ABSTRACT

Introduction and objectives: When using radial access established as the approach of choice to perform coronary angiographies it is important to avoid radial spasm as it is the leading cause of access failure. This study aims to determine whether a topical anesthetic cream reduces the rate of radial spasm, as well as the increased gain with the use of different vasodilators.

Methods: Randomized, double-blind, and single-center clinical trial. Patients will be randomized to receive the anesthetic cream vs placebo, and 4 types of different vasodilator cocktails will be used in each group. The presence—or not—of radial spam and caliper gain will be analyzed.

Conclusions: Demonstrating the efficacy of the anesthetic cream, and different vasodilators to reduce radial spam would have a significant clinical impact, and justify its systematic use when performing coronary angiographies.

Registered at The Spanish Agency of Medicines and Medical Devices (AEMPS) EudraCT number: 2017-000321-12.

Keywords: Radial spasm. Anesthetic cream. Vasodilators. Coronary angiography. Luminal diameter.

RESUMEN

Introducción y objetivos: Con el abordaje radial establecido como técnica de elección para la coronariografía, es importante evitar el espasmo radial como principal causa de fallo en el acceso intravascular. En este estudio se pretende demostrar si la anestesia tópica en crema disminuye la incidencia de espasmo radial, así como conocer la ganancia de calibre con el uso de diferentes vasodilatadores.

Métodos: Ensayo clínico aleatorizado doble ciego en un solo centro. Los pacientes se aleatorizarán para recibir crema anestésica o placebo, y se utilizarán 4 tipos de cócteles vasodilatadores en cada grupo. Se analizará la presencia o no de espasmo radial y la ganancia de calibre como objetivos primarios.

Conclusiones: La demostración de la eficacia de la crema anestésica y de los diferentes vasodilatadores en la disminución del espasmo radial tendría un impacto clínico importante y justificaría su uso sistemático en la coronariografía.

Registrado en la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) con n.º EudraCT: 2017-000321-12.

Palabras clave: Espasmo radial. Crema anestésica. Vasodilatadores. Coronariografía. Diámetro luminal.

Abbreviations MLD: mean luminal diameter. RS: radial spasm. TA: topical anesthesia.

INTRODUCTION

Radial approach for cardiac catheterizations has become the most widely used across the world. In Spain it represents up to 75% of all the procedures performed and, in some centers, up to 91.1%.1 Compared to traditional femoral approach, this access has clearly proven its superiority from the safety standpoint of the procedures.2

Arterial canalization failure is often due to radial spasm (RS), and it can occur in up to 10% of all attempts. Also, it is associated with feminine sex, young age, low weight3 or deficits of certain enzymes that act on the endothelium.4 The special histological characteristics of this artery—with a high density of alpha-adrenergic receptors and smooth muscle cells—make it more prone to spasm.5

On the other hand, pain during lumbar puncture contributes to arterial canalization failure due to a higher frequency of appearance of spasm, vasovagal reaction with hypotension and discomfort for patient and operator, and the patient’s possible hemodynamic instability. Similarly, several patients complain of discomfort. As a matter of fact, the arterial puncture is described by many patients as the main moment of discomfort.5

Former studies have reported on the greater success achieved with isolated punctures for arterial gas analysis in the radial artery with the use of anesthesia injected around the puncture site. Also, more comfort and less pain have been reported by the patients.6 However, for many professionals injected anesthesia is ill-advised due to the pain caused by the injection. Also, because there are times that pain leads discomfort, and eventually RS.7 Despite of all this, the use of injected anesthesia is a common thing in procedures performed via radial access.

On the other hand, in the pediatric population as well as in different anatomical locations or in skin surgery, the use of topical anesthesia (TA) in the form of gel, cream or ointment has proven to minimize the pain associated with venous or arterial punctures, and some procedures too.8 The use of this type of anesthetic agents has not been properly studied in the cardiac catheterization setting. However, it could minimize the rate of RS, reduce pain when using this access, and improve the patient’s perception.

Together with TA, the use of different vasodilator drug combinations with unfractionated heparin (the so-called «radial cocktail»)—after successful arterial access—has proven to reduce the rates or arterial spasm and radial occlusion after the procedure.9-12 In particular drugs like verapamil, nitroglycerin, nitroprusside, nicorandil, isosorbide dinitrate or phentolamine in different doses have been compared with one another and also with placebo with heterogeneous results with arterial spams having been reported in 4% to 12% of the cases. Verapamil in doses of 5 mg and nitroglycerin 200 µg have yielded the best results so far. However, to this date, no comparison studies between the 2 drugs at these doses have ever been drawn or randomized for this matter.13 Therefore, it has not been fully established which is the best drug combination to prevent spasm and radial occlusion.

At our center, the current radial puncture procedure includes the use of injected anesthesia around the puncture site plus a cocktail of 5000 IU of unfractionated heparin, and 2.5 mg of verapamil. The rate of RS in our cath lab is around 10% of all punctures performed. In some patients, other drugs commonly available in our setting are often used—at the operator’s criterion—like nitroprusside, nitroglycerin or high doses of verapamil.

The objective of this study is to demonstrate whether the administration of topical anesthesia reduces the rate of RS and improves the patient’s perception regardless of the vasodilator used. Also, to compare arterial caliber gain with different vasodilators.

METHODS

Study design

Double-blind randomized clinical trial conducted at a single center to analyze the rate of RS in patients treated with TA in cream with lidocaine 25 mg/g + prilocaine 25 mg/g (Emla) in topical solution compared to placebo, as well as the effect of vasodilators (table 1) (verapamil 2.5 mg or 5 mg, nitroglycerin 200 µg, nitroprusside 150 µg) in the arterial caliber while attempting vascular access to perform diagnostic transradial cardiac catheterization.


Table 1. Inclusion and exclusion criteria of the E-RADIAL study

Composition of the radial cocktail Type of dilution
Cocktail #1 (verapamil 2.5 mg): 12.5 mg of verapamil are diluted in 95 mL of FSS at 0.9%. A total of 20 mL are loaded in the syringe and fully administered.
Cocktail #2 (verapamil 5 mg): 25 mg of verapamil are diluted in 90 mL of FSS at 0.9%. A total of 20 mL are loaded in the syringe and fully administered.
Cocktail #3 (nitroglycerin 0.2 mg): 5 mg of nitroglycerin are diluted in 95 mL of FSS at 0.9%. A total of 4 mL of this solution are loaded in a 20 mL-syringe that is completed with FSS at 0.9%. The entire load of the syringe is administered.
Cocktail #4 (nitroprusside 0.150 mg): 50 mg are diluted in 10 mL of FSS at 0.9% followed by the extraction of 1 mL of this solution that is diluted again in 100 mL of FSS at 0.9%. A total of 3 mL of the latter solution are loaded in a 20 mL-syringe that is completed with FSS at 0.9%. The entire load of the syringe is administered.

FSS, physiological saline solution.


Study population

The study will be conducted entirely at Unidad de Hemodinámica y Cardiología Intervencionista of Complejo Hospitalario Universitario de Albacete, Spain. All consecutive patients treated with diagnostic cardiac catheterization via radial access from November 2020 until completing the sample estimated will be included. Patients will need to meet the inclusion criteria and none of the exclusion ones (table 2).


Table 2. Inclusion and exclusion criteria of the E-RADIAL study

Inclusion criteria Exclusion criteria
Age > 18 years Allergy or intolerance to any of the drugs used in the study.
Informed consent signing Baseline systolic arterial blood pressure < 90 mmHg.
Elective diagnostic cardiac catheterization with intended radial access

Impossibility to understand the study or give the corresponding informed consent.

Introductor 5 French

Ethical aspects

The study has been approved by the center ethics committee, and a favorable resolution was obtained. The study has been registered by Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) with registration No. EudraCT: 2017-000321-12. The study will observe the principles established in the Declaration of Helsinki. Also, written informed consent will be obtained from all the patients before joining the study.

Study endpoints

Primary endpoints

– Study the rate of RS using a topical anesthetic cream before radial puncture.

– Study radial artery caliber gain using different vasodilators.

Secondary endpoints

– Study the rate of radial-radial, and radial-femoral crossing with each strategy.

– Study the rate of vasovagal reactions requiring treatment in each group.

– Study parameters associated with pain during radial artery canalization using pain assessment analogue scales.

– Subjective assessment of pain and comfort by the patient using pain assessment analogue scales, and dedicated tests.

– Subjective assessment of the difficulty involved in the puncture and perception of RS by the operator using dedicated tests.

Study development

The administration of TA/placebo plus cocktail (table 1) will be fully randomized (figure 1). Both the patient and the treating interventional cardiology will be blind to the group they’ll be assigned to. If certain circumstances or complications occur, and if deemed necessary, the chain of secrecy can be broken only if investigators abide, and only under strict clinical judgement.


Figure 1. Flowchart of patients from the E-RADIAL study. NTG, nitroglycerin; NTP, nitroprusside; UFH, unfractionated heparin.


Placebo with cream of similar color, consistency, and characteristics to Emla will be prepared, and they both will be marked with letters A (Emla) and B (placebo). Both placebo and the TA will be prepared by personnel from the hospital pharmacy unit. The nursing team in charge of the patients while waiting for cardiac catheterization at the cath lab will randomize each patient, and the only blind element of the study. TA or placebo will be administered in both wrists and, at least, 1 hour before the procedure.

Prior to puncture, 25 mg of subcutaneous local anesthesia will be injected into the puncture area (mepivacaine at 2%). Another 1-2 minutes will need to pass before it starts to work.

Different cocktails (table 1) will be prepared at the dilution often used at Complejo Hospitalario Universitario de Albacete cath lab in 100 mL-jars of physiological saline solution (NaCl at 0.9%). Each jar will be marked with an alphanumeric code and its content will remain blind to everyone but the nursing team in charge of randomization.

Variable quantification during puncture

After monitoring the patient, arterial blood pressure will be determined invasively, as well as the baseline heart rate before administering the cocktail that will be used just after the introduction of hydrophilic guidewire (Radiofocus 5-Fr, Terumo, Japan). Similarly, arterial blood pressure will be recorded 2 minutes after the cocktail administration, as well as the maximum heart rate during puncture.

All vagal data that can occur and any other complications associated with access will be written down. The crossing rate to other accesses will also be studied prioritizing homolateral (cubital, distal radial) or contralateral access. Unless the operator specifies otherwise, femoral access will be set aside as the third go-to option.

Radial spasm determination and caliber gain quantification

RS will be defined as yes/no—both qualitative and dichotomically—and considered as sudden, transient, and abrupt narrowing of the radial artery during puncture. It will be clinically determined by, at least, 1 of the following events: loss of pulse during puncture, pain in the upper limb during catheter manipulation or entrapment. Its presence can also be determined through the angiography if spasm is seen during contrast injection.

Caliber gain will be determined through quantitative analysis of the radial artery luminogram. Therefore, an angiography will be immediately performed after the insertion of the introducer sheath plus another one 2 minutes after the injection of the antispasmodic cocktail. The radial artery caliber will be measured in the segment located between the tip of the arterial introducer sheath—2 cm away from it—and the location where it meets the humeral artery. Measurements will be acquired through computerized quantitative analysis (Xcelera, Philips, United States) after previous calibration of the arterial introducer sheath in the same segment before and after the cocktail injection to determine the mean luminal diameter (MLD).

Caliber gain will be estimated in percentage according to the following formula:

Caliber gain = × 100

Postoperative patient assessment

The patient will be asked to give his opinion on the radial puncture through the pain qualitative analogue scale, and the comfort scale consisting of 4 questions (annex of the supplementary data).

Similarly, the interventional cardiologist will give his evaluation through a survey including 2 questions (annex of the supplementary data), the difficulties found while performing the puncture, and how the procedure was accomplished via the access used.

Statistical analysis

The analysis will be conducted using the SPSS statistical software package for Windows v 21.0.

