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

Palabras clave: Oclusión total crónica Realidad virtual Ansiedad

INTRODUCTION

Chronic total coronary occlusions (CTO) are diagnosed in up to 15% of patients with coronary artery disease undergoing coronary angiography.1 Percutaneous coronary interventions (PCI) of CTOs are one of the greatest challenges we face in interventional cardiology due to the complexity of these procedures and the increased risk of complications.2 Over the past few decades, advances in techniques and devices have made it possible to obtain better results while reducing the associated complications.3-5 Anxiety and pain during these procedures are often treated with oral benzodiazepines plus opioids or IV benzodiazepines upon request during the procedure. The possibility of performing these procedures without anesthesia or sedation avoids the risks associated with these therapies. On the contrary, it submits the patient to pain and anxiety during the procedure. Several factors such as long procedures, patient immobility (especially in biradial access), and monotonous and hostile environments (operating rooms or cath labs) influence patient anxiety. Virtual reality (VR) has been successfully used in several clinical settings such as transcatheter aortic valve implantation6 or atrial fibrillation ablation7 to reduce intraoperative anxiety. There is no evidence on the use of VR reducing perioperative patient anxiety during PCI, specifically in CTO PCI. Compared to standard PCI, this procedure could benefit even further from VR due to its longer duration, use of double arterial access, and possibility of triggering ischemia and chest pain.

The objective of this study is to determine whether the use of a VR system in PCIs on CTOs decreases the level of anxiety and pain during CTO procedures compared to conventional management.

METHODS

Overall study design

The Decreasing patient anxiety during revascularization of chronic total coronary occlusions using virtual reality glasses (ReViCTO) trial (ClinicalTrials.gov Identifier: NCT05458999) was designed as a randomized, controlled, open-label, superiority clinical trial with 2 parallel arms (procedural use of VR goggles vs conventional management) with a primary endpoint of maximum level of anxiety perceived by the patient measured through the visual analogue scale of anxiety (VASA).

The study will be conducted in full compliance with the principles set forth in the Declaration of Helsinki (1996) and the International Conference on Harmonization Good Clinical Practice Guideline. The study protocol was approved by the Clinical Research Ethics Committee (CREC) of Hospital Clínico Universitario de Valencia, Spain. All patients signed an informed consent form. The study is registered at clinicaltrials.gov (NCT05458999). The World Health Organization minimum standard list of items for clinical trials are listed in table 1 of the supplementary data. This protocol follows the SPIRIT 2013 Statement: Defining Standard Protocol Items for Clinical Trials.8

Study setting and eligibility criteria

The trial will be conducted at Hospital Clínico Universitario de Valencia, Spain, a reference teaching hospital on interventional cardiology that treats nearly 800 000 patients both from rural and metropolitan areas. Since this is a preliminary study it is designed as a single-center trial. All procedures will be performed by a team of 2 interventional cardiologists experienced in CTO revascularization. Patient enrolment started back in December 2021. On Dec. 25^th 2022, 25 patients had already been enrolled in the study (43% of the target population). Patients with visual impairment, dementia, language barriers or any situations that would prevent the use of VR glasses will be excluded. Inclusion and exclusion criteria are listed in table 1. All patients must meet all the inclusion criteria and none of the exclusion criteria.

 

Table 1. Inclusion and exclusion criteria

Inclusion criteria

Age > 18 years

Elective percutaneous coronary intervention on chronic total coronary occlusion

Physical and mental ability to wear virtual reality glasses

Exclusion criteria

Unable to or unwilling to give informed consent

Visual impairment

Dementia

Language barrier (unable to communicate fluently in Spanish or English)

Any other situations that would prevent the use of virtual reality glasses

 

Assignment of interventions

Each patient will be randomized on a 1:1 ratio to the intervention (use of VR goggles during the CTO procedure) or the control arm (routine clinical practice). Given the small sample size estimated, permuted block randomization was used to guarantee an equal number of participants per arm.9 Random sequence was computer generated using blocks with a size unknown to the investigators until the end of recruitment. Patient enrolment and arm assignment will be performed by the investigators. Allocation concealment will be ensured using a web application that assigns a unique identification number and the assigned arm once the patient has been recruited for the trial. This system prevents changes to the identification number or arm deleting patients after randomization. Because of the nature of the trial no masking or blinding will be applied at any level.

Participant timeline

Since there is no follow-up, this study has a very simple timeline. Upon arrival to the cath lab, all patients scheduled for elective CTO PCI will be screened and checked to see if they meet all the inclusion criteria and none of the exclusion criteria. If they don’t meet these criteria, they will be considered a screening failure and will not participate in the study. If all criteria are met by the patients, the investigators will need to obtain their written informed consent right before patients arrive at the cath lab. The functioning of the trial will be explained orally and reading of the informed consent will be offered allowing enough time, if necessary. Patients will be randomized to wear VR goggles or to the control arm. During the PCI, all measures regarding anxiety will be applied regardless of the allocation arm. Also, all drug therapies administered will be registered by the study nurse. After the procedure, the patient’s perceived anxiety and pain will be assessed by the study nurse, this being the end of the trial for the patient (figure 1).

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Figure 1. Central illustration. Trial flowchart.

 

Data collection

Demographics, the past medical history, preoperative (indication for revascularization, blood tests, left ventricular ejection fraction…), and perioperative variables [arterial access, radiation dose, maximum level of anxiety (VASA), and visual analogue scale of pain (VASP) perceived by the patient measured through visual analogue scale, nausea, and dizziness during the procedure] will be collected (table 2 of the supplementary data).

Clinical variables will be collected from the local and regional electronic clinical data system and asked directly to the patient when lacking. Blood test results will be collected from the local laboratory system using the last available determination. Echocardiographic and magnetic resonance imaging data will be collected from the local electronic clinical data system. The Seattle Angina Questionnaire, VASA, VASP, the presence of nausea or dizziness, overall satisfaction with the procedure, and overall satisfaction will be assessed by the study nurse and included in a dedicated form (table 3 of the supplementary data). All these data will be transferred to a dedicated database in 1 single local computer. This database is designed with range check for numerical variables to prevent erroneous data entry. Also, the database will check for duplicates when entering the hospital identification number. All data will be stored in a database kept in a dedicated computer with no Internet connection to avoid unwanted leaks or stole information. The investigators will have access to this database only.

Trial intervention

Eligible patients will be randomized to the intervention (VR goggles) or the control arm (routine clinical practice).

Virtual reality goggles

A commercial Oculus Quest 2 VR goggle system (Meta Platforms, Inc., United States) will be used. The viewing consisted of using the capabilities of the VR goggles to recreate a 2D playback that simulates the size of a large-format movie screen. Using Netflix video streaming system (Netflix Inc. United States), the documentary series “Our Planet” [Silverback Films, United Kingdom]10 will be played for all patients starting with chapter 1, and sequentially and automatically playing the following chapters. Before the procedure, the patient will be informed on the VR goggle system-based operation, possible side effects (nausea or dizziness), and the possibility to remove it at any time. Before the arterial puncture, the VR goggle system will be put on and checked for proper functioning. It will be removed before removing arterial introducers, when the patient wishes to do so or if serious complications occur. During the procedure, the patient’s general condition will be checked every 30 min.

The system will be prepared following these steps: 1) drawing the security perimeter with the controller; 2) starting the Netflix application; 3) selecting the “Void Theater” option; 4) searching for the documentary series “Our Planet” and playing the first episode; 5) adjusting the screen size with the controller; 6) selecting travel mode; 7) putting the VR goggles on the patient (figure 2); 8) asking the patient if he can watch and hear correctly. If not, the VR goggles should be repositioned.

