designed Jostent Graftmaster coronary stent graft system (Abbott Vascular, United States) (nearly 65%). It is composed of a PTFE layer between 2 stainless-steel stents that may have influenced the results. As a matter of fact, in our setting, Jurado-Román et al.15 conducted a multicenter registry on a certain state-of-the-art stent-graft. They proved that, in several real-life indications, the rate of events is reasonable (MACE, 7.1% at an average 22 months). However, the rate of stent thrombosis was slightly higher (3%) compared to the rate reported by drug-eluting stents in common uses.

The use of intracoronary imaging modalities to perform angioplasties in patients with coronary aneurysms possibly has prognostic implications as it happens in other complex clinical situations (diagnostic doubts, left main coronary artery, bifurcations). In this series, although they were more widely used in the group with stent-grafts implanted, no statistically significant differences were seen on the development of MACE (figure 2). This possibly has to do with the size of the study sample. Also, a tendency was seen towards fewer events in the group of patients with procedures optimized through intracoronary imaging guidance whether intravascular ultrasound or optical coherence tomography.

Limitations

This study has limitation associated with the particular design of the study. Also, a relatively small number of participants was included, which may have complicated the detection of differences in the analyses due to the lack of statistical power. The decision to implant stent-grafts or drug-eluting stents was entirely left to each patient’s medical team, which may have been associated with a certain degree of heterogeneity in the protocols that could have also been more dynamic in time. At the very complete follow-up from the clinical standpoint, control angiographies became available for a limited number of patients only (32%) who met the criterion set by the treating physicians. This may have underestimated the rate of complications, especially the subclinical ones, or be associated with selection biases in both groups.

However, this study is an approach to real-life clinical practice for a relatively rare heart disease on which there is little information available. It also includes a long-term clinical follow-up.

CONCLUSIONS

Stents-grafts can be used to treat coronary aneurysms and are safe in the long-term. Randomized clinical trials are needed to decide what the best treatment is for this type of complex coronary lesions.

FUNDING

None.

AUTHORS’ CONTRIBUTIONS

I. J. Núñez-Gil, CAAR coordinator: study design, data analysis, and draft writing. E. Cerrato, M. Bollati, L. Nombela-Franco, and A. Fernández-Ortiz: study design. E. Cerrato, M. Bollati, B. Terol, E. Alfonso-Rodríguez, S. J. Camacho-Freire, P. A. Villablanca, I. J. Amat-Santos, J.M. de la Torre-Hernández, I. Pascual, C. Liebetrau, B. Camacho, M. Pavani, R. A. Latini, F.Varbella, V. A. Jiménez Díaz, D. Piraino, MM, F. Alfonso, J. Antonio Linares, J. M. Jiménez-Mazuecos, J. Palazuelos- Molinero, and I. Lozano: data mining and recruitment. E. Cerrato, M. Bollati, B. Terol, L. Nombela-Franco, E. Alfonso-Rodríguez, S. J. Camacho-Freire, P. A. Villablanca, I. J. Amat-Santos J.M. de la Torre-Hernández, I. Pascual, C. Liebetrau, B. Camacho, M. Pavani, R. A. Latini, F.Varbella, V. A. Jiménez Díaz, Davide Piraino, M. Mancone, F. Alfonso, J. A. Linares, J. M. Jiménez-Mazuecos, J. Palazuelos- Molinero, IÍ. Lozano, and A. Fernández-Ortiz: reading and critical review of the manuscript.

CONFLICTS OF INTEREST

J. M. de la Torre Hernández is the editor-in-chief of REC: Interventional Cardiology, and F. Alfonso is an associate editor of this journal. The journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. No other conflicts of interest have been declared whatsoever.

SUPPLEMENTARY DATA

REFERENCES