In descriptive statistics frequencies and percentages will be used to express discrete variables while mean, median, mode, standard deviation, and ranges will be used to express continuous variables. The rate of spams and other study components will be described through frequencies and percentages. The statistical analysis of the main variables will be conducted by intention-to-treat analysis. The chi-square test will be used to study differences among proportions while the continuous variables will be analyzed using the Student t test if normally distributed or else non-parametric tests if not normally distributed. In the presence of non-homogeneous distribution of confounding variables between the groups that will be analyzed, a logistic regression analysis will be conducted that should collect those clinically significant and non-homogeneously distributed parameters.

It is our will to conduct an intermediate analysis after which the study will move on or not (existence of a significant difference in the primary endpoint of RS > 7,5% between both groups).

Estimate of the sample size

According to former studies, it is estimated that the proportion of patients who will have RS in the control group will be 10%3,5 being the criterion of clinical effectiveness the reduction of this percentage off by 50%, which is why it will be necessary to have a minimum sample of 668 patients.

This volume of patients will allow us to confirm the statistical significance of the variations described in radial artery vasodilation with different types of vasodilators.

DISCUSSION

Currently, the arterial approach via radial access is used in 91.1%1 of all diagnostic and therapeutic coronary angiographies performed. In particular, the rates of bleeding complications have dropped thus contributing to the patients’ comfort. This access has facilitated the implementation of safe coronary angiography and outpatient angioplasty programs even in complex settings.14-16

Hand in hand with this and assuming pain hypothesis and adrenergic discharge are caused by puncture and risk factors for RS, different strategies have come up to contribute to the proper administration of anesthesia promoting patients’ comfort, and looking to reduce the rate of RS. As it happens in other places, at our center the use of subcutaneously injected anesthesia is the common practice since the direct correlation between less RS and proper anesthetic release in the punction area has already been confirmed.5 This study paves the way for a possible change in the routine clinical practice that could be associated—or not—with TA in cream pharmaceutical form. The medical literature includes different and very heterogeneous studies that, whether randomized or not, have tried to assess the utility of this type of creams. However, all of them include small samples (usually less than 100 patients), which makes it difficult to extrapolate the results.

We have a few examples of injected anesthesia vs a composite of TA plus injected anesthesia with favorable results from the latter.17,18 As far as we know, the heterogeneity of designs, and the small sample sizes make us question studies like these.

Although subcutaneous anesthesia—often with lidocaine—has proven to improve pain at the puncture site and reduce the rate of RS compared to TA there is a huge controversy regarding the active principles and drug combination that should be used, the specific action times of these drugs or which are the best pharmaceutical forms. However, it seems that the cream/ointment formulation, and the lidocaine/prilocaine combination (Emla type) yield the best results of all.18

Assuming that this type of formulation is the most widely studied and looking to achieve an adequate design with a representative sample, the E-RADIAL trial (Effectiveness in preventing radial spasm of different vasodilators and topic local anesthesia during transradial cardiac catheterization) has just been started. Although it is not the first trial to propose this hypothesis, it is the first one indeed to confirm it on a double-blind randomized clinical trial and compare it to different radial cocktails and a wide sample size.

This vasolidator comparison is a particularly new approach of our trial. There is some controversy on the use, or not, of such drugs: although some centers in our country do not use vasodilators on a routine basis, it seems to be proven that, overall, its use promotes arterial dilatation and, therefore, the navigability of catheters with lower rates of spasm.9,13 Currently, no such thing as head-on comparisons of cocktails have been drawn in trials to assess their efficacy and safety profile.19 Therefore, we designed our study taking into consideration that a comparison can be drawn among these different drugs in quantitative terms using MLD gain.

Although not part of our study primary endpoints we assume that—with radial access clearly established in the routine clinical practice of cath labs—the operator’s experience, his learning curve or even the rotating fellow/resident’s learning curve can have an impact on the rate of success of puncture, RS, as well as on other complications. This can be an interesting aspect we could discuss. As far as we know both in the current medical literature and good practice recommendations regarding the radial access20—although with limitations depending on the study analyzed—it seems reasonable to assume that the threshold to overtake the learning curve would be at around 30-5021 cases for conventional diagnostic coronary angiography, and > 100-200 cases for complex coronary anatomies22,23 or even in the ST-segment elevation acute coronary syndrome setting. In the E-RADIAL study, all operators widely exceed the number of cases recommended for this curve in diagnostic coronary angiography. Even so, while collecting data for the E-RADIAL we’ll have the possibility to know the identity of the operator who will perform the puncture, his years of experience using radial access, and whether a resident or a novel interventional cardiology (< 2 years of experience) was involved. Also, we will try to know descriptively the rate of puncture success, and whether any RS differences or other complications occurred.

The design of this clinical trial used 4 types of radial cocktail (table 1) from the ones most widely used ones in today’s clinical practice. However, this is also a controversial issue. On the one hand, some centers don’t use vasodilators systematically after radial puncture. On the other hand, choosing one over the other at the cath labs where they’re used is often based on the good clinical results obtained empirically in the routine clinical practice. Unlike the use of heparin to prevent radial occlusion, evidence is scarce regarding benefits from vasodilators, and no homogeneous head-on comparisons have been drawn among different drug cocktails. Verapamil in doses of 5 mg, and nitroglycerin in doses of 200 µg have yielded the best results so far. However, to this date, they have never been compared to one another at these doses or in a randomized way.13 Certain clinical features of the patients can turn the use of these cocktails into a controversial issue. As an example of this, in patients with very severe left ventricular dysfunction or severe aortic stenosis the use of these drugs can trigger significant adverse reactions, mainly hypotension or significant hemodynamic changes. Although, in theory, overall, these drugs are contraindicated in these clinical settings, the dose used, slow infusion, and other factors like the patients’ clinical stability, the existence—or not—of associated heart failure or different comorbidities can turn the use of these drugs into a safe practice. In its design the E-RADIAL study includes a head-on comparison of cocktails and some of the aforementioned drugs and doses. Therefore, it is an opportunity to know what the clinical implication of these drugs really is regarding adverse events.

One of the possible weaknesses or aspects that should be discussed in this trial is pain assessment and quantification. A reproducible design was attempted while assuming the difficulties posed by individual subjectivity. Therefore, following in the footsteps of former studies and registries, we decided to use the most standardized method available to this date in the medical literature: analogue scales.

Another possible weakness or cofounding factor in the study design is the systematic use of sodium heparin via arterial access as standard prevention against radial occlusion.20 According to the drug label24 the heparin-induced cardiac tamponade solution is often an acid solution with a pH between 5.0 and 7.5. The mean arterial pH is between the traditional values of 7.35 and 7.45, and could be partially altered when in contact with heparin solutions thus favoring, through different mechanisms, the development of RS, something not clearly established to this date. To solve this possible bias, the IV—not intraarterial use—of heparin was selected. Although evidence is certainly scarce and heterogeneous the IV use of heparin does not seem to increase the rate of radial occlusion, which is more associated with the heparin dose used and factors like compression time, type of material or size of the radial introducer sheath used that are well established as predictors of radial occlusion.25,26

CONCLUSIONS

The E-RADIAL study is the first randomized clinical trial to assess, on the one hand, the implications of less RS due to topical anesthesia and, on the other, arterial caliber gain with the use of different vasodilators.

FUNDING

None whatsoever.

AUTHORS’ CONTRIBUTIONS

J. J. Portero-Portaz: idea, methodology, validation, formal analysis, drafting of the original project; J. G. Córdoba-Soriano: idea, methodology, review and edition of the manuscript; A. Gutiérrez-Díez: idea, methodology, validation, formal analysis, review and edition of the manuscript; A. Gallardo-López, and D. Melehi El-Assali: idea, methodology, review and edition of the manuscript; L. Expósito-Calamardo, and A. Prieto-Lobato: research, review, and edition of the manuscript; E. García-Martínez, S. Ruiz-Sánchez, M. R. Ortiz Navarro, and E. Riquelme-Bravo: methodology, review, and edition of the manuscript; J. Jiménez-Mazuecos: idea, methodology, review and edition of the manuscript.

CONFLICTS OF INTEREST

Authors declared having no affiliation or participation in any organization or entity with any financial or non-financial interest in the topic at stake or in the materials discussed in this manuscript.

ACKNOWLEDGEMENTS

We wish to thank the nursing personnel of our unit for their work, dedication, and availability during the entire study.

WHAT IS KNOWN ABOUT THE TOPIC?

  • RS is the leading cause of access failure in diagnostic or therapeutic coronary angiographies.
  • The use of injected local anesthesia is standardized and reduces the rate of RS.
  • There is no consensus on the use or non-use of vasodilators, which depends on the characteristics and routine clinical practice of each center.

WHAT DOES THIS STUDY ADD?

  • The E-RADIAL study can pave the way to systematization in the use of other type of anesthesia.
  • It will provide relevant information on the effectiveness of different vasodilators through head-on comparisons of the most widely used agents.

SUPPLEMENTARY DATA


REFERENCES

1. Romaguera R, Ojeda S, Cruz-González I, Moreno R. Registro Español de Hemodinámica y Cardiología Intervencionista. XXX Informe Oficial de la Asociación de Cardiología Intervencionista de la Sociedad Española de Cardiología (1990-2020) en el año de la pandemia de la COVID-19. Rev. Esp Cardiol. 2021;74:1095-1105.

2. Rao SV, Turi ZG, Wong SC, Brener SJ, Stone GW. Radial versus femoral access. J Am Coll Cardiol. 2013;62(17 Suppl):S11-20.

3. Dandekar VK, Vidovich MI, Shroff AR. Complications of transradial catheterization. Cardiovasc Revasc Med. 2012;13:39-50.

4. Kocayigit I, Cakar MA, Kahyaog˘lu B, Aksoy MNM, Tatli E, Akdemir R. The relationship between serum asymmetric dimethylarginine levels and radial artery spasm. Anatol J Cardiol. 2020;23:228-232.

5. Ho HH, Jafary FH, Ong PJ. Radial artery spasm during transradial cardiac catheterization and percutaneous coronary intervention: incidence, predisposing factors, prevention, and management. Cardiovasc Revasc Med. 2012;
13:193-195.

6. Hudson TL, Dukes SF, Reilly K. Use of local anesthesia for arterial punctures. Am J Crit Care. 2006;15:595-599.

7. France JE, Beech FJ, Jakeman N, Benger JR. Anaesthesia for arterial puncture in the emergency department: a randomized trial of subcutaneous lidocaine, ethyl chloride or nothing. Eur J Emerg Med. 2008;15:218-220.

8. Tran NQ, Pretto JJ, Worsnop CJ. A randomized controlled trial of the effectiveness of topical amethocaine in reducing pain during arterial puncture. Chest. 2002;122:1357-1360.

9. Boyer N, Beyer A, Gupta V, et al. The effects of intra-arterial vasodilators on radial artery size and spasm: implications for contemporary use of trans-radial access for coronary angiography and percutaneous coronary intervention. Cardiovasc Revasc Med. 2013;14:321-324.

10. Ruiz-Salmerón RJ, Mora R, Vélez-Gimón M, et al. Espasmo radial en el cateterismo cardíaco transradial. Análisis de los factores asociados con su aparición y de sus consecuencias tras el procedimiento. Rev Esp Cardiol. 2005;58:504-511.

11. Majure DT, Hallaux M, Yeghiazarians Y, Boyle AJ. Topical nitroglycerin and lidocaine locally vasodilate the radial artery without affecting systemic blood pressure: a dose-finding phase I study. J Crit Care. 2012;27:532.e9-13.

12. Beyer AT, Ng R, Singh A, et al. Topical nitroglycerin and lidocaine to dilate the radial artery prior to transradial cardiac catheterization: a randomized, placebo-controlled, double-blind clinical trial: the PRE-DILATE Study. Int J Cardiol. 2013;168:2575-2578.

13. Kwok CS, Rashid M, Fraser D, Nolan J, Mamas M. Intra-arterial vasodilators to prevent radial artery spasm: a systematic review and pooled analysis of clinical studies. Cardiovasc Revasc Med. 2015;16:484-490.

14. Córdoba-Soriano JG, Rivera-Juárez A, Gutiérrez-Díez A, et al. The Feasibility and Safety of Ambulatory Percutaneous Coronary Interventions in Complex Lesions. Cardiovasc Revasc Med. 2019;20:875-882.