Figure 2. Real patient wearing virtual reality goggles during a chronic total coronary occlusion revascularization procedure using double radial artery access.

 

Control arm

The comparator chosen is the current clinical practice with no VR goggles. A possible comparator using a VR goggle with no content was discarded because of the high chances of claustrophobia or mental discomfort.

Both arms will receive drugs upon request to reduce perceived pain and anxiety. In both arms, anxiolytic drugs (morphine chloride or midazolam at 1 mg boluses) will be administered by the circulating nurse if the patient explicitly expresses the need for such treatment or if external signs of anxiety or pain (agitation, complaints...) are observed. The last decision on treatment administration will be left to the lead operator. The remaining actions for the management of pre- and perioperative anxiety will be identical in both arms. Preoperative anxiolytic treatment was not routinely administered to all patients, only upon the patient’s request.

Endpoints

The primary endpoint will be to assess changes to the maximum level of anxiety perceived by the patient during the procedure. Secondary endpoints will be to assess a) changes to the maximum level of pain perceived by the patient during the procedure; b) differences in the need for intraoperative anxiolytic drug therapy or doses of anxiolytic drugs (midazolam or morphine chloride) administered during the procedure; and c) the overall satisfaction experienced with the VR goggles.

Both the primary (anxiety) and secondary endpoints of pain will be measured through the VASA11 and pain (VASP)12 that go from 1 to 10. Both VASA and VASP will be collected by a specialized nurse right after the end of the procedure before leaving the room through a specific survey on the maximum level of anxiety or pain perceived during the procedure (table 3 of the supplementary data).

The VAS will be used to quantify the patients’ responses objectively. The VAS eliminates the examiner influence or bias that often comes with verbal questioning and is a more appealing method of evaluation for participants. Although this method is not perfect, it remains a common way to assess anxiety and pain.13,14 The patient will also be asked if he’d like VR to be used in other similar settings. Total doses of benzodiazepines (midazolam) or opioids (morphine) administered during the procedure will be registered in total milligrams.

Sample size estimate

The sample size was estimated based on the primary endpoint. In former studies that assessed anxiety during catheterization the standard deviation of VASA was 2.715,16 (σ). VASA > 2 (μ₁ – μ₂) was descriptive of clinically significant differences. To detect differences ≥ 2 in VASA assuming a normal distribution, alpha and beta risks of 0.05 (α) and 0.2 (β) in bilateral contrast in a sample size of 58 patients (29 in each arm) were estimated.

Statistical analysis

Quantitative variables will be expressed as mean ± standard deviation when they follow a normal distribution and as median [interquartile range] if they don’t. Qualitative ones will be expressed as percentages (absolute value). Fisher’s exact test or the chi-square test will be used to compare qualitative variables. Also, the Student t test or the Mann-Whitney U test will be used if quantitative variables don’t follow a normal distribution.

The primary endpoint (VASA), VASP, and dosage of drugs will be compared in both arms using the Student t test. The use or non-use of drugs during the procedure, the presence or absence of dizziness or nausea will be compared using Fisher’s exact test or the chi-square test. Subgroup analyses will be performed based on sex, age, and previous experience with new technologies.

All statistical tests will be bilateral and considered significant if P < .05. Statistical analyses will be performed with R Core Team (2020) statistical software package (R Foundation for Statistical Computing, Austria).

DISCUSSION

CTOs are present in up to 20% of the patients with coronary artery disease. These numbers increase parallel to age (up to 40% in diabetics or patients with heart failure).17,18 In the past, most of these patients were referred for revascularization surgery due to poorly successful PCIs in this kind of lesions. Over the past few decades, several advances have been made regarding devices and technical materials, organization, and concentration of complex procedures in reference centers. Also, increased operator experience has led to a high success rate of 90%, and a very low rate of severe complications19,20 with the corresponding increase in the number indications for PCI CTO.

Although PCIs are a common and relatively low risk procedure, many patients undergoing these treatments experience anxiety (up to 37% in some populations).21-23 Anxiety involves feelings of fear, tension or panic or the prospect that something unpleasant is about to happen. State anxiety may be more clinically relevant for patients undergoing PCI because it is transient in nature and amenable to clinical procedures. Patients undergoing PCI have multiple sources of anxiety including their own concerns. These concerns can include fear of discomfort, uncertainty, and fear associated with survival that can be more distressing than chest pain itself.24

PCI CTO creates more anxiety for the patients compared to other interventional procedures for several reasons. In the first place, double access with high-calibre sheaths is frequently used, even biradial. Repeated access punctures with consequently an increased pain and limited patient mobility contributes to more discomfort and higher anxiety levels. Secondly, the duration of the procedure is long, and can be up to 3 to 4 hours or more in some special scenarios. Being exposed to immobility in a monotone and hostile scenario for such a long time is a reasonable cause for anxiety. Thirdly, cath labs are often strange environments for the patient with machinery and equipment that may be frightening for him at first. Furthermore, discussion with the treating team, the use of terms unfamiliar to the patient or the existence of beeps and alarms can make the patient think that something bad might happen to him, thus increasing the levels of anxiety. Fourthly, patients undergoing elective PCI CTO usually undergo, at best, at least, 1 invasive coronary angiography, and commonly up to several coronary interventions including failed CTO revascularization attempts. Previous procedures could be remembered as painful or stressful and anticipation anxiety could appear. Stress and anxiety associated with needle-related procedures may lead to needle phobia,25 which could also contribute to a high level of anxiety. Fifthly, chest pain is an important factor of procedural anxiety during CTO PCI, and it occurs in a large number of patients. For example, with retrograde approaches, the flow of collateral branches on which the CTO-related myocardial territory is completely dependent is interrupted due to their occupation by the guidewire or microcatheter, thus causing ischemia and pain). Therefore, there is a potential high anxiety level in patients undergoing CTO PCI that depends on multiple factors and mechanisms that feed from one another.

At the end of the 20th century, it was noted that both behavioral and pharmaceutical interventions should be used to manage pain during medical procedures.26 Distraction techniques may be effective reducing the patients’ pain during various invasive procedures because pain involves both physical stimuli and emotional responses. Studies have shown that various distraction techniques like music, massage, breathing exercises, and behavioral therapy can effectively reduce the feeling of pain and stress symptoms during painful procedures.27,28

VR is a computer-generated simulation of the physical world that allows people to experience it in a realistic way. VR goggles achieve visual and auditory semi-isolation that, together with the images projected, evade the patient while act on environmental and emotional factors of anxiety. VR has proven superior to other distraction methods such as television, listening to music or playing games.29,30 VR has been used to relieve anxiety and pain in patients undergoing several kinds of procedures as needle-related interventions,31 burn wound debridement,32,33 physical therapy,34 dental procedures,35 colonoscopy,36 minor surgical procedures,37 nasal endoscopy38 or chemotherapy.39 A total of 4 randomized clinical trials have been conducted to study the level of anxiety experienced by adults undergoing different medical procedures like hysteroscopy,40 labor,41 and colonoscopy.42 The studies used various measurement tools such as the VAS scale from 0 to 10, the 5-point Likert scale 0-5, and the State-Trait Anxiety Inventor.

Experiences with VR in interventional cardiology during procedures are scarce. Back In 2020, Bruno et al.6 used a randomized clinical trial to prove the that the use of a VR-based system was safe and feasible during TAVI and that VAS score was reduced by 3 points with the use of VR without impacting nausea or vomiting. Almost all patients said they would use this technology in a similar setting. It is remarkable that this study population was an old population (mean age, 83 years) without previous experience with VR and limited experience with new technologies. This shows that even in a population not used to new technologies that could be expected to reject or not tolerate VR goggles, its use was tolerated and effective. Moreover, this study found that it was important not only that patients accepted the new technology, but also that interventional cardiologists approved it. At first, their reaction went from full support to slight rejection. Those who hesitated to use this new approach thought that their interaction with the patient during the procedure might be limited. However, over time, when they saw that this was not the case, acceptance increased. Similarly, Roxburgh et al.7 tested the utility of VR in patients undergoing atrial fibrillation ablation in an observational study of 48 patients. They showed that VR reduced perceived pain during the procedure and that VR can be easily incorporated into the standard procedure workflow. As far as we know, no studies have ever been conducted on the use of VR during PCI CTO.