15. Córdoba-Soriano JG, Jiménez-Mazuecos J, Rivera Juárez A, et al. Safety and Feasibility of Outpatient Percutaneous Coronary Intervention in Selected Patients: A Spanish Multicenter Registry. Rev Esp Cardiol. 2017;70:535-542.

16. Gallego-Sánchez G, Gallardo-López A, Córdoba-Soriano JG, et al. Safety of transradial diagnostic cardiac catheterization in patients under oral anticoagulant therapy. J Cardiol. 2017;69:561-564.

17. Tatlı E, Adem Yılmaztepe M, Gökhan Vural M, et al. Cutaneous analgesia before transradial access for coronary intervention to prevent radial artery spasm. Perfusion. 2018;33:110-114.

18. Youn YJ, Kim WT, Lee JW, et al. Eutectic mixture of local anesthesia cream can reduce both the radial pain and sympathetic response during transradial coronary angiography. Korean Circ J. 2011;41:726-732.

19. Shehab A, Bhagavathula AS, Kaes AA, et al. Effect of Vasodilatory Medications on Blood Pressure in Patients Undergoing Transradial Coronary Angiography: A Comparative Study. Heart Views. 2020;21:75-79.

20. Shroff AR, Gulati R, Drachman DE, et al. SCAI expert consensus statement update on best practices for transradial angiography and intervention. Catheter Cardiovasc Interv. 2020;95:245-252.

21. Hess CN, Peterson ED, Neely ML, et al. The learning curve for transradial percutaneous coronary intervention among operators in the United States: a study from the National Cardiovascular Data Registry. Circulation. 2014;
129:2277-2286.

22. Azzalini L, Ly HQ. Letter by Azzalini and Ly regarding article, “The learning curve for transradial percutaneous coronary intervention among operators in the United States: a study from the National Cardiovascular Data Registry”. Circulation. 2015;131:e357.

23. Hamon M, Pristipino C, Di Mario C, et al. European Association of Percutaneous Cardiovascular Interventions; Working Group on Acute Cardiac Care of the European Society of Cardiology; Working Group on Thrombosis on the European Society of Cardiology. Consensus document on the radial approach in percutaneous cardiovascular interventions: position paper by the European Association of Percutaneous Cardiovascular Interventions and Working Groups on Acute Cardiac Care** and Thrombosis of the European Society of Cardiology.EuroIntervention. 2013; 8:1242–1251.

24. Ficha técnica de la heparina sódica. Agencia Española de Medicamentos y Productos Sanitarios. Available online: https://cima.aemps.es/cima/dochtml/ft/56029/FT_56029.html. Accessed 20 Nov 2021.

25. Pancholy SB. Comparison of the effect of intra-arterial versus intravenous heparin on radial artery occlusion after transradial catheterization. Am J Cardiol. 2009;104:1083-1085.

26. Rashid M, Kwok CS, Pancholy S, et al. Radial Artery Occlusion After Transradial Interventions: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 201625;5:e002686.

* Corresponding author:

E-mail address: juanjose.porteroportaz@gmail.com (J.J. Portero-Portaz).

ABSTRACT

Introduction and objectives: During the lockdown due to the pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a decrease in the number of admissions due to acute coronary syndrome (ACS) was observed. The objective of our study was to evaluate the impact lockdown had on the incidence, morbidity and mortality, and management of ACS.

Methods: A retrospective and multicenter study was conducted including patients admitted due to ACS from February 14 through June 24, 2020. Patients with acute myocardial infarction and coronary arteries without significant lesions were excluded. The following groups were established based on the period of admission: a) 1 month before lockdown; b) during lockdown; and c) 1 month after lockdown. The differences in mortality seen among the 3 groups were evaluated, as well as the temporal differences reported between symptom onset and the first medical contact (FMC).

Results: a total of 634 patients were included (group a, 205; group b, 303, and group c, 126). A 41% decrease in the number of admissions due to ACS was observed during the first month of lockdown compared to the previous month, as well as diagnostic delay during this same period (group a, 66 minutes (45-180), group b, 120 minutes (60-240), and group c, 120 minutes (60-240), P = .007). However, a higher mortality rate during confinement was not reported (RR, 1.26; 95%CI, 0.53-2.97; P = .60).

Conclusions: During lockdown, a remarkable decrease in the number of admissions due to ACS was observed, and although there was an increase in the time elapsed from symptom onset to the FCM in this period in patients with STEMI, the mortality rate was similar in the 3 groups studied.

Keywords: COVID-19. SARS-CoV-2. Acute coronary syndrome. Pandemic. Revascularization. Lockdown.

RESUMEN

Introducción y objetivos: Durante el confinamiento por la pandemia provocada por el coronavirus del síndrome respiratorio agudo grave de tipo 2 (SARS-CoV-2) se observó un descenso en los ingresos por síndrome coronario agudo (SCA). El objetivo de este estudio fue evaluar el impacto del confinamiento en la incidencia, la morbimortalidad y el tratamiento del SCA.

Métodos: Estudio retrospectivo y multicéntrico, en el que se incluyeron los pacientes ingresados por SCA entre el 14 de febrero y el 24 de junio de 2020. Se excluyeron los pacientes con infarto agudo de miocardio y coronarias sin lesiones significativas. Se establecieron 3 grupos en función del periodo de ingreso: a) 1 mes antes del confinamiento; b) durante el confinamiento; y c) 1 mes después del confinamiento. Se evaluaron las diferencias en la mortalidad entre los 3 grupos, así como las diferencias temporales entre el inicio de los síntomas y el primer contacto médico.

Resultados: Se incluyeron 634 pacientes (grupo A: 205; grupo B: 303; grupo C: 126). Se observó un descenso del 41% en los ingresos por SCA durante el primer mes del confinamiento respecto al mes previo, así como un retraso en el diagnóstico durante este mismo periodo: grupo A, 66 minutos (45-180); grupo B, 120 minutos (60-240); grupo C, 120 minutos (60-240) (p = 0,007). Sin embargo, no hubo mayor mortalidad durante el confinamiento (riesgo relativo, 1.26; intervalo de confianza del 95%, 0.53-2.97; p = 0,60).

Conclusiones: Durante el confinamiento se produjo un marcado descenso en los ingresos por SCA y, a pesar de que se dilató el tiempo desde el inicio de los síntomas hasta el primer contacto médico en este periodo en los pacientes con SCA con elevación del segmento ST, la mortalidad fue similar en los 3 grupos estudiados.

Palabras clave: COVID-19. SARS-CoV-2. Síndrome coronario agudo. Pandemia. Revascularización. Confinamiento.

Abbreviations ACS: acute coronary syndrome. SARS-CoV-2: severe acute respiratory syndrome coronavirus 2. STEMI: ST-segment elevation myocardial infarction.

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

Variable Total (N = 634) Group A (N = 205) Group B (N = 303) Group C (N = 126) P
Age 66.3 ±12.6 67.4 ±11.6 64.8 ±12.7 68.2 ±13.6 .012
Sex, male 494 (77.9) 158 (77.1) 241 (79.5) 95 (75.4) .603
AHT 400 (63.1) 143 (69.8) 176 (58.1) 81 (64.3) .027
DM 191 (30.1) 71 (35.1) 89 (29.4) 30 (23.8) .086
DL 368 (58.0) 137 (66.8) 164 (54.1) 67 (53.2) .008
Smoking 364 (57.4) 124 (60.5) 182 (60.1) 58 (46.0) .015
PVD 36 (5.7) 15 (7.3) 16 (5.3) 5 (4.0) .405
Stroke 37 (5.8) 11 (5.4) 16 (5.3) 110 (7.9) .531
CKD (GF < 60) 30 (4.7) 18 (8.8) 7 (2.3) 5 (4.0) .003
COPD 45 (7.1) 14 (6.8) 22 (7.3) 9 (7.1) .981
AF 40 (6.3) 16 (7.8) 16 (5.3) 8 (6.4) .517
IHD 150 (23.7) 79 (38.5) 46 (15.2) 25 (19.8) < .001
AMI 103 (16.3) 52 (25.4) 31 (10.2) 20 (15.9) < .001
PCI 117 (18.5) 60 (29.3) 36 (11.9) 21 (16.7) < .001
CABG 23 (3.6) 12 (5.9) 7 (2.3) 4 (3.2) .112
Diagnoses
 UA 83 (13.1) 36 (17.6) 27 (8.9) 20 (15.9) .003
 NSTEMI 195 (30.8) 67 (32.7) 83 (27.4) 45 (35.7) .003
 STEACS 356 (56.2) 102 (49.8) 193 (63.7) 61 (48.4) .003
 GRACE 120.1 ±35.6 118.4 ±35.4 119.1 ±34.6 124.8 ±38.3 .264
 CRUSADE 31.4 ±13.8 34.1 ±15.2 30.4 ±13.3 29.7 ±11.8 .001
 Cardiac catheterization 616 (97.5) 198 (96.6) 295 (97.7) 123 (98.4) .565
 Emergency 375 (59.5) 112 (54.9) 190 (63.1) 73 (58.4) .447
 Deferred 242 (38.4) 87 (42.7) 105 (34.9) 50 (40.0) .447
 Fibrinolysis 29 (5.1) 10 (5.7) 13 (4.5) 6 (6.1) .652
 PCI 534 (94.3) 165 (93.2) 276 (95.2) 93 (94.0) .652
 CABG 29 (4.6) 11 (5.4) 8 (2.7) 10 (8.1) .045
 LMCA or 3-vessel disease 136 (21.5) 52 (25.4) 55 (18.6) 29 (23.0) .135
 CABG (LMCA or 3-vessels) 22 (16.3) 9 (17.7) 3 (5.5) 10 (34.5) .003
 Conservative treatment 3 (0.5) 2 (1.1) 1 (0.3) 0 (0) .652
 Complete revascularization 456 (75.6) 138 (74.6) 223 (76.1) 95 (76.0) .926
 LVEF at discharge 49.2 ±11.1 49.7 ±11.6 48.6 ±11.2 49.9 ±10.0 .421

AF, atrial fibrillation; AHT, arterial hypertension; AMI, acute myocardial infarction; CABG, coronary artery bypass graft; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DL, dyslipidemia; DM, diabetes mellitus; GF, glomerular filtration; HT, arterial hypertension; IHD, ischemic heart disease; LMCA, left main coronary artery; LVEF, left ventricular ejection fraction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease; STEACS, ST-segment elevation acute coronary syndrome; UA, unstable angina. Data are expressed as no. (%) or mean ± standard deviation.


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

Variable Total (N = 634) Group A (N = 205) Group B (N = 303) Group C (N = 126) P
All-cause mortality 36 (5.7) 15 (7.3) 13 (4.3) 8 (6.4) .327
Cardiac death 22 (64.7) 7 (50) 9 (75) 6 (75) .427
Stroke 20 (3.2) 9 (4.4) 8 (2.6) 3 (2.4) .551
Re-AMI 4 (0.7) 1 (0.5) 2 (0.7) 1 (0.8) 1.000
Stent thrombosis 12 (2.0) 8 (4.1) 1 (0.3) 3 (2.4) .006
New revascularization 6 (1.0) 4 (2.0) 2 (0.7) 0 (0) .259
CV death + stroke + Re-AMI + stent thrombosis + new revascularization 57 (9.0) 24 (11.7) 20 (6.6) 13 (10.3) .120

CV, cardiovascular; Re-AMI, new acute myocardial infarction. Data are expressed as no. (%).


Table 3. In-hospital events

Variable Total (N = 634) Group A (N = 205) Group B (N = 303) Group C (N = 126) P
Inotropic agents 53 (8.5) 17 (8.4) 27 (9.0) 9 (7.2) .836
PM at admission 12 (1.9) 4 (2.0) 8 (2.7) 0 (0) .188
IABP 11 (1.7) 7 (3.4) 4 (1.3) 0 (0) .048
OTI 41 (6.5) 15 (7.3) 21 (7.0) 5 (4.0) .444
NIMV 18 (2.9) 6 (2.9) 7 (2.3) 5 (4.0) .604
RRT 10 (1.6) 6 (3) 3 (1.0) 1 (0.8) .192
AVB 20 (3.2) 7 (3.4) 12 (4.0) 1 (0.8) .227
SMVT 18 (2.9) 6 (2.9) 9 (3.0) 3 (2.4) 1.000
VF 29 (4.6) 12 (5.9) 12 (4.0) 5 (4.0) .582
AF at admission 42 (6.7) 11 (5.4) 23 (7.6) 8 (6.4) .597
BARC bleeding type > 3 16 (2.5) 2 (1.0) 9 (3.0) 5 (4.0) .161
Infection 57 (9.0) 12 (6.0) 28 (10.1) 17 (11.0) .184
ARDS 12 (1.9) 1 (0.5) 7 (2.5) 4 (2.6) .208
Mechanical complications 10 (1.6) 3 (1.5) 6 (2.0) 1 (0.8) .774
Killip III or IV 62 (9.8) 20 (9.8) 31 (10.3) 11 (8.8) .898

AF, atrial fibrillation; ARDS, acute respiratory distress syndrome; AVB, atrioventricular block; BARC, Bleeding Academic Research Consortium; IABP, intra-aortic balloon pump; NIMV, non-invasive mechanical ventilation; OTI, orotracheal intubation; PM, pacemaker; RRT, renal replacement therapy; SMVT, sustained monomorphic ventricular tachycardia; VF, ventricular fibrillation. Data are expressed as no. (%).


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

Variable Total Grupo A Grupo B Grupo C p
Symptom onset-first medical contact (N = 332) 120 [60-240] 66 [45-180] (N = 97) 120 [60-240] (N = 180) 120 [60-240] (N = 55) .007
Diagnosis-reperfusion (N = 322) 120 [60-180] 120 [60-186] (N = 93) 120 [60-225] (N = 176) 60 [60-120] (N = 53) .025

Data are expressed as median [interquartile range].


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.

WHAT IS KNOWN ABOUT THE TOPIC?

  • Admissions due to STEACS decreased during the lockdown.
  • More mechanical complications were reported during the pandemic due to delayed treatments.

WHAT DOES THIS STUDY ADD?

  • Unlike former studies that mainly focused on patients with STEACS, this study includes patients admitted before, during, and 1 month after lockdown with a diagnosis of ACS (including STEACS and non-ST-segment elevation acute coronary syndrome).
  • Fewer myocardial revascularization procedures were performed during the lockdown despite the growing number of patients with left main coronary artery disease or 3-vessel disease.
  • Although time between symptom onset and the first medical contact was longer in the group of patients with STEACS, the mortality rate was similar before, during, and after lockdown, as it happened with mechanical complications.

REFERENCES

1. WHO. World Health Organization. Pneumonia of Unknown Cause –China. 2020. Available online:https://www.who.int/emergencies/disease-outbreak-news/item/2020-DON229. Accessed 20 Sep 2021.

2. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382:727-733.

3. Morelli N, Rota E, Terracciano C, et al. The Baffling Case of Ischemic Stroke Disappearance from the Casualty Department in the COVID-19 Era. Eur Neurol. 2020;83:213-215.

4. Babu N, Kohli P, Mishra C, et al. To evaluate the effect of COVID-19 pandemic and national lockdown on patient care at a tertiary-care ophthalmology institute. Indian J Ophthalmol. 2020;68:1540-1544.

5. De Vincentiis L, Carr RA, Mariani MP, Ferrara G. Cancer diagnostic rates during the 2020 âlockdown', due to COVID-19 pandemic, compared with the 2018-2019:An audit study from cellular pathology. J Clin Pathol. 2021;74:187-189.

6. De Rosa S, Spaccarotella C, Basso C, et al. Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era. Eur Heart J. 2020;41:2083-2088.

7. Rodríguez-Leor O, Cid-Álvarez B, Ojeda S, et al. Impacto de la pandemia de COVID-19 sobre la actividad asistencial en cardiología intervencionista en España. REC Interv Cardiol. 2020;2:82-89.

8. Romaguera R, Cruz-González I, Jurado-Román A, et al. Consideraciones sobre el abordaje invasivo de la cardiopatía isquémica y estructural durante el brote de coronavirus COVID-19. REC Interv Cardiol. 2020;2:112-117.

9. Garcia S, Albaghdadi MS, Meraj PM, et al. Reduction in ST-Segment Elevation Cardiac Catheterization Laboratory Activations in the United States During COVID-19 Pandemic. J Am Coll Cardiol. 2020;75:2871-2872.

10. Metzler B, Siostrzonek P, Binder RK, Bauer A, Reinstadler SJ. Decline of acute coronary syndrome admissions in Austria since the outbreak of COVID-19:The pandemic response causes cardiac collateral damage. Eur Heart J. 2020;41:1852-1853.

11. Pessoa-Amorim G, Camm CF, Gajendragadkar P, et al. Admission of patients with STEMI since the outbreak of the COVID-19 pandemic:A survey by the european society of cardiology. Eur Heart J Qual Care Clin Outcomes. 2020;6:210-216.

12. Salinas P, Travieso-González A, Vergara-Uzcategui CE, Macaya F, Núñez-Gil IJ, Fernández-Ortiz A. Relación temporal entre ingresos por síndrome coronario agudo con tratamiento invasivo y confinamiento durante la pandemia de COVID-19. REC Interv Cardiol. 2020;2:307-309

13. Laura E. Wong;MD;PhD;Jessica E. Hawkins;MSEd;Simone Langness;Karen L. Murrell;Patricia Iris;MD &Amanda Sammann;MPH. Where Are All the Patients?Addressing Covid-19 Fear to Encourage Sick Patients to Seek Emergency Care. NEJM Catal. 2020. Available online:https://catalyst.nejm.org/doi/full/10.1056/CAT.20.0193. Accessed 20 Sep 2021.

14. Lai PH, Lancet EA, Weiden MD, et al. Characteristics Associated with Out-of-Hospital Cardiac Arrests and Resuscitations during the Novel Coronavirus Disease 2019 Pandemic in New York City. JAMA Cardiol. 2020;5:1154-1163.

15. Marijon E, Karam N, Jost D, et al. Out-of-hospital cardiac arrest during the COVID-19 pandemic in Paris, France:a population-based, observational study. Lancet Public Health. 2020;5:e437-e443.

16. Baldi E, Sechi GM, Mare C, et al. Out-of-Hospital Cardiac Arrest during the Covid-19 Outbreak in Italy. N Engl J Med. 2020;383:496-498.

17. Tam CCF, Cheung KS, Lam S, et al. Impact of Coronavirus Disease 2019 (COVID-19) Outbreak on ST-Segment-Elevation Myocardial Infarction Care in Hong Kong, China. Circ Cardiovasc Qual Outcomes. 2020;13:e006631.

18. Gluckman TJ, Wilson MA, Chiu ST, et al. Case Rates, Treatment Approaches, and Outcomes in Acute Myocardial Infarction during the Coronavirus Disease 2019 Pandemic. JAMA Cardiol. 2020;5:1419-1424.

19. Wu J, Mamas M, Rashid M, et al. Patient response, treatments, and mortality for acute myocardial infarction during the COVID-19 pandemic. Eur Heart J Qual Care Clin Outcomes. 2021;7:238-246.

20. Franchini S, Spessot M, Landoni G, et al. Stranger months:How SARS-CoV-2, fear of contagion, and lockdown measures impacted attendance and clinical activity during February and March 2020 at an urban Emergency Department in Milan. Disaster Med Public Health Prep. 2020;15(5):e33-e42.

21. Baldi E, Savastano S. Fear of contagion:One of the most devious enemies to fight during COVID-19 pandemic. Disaster Med Public Health Prep. 2021;15:e8-e9.

22. Rodríguez-Leor O, Cid-Álvarez B, Pérez de Prado A, et al. Impact of COVID-19 on ST-segment elevation myocardial infarction care. The Spanish experience. Rev Esp Cardiol. 2020;73:994-1002.

23. Mafham MM, Spata E, Goldacre R, et al. COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England. Lancet. 2020;39:381-389.

24. Álvarez Gallego M, Gortázar de las Casas S, Pascual Migueláñez I, et al. SARS-CoV-2 pandemic on the activity and professionals of a General Surgery and Digestive Surgery Service in a tertiary hospital. Cir Esp. 2020;98:320-327.

* Corresponding author:

E-mail address: juliocecharte@gmail.com (J. Echarte Morales).

ABSTRACT

Introduction and objectives: Coronary artery disease and mental health disorders are often coexistent. Selective serotonin reuptake inhibitors (SSRIs) are often used in this context but have been associated with an increased risk of bleeding due to platelet dysfunction. Previous studies have assessed this risk in patients treated with clopidogrel-based dual antiplatelet therapy (DAPT) with contradictory results. However, there is no data regarding the use of SSRIs and potent P2Y12 inhibitors or triple antithrombotic therapy after percutaneous coronary intervention (PCI). The purpose of this study was to assess the impact of SSRIs on bleeding outcomes after PCI in patients treated with clopidogrel, prasugrel or ticagrelor-based DAPT or triple antithrombotic therapy.

Methods: Retrospective study including all patients undergoing PCI at a high-volume center during 2018. Patients on SSRIs were propensity-score-matched on a 1:1 ratio with patients naive to SSRIs adjusting for the baseline differences. The primary endpoint was major bleeding (BARC type 3 or 5 bleeding) at the 1-year follow-up. Secondary endpoints were a composite of major/non-major clinically relevant bleeding (BARC type 2, 3 or 5 bleeding), and a composite of major adverse cardiovascular events.

Results: Out of a total of 1063 patients treated with PCI during the study period, 1002 met the selection criteria, and 139 (13.9%) were on SSRIs. The latter had a higher bleeding risk before matching [PRECISE-DAPT, 16 [10-24] vs 13 [9-21]; P = .040]. No differences were reported in major bleeding (2.9% vs 2.9%, P = .991), major/non-major clinically relevant bleeding (2.9% vs 7.2%, P = .120) or in major adverse cardiovascular events (7.9% vs 7.9%, P = .979) in patients treated with SSRIs.

Conclusions: The use of SSRIs was frequent in patients treated with PCI, and although it was a marker of a higher bleeding risk at baseline, this was not associated with an additional bleeding liability.

Keywords: Bleeding. Coronary artery disease. Percutaneous coronary intervention. Selective serotonin reuptake inhibitors. Antithrombotic therapy.

RESUMEN

Introducción y objetivos: La cardiopatía isquémica y la enfermedad mental coexisten a menudo. Los inhibidores selectivos de la recaptación de serotonina (ISRS) se utilizan con frecuencia en este contexto, pero se han asociado con un incremento en el riesgo hemorrágico. Los estudios previos han evaluado este fenómeno en pacientes tratados con clopidogrel, con resultados contradictorios. No hay datos sobre el uso de ISRS e inhibidores del P2Y12 potentes o triple terapia antitrombótica. El objetivo de este estudio fue examinar el impacto de los ISRS en los eventos hemorrágicos en pacientes tratados con doble (incluyendo clopidogrel, prasugrel o ticagrelor) o triple terapia antitrombótica tras una intervención coronaria percutánea (ICP).

Métodos: Estudio retrospectivo en el que se incluyeron todos los pacientes tratados con ICP en un centro de alto volumen durante 2018. Los pacientes en tratamiento con ISRS fueron emparejados mediante puntaje de propensión con pacientes sin ISRS. El objetivo primario fue el sangrado mayor al año de seguimiento (BARC 3 o 5). Los objetivos secundarios fueron un combinado de sangrado mayor o menor clínicamente relevante (BARC 2, 3 o 5) y un combinado de eventos cardiovasculares adversos mayores.

Resultados: De los 1.063 pacientes tratados con ICP durante el periodo del estudio, 1.002 cumplieron los criterios de selección y 139 (13,9%) recibían ISRS. Los pacientes con ISRS tenían un mayor riesgo de sangrado antes del emparejamiento (PRECISE-DAPT: 16 [10-24] frente a 13 [9-21]; p = 0,040). No hubo diferencias en el objetivo primario (2,9% frente a 2,9%; p = 0,991) ni en los objetivos secundarios de sangrado mayor o menor clínicamente relevante (2,9 frente a 7,2%; p = 0,120) y eventos cardiovasculares adversos mayores (7,9 frente a 7,9%; p = 0,979).