Most studies on VR technology have been observational and not standardized, which complicates comparing results and drawing solid conclusions. Additionally, currently, no guidelines or consensus have ever been published on how to incorporate VR technology to cardiac procedures.43 To address these challenges, an expert taskforce from the international scientific community may be useful to identify evidence gaps, set priorities, standardize research protocols, and create guidelines to implement VR technology in heart procedures.

Limitations

Some limitations should be taken in account in this clinical trial. First, the open-label nature of the trial could lead to bias favorable to the RV group due to the lack of blinding and potential for patients and investigators to influence the outcomes. The entire staff will be warned on this possible bias and advised to prevent it before each procedure. Second, some uncontrolled confounding factors may play a role in the differences seen in the administration of drug therapy between RV and the control groups. We will try to prevent or, at least, mitigate this treatment only if the patient explicitly wishes to do so or if outward signs of anxiety or pain are observed. Third, the results of this trial should be interpreted and applied with caution to other scenarios due to the single-center nature of this trial. Fourth, the primary and secondary endpoints of anxiolytic treatment needed could be closely correlated. Our objective is to determine whether the use of VR goggles decreases anxiety. However, it could happen that both groups have similar levels of anxiety and a greater need for anxiolytic treatment (which is a surrogate of increased anxiety, on the one hand, that could also expose patients to a higher risk of adverse effects, on the other). The choice of the primary and secondary endpoints of anxiety and need for anxiolytic treatment allows us to explore this possibility. Finally, the drug therapy of anxiety was not protocolized but left to the operator’s discretion.

CONCLUSIONS

The ReViCTO trial is the first randomized clinical trial ever designed to evaluate the use of VR during CTO PCI. Results will show the utility of this technology reducing anxiety and pain in PCI CTO.

FUNDING

None whatsoever.

AUTHORS’ CONTRIBUTIONS

A. Fernández-Cisnal, and G. Miñana: study idea or design, data curation, analysis, and interpretation, drafting, and final approval of the version submitted for publication. B. Silla, J.M. Ramón, E. Valero, and S. García-Blas: data curation, analysis, and interpretation, revision of the manuscript regarding significant intellectual content, and final approval of the version submitted for publication. J. Núñez, V. Bodí, and J. Sanchis: data analysis and interpretation, revision of the manuscript regarding significant intellectual content, and final approval of the version submitted for publication. A. Fernández-Cisnal, and G. Miñana agree to take full responsibility for all aspects of the manuscript, and investigate and resolve all questions regarding the accuracy and truthfulness of the study as a whole.

CONFLICTS OF INTEREST

J. Núñez received fees for participating in the advisory boards and educational activities from Astra Zeneca, Boehringer-Ingelheim, NovoNordisk, Bayer, and Novartis. J. Sanchis received speaker fees from Abbott Vascular, and Prosmedica. G. Miñana received speaker fees from Abbott Vascular, and Teleflex, and support for attending meetings from Medtronic and World Medical. The remaining authors declared no other conflicts of interest whatsoever.

REFERENCES

INTRODUCTION

Infarction Code networks are key to treat ST-segment elevation myocardial infarction (STEMI) in the shortest time possible while optimizing reperfusion therapy.1 In Spain we have 17 different public regional STEMI networks, 1 in each autonomous community (AC) for a total of 83 pPCI-capable hospitals in programs on a 24/7/365 basis.2 According to data from the Annual Activity Registry of the Interventional Cardiology Association of the Spanish Society of Cardiology (ACI-SEC), back in 2019, a total of 22 529 interventional procedures were performed in patients with infarction.3 Recently, an analysis of the ACI-SEC Infarction Code Registry revealed the characteristics of infarction care in Spain with 87.5%, 4.4%, and 8.1% of the patients with STEMI being treated with pPCI, fibrinolysis, and without reperfusion, respectively. The 30-day mortality rate of STEMI was 7.9% dropping down to 6.8% in patients treated with pPCI.4

The geographical differences and heterogeneity of the organizational infrastructure among the different Infarction Code programs available can lead to regional differences as a survey conducted among health professionals involved in these programs revealed recently.5 These organizational differences can have an impact on the management of patients with STEMI. Their analysis and AC-based comparison facilitates finding matters where there is room for improvement to optimize treatment.

This analysis compared the incidence rate, clinical characteristics, type and time to reperfusion, the characteristics of pPCI, and the 30-day mortality rate of 17 different regional programs of the Infarction Code in Spain.

METHODS

Study design

The Registry design has already been introduced4. In conclusion, this was a national, observational, and prospective study of 83 centers from 17 different regional STEMI networks. The patients’ recruitment period was 3 months—from April 1 through June 30, 2019—with a 30-day clinical follow-up.

Registry protocol was approved by the reference central ethics committee that did not deem the obtention of the informed consent necessary since data anonymity was guaranteed at any time.

Inclusion criteria

All consecutive patients who, during the study period, triggered the activation of different regional infarction care networks with a final diagnosis of STEMI and met the following criteria were included in the study: a) diagnosis of ST-segment elevation acute coronary syndrome with symptoms consistent with acute coronary syndrome, electrocardiogram showing ST-segment elevation or new-onset left bundle branch block or suspected posterior infarction of, at least, 24-hour evolution since symptom onset or b) recovered cardiac arrest with suspected coronary etiology or c) cardiogenic shock with suspected coronary etiology.

Definition and collection of variables

Clinical variables were registered in an online form and previously published.4 The definitions of the different time intervals since symptom onset until reperfusion were given based on the recommendations established by the European clinical practice guidelines on the management of STEMI.1 Subjective judgment from a local investigator was requested on the delay sustained by the patient since his first medical contact (existence of unjustified delay—yes/no—and reason why). To estimate the incidence rate (number of cases per million inhabitants) population data from the National Statistics Institute from 2019 were used.6 Regarding the mortality adjusted analysis, the following characteristics of the care network were defined: the individual responsible for the first medical contact (emergency medical services, health center, non-pPCI-capable hospital, pPCI-capable hospital), time to reperfusion, and location where critical care was administered (intensive care unit or cardiac surgery intensive care unit).

Statistical analysis

Continuous variables were expressed as mean ± standard deviation. The categorical ones were expressed as frequencies and percentages. Inter-group comparisons of baseline variables were conducted using the chi-square test or the Student t test, when appropriate. Times to reperfusion were expressed as median and interquartile range and compared using the Mann-Whitney U test.

Poisson regression coefficient was used to estimate the 30-day mortality rate of each AC including patient-dependent factors (the confounding factors included were age, sex, hypertension, diabetes, dyslipidemia, smoking, previous ischemic heart disease, Killip classification, and anterior location of STEMI), and the healthcare network involved (location of the first medical contact, time between the onset of pain and reperfusion, and location where critically ill patients were treated).

The variable AC was introduced in the model in a second step, and a test of ratio of verisimilitude was performed to verify its statistical significance. When the AC variable was added, adjusted associations were obtained between AC and mortality. The Poisson regression coefficients became incidence rates using the marginal effect function. The estimated 30-day mortality rate for each AC was obtained from a mean distribution of confounding factors, which facilitated comparing mortality rate across the different AC. This method had been previously used in the acute myocardial infarction setting.7-9 Since there could be a selection bias across the different AC in patients without reperfusion therapy, these were not included in the adjusted mortality analysis.