Conclusiones: El uso de ISRS fue frecuente en los pacientes tratados con ICP, y aunque fue un marcador de riesgo hemorrágico basal, no se asoció con un mayor riesgo de sangrado en el seguimiento.

Palabras clave: Sangrado. Enfermedad coronaria. Intervencionismo coronario percutáneo. Inhibidores selectivos de la recaptación de serotonina. Terapia antitrombótica.

Abbreviations DAPT: dual antiplatelet therapy. PCI: percutaneous coronary intervention. SSRIs: selective serotonin reuptake inhibitors.

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

Variable Overall (N = 1002) SSRI (N = 139) Non-SSRI (N = 863) P
Age, years 66 [58-75] 67 [60-76] 66 [57-75] .530
Sex, male 745 (74.4) 76 (54.7) 669 (77.5) .001*
BMI 28.7 [25.9-31.8] 30.0 [25.8-32.0] 28.6 [25.9-31.7] .067
Hypertension 688 (68.7) 112 (80.6) 576 (66.7) .001*
Diabetes mellitus 370 (36.9) 64 (46.0) 306 (35.5) .017*
Hyperlipidemia 525 (52.4) 83 (59.7) 442 (51.2) .059
Smoking (current or former) 260 (25.9) 34 (24.5) 226 (26.2) .709
Previous revascularization 248 (24.8) 41 (29.5) 207 (24.0) .174
COPD 67 (6.7) 10 (7.2) 57 (6.6) .740
Chronic kidney disease 115 (11.5) 17 (12.2) 98 (11.4) .774
Cancer 98 (9.8) 20 (14.4) 78 (9.0) .044*
Liver disease 37 (3.7) 8 (5.8) 29 (3.4) .166
Hematologic disease or anemia 99 (9.9) 25 (18) 74 (8.6) .001*
Previous relevant bleeding 31 (3.1) 9 (6.5) 22 (2.5) .010*
Atrial fibrillation 87 (8.7) 11 (7.9) 76 (8.8) .871
Oral anticoagulant 102 (10.2) 9 (6.5) 93 (10.8) .119
Potent P2Y12 inhibitors 684 (68.3) 90 (64.7) 594 (68.8) .323
Ticagrelor, no. (%) 660 (65.9) 86 (61.8) 574 (66.5) .543
Prasugrel 24 (2.4) 4 (2.9) 20 (2.3) .543
DAPT duration (months) 8 [6-12] 6 [6-12] 8 [6-12] .440
PRECISE-DAPT 13 [9-22] 16 [10-24] 13 [9-21] .040*
PRECISE-DAPT ≥ 25 195 [19.5] 34 [24.5] 161 [18.7] .109
HAS-BLED 2 (2-3) 3 (2-3) 2 (2-3) .034*
Creatinine clearance, mL/min/1.73 m2 100 [82.3-124.1] 94.8 [72.9-125.2] 100 [82.7-124.1] .154
Clinical presentation
 CCS 441 (44.0) 66 (47.5) 375 (43.5) .375
 ACS 561 (56.0) 73 (52.5) 488 (56.5)

ACS, acute coronary syndrome; BMI, body mass index (kg/m2); CCS, chronic coronary syndrome; COPD, chronic obstructive pulmonary disease; DAPT, dual antiplatelet therapy; SSRI, selective serotonin reuptake inhibitors.

Data are expressed as no. (%), mean ± standard deviation or median [interquartile range].

* Indicates a statistically significant difference with P values < .05.


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

Variable Univariable analysis Multivariable analysis
HR (95%CI) P HR (95%CI) P
Age, years 1.06 (1.02-1.11) .008
Sex, male 0.47 (0.19-1.18) .107
BMI 0.98 (0.89-1.09) .756
Hypertension 0.99 (0.38-2.61) .989
Diabetes mellitus 1.91 (0.78-4.79) .160
Hyperlipidemia 0.82 (0.33-2.01) .664
Chronic kidney disease 3.67 (1.39-9.66) .008
Cancer 2.47 (0.82-7.46) .107
Liver disease 1.48 (0.19-11.05) .705
Hematologic disease or anemia 2.47 (0.82-7.46) .107
Previous relevant bleeding 3.91 (0.90-16.91) .068
Atrial fibrillation 5.45 (2.05-14.53) .001
Oral anticoagulant 8.22 (3.34-20.23) .001 6.99 (2.78-17.64) .001
Potent P2Y12 inhibitors 0.16 (0.06-0.45) .001
PRECISE-DAPT ≥ 25 4.77 (1.94-11.75) .001 3.59 (1.44-8.98) .006
HAS-BLED 1.69 (1.17-2.43) .005
Creatinine clearance 0.98 (0.97-0.99) .024
SSRI 1.68 (0.56-5.07) .356 1.95 (0.64-5.93) .241

95%CI, 95% confidence interval; BMI, body mass index (kg/m2); HR, hazard ratio; SSRI, selective serotonin reuptake inhibitors.


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

Variable SSRI (N = 139) Non-SSRI (N = 139) P
Chronic obstructive pulmonary disease
 Age, years 68 [60-76] 67 [58-75] .757
 Sex, male 76 (54.7) 73 (52.5) .810
 BMI 30.0 [25.8-32.0] 28.4 [25.3-32.4] .143
 Hypertension 112 (80.6) 109 (78.4) .656
 Diabetes mellitus 64 (46.0) 48 (34.5) .050
 Hyperlipidemia 83 (59.7) 67 (48.2) .045
 Smoking (current or former) 34 (24.5) 28 (20.1) .330
 Previous revascularization 41 (29.5) 30 (21.6) .153
 COPD 10 (7.2) 9 (6.5) .816
 Chronic kidney disease 17 (12.2) 19 (13.7) .721
 Cancer 20 (14.4) 18 (12.9) .727
 Liver disease 8 (5.8) 10 (7.2) .626
 Hematologic disease or anemia 25 (18) 21 (15.1) .519
 Previous relevant bleeding 9 (6.5) 10 (7.2) .812
 Atrial fibrillation 11 (7.9) 11 (7.9) 1.000
 Oral anticoagulant 9 (6.5) 9 (6.5) 1.000
 Potent P2Y12 inhibitors 90 (64.7) 97 (69.8) .371
 Ticagrelor 86 (61.8) 91 (65.5) .749
 Prasugrel 4 (2.9) 6 (4.3) .749
 DAPT duration, months 6 [6-12] 6 [6-12] .810
 PRECISE-DAPT 16 [10-24] 15 [10-24] .863
 PRECISE-DAPT ≥ 25 34 (24.5) 32 (23.0) .778
 HAS-BLED 3 [2-3] 3 [2-3] .560
 Creatinine clearance,
 mL/min/1.73 m2 94.8 [72.9-125.2] 100 [82.7-114.0] .747
Clinical presentation
 CCS 66 (47.5)
73 (52.5)
63 (45.3)
76 (54.7)
.718
 ACS

ACS, acute coronary syndrome; BMI, body mass index (kg/m2); CCS, chronic coronary syndrome; COPD, chronic obstructive pulmonary disease; DAPT, dual antiplatelet therapy; SSRI, selective serotonin reuptake inhibitors.

Data are expressed as no. (%), mean ± standard deviation or median [interquartile range].


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.

WHAT IS KNOWN ABOUT THE TOPIC?

  • Coronary artery disease and mental health disorders frequently coexist. The combination of SSRIs and potent antithrombotic therapies is common.
  • Bleeding events after PCI worsen prognosis same as recurrent ischemic events.
  • SSRIs have been potentially associated with an increased risk of bleeding. Data regarding the concomitant use of SSRIs and potent antithrombotic therapies is scarce and inconclusive.

WHAT DOES THIS STUDY ADD?

  • This is the first study to assess the impact of SSRIs on the bleeding outcomes in the current PCI practice using potent P2Y12 inhibitors or triple antithrombotic therapy.
  • SSRIs users have a higher bleeding risk profile.
  • The use of SSRIs was not associated with a higher risk of major bleeding after adjusting for the potential confounders.

REFERENCES

1. De Hert M, Detraux J, Vancampfort D. The intriguing relationship between coronary heart disease and mental disorders. Dialogues Clin Neurosci. 2018;20:31-40.

2. Jha MK, Qamar A, Vaduganathan M, Charney DS, Murrough JW. Screening and Management of Depression in Patients With Cardiovascular Disease:JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73:1827-1845.

3. Lane D, Carroll D, Ring C, Beevers DG, Lip GY. The prevalence and persistence of depression and anxiety following myocardial infarction. Br J Health Psychol. 2002;7:11-21.

4. Gehi A, Haas D, Pipkin S, Whooley MA. Depression and medication adherence in outpatients with coronary heart disease:findings from the Heart and Soul Study. Arch Intern Med. 2005;165:2508-2513.

5. Sin NL, Kumar AD, Gehi AK, Whooley MA. Direction of Association Between Depressive Symptoms and Lifestyle Behaviors in Patients with Coronary Heart Disease:the Heart and Soul Study. Ann Behav Med. 2016;50:523-532.

6. Meijer A, Conradi HJ, Bos EH, et al. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events:a meta-analysis of 25 years of research. Gen Hosp Psychiatry. 2011;33:203-216.

7. Carney RM, Blumenthal JA, Freedland KE, et al. Depression and late mortality after myocardial infarction in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study. Psychosom Med. 2004;66:466-474.

8. Valgimigli M, Garcia-Garcia HM, Vrijens B, et al. Standardized classification and framework for reporting, interpreting, and analysing medication non-adherence in cardiovascular clinical trials:a consensus report from the Non-adherence Academic Research Consortium (NARC) [published correction appears in Eur Heart J. 2019;40:2774]. Eur Heart J. 2019;40:2070-2085.

9. Ghaffari Darab M, Hedayati A, Khorasani E, Bayati M, Keshavarz K. Selective serotonin reuptake inhibitors in major depression disorder treatment:an umbrella review on systematic reviews. Int J Psychiatry Clin Pract. 2020;24:357-370.

10. Bandelow B. Current and Novel Psychopharmacological Drugs for Anxiety Disorders. Adv Exp Med Biol. 2020;1191:347-365.

11. Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355-366.

12. Abdelmalik N, RuhéHG, Barwari K, et al. Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism. J Thromb Haemost. 2008;6:2168-2174.

13. De Abajo FJ. Effects of selective serotonin reuptake inhibitors on platelet function:mechanisms, clinical outcomes and implications for use in elderly patients. Drugs Aging. 2011;28:345-367.

14. Hougardy DM, Egberts TC, van der Graaf F, Brenninkmeijer VJ, Derijks LJ. Serotonin transporter polymorphism and bleeding time during SSRI therapy. Br J Clin Pharmacol. 2008;65:761-766.

15. Yuan Y, Tsoi K, Hunt RH. Selective serotonin reuptake inhibitors and risk of upper GI bleeding:confusion or confounding?Am J Med. 2006;119:719-727.

16. Valgimigli M, Costa F, Lokhnygina et al. Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome:lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial. Eur. Heart J. 2017;38:804-810.

17. Mehran R, Pocock SJ, Stone GW, et al. Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes:a risk model from the ACUITY trial. Eur Heart J. 2009;30:1457-1466.

18. Mehran R, Pocock SJ, Nikolsky E, et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol. 2010;55:2556-2566.

19. Costa F, van Klaveren D, James S, et al. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score:a pooled analysis of individual-patient datasets from clinical trials. Lancet. 2017;389:1025-1034.

20. Kang DO, An H, Park GU, et al. Cardiovascular and Bleeding Risks Associated With Nonsteroidal Anti-Inflammatory Drugs After Myocardial Infarction. J Am Coll Cardiol. 2020;76:518-529.

21. Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction. CMAJ. 2011;183:1835-1843.

22. Iasella CJ, Kreider MS, Huang L, Coons JC, Stevenson JM. Effect of Selective Serotonin Reuptake Inhibitors on Cardiovascular Outcomes After Percutaneous Coronary Intervention:A Retrospective Cohort Study. Clin Drug Investig. 2019;39:543-551.

23. Bykov K, Schneeweiss S, Donneyong MM, Dong YH, Choudhry NK, Gagne JJ. Impact of an Interaction Between Clopidogrel and Selective Serotonin Reuptake Inhibitors. Am J Cardiol. 2017;119:651-657.

24. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS:The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39:213-260.

25. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials:a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123:2736-2747.

26. Austin PC. An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. Multivariate Behav Res. 2011;46:399-424.

27. Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Stürmer T. Variable selection for propensity score models. Am J Epidemiol. 2006;163:1149-1156.

28. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28:3083-3107.

29. Fernandes N, Prada L, Rosa MM, et al. The impact of SSRIs on mortality and cardiovascular events in patients with coronary artery disease and depression:systematic review and meta-analysis. Clin Res Cardiol. 2021;110:183-193.

30. Zhang WY, Nan N, Song XT, Tian JF, Yang XY. Impact of depression on clinical outcomes following percutaneous coronary intervention:a systematic review and meta-analysis. BMJ Open. 2019;9:e026445.

31. Price MJ, Tantry US, Gurbel PA. The influence of CYP2C19 polymorphisms on the pharmacokinetics, pharmacodynamics, and clinical effectiveness of P2Y(12) inhibitors. Rev Cardiovasc Med. 2011;12:1-12.

32. Patel A, Goodman SG, Tan M, et al. Contemporary use of guideline-based higher potency P2Y12 receptor inhibitor therapy in patients with moderate-to-high risk non-ST-segment elevation myocardial infarction:Results from the Canadian ACS reflective II cross-sectional study. Clin Cardiol. 2021;44:839-847.

33. De Luca L, Zeymer U, Claeys MJ, et al. Comparison of P2Y12 receptor inhibitors in patients with ST-elevation myocardial infarction in clinical practice:a propensity score analysis of five contemporary European registries. Eur Heart J Cardiovasc Pharmacother. 2021;7:94-103.

34. Costa F, Garcia-Ruiz V, Licordari R, Fimiani L. The High Bleeding Risk Patient with Coronary Artery Disease. Cardiol Clin. 2020;38:481-490.

35. Quinn GR, Singer DE, Chang Y, et al. Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. Am J Cardiol. 2014;114:583-586.

36. Schelleman H, Brensinger CM, Bilker WB, Hennessy S. Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study [published correction appears in PLoS One. 2015;10:e0121926]. PLoS One. 2011;6:e21447.

37. Quinn GR, Hellkamp AS, Hankey GJ, et al. Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation:An Analysis From the ROCKET AF Trial. J Am Heart Assoc. 2018;7(15):e00∳.

38. Sansone RA, Sansone LA. Warfarin and Antidepressants:Happiness without Hemorrhaging. Psychiatry (Edgmont). 2009;6:24-29.

39. Costa F, Valgimigli M, Steg PG, et al. Antithrombotic therapy according to baseline bleeding risk in patients with atrial fibrillation undergoing percutaneous coronary intervention:applying the PRECISE-DAPT score in RE-DUAL PCI [published online ahead of print, 2020 Dec 1]. Eur Heart J Cardiovasc Pharmacother. 2020;pvaa135.

* Corresponding author: Servicio de Cardiología, Hospital Universitario Reina Sofía, Av. Menéndez Pidal s/n, 14004 Córdoba, Spain.

E-mail address: soledad.ojeda18@gmail.com (S. Ojeda).

ABSTRACT

Introduction and objectives: Coronary lesions with stent overlapping are associated with higher neointimal proliferation that leads to more restenosis. Furthermore, the tapering of coronary arteries is a major challenge when treating long coronary lesions. This study attempted to assess the safety and clinical level of performance of long nontapered sirolimus-eluting coronary stent systems (> 36 mm) to treat long and diffused de novo coronary lesions in real-world scenarios.

Methods: This was a prospective, non-randomized, multicentre study that included 696 consecutive patients treated with the long nontapered BioMime sirolimus-eluting coronary stent system in long and diffused de novo coronary lesions. The safety endpoint was major adverse cardiovascular events defined as a composite of cardiac death, myocardial infarction, clinically driven target lesion revascularization, stent thrombosis, and major bleeding at the 12-month follow-up.

Results: Of a total of 696 patients, 38.79% were diabetic. The mean age of all the patients was 64.6 ± 14 years, and 80% were males. The indication for revascularization was acute coronary syndrome in 63.1%. A total of 899 lesions were identified out of which 742 were successfully treated with long BioMime stents (37 mm, 40 mm, 44 mm, and 48 mm). The cumulative incidence of major adverse cardiovascular events was 8.1% at the 12-month follow-up including cardiac death (2.09%), myocardial infarction (1.34%), and total stent thrombosis (0.5%).

Conclusions: This study confirms the safety and good performance of long nontapered BioMime coronary stents to treat de novo coronary stenosis. Therefore, it can be considered a safe and effective treatment for long and diffused de novo coronary lesions in the routine clinical practice.

Keywords: Coronary angioplasty. Drug-eluting stent. Nontapered stents.

RESUMEN

Introducción y objetivos: Las lesiones coronarias largas y difusas, cuando se tratan percutáneamente, requieren a menudo superposición de los stents, que se asocia a una mayor tasa de reestenosis. Por otro lado, el adelgazamiento progresivo de las arterias dificulta el tratamiento de las lesiones largas. En este estudio se analizan la seguridad y la eficacia clínica de los stents liberadores de sirolimus largos no cónicos (> 36 mm) para el tratamiento de lesiones largas de novo en un escenario real.

Métodos: Estudio prospectivo, no aleatorizado, multicéntrico, con 696 pacientes consecutivos con implantación de stent BioMime largo no cónico para el tratamiento de lesiones coronarias de novo largas y difusas. El criterio de valoración de seguridad fueron los eventos adversos cardiovasculares mayores en el seguimiento, definidos como la combinación de muerte cardiaca, infarto de miocardio, necesidad de nueva revascularización en la misma lesión guiada por la clínica, trombosis del stent o hemorragia mayor a los 12 meses.

Resultados: De los 696 pacientes incluidos, el 38,79% eran diabéticos. La edad media fue de 64,6 ± 14 años y el 80% eran varones. La indicación de revascularización fue un síndrome coronario agudo en el 63,1%. Se identificaron 899 lesiones, de las que 742 se trataron con éxito con stents BioMime (37-40-44-48 mm). La incidencia acumulada de eventos adversos cardiovasculares mayores fue del 8,1% a los 12 meses, con un 2,09% de muertes de causa cardiaca, un 1,34% de infartos de miocardio y un 0,5% de trombosis del stent.

Conclusiones: El presente estudio confirma la seguridad y el buen perfil clínico a 12 meses del stent BioMime largo no cónico para el tratamiento de lesiones coronarias de novo largas y difusas, por lo que debe considerarse un tratamiento seguro y eficaz para este tipo de lesiones en la práctica clínica habitual.

Palabras clave: Angioplastia coronaria. Stents farmacoactivos. Stents largos no cónicos.

Abbreviations CAD: coronary artery disease. DES: drug-eluting stent. MACE: major adverse cardiovascular events. PCI: percutaneous coronary intervention. SES: sirolimus-eluting stent. ST: stent thrombosis.

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

Patients N = 696
Patients, demographics
 Age, years 64.6 ± 14
 Male 556 (80.1)
Baseline past medical history
 Diabetes mellitus 271 (38.79)
 Hypertension 466 (66.80)
 Dyslipidemia 452 (64.80)
 Active smoker 180 (26.44)
 Previous CABG 57 (8.54)
 Previous PCI 223 (32.07)
 Vascular peripheral disease 69 (10.64)
 Previous MI 181 (25.63)
Cardiac status at the index procedure
 Stable angina 254 (36.49)
 Unstable angina 29 (4.16)
 STEMI 227 (32.61)
 NSTEMI 186 (26.72)
Left ventricular ejection fraction < 30% 181 (26)

CABG, coronary artery bypass graft; NSTEMI, non-ST-elevation acute myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.

Data are expressed as no. (%) or mean ± standard deviation.


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

Patients N = 696
Total no. of lesions treated with the BioMime Morph SES system 742
Total no. of lesions treated with other stents 157
BioMime target lesion location
Left anterior descending coronary artery
 Proximal LAD 146 (21.40)
 Mid LAD 216 (30.80)
 Distal LAD 28 (4.50)
 Diagonal 11 (1.60)
Right coronary artery
 Proximal RCA 174 (25.10)
 Mid RCA 257 (36.80)
 Distal RCA 97 (14.10)
Left circumflex artery
 Proximal LCX 56 (8.20)
 Mid LCX 90 (12.90)
 Distal LCX 28 (4.10)
Left main coronary artery 26 (3.80)
Diseased vessel 1.84 ± 0.78

LAD, left anterior descending coronary artery; LCX, left circumflex artery; RCA, right coronary artery; SES, sirolimus-eluting stent.

Data are expressed as no. (%).


Table 3. BioMime sirolimus-eluting stent system characteristics

Stent lenght (mm)
 37 100
 40 189
 44 128
 48 325
 Average stent length (mm) 43.80
Stent diameter (mm)
 2.25 42
 2.5 153
 2.75 84
 3 263
 3.5 185
 4 13
 4.5 2
Maximum pressure
 Predilatation 298 (86)
 Postdilatation 376 (54)
 Maximum pressure 14.6 ± 3.2
Average stent diamenter used (mm) 3.1

Data are expressed as no. (%).


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

% of patients MACE
Follow-up
 1 month 682 (97.99) 13 (2.2)
 6 to 9 months 675 (97.27) 44 (6.57)
 12 months 668 (96.12) 53 (8.1)
MACE
 Bleeding at 1-M 20 (0.29)
 Death at 1-M 41 (0.59)
 MI at 1-M 41 (0.59)
 Bleeding at 12-M 5 (0.75)
 Death at 12-M 13 (2.09)
 MI at 12-M 9 (1.34)
 Total ST at 12-M 3 (0.50)

MACE, major adverse cardiovascular events; M, month; MI, myocardial infarction; ST, stent thrombosis.

Data are expressed as no. (%).


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

  • Gerard Marti Aguasca. Hospital Universitario Vall d’Hebron, Servicio de Cardiología.

  • Vicenç Serra García. Hospital Universitario Vall d’Hebron, Servi- cio de Cardiología.

  • Bernat Serra Creus. Hospital Universitario Vall d’Hebron, Ser- vicio de Cardiología.

  • Neus Bellera Gotarda. Hospital Universitario Vall d’Hebron, Servi- cio de Cardiología.

  • Jorge Salgado Fernández. Complejo Hospitalario Universitario A Coruña, Servicio de Cardiología.

  • Montserrat Gracida Blancas. Hospital Universitari de Bellvitge, Servicio de Cardiología.

  • Lara Fuentes Castillo. Hospital Universitari de Bellvitge, Servicio de Cardiología.

  • Eduard Fernández-Nofrerias, Hospital Germans Trias i Pujol, Servicio de Cardiología.

  • Oriol Rodríguez-Leor. Hospital Germans Trias i Pujol, Servicio de Cardiología.

  • Omar Abdul Jawad Altisent. Hospital Germans Trias i Pujol, Servicio de Cardiología.

  • Gabriel Galache. Hospital Universitario Miguel Servet, Servicio de Cardiología.

  • Rosario Hortas. Hospital Universitario Miguel Servet, Servicio de Cardiología.

  • Eduard Bosch. Parc Taulí Hospital Universitari, Servicio de Cardiología.

  • Daniel Valcarcel. Parc Taulí Hospital Universitari, Servicio de Cardiología.

  • Maite Alfageme. HUA – Txagorritxu, Servicio de Cardiología.

  • Merche Sanz. HUA – Txagorritxu, Servicio de Cardiología.

  • Melisa Santás Álvarez. Hospital Lucus Augusti, Servicio de Cardiología.

  • Diego López Otero. Hospital Clínico Universitario de Santiago – CHUS, Servicio de Cardiología.