P values < .05 were considered statistically significant. The STATA statistical software package version 15 SE (Stata Corp, College Station, United States) was used.

RESULTS

Patients

The registry included a total of 5401 patients, 4366 (81.2%) of whom had a final diagnosis of STEMI. The 888 patients (16.4%) with a diagnosis different from STEMI and the 147 (2.7%) without a final diagnosis were excluded from the analysis. Figure 1 shows the flow of patients and the AC-based distribution. Figure 2 shows the number of patients treated across the different AC plus the final diagnosis achieved adjusted by million inhabitants.6 Table 1 shows the clinical characteristics of patients with STEMI across the different AC.

Figure 1. Flow of patients and distribution across the different autonomous communities (AC) based on participant centers, number of codes activated, and number of patients with ST-segment elevation myocardial infarction (STEMI) as final diagnosis.

Figure 2. Patients treated across the different autonomous communities (AC) adjusted for million inhabitants. AC were arranged from largest to smallest number of patients treated per million inhabitants. Regarding the population estimate per million inhabitants, population data from the National Statistics Institute were used.⁶ STEMI, ST-segment elevation myocardial infarction.

Table 1. Clinical characteristics of patients with ST-segment elevation myocardial infarction treated in the Infarction Code networks per autonomous community

	Age, years	Sex, women	AHT	Diabetes	Dyslipidemia	Active smoking	Previous IHD	Previous PCI	Previous stroke	Early Killip I	Early Killip IV	Anterior location
Andalusia	63 ± 13	110/563 (19.5)	297/560 (53.0)	159/558 (28.5)	252/559 (45.1)	264/557 (47.4)	60/561 (10.7)	59/559 (10.6)	31/556 (5.6)	423/541 (78.2)	31/541 (5.7)	223/521 (42.8)
Aragon	65 ± 14	30/127 (23.6)	62/127 (48.8)	28/125 (22.4)	56/127 (44.1)	59/124 (47.6)	13/124 (10.5)	17/126 (13.5)	7/122 (5.7)	99/124 (79.8)	13/124 (10.5)	56/120 (46.7)
Principality of Asturias	66 ± 13	40/124 (32.3)	61/124 (49.2)	34/122 (27.9)	54/124 (43.6)	41/123 (33.3)	20/123 (16.3)	19/123 (15.4)	7/123 (5.6)	96/123 (78.1)	11/123 (8.9)	57/122 (46.7)
Balearic Islands	63 ± 12	28/97 (28.9)	44/94 (46.8)	21/94 (22.3)	49/93 (52.7)	49/93 (52.7)	14/93 (15.1)	14/94 (14.9)	4/92 (4.4)	71/96 (74.0)	5/96 (5.2)	30/92 (32.6)
Canary Islands	60 ± 12	40/178 (22.5)	99/178 (55.6)	52/178 (29.2)	102/177 (57.6)	93/178 (52.3)	22/178 (12.4)	18/178 (10.1)	8/176 (4.6)	146/168 (86.9)	14/168 (8.3)	65/163 (39.9)
Cantabria	62 ± 13	15/59 (25.4)	31/59 (52.5)	21/58 (36.2)	27/58 (46.6)	31/57 (54.4)	10/58 (17.2)	10/59 (17.0)	3/57 (5.3)	46/56 (83.9)	2/56 (3.6)	25/58 (43.1)
Castile and Leon	64 ± 13	56/296 (18.9)	146/293 (49.8)	73/291 (25.1)	126/292 (43.2)	117/292 (40.1)	31/293 (10.6)	31/294 (10.5)	12/176 (4.1)	236/287 (82.2)	17/287 (5.9)	138/280 (49.3)
Castile-La Mancha	64 ± 13	26/197 (13.2)	108/194 (55.7)	58/192 (30.2)	99/196 (50.5)	92/193 (47.7)	19/192 (9.9)	18/194 (9.3)	9/194 (4.6)	157/196 (80.1)	12/196 (6.1)	89/194 (45.9)
Catalonia	63 ± 13	195/854 (22.8)	393/854 (46.0)	198/854 (23.2)	340/854 (39.8)	354/854 (41.4)	60/854 (7.0)	62/854 (7.3)	30/854 (3.5)	683/826 (82.7)	67/826 (8.1)	351/767 (45.8)
Extremadura	63 ± 13	18/127 (14.2)	74/127 (58.3)	26/126 (20.6)	52/126 (41.3)	48/127 (37.8)	17/126 (13.5)	14/126 (11.1)	4/127 (3.2)	91/122 (74.6)	11/122 (9.0)	56/121 (46.3)
Galicia	63 ± 13	63/264 (23.9)	130/262 (49.6)	48/259 (18.5)	138/261 (52.9)	100/215 (46.5)	18/261 (6.9)	25/262 (9.5)	12/263 (4.6)	195/251 (77.7)	31/251 (12.4)	103/233 (44.2)
La Rioja	59 ± 12	8/34 (23.5)	14/34 (41.2)	3/34 (8.8)	16/34 (46.1)	20/34 (58.8)	1/34 (3.0)	2/34 (5.9)	0/34 (0)	30/34 (88.2)	3/34 (8.8)	11/34 (32.4)
Community of Madrid	63 ± 13	105/436 (24.1)	212/432 (49.1)	88/430 (20.5)	208/431 (48.3)	177/428 (41.4)	41/429 (9.6)	43/429 (10.0)	11/429 (2.6)	347/424 (81.8)	35/424 (8.3)	174/419 (41.5)
Region of Murcia	64 ± 13	43/238 (18.1)	127/237 (53.6)	71/237 (30.0)	100/237 (42.4)	110/237 (46.4)	41/237 (17.3)	24/151 (15.9)	3/151 (2.0)	196/237 (82.7)	18/237 (7.6)	101/231 (43.7)
Chartered Community of Navarre	65 ± 14	14/45 (31.1)	18/44 (40.9)	9/45 (20.0)	29/45 (64.4)	16/45 (35.6)	3/45 (6.7)	4/44 (9.1)	3/45 (6.7)	31/43 (72.1)	4/43 (9.3)	16/44 (36.4)
Basque Country	64 ± 14	52/200 (26.0)	101/197 (51.3)	39/197 (19.8)	101/198 (51.0)	89/197 (45.2)	26/195 (13.3)	32/196 (16.3)	11/193 (5.7)	169/200 (84.5)	12/200 (6.0)	83/199 (41.7)
Valencian Community	63 ± 13	119/526 (22.6)	293/519 (56.5)	163/514 (31.7)	212/514 (41.3)	235/514 (45.7)	56/515 (10.9)	53/511 (10.4)	21/513 (4.1)	445/520 (85.6)	34/520 (6.5)	217/503 (43.1)
P	.054	.003	.038	< .0001	< .0001	.007	< .0001	.011	.61	.016	.25	.44
Total	63 ± 13	962/4365 (22.0)	2210/4335 (51.0)	1091/4314 (25.3)	1961/4326 (45.3)	1895/4268 (44.4)	452/4318 (10.5)	445/4234 (10.5)	176/4222 (4.2)	3462/4248 (81.5)	320/4248 (7.5)	1795/4101 (43.8)
AHT, arterial hypertension; IHD, ischemic heart disease; PCI, percutaneous coronary intervention. Data are expressed as no. (%) or mean ± standard deviation.