  • Juan Carlos Sanmartin Pena. Hospital Clínico Universitario de Santiago -CHUS, Servicio de Cardiología.

  • Ana Belén Cid Álvarez. Hospital Clínico Universitario de Santiago -CHUS, Servicio de Cardiología.

REFERENCES

1. Tan CK, Tin ZL, Arshad MKM, et al. Treatment with 48-mm everolimus eluting stents:Procedural safety and 12-month patient outcome. Herz. 2019;44:419-424.

2. Roach MR, MacLean NF. The importance of taper proximal and distal to Y-bifurcations in arteries. Front Med Biol Eng. 1993;5:127-133.

3. Zubaid M, Buller C, Mancini GB. Normal angiographic tapering of the coronary arteries. Can J Cardiol. 2002;18:973-980.

4. Sgueglia GA, Belloni F, Summaria F, et al. One-year follow-up of patients treated with new-generation polymer-based 38 mm everolimus-eluting stent:the P38 study. Catheter Cardiovasc Interv. 2015;85:218-224.

5. Timmins LH, Meyer CA, Moreno MR, Moore JE, Jr. Mechanical modeling of stents deployed in tapered arteries. Ann Biomed Eng. 2008;36:2042-2050.

6. Ellis SG, Holmes DR. Strategic approaches in coronary intervention. 2006:Lippincott Williams &Wilkins. P. 299-304.

7. Raber L, Juni P, Loffel L, et al. Impact of stent overlap on angiographic and long-term clinical outcome in patients undergoing drug-eluting stent implantation. J Am Coll Cardiol. 2010;55:1178-1188.

8. Mendis S, Thygesen K, Kuulasmaa K, et al. World Health Organization definition of myocardial infarction:2008- 09 revision. Int J Epidemiol. 2011;40:139-146.

9. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials:a case for standardized definitions. Circulation. 2007;115:2344-2351.

10. Banka VS, Baker HA, 3rd, Vemuri DN, Voci G, Maniet AR. Effectiveness of decremental diameter balloon catheters (tapered balloon). Am J Cardiol. 1992;69:188-193.

11. Kitahara H, Okada K, Kimura T, et al. Impact of stent size selection on acute and long-term outcomes after drug-eluting stent implantation in de novo coronary lesions. Circ Cardiovasc Interv. 2017;10:e004795.

12. Sinha SK, Mahrotra A, Abhishekh NK, et al. Acute stent loss and its retrieval of a long, tapering morph stent in a tortuous, calcified lesion. Cardiol Res. 2018;9:63-67.

13. Zivelonghi C, van Kuijk JP, Nijenhuis V, et al. First report of the use of long-tapered sirolimus-eluting coronary stent for the treatment of chronic total occlusions with the hybrid algorithm. Catheter Cardiovasc Interv. 201;5:1-9.

14. Matchin YG, Atanesyan RV, Kononets EN, Danilov NM, Bubnov DS, Ageev FT. The first experience of using very long stents covered with sirolimus (4060 mm) in the treatment of patients with extensive and diffuse lesions of the coronary arteries. Kardiologiia. 2017;57:19-26.

15. Timmins LH, Meyer CA, Moreno MR, Moore Jr. JE. Mechanical modeling of stents deployed in tapered arteries. Ann Biomed Eng. 2008;36:2042-2050.

16. Xiang Shen, Yong-Quan Deng, Song Ji, Zhong-Min Xie. Flexibility behavior of coronary stents:the role of linker investigated with numerical simulation. J Mech Med Biol. 2017. https://doi.org/10.1142/S0219519417501123.

17. Mushahwar SS, Pyatt JR, Lowe R, Morrison WL, Perry RA, Ramsdale DA. Clinical outcomes of long coronary stents:a single-center experience. Int J Cardiovasc Intervent. 2001;4:29-33.

18. Sim HW, Thong EH, Loh PH, et al. Treating very long coronary artery lesions in the contemporary drug-eluting-stent era:single long 48 mm stent versus two overlapping stents showed comparable clinical results. Cardiovasc Revasc Med. 2020;21:1115-1118.

19. Peter Jüni RL, Löffel L, Wandel S, et al. Impact of Stent Overlap on Angiographic and Long-Term Clinical Outcome in Patients Undergoing Drug-Eluting Stent Implantation. J Am Coll Cardiol. 2010;55:1178–1188.

20. Lagache M, Coppel R, Finet G, et al. Impact of Malapposed and Overlapping Stents on Hemodynamics:A 2D Parametric Computational Fluid Dynamics Study. Mathematics. 2021;9:795.

21. Jurado-Román A, Abellán-Huerta J, Antonio Requena J, et al. Comparison of Clinical Outcomes Between Very Long Stents and Overlapping Stents for the Treatment of Diffuse Coronary Disease in Real Clinical Practice. Cardiovasc Revasc Med. 2019;20:681-686.

22. Patted SV, Jain RK, Jiwani PA, et al. Clinical Outcomes of Novel Long-Tapered Sirolimus Eluting Coronary Stent System in Real-World Patients With Long Diffused De Novo Coronary Lesions. Cardiol Res. 2018;9:350-357.

* Corresponding author: Unitat de Hemodinàmica, Hospital Universitari Vall d’Hebron, Passeig de la Vall d’Hebron 119-129, 08035 Barcelona, Spain.

E-mail address: edrcg@hotmail.com (E. Domingo Ribas).

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ABSTRACT

Introduction and objectives: Coronary artery aneurysms are a complex situation. Our main objective is to describe the frequency of use of covered stents (grafts) for their management, as well as to characterize their long-term results compared to drug-eluting stents.

Methods: Ambispective observational study with data from the International Coronary Artery Aneurysm Registry (CAAR) (NCT-02563626). Only patients who received a stent-graft or a drug-eluting stent where the aneurysm occurred were selected.

Results: A total of 17 patients received, at least, 1 stent-graft while 196 received 1 drug-eluting in the aneurysmal vessel. Male predominance, a higher rate of dyslipidemia, a past medical history of coronary artery disease, previously revascularized coronary artery disease, and giant aneurysms were reported in the stent-graft cohort. The independent predictive variables of the composite endpoint of all-cause mortality, heart failure, unstable angina, reinfarction, stroke, systemic embolism, bleeding or any aneurysmal complications at the median follow-up of 38 months were suggestive of the existence of connective tissue diseases (HR, 5.94; 95%CI, 1.82-19.37), left ventricular dysfunction ≤ 55% (HR, 1.84; 95%CI, 1.09-3.1), and an acute indication for heart catheterization (HR, 2.98; 95%CI, 1.39-6.3). The use of stent-grafts was not associated with the occurrence of more composite endpoints (23.5% vs 29.6%; P = .598).

Conclusions: The use of stent-grafts to treat coronary aneurysms is feasible and safe in the long-term. Randomized clinical trials are needed to decide what the best treatment is for these complex lesions.

Keywords: Coronary aneurysm. Registry. Stent. Stent graft. Angioplasty.

RESUMEN

Introducción y objetivos: Los aneurismas coronarios son una situación compleja. Planteamos como objetivo principal describir la frecuencia de utilización de stents recubiertos (grafts) para su tratamiento y caracterizar sus resultados a largo plazo en comparación con stents farmacoactivos.

Métodos: Estudio observacional ambispectivo, con información procedente del Registro Internacional de Aneurismas Coronarios (CAAR) (NCT-02563626). Se seleccionaron los pacientes que recibieron un stent-graft o un stent farmacoactivo en la zona del aneurisma.

Resultados: Un total de 17 pacientes recibieron al menos un stent-graft y 196 un stent farmacoactivo en la zona aneurismática. Se observa un predominio del sexo masculino y una mayor frecuencia de dislipemia, antecedentes de coronariopatía, enfermedad coronaria revascularizada previamente y aneurismas gigantes en la cohorte de stent-graft. Como variables independientes predictoras del desarrollo del evento combinado (muerte por cualquier causa, insuficiencia cardiaca, angina inestable, reinfarto, ictus, embolia sistémica, sangrado o cualquier complicación en el aneurisma), tras una mediana de seguimiento de 38 meses, destacaron la existencia de conectivopatías (hazard ratio [HR] = 5,94; intervalo de confianza del 95% [IC95%], 1,82-19,37), la disfunción del ventrículo izquierdo ≤ 55% (HR = 1,84; IC95%, 1,09-3,1) y la indicación aguda del cateterismo índice (HR = 2,98; IC95%, 1,39-6,3). El uso de stent-grafts comparado con el de stents farmacoactivos no se asoció al desarrollo de más eventos combinados (23,5 frente a 29,6%; p = 0,598).

Conclusiones: El uso de stents recubiertos en aneurismas coronarios es factible y seguro a largo plazo. Se necesitan estudios clínicos aleatorizados para decidir el mejor tratamiento de este tipo de lesiones complejas.

Palabras clave: Aneurismas coronarios. Registro. Resultados. Stent. Stent-graft. Angioplastia.

Abbreviations LVEF: Left ventricular ejection fraction.

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

Patients Stent-graft (N = 17) Drug-eluting stent (N = 196) P
Clinical characteristics
Age, years 61.47 ± 13.8 63.84 ± 12.8 .467
Sex, male 16 (94.1) 146 (74.5) .069
Arterial hypertension 11 (64.7) 142 (72.4) .496
Dyslipidemia 15 (88.2) 119 (60.7) .024
Diabetes 3 (17.6) 58 (29.6) .296
Smoking habit .218
 Active smoker 10 (58.8) 82 (41.8)
 Former smoker 3 (17.6) 25 (12.8)
Family history of coronary arteriopathy 7 (41.2) 14 (7.1) < .001
Kidney disease (CrCl < 30) 1 (5.9) 14 (7.1) .846
Peripheral vasculopathy 1 (5.9) 18 (9.2) .647
Aortopathy – aneurysms 1 (5.9) 6 (3.1) .531
Atrial fibrillation 1 (5.9) 7 (3.6) .631
Connective tissue disease 0 3 (1.5) .607
LVEF 56.8 ± 6.1 55.6 ± 11.4 .657
Previous revascularization 8 (47.0) 41 (20.9) .014
Angiographic characteristics
Right dominance 14 (82.4) 166 (84.7) .641
Serious coronary stenoses 15 (88.2) .132
 1 vessel disease 4 (23.5) 62 (31.6)
 2-vessel disease 6 (35.3) 68 (34.7)
 3-vessel disease 5 (29.4) 62 (31.6)
Location of the aneurysma
 Left main coronary artery 0 3 (1.5) .607
 LAD 7 (41.2) 125 (63.8) .066
 LCX 4 (23.5) 49 (25) .893
 RCA 6 (35.3) 53 (27.0) .466
Type of aneurysmb .450
 Fusiform 5 (29.4) 85 (43.8)
 Saccular 12 (70.6) 107 (55.2)
Giant aneurysm 3 (17,6) 5 (2,6) .02
Number of aneurysms per patient .940
 1 15 (88.2) 155 (79.1.2)
 2 2 (6.3) 30 (15.3)
 3 0 6 (3.1)
 4 or more 0 5 (2.5)
Indication for catheterization, acute 11 (64.7) 144 (73.5) .436
Indication for catheterization .179
 STEACS 6 (35.3) 49 (25.0)
 NSTEACS 4 (23.5) 91 (46.4)
 Heart failure 1 (5.9) 2 (1)
 Stable angina 6 (35.3) 32 (16.3)
 Other 0 22 (11.2)
Type of stent
 Aneugraft 4 (23.5)
 Jostent-graftmaster 11 (64.7)
 Papyrus 1 (5.9)
 Undetermined stent-graft 1 (5.9)
  ABSORB 2 (1.0)
  ACTIVE 28 (14.3)
  BIOFREEDOM 1 (0.5)
  BIOMATRIX 4 (2.0)
  COMBO 2 (1.0)
  COROFLEX 1 (0.5)
  CRE8 8 (4.1)
  CYPHER 3 (1.5)
  GENOUS 1 (0.5)
  JANUS 2 (1.0)
  NO ESPECIF 8 (4.1)
  ONYX 1 (0.5)
  ORSIRO 3 (1.5)
  PROMUS 20 (10.2)
  RESOLUTE 23 (11.7)
  STENTYS 6 (3.1)
  SYNERGY 12 (6.1)
  XIENCE 47 (24.0)
  TAXUS 22 (11.2)
  YUKON 2 (1.0)
Size of the stent-graft, medians
 Diameter 3.5 (3.5-4.0) 3.5 (3.0-3.75) .336
 Length 18.0 (16.0-26.0) 20.0 (15.0-28.0) .014
Intracoronary imaging modalities
 IVUS 5 (29.4) 19 (9.7) .014
 OCT 1 (5.9) 7 (3.6) .631
 Any or both 6 (35.3) 26 (13.3) .015
Follow-up
Median follow-up, months 29.9 (2.33-51.54) 46.95 (11.92-76.75) .093
Dual antiplatelet therapy at discharge 17 (100) 193 (99.5) .767
Duration of dual antiplatelet therapy, median 12.0 (11.0-12.0) 12 (12.0-12.0) .372
Oral anticoagulation/new indication 2/0 9/0
Adverse events
 Heart failure 0 3 (1.5) .607
 Unstable angina 2 (11.8) 20 (10.2) .839
 Reinfarction 1 (5.9) 16 (8.2) .739
 Clinically relevant bleeding 1 (5.9) 8 (4.1) .723
 Embolism 0 1 (0.5) .768
 Stroke 0 2 (1) .676
 Dead 0 20 (10.2) .166
 All of the above or complicated aneurysm (MACE) 4 (23.5) 58 (29.6) .598
Coronary angiography at the follow-up 8 (47.0) 61 (31.1) .187
 Control 3 (17.6) 16 (8.2)
 Stable angina 3 (17.6) 6 (3.1)
 NSTEACS 2 (11.8) 25 (12.8)
 STEACS 0 6 (3.1)
 Other 0 8 (4.0)
Aneurysmal complications on the angiographyc
 Growth 0 7 (11.5) .312
 New aneurysms 0 3 (4.9) .521
 Thrombosis 0 6 (9.8) .353
 In-stent restenosis 1 (12.5) 0 .005

Cr, creatinine; IVUS, intravascular ultrasound; LAD, left anterior descending coronary artery; LCX, left circumflex artery; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular events; NSTEACS, non-ST-segment elevation acute coronary syndrome; OCT, optical coherence tomography; RCA, right coronary artery; STEACS, ST-segment elevation acute coronary syndrome. Data are expressed as no. (%) or mean ± standard deviation.

a There are more aneurysms than patients because the same patient can have several aneurysms.

b Aneurysm was categorized as mixed (fusiform and saccular) in 2 patients.

c Statistics is performed on a lower N, only in those with a coronary angiography at the follow-up.


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-upa

Patients Without events (N = 151) Some MACE (N = 62) P
Clinical characteristics
Age, years 62.99 ± 12.37 65.29 ± 13.93 .234
Sex, make 115 (76.2) 47 (75.8) .956
Arterial hypertension 107 (70.9) 456 (74.2) .623
Dyslipidemia 93 (61.6) 41 (66.1) .533
Diabetes 39 (25.8) 22 (35.5) .157
Smoking habit .808
 Active smoker 64 (42.4) 28 (30.4)
 Former smoker 19 (12.6) 9 (14.5)
Family history of coronary arteriopathy 17 (11.3) 4 (6.5) .285
Kidney disease (CrCl < 30) 8 (5.3) 7 (11.3) .120
Peripheral vasculopathy 9 (6.0) 10 (16.1) .018
Aortopathy – aneurysms 3 (2.0) 4 (6.5) .097
Atrial fibrillation 5 (3.3) 3 (4.8) .594
Connective tissue disease 0 3 (4.8) .006
LVEF 56.62 ± 9.74 53.67 ± 13.44 .080
Previous revascularization 36 (23.8) 13 (21.0) .651
Angiographic characteristics
Right dominance 127 (84.1) 53 (85.5) .237
Serious coronary stenoses 147 (97.4) 60 (96.8) .817
 1 vessel disease 47 (31.1) 19 (30.6)
 2-vessel disease 52 (34.4) 22 (35.5)
 3-vessel disease 48 (31.8) 19 (30.6)
Location of the aneurysmb .429
 Left main coronary artery 3 (2.0) 0
 LAD 88 (58.3) 44 (71)
 LCX 41 (27.2) 12 (19.4)
 RCA 41 (27.2) 18 (29.0)
Type of aneurysmc .676
 Fusiform 62 (41.1) 28 (45.2)
 Saccular 86 (57.0) 33 (53.2)
Giant aneurysm 4 (2.6) 4 (6.5) .185
Number of aneurysms per patient
 1 122 (80.8) 48 (77.4)
 2 20 (13.2) 12 (19.4)
 3 6 (4.0) 0
 4 or more 3 (2.0) 2 (3.2)
Indication for catheterization, acute 101 (66.9) 54 (87.1) .002
Indication for catheterization .053
 STEACS 38 (25.1) 17 (27.4)
 NSTEACS 61 (40.4) 34 (54.8)
 Heart failure 2 (1.3) 1 (1.6)
 Stable angina 33 (21.8) 5 (8.1)
 Other 17 (11.2) 5 (8.1)
Type of stent .598
 Stent-graft 13 (8.6) 4 (6.5)
 Drug-eluting stent 138 (91.4) 58 (93.5)
Size of the stent-graft, medians
 Diameter 3.38 (3.0-4.0) 3.28 (3.0-3.5) .521
 Length 22.00 (15.0-28.0) 21.74 (15.0-25.0) .843
Intracoronary imaging modalities
 IVUS 17 (11.3) 7 (11.3) .995
 OCT 8 (5.3) 0 .065
Median follow-up, months 34.0 (12.0-76.0) 46.93 (18.75-79.75) .646

CD: coronaria derecha; CX: circunfleja; Cr: creatinina; DA: descendente anterior; FEVI: fracción de eyección del ventrículo izquierdo; IVUS: ecocardiografía intravascular; MACE: eventos adversos cardiovasculares mayores; OCT: tomografía de coherencia óptica; SCACEST: síndrome coronario agudo con elevación del segmento ST; SCASEST: síndrome coronario agudo sin elevación del segmento ST. Los datos se expresan como n (%) o media ± desviación estándar.

a Se consideró como MACE el combinado de muerte de cualquier causa, ingreso por insuficiencia cardiaca, angina inestable, reinfarto, ictus, embolia sistémica, sangrado que precisó atención médica o cualquier complicación del aneurisma (crecimiento, nuevo aneurisma, reestenosis o trombosis).

b Hay más aneurismas que pacientes, porque cada enfermo puede presentar varios.

c En varios pacientes (3 y 1, respectivamente) el aneurisma fue considerado mixto.


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.

WHAT IS KNOWN ABOUT THE TOPIC?

  • Coronary aneurysms are a complex entity whose incidence rate is between 0.3 and 12% in the different series already published.
  • Treatment, like the presentation and the clinical profile, is varied. However, revascularization is often required.
  • In this sense, over the last few years, some of the alternatives available propose the use of stent-grafts for the exclusion of coronary aneurysms.

WHAT DOES THIS STUDY ADD?

  • The main goal of this paper was to describe the frequency of use of this type of stents to treat coronary aneurysms and then characterize its long-term results.
  • From a total of 829 patients with coronary aneurysms treated with some type of percutaneous revascularization, data on the use of stent-grafts and drug-eluting stents was collected in 17 and 196 patients, respectively.
  • It seems obvious that patients treated with stent-grafts for the management of coronary aneurysms have a high ischemic load, often complex anatomies, and even more often giant aneurysms.
  • The use of stent-grafts for the management of coronary aneurysms is feasible and safe in the long-term. However, randomized clinical trials are still needed to decide what the best therapy is for this type of complex coronary lesions.
  • SUPPLEMENTARY DATA


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    REFERENCES

    1. Bourgon A. Biblioth Med. 1812;37:183. Citado por Scott DH. Aneurysm of the coronary arteries. Am Heart J. 1948;36:403-421.

    2. Packard M, Wechsler H. Aneurysms of coronary arteries. Arch Intern Med. 1929;43:1-14.

    3. Swaye PS, Fisher LD, Litwin P, et al. Aneurysmal coronary artery disease. Circulation. 1983;67:134-138.

    4. Cohen P, O'Gara PT. Coronary artery aneurysms:a review of the natural history, pathophysiology, and management. Cardiol Rev. 2008;16:301-304.

    5. Núñez-Gil IJ, Cerrato E, Bollati M, et al. Coronary artery aneurysms, insights from the international coronary artery aneurysm registry (CAAR). Int J Cardiol. 2020;299:49-55.

    6. Núñez-Gil IJ, Terol B, Feltes G, et al. Coronary aneurysms in the acute patient:Incidence, characterization and long-term management results. Cardiovasc Revasc Med. 2018;19(5 Pt B):589-596.

    7. Kawsara A, Núñez Gil IJ, Alqahtani F, Moreland J, Rihal CS, Alkhouli M. Management of Coronary Artery Aneurysms. JACC Cardiovasc Interv. 2018;11:1211-1223.

    8. Will M, Kwok CS, Nagaraja V, et al. Outcomes of patients who undergo elective covered stent treatment for coronary artery aneurysms. Cardiovasc Revasc Med. 2021:S1553-8389(21)00264-5.

    9. Núñez-Gil IJ, Alberca PM, Gonzalo N, Nombela-Franco L, Salinas P, Fernández-Ortiz A. Giant coronary aneurysm culprit of an acute coronary syndrome. Rev Port Cardiol (Engl Ed). 2018;37:203.e1-203.e5.

    10. Cha JJ, Kook H, Hong SJ, et al. Successful Long-term Patency of a Complicated Coronary Aneurysm at a Prior Coronary Branch Stent Treated with a Stent-graft and Dedicated Bifurcation Stent. Korean Circ J. 2021;51:551-553.

    11. Khubber S, Chana R, Meenakshisundaram C, et al. Coronary artery aneurysms:outcomes following medical, percutaneous interventional and surgical management. Open Heart. 2021;8:e001440.

    12. Arbas-Redondo E, Jurado-Román A, Jiménez-Valero S, Galeote-García G, Gonzálvez-García A, Moreno-Gómez R. Acquired coronary aneurysm after stent implantation at a bifurcation excluded with a Papyrus covered stent subsequently fenestrated. Cardiovasc Interv Ther. 2022;37:215-216.

    13. Della Rosa F, Molina-Martin de Nicolas J, Bonfils L, Fajadet J. Symptomatic giant coronary artery aneurysm treated with covered stents. Coron Artery Dis. 2020;31:658-659.

    14. Tehrani S, Faircloth M, Chua TP, Rathore S. Percutaneous coronary intervention in coronary artery aneurysms;technical aspects. Report of case series and literature review. Cardiovasc Revasc Med. 2021;28S:243-248.

    15. Jurado-Román A, Rodríguez O, Amat I, et al. Clinical outcomes after implantation of polyurethane-covered cobalt-chromium stents. Insights from the Papyrus-Spain registry. Cardiovasc Revasc Med. 2021;29:22-28.

    16. Núñez-Gil IJ, Nombela-Franco L, Bagur R, et al. Rationale and design of a multicenter, international and collaborative Coronary Artery Aneurysm Registry (CAAR). Clin Cardiol. 2017;40:580-585.

    17. Jiang X, Zhou P, Wen C, et al. Coronary Anomalies in 11,267 Southwest Chinese Patients Determined by Angiography. Biomed Res Int. 2021;2021:6693784.

    18. D'Ascenzo F, Saglietto A, Ramakrishna H, et al. Usefulness of oral anticoagulation in patients with coronary aneurysms:Insights from the CAAR registry. Catheter Cardiovasc Interv. 2021;98(5):864-871.

    * Corresponding author: Cardiovascular Institute. Hospital Clínico San Carlos. Avda. Profesor Martín Lagos S/N. 28040 Madrid, Spain

    E-mail address: ibnsky@yahoo.es (I.J. Núñez-Gil).

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