 

Reperfusion therapy used in patients with ST-segment elevation myocardial infarction

Out of the 4366 patients with STEMI, 3792 (86.9%) received pPCI, 189 (4.3%) fibrinolysis, and 353 (8.1%) no reperfusion therapy whatsoever. No reperfusion therapy was reported in 32 patients (0.7%). Figure 3 shows treatment distribution based on AC. Table 2 shows, across different AC and patients treated with cardiac catheterization, the angiographic findings and characteristics of interventional therapy had this procedure been performed.

Figure 3. Distribution of reperfusion therapy in patients with ST-segment elevation myocardial infarction by autonomous communities. pPCI, primary percutaneous coronary intervention.

Table 2. Angiographic findings and characteristics of interventional procedures in patients with ST-segment elevation myocardial infarction treated with cardiac catheterization per autonomous community

	Radial access	No. of diseased vessels	Early TIMI grade-0/1 flow	Final TIMI grade-3 flow	Need for hemodynamic support	Thrombus aspiration in IRA	BMS implantation in IRA	DES implantation in IRA	pPCI	Bailout PCI	Elective PCI after fibrinolysis	Coronary angiography without PCI
Andalusia	456/534 (85.4)	1.49 ± 0.69	416/535 (77.8)	502/536 (93.7)	15/563 (2.7)	76/563 (13.5)	48/563 (8.5)	456/563 (81.0)	471/557 (84.6)	36/557 (6.5)	27/557 (4.9)	23/557 (4.1)
Aragon	111/122 (91.0)	1.62 ± 0.78	90/120 (75.0)	114/122 (93.4)	5/127 (3.9)	41/127 (32.3)	0/127 (0)	103/127 (81.1)	108/124 (87.1)	6/124 (4.8)	1/124 (0.8)	9/124 (7.3)
Principality of Asturias	99/121 (81.8)	1.54 ± 0.77	106/121 (87.6)	111/121 (91.7)	5/124 (4.0)	39/124 (31.5)	10/124 (8.1)	98/124 (79.0)	118/123 (95.9)	0/123 (0)	0/123 (0)	5/123 (4.1)
Balearic Islands	79/92 (85.9)	1.46 ± 0.67	67/92 (72.8)	85/92 (92.4)	0/124 (0)	27/97 (27.8)	4/97 (4.1)	80/97 (82.5)	89/96 (92.7)	4/96 (4.2)	0/96 (0)	3/96 (3.1)
Canary Islands	138/169 (81.7)	1.54 ± 0.76	131/170 (77.1)	155/169 (91.7)	6/179 (3.6)	29/179 (16.2)	3/179 (1.7)	150/179 (83.8)	145/176 (82.4)	6/176 (3.4)	15/176 (8.5)	10/176 (5.7)
Cantabria	17/56 (30.4)	1.50 ± 0.68	51/57 (89.5)	55/56 (98.2)	1/59 (1.7)	31/59 (52.5)	0/59 (0)	51/59 (86.4)	57/59 (96.6)	0/59 (0)	1/59 (1.7)	1/59 (1.7)
Castile and Leon	263/281 (93.6)	1.55 ± 0.74	192/241 (79.7)	225/247 (91.1)	15/296 (5.1)	27/296 (9.1)	9/296 (3.0)	249/296 (84.1)	255/291 (96.6)	12/291 (4.1)	16/291 (5.5)	8/291 (2.8)
Castile-La Mancha	164/191 (85.9)	1.68 ± 0.73	164/192 (85.4)	186/190 (97.9)	9/197 (4.6)	75/197 (38.1)	10/197 (5.1)	172/197 (97.3)	185/196 (94.4)	2/196 (1.0)	4/196 (2.0)	5/196 (2.6)
Catalonia	727/781 (93.1)	1.48 ± 0.70	594/844 (70.4)	787/827 (95.2)	ND	259/854 (30.3)	117/854 (13.7)	653/854 (76.5)	807/849 (95.1)	8/849 (0.9)	3/849 (0.4)	31/849 (3.7)
Extremadura	119/121 (98.4)	1.65 ± 0.79	104/122 (85.3)	104/122 (85.3)	6/127 (4.7)	18/127 (14.2)	12/127 (11.0)	98/127 (77.2)	112/126 (88.9)	8/126 (6.4)	2/126 (1.6)	4/126 (3.2)
Galicia	228/242 (94.2)	1.53 ± 0.84	182/229 (79.5)	214/229 (93.5)	20/264 (7.6)	77/264 (29.2)	4/264 (1.5)	215/264 (81.4)	246/264 (93.2)	0/264 (0)	0/264 (0)	18/264 (6.8)
La Rioja	29/34 (85.3)	1.15 ± 0.36	30/34 (88.2)	31/34 (91.2)	0/24 (0)	10/34 (29.4)	3/34 (8.8)	27/34 (79.4)	33/34 (97.1)	0/34 (0)	0/34 (0)	1/34 (2.9)
Community of Madrid	395/421 (93.8)	1.48 ± 0.69	329/402 (81.8)	392/425 (92.2)	23/436 (5.3)	80/436 (18.4)	15/436 (3.4)	352/436 (80.5)	421/434 (97.0)	3/434 (0.7)	0/434 (0)	10/434 (2.3)
Region of Murcia	213/237 (89.9)	1.48 ± 0.64	175/234 (74.8)	223/236 (94.5)	4/238 (1.7)	56/238 (23.5)	5/238 (2.1)	209/238 (87.2)	226/238 (95.0)	7/238 (2.9)	0/238 (0)	5/238 (2.1)
Chartered Community of Navarre	31/36 (86.1)	2.00 ± 0.86	34/43 (79.1)	39/45 (86.7)	6/45 (13.3)	22/45 (48.9)	2/45 (4.4)	39/45 (86.7)	44/45 (97.8)	0/45 (0)	0/45 (0)	1/45 (2.2)
Basque Country	179/198 (90.4)	1.51 ± 0.67	153/198 (77.3)	191/199 (96.0)	7/200 (3.5)	100/200 (50.0)	3/200 (1.5)	174/200 (87.0)	194/199 (97.5)	4/199 (2.0)	1/199 (0.5)	0/199 (0)
Valencian Community	484/514 (94.2)	1.59 ± 0.76	390/496 (78.6)	461/497 (92.8)	8/256 (1.5)	145/526 (27.6)	34/526 (6.5)	423/526 (80.4)	482/518 (93.1)	10/518 (1.9)	4/518 (0.8)	22/518 (4.3)
P	< .0001	.84	< .0001	.002	< .0001	< .0001	< .0001	.004	< .0001
Total	3732/4150 (89.9)	1.50 ± 0.71	3208/4130 (77.7)	3875/4147 (93.4)	110/4366 (2.5)	1112/4366 (25.5)	281/4366 (6.4)	3548/4366 (81.3)	3992/4329 (92.2)	106/4329 (2.5)	74/4329 (1.7)	157/4329 (3.6)
BMS, bare metal stent; CL, cath lab; DES, drug-eluting stent; ECG, electrocardiogram; EMS, emergency medical services; FMC, first medical contact; IRA, infarct-related artery; PCI, percutaneous coronary intervention; pPCI, primary percutaneous coronary intervention. The type of procedure performed (pPCI, bailout angioplasty, elective PCI after fibrinolysis or coronary angiography without PCI) is on the total number of patients treated with coronary angiography, not on the total number of patients with ST-segment elevation myocardial infarction. Data are expressed as no. (%).

 

Time intervals between symptom onset and reperfusion in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention

Table 3 shows time intervals between symptom onset and reperfusion. Figure 4 shows the different time intervals analyzed for every AC with significant differences in all of them. Figure 5 summarizes the causes of unjustified delays between the first medical contact and reperfusion for every AC.

 

Table 3. Location of the first medical contact and time intervals between the first medical contact and reperfusion per autonomous community

	First EMS care	First care provided at the health center	First non-pPCI-capable center care	First pPCI-capable center care	Transfer without going to the CL right away*	Time of onset of pain to FMC	Time of FMC to ECG	Time of FMC to pPCI-capable center in transferred patients	Time from FMC to reperfusion	Time from onset of pain to reperfusion
Andalusia	206/537 (38.4)	138/537 (25.7)	93/537 (17.3)	100/537 (18.6)	188/427 (44.0)	60 [30-123]	5 [3-10]	80 [50-120]	113 [70-170]	195 [135-330]
Aragon	46/123 (37.4)	23/123 (18.7)	42/123 (34.1)	12/123 (9.8)	23/110 (20.9)	62.5 [18.5-170]	7 [4-12.5]	84.5 [45-145]	116.5 [70.5-177.5]	229 [126-345]
Principality of Asturias	32/123 (26.0)	18/123 (14.6)	36/123 (29.3)	37/123 (30.1)	4/86 (4.7)	80 [32-210]	10 [5-22]	85 [60-119]	108 [73-137]	215 [134.5-351]
Balearic Islands	33/95 (34.7)	26/95 (27.4)	27/95 (28.4)	9/95 (9.5)	3/85 (3.5)	70 [30-164]	6 [5-10]	100 [55-139]	124 [85-169]	197.5 [143.5-391]
Canary Islands	28/178 (15.7)	103/178 (57.9)	22/178 (12.4)	25/178 (14.0)	77/152 (50.7)	75 [37.5-150]	9 [5-15]	85 [55-133]	122 [95-172]	220 [159-385]
Cantabria	15/58 (25.9)	19/58 (32.8)	13/58 (22.4)	11/58 (19.0)	26/46 (56.5)	53 [25-145]	5 [4.5-10]	60 [35-93]	110 [81-188]	210 [134-303.5]
Castile and Leon	97/290 (33.5)	70/290 (27.2)	68/290 (23.5)	46/290 (15.9)	70/237 (29.5)	90 [35-221]	8 [4-15]	115 [70-165]	135 [85-197]	242.5 [163-432.5]
Castile-La Mancha	69/196 (35.2)	61/196 (31.1)	30/196 (17.3)	36/196 (18.4)	49/160 (30.6)	68 [30-160]	10 [5-15]	86.5 [58-114]	109 [80-155]	205 [150-322]
Catalonia	332/847 (39.2)	161/847 (19.0)	256/847 (30.2)	98/847 (11.6)	115/730 (15.8)	63 [30-160]	6 [3-14]	75 [55-105]	104 [80-138]	180 [127-288]
Extremadura	43/126 (34.1)	36/126 (28.6)	22/126 (17.5)	25/126 (19.8)	27/93 (29.0)	81.5 [44-135]	10 [5-12]	91.5 [60-143]	121 [90-178]	240 [160-360]
Galicia	84/264 (31.8)	111/264 (42.1)	28/264 (10.6)	41/264 (15.5)	ND	60 [26-179]	9 [5-19]	95 [70-140]	115 [88.5-163]	194 [134-353]
La Rioja	10/34 (29.4)	9/34 (26.5)	6/34 (17.7)	9/34 (26.5)	3/25 (12.0)	76.5 [35-110]	4.5 [1-10]	70 [46-86]	90.5 [67-114]	159.5 [118.5-212.5]
Community of Madrid	196/429 (45.7)	37/429 (8.6)	80/429 (18.7)	116/429 (27.0)	142/309 (45.6)	63 [35-140]	6 [3-12]	60 [42-85]	95 [75-130]	178.5 [135-257.5]
Region of Murcia	102/238 (42.9)	36/238 (15.1)	74/238 (31.1)	26/238 (10.9)	25/212 (11.8)	56.5 [24-131]	5 [5-10]	80 [60-120]	103 [79-160]	175 [130-305]
Chartered Community of Navarre	22/45 (48.9)	7/45 (15.6)	3/45 (6.7)	13/45 (28.9)	12/32 (37.5)	63.5 [29.5-124.5]	1 [0-5]	50 [35-91]	90 [69-140]	175 [128-262]
Basque Country	76/199 (38.2)	28/199 (14.1)	37/199 (18.6)	58/199 (29.2)	61/138 (44.2)	80 [32-184]	6.5 [3-11]	61 [49-77]	97 [75-135]	210 [134-345]
Valencian Community	128/521 (24.6)	146/521 (28.0)	128/521 (24.6)	119/521 (22.8)	98/398 (24.6)	82 [35-180]	5 [0-10]	94 [65-135]	120 [93-165]	220 [146-348]
P	< .0001	< .0001	< .0001	< .0001	< .001	.001	.0001	.0001	.0001	.0001
Total	1519/4303 (35.3)	1038/4303 (24.1)	965/4303 (22.4)	781/4303 (18.2)	923/3240 (28.5)	67 [30-165]	7 [4-15]	80 [55-120]	110 [80-154]	197 [135-330]
CL, cath lab; ECG, electrocardiogram; EMS, emergency medical services; FMC, first medical contact; pPCI, primary percutaneous coronary intervention. * Patients treated early in a non-pPCI-capable center requiring immediate transfer to a pPCI-capable center. Data are expressed as no. (%) or mean [interquartile range]. Times are expressed in minutes.

Figure 4. Time intervals between symptom onset and reperfusion in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention (pPCI) for every autonomous community. A: time in min from the onset of pain to the first medical contact. B: time in min from the first medical contact to the electrocardiogram (ECG). C: time in min from the first medical contact to reperfusion. D: time in min from the onset of pain to reperfusion. E: time in min from the first medical contact to the arrival at the pPCI-capable center in patients requiring transfer from a non-pPCI-capable center.

Figure 5. Causes of unjustified time delays between the first medical contact and reperfusion. Unjustified time delays did not imply, necessarily, that the time between the first medical contact and reperfusion was > 120 min. As a matter of fact, overall, in 53.2% of the cases the time between the first medical contact and reperfusion was < 120 min, and, among these, excessive time delays were reported in 21.5%. EMS, emergency medical services; pPCI, primary percutaneous coronary intervention.

 

Mortality analysis in patients with ST-segment elevation myocardial infarction

Table 4 includes unadjusted mortality data at hospital admission and 30 days, and mortality for the adjusted model.

 

Table 4. Mortality analysis in patients treated with primary percutaneous coronary intervention per autonomous community

	Unadjusted hospital mortality	Unadjusted 30-day mortality	Adjusted 30-day mortality
Andalusia	30/563 (5.3)	37/523 (7.1)	6.0 [5.3-6-7]
Aragon	8/127 (6.3)	8/124 (6.5)	5.5 [4.0-6.9]
Principality of Asturias	9/124 (7.3)	10/118 (8.5)	6.7 [5.4-8.0]
Balearic Islands	6/97 (6.2)	6/88 (6.8)	5.0 [3.3-6.7]
Canary Islands	15/179 (8.4)	15/155 (9.7)	7.0 [5.5-8.6]
Cantabria	0/59 (0)	0/59 (0)	0
Castile and Leon	18/296 (6.1)	23/270 (8.5)	8.4 [7.1-9.8]
Castile-La Mancha	9/197 (4.6)	10/191 (5.2)	3.1 [2.3-3.8]
Catalonia	29/854 (3.4)	58/801 (7.2)	6.0 [5.4-6.6]
Extremadura	12/127 (9.5)	16/125 (12.8)	8.1 [6.6-9.5]
Galicia	22/264 (8.3)	28/260 (10.8)	6.8 [5.6-7.9]
La Rioja	1/34 (2.9)	1/33 (3.0)	5.6 [2.3-8.9]
Community of Madrid	14/436 (3.2)	21/421 (5.0)	3.9 [3.3-4.6]
Region of Murcia	21/237 (8.9)	24/226 (10.6)	9.2 [8.0-10.5]
Chartered Community of Navarre	5/45 (11.1)	5/45 (11.1)	9.5 [6.7-12.3]
Basque Country	12/200 (6.0)	16/197 (8.1)	8.9 [7.4-10.4]
Valencian Community	47/526 (8.9)	55/499 (11.0)	10.2 [9.2-11.2]
P	< .001	< .001	.19
Total	258/4365 (5.9)	337/4166 (8.1)	–
Data are expressed as no. (%) or mean [interquartile range].

 

30-day mortality rate was different across different AC (P < .001). When the analysis was adjusted for patient-dependent factors and the healthcare network, mortality difference across the AC lost its statistical significance (P = .19).

DISCUSSION

This study is a comparative of how the different STEMI care programs work in Spain. Results show differences in the incidence rate, the patients’ clinical profile, revascularization therapy, the characteristics of the interventional procedure performed, infarction care times, and the 30-day unadjusted mortality rate. Although mortality differences reduce, they’re still significantly different after adjusting for the patients’ risk and clinical characteristics. Also, they disappear after adjusting for whoever is responsible for the first medical contact, time to reperfusion, and location where critical care is administered, all of them factors associated with the way each network is organized.

Both functioning and results of infarction care networks are highly influenced by different factors like geography, the number of capable centers, transfer times, the availability of the right resources, infrastructure, and the characteristics of each healthcare system.2 In Spain, the plan of each AC has been designed independently. Also, the services rendered by the different AC is not homogeneous since resource allocation by the different administrations of the 17 Spanish AC is decentralized2 in such a way that there are inequalities in the ways these networks are organized.2,5,10,11 A recent consensus document on the requirements and sustainability of pPCI programs in Spain proposed measures to homogenize and secure their sustainability.2,12 Our study data reinforce the need for taking measures like the proposals made in the said consensus document.

Differences in the patients’ clinical profile

Registry data demonstrated a difference in the number of codes activated per million inhabitants. Also, in the number of patients with STEMI per million inhabitants across the different AC. These differences are multifactorial and can be seen, historically, in the ACI-SEC annual activity registry reports.3 Some AC have older populations and more cardiovascular risk factors, which could account for the higher rate of infarction reported.6 However, the lack of a unified criterion on the indication for Infarction Code activation could also account for these differences seen.5

Differences in reperfusion therapy

pPCI is the treatment of choice for the management of STEMI.1 The geographical (populations far from pPCI-capable centers) and organizational characteristics (availability of medical service transport with ECG monitorization) across the different AC lead to a variable number of patients be treated with fibrinolysis. A previous analysis of data on the Codi Infart in Catalonia revealed that patients treated with fibrinolysis in non- pPCI-capable centers had worse disease progression compared to those transferred to pPCI-capable centers within the first 140 min after diagnosis.13

Different time delays to reperfusion

Patient-dependent time delays (from symptom onset to first medical contact) were highly variable. Although the geographic distribution of the population could partially account for these differences, public campaigns should be run to increase awareness on STEMI symptoms and the need for calling out-of-hospital emergency care.1

System-dependent time delays (from first medical contact to reperfusion) is much easier to change with organizational measures. Also, it determines prognosis.14 Time delays to reperfusion depend on whoever is involved in the first medical contact. Therefore, patients treated by emergency medical services—those with the shortest times—showed high variability across the different programs. Better access to these systems for the population would also improve time delays to reperfusion.15

European clinical practice guidelines on the management of STEMI describe quality indicators that should be observed by the infarction networks to reduce the time to reperfusion, among these, a single coordination centralized center, interpreting the ECG before arriving at the hospital to achieve diagnosis and activate the system early, the direct transfer of patients to the cath lab without ER or ICU admissions or the follow-up of infarction care times, among other.1 Our study demonstrated that not all programs meet these recommendations meaning that, in many cases, there is a huge room for improvement. For example, currently, it does not seem reasonable that a significant number of patients who need to be transferred to the pPCI (up to 50% in some cases) wouldn’t end up at the cath lab right away. This simple measure can reduce time to reperfusion in 20 min and have a direct impact on prognosis.16,17

The presence of unjustified delayed reperfusion times was highly variable across the different AC, as well as the causes for these delays, which is indicative of the characteristics of each AC.

Mortality differences

A study conducted by Cequier et al.18 analyzed standardized mortality based on the risk of patients with STEMI across different AC from 2003 through 2012 and detected significant differences. However, across this period, not all regions had implemented Infarction Code programs and the rate of pPCI was highly variable. Our study demonstrated that there are still differences in crude mortality that disappear after adjusting for the clinical variables and care network-related variables (location of first medical contact, delay to reperfusion, and management of critically ill patients). We have already mentioned the importance that the first medical contact should be performed by emergency medical services and the measures used to reduce time to reperfusion. Regarding the management of critically ill patients, a study conducted by Sánchez-Salado et al.19 of 20 000 patients with cardiogenic shock demonstrated that the availability of cardiac surgery intensive care units was associated with a lower mortality rate. Data from this study added to the finding of our registry support the need for expanding the availability of cardiac surgery intensive care units in large volume centers of patients with acute coronary syndrome. In conclusion, the results of mortality study suggest that the organization of the different networks would increase the crude mortality rate seen in some AC.

Limitations

This study has some limitations. In the first place, it is based on self-reported data without external auditing. However, data on interventional cardiology are rather standardized across the world, and the electronic form for data curation was designed to be applied both intuitively and universally. Also, data from Catalonia and Galicia were collected from their official registries, reviewed, and then audited.

Secondly, the profile of patients may have been different across the different AC. To address this limitation and its possible impact on the different crude mortality rates reported, a mortality study was conducted across different AC after adjusting for different clinical variables and care networks. Therefore, some models may be over-adjusted, which is why formal statistical comparisons across AC should be interpreted as cautious as the associations described in any observational trial. The model did not include patients lacking some of the variables included in the model. Table 1 of the supplementary data shows patients discarded from the study for every AC.

Thirdly, patients with STEMI treated outside the infarction networks were not included in this study, although this is probably indicative of a mild selection bias due to its reduced number. Therefore, the greater bias occurs in patients without reperfusion therapy, who, at times, are not covered by these networks. For this reason, these patients were not considered in the mortality analysis. Similarly, patients with myocardial infarction and subacute presentation without emergency reperfusion criteria were not included in the study.

Fourthly, the way of collecting times may have presented some differences between centers and AC. However, since this was a prospective study with previously established definitions, we believe that these differences may have been minimized.

In the fifth place, the data presented date back to 2019. Since then, no big organizational changes have occurred to justify changes in the dynamics of functioning or relevant changes have been made in the European guidelines on the management of STEMI (published back in 2017). Also, in a study conducted during the first wave of the COVID-19 pandemic no differences were seen regarding the type of reperfusion therapy used or time between the first medical contact and reperfusion. However, an increased mortality rate was seen attributed, among other causes, to longer ischemia times.20

Finally, this study only included patients for a period of 3 months. However, we think these data can be generalized to what happens in a much larger period.

CONCLUSIONS

This registry showed significant differences in STEMI care across the different Spanish AC regarding incidence rate, the patients’ clinical characteristics, reperfusion therapy, time delays to reperfusion, and 30-day crude mortality rate. After adjusting for the clinical characteristics and variables associated with the care network, no differences mortality differences were reported across the different AC.

Standardizing the organization and functioning of Infarction Code networks could correct some of the differences seen in the management of STEMI.

FUNDING

None whatsoever.

AUTHORS’ CONTRIBUTIONS

Drafting of the manuscript: O. Rodríguez-Leor, A.B. Cid-Álvarez, A. Pérez de Prado, and X Rosselló. Process of manuscript revision: all the authors. Statistical analysis: O. Rodríguez-Leor, and X. Rosselló. Database review: O. Rodríguez-Leor, A.B. Cid-Álvarez, and A. Pérez de Prado. Data coordination across the different regional network: all the authors.

CONFLICTS OF INTEREST

A. Pérez de Prado received numerous personal fees from iVascular, Boston Scientific, Terumo, Bbraun, and Abbott Vascular. Á. Cequier received personal fees from Ferrer International, Terumo, Astra Zeneca, and Biotronik. R. Moreno, S. Ojeda, R. Romaguera, and A. Pérez de Prado are associate editors of REC: Interventional Cardiology. The journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. The remaining authors did not declare any conflicts of interest associated with the content of this manuscript.

ACKNOWLEDGEMENTS

The authors wish to thank all health professionals involved in STEMI care programs for their not always rewarded work, effort, and dedication. Also, they wish to thank Meia Faixedas, and Josepa Mauri from the Departament de Salut de la Generalitat de Catalunya for granting us access to data from the Catalonian Registre de Codi Infart, and the entire personnel from Servicio Gallego de Salud (SERGAS) involved in the coordination of the REGALIAM registry for facilitating access to its data.

REFERENCES

INTRODUCTION

Despite increasingly effective primary and secondary preventive treatments, coronary artery-related events continue to be the leading cause of morbidity and mortality worldwide.1,2 Lifestyle changes (eg, weight loss, low-salt diet, smoking cessation), medical therapy (eg, anti-hypertensive, lipid-lowering, glucose-lowering, and antithrombotic regimens) in addition to coronary revascularization via percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) constitute the multifaceted approach of this disease. Yet despite the advances made in this multimodality approach, cardiovascular morbidity and mortality remain high.

More recently, the central role played by inflammation in the pathogenesis of coronary artery disease from atherosclerotic plaque formation to acute coronary syndrome (ACS), and PCI itself have gained important recognition. Colchicine, an anti-inflammatory agent indicated for multiple inflammatory conditions including pericarditis, gout, and familial Mediterranean fever, has gained attention as a potential attenuator of atherosclerotic inflammation. Acting via the inhibition of tubulin polymerization and eventually blunting immune cell activation and inflammatory response,3,4 recent evidence suggests a benefit of colchicine in the management of the cardiovascular events of patients with clinical signs of coronary artery disease.5 However, its impact among patients in the peri-PCI period remain controversial.

Recent trials have begun exploring the effects of colchicine in the PCI setting, albeit with mixed results. In the Colchicine-PCI trial of patients with non-ST-segment elevation acute coronary syndrome, the administration of colchicine immediately before and after PCI resulted in lower interleukin-6 and high-sensitivity C-reactive protein (hsCRP) levels at 24 hours, but did not show fewer PCI-related myocardial injuries.6 This trial was followed by COPE-PCI that found that when administered 6-to-24 hours before the PCI, colchicine did in fact reduce PCI-related myocardial injuries in a population of patients with stable angina and non-ST-elevation acute myocardial infarction (NSTEMI).7 Nevertheless, the more recent COVERT-MI trial8 found no difference in infarct size or left ventricular remodeling on the cardiac magnetic resonance imaging in patients treated with colchicine compared to those untreated with this agent.

These individual studies may not provide properly powered analyses, particularly in low-rate events such as strokes, on the impact of colchicine regarding secondary prevention in patients in the peri-PCI period, thus prompting the need for a systematic appraisal and meta-analysis of the quality of evidence and treatment effects on major adverse cardiovascular events.

METHODS

Protocol

The search process of this meta-analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and is registered with PROSPERO (CRD42021247704). The meta-analysis did not require specific institutional review board approval since it utilized results published in former studies. All relevant information can be found in the trials included. The corresponding author had full access to all the data and final responsibility on the decision to submit the manuscript for publication. The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Search strategy

We performed a comprehensive literature search of all published studies—retrospective, observational, and randomized controlled trials—available on Web of Science, Embase, PubMed, Ovid MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov (inception through August 23, 2021, without language restrictions. Case reports, letters to the editor, reviews, and book chapters were not included in this meta-analysis. The keywords used in the search were ‘colchicine,’ ‘coronary artery disease,’ ‘coronary heart disease,’ ‘angina,’ ‘myocardial infarction,’ ‘acute myocardial infarction,’ ‘myocardial ischemia,’ ‘acute coronary syndrome,’ ‘ischemic heart disease,’ ‘percutaneous coronary intervention,’ ‘percutaneous transluminal angioplasty,’ ‘percutaneous coronary revascularization,’ and ‘myocardial revascularization’ including their subheadings, MeSH terms, and all synonyms. References for each of the studies se lected were also screened (the detailed search strategy can be found on the supplementary data). The search process was reported according to the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Selection criteria

Studies were eligible if they included any the following criteria: a) compared the efficacy of colchicine treatment, at any dose and for any duration, to standard medical treatment with or without placebo; b) included populations of patients treated with PCI regardless of the indication; and c) reported, at least, 1 of the following cardiovascular outcomes: all-cause mortality, cardiovascular mortality, myocardial infarction (MI), stroke or urgent coronary revascularization. Study selection was conducted by 2 independent reviewers (C.E. Soria Jiménez, and J. Chang) first by screening titles and abstracts and then by reviewing full texts and their corresponding references. In case of disagreement over eligibility, a third reviewer (H.M. García-García) assessed discrepancy, and decisions were reached by consensus.

Data collection and study endpoints

Data on study characteristics, patient characteristics, and endpoint event rates were independently drawn and organized into a structured dataset by 2 reviewers (C.E. Soria Jiménez, and F. Hayat), and then compared. All discrepancies resulted in the re-evaluation of primary data and involvement of a third reviewer (H.M. García García). Disagreements were resolved by consensus.

Endpoints

The prespecified primary endpoint was all-cause mortality. Secondary clinical endpoints were cardiovascular mortality, MI, stroke, and any revascularization. Each endpoint was assessed according to the definitions reported in the original study protocols (summarized on table 1 of the supplementary data).

Risk of bias

The risk of bias in each study was assessed using the revised Cochrane Risk of Bias tool (RoB 2.0) for randomized controlled trials (RCTs), and the Risk of Bias in Non-randomized Studies of Interventions assessment Tool from the Cochrane handbook (ROBINS-I) for observational studies. Two investigators (C.E. Soria Jiménez, and J. Sanz Sánchez) independently assessed 5 domains of bias in RCTs: (1) randomization process, (2) deviations from intended procedures, (3) missing outcome data, (4) outcome measurement, and (5) selection of results reported. The same investigators independently assessed 7 domains of bias in observational studies: (1) confounding, (2) selection of participants, (3) classification of procedures, (4) deviations from intended interventions, (5) missing outcome data, (6) outcome measurement, and (7) selection of results reported (table 2 and 3 of the supplementary data).

Statistical analysis

Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated using the DerSimonian and Laird random-effects model with the estimate of heterogeneity taken from the Mantel-Haenszel method. The presence of heterogeneity among the studies was evaluated using the Cochran Q test referred to chi-square distribution (P ≤ .10 was considered statistically significant) plus the I² test to assess inconsistencies. Values of 0% indicated no observed heterogeneity, and values ≤ 25%, ≤ 50%, and > 50% indicated low, moderate, and high heterogeneity, respectively. The presence of publication bias was investigated using Harbord test and visual estimation with funnel plots. We conducted a leave-one-out sensitivity analysis for all outcomes by iteratively removing 1 study at a time to confirm that our findings were not driven by any single study. To account for the different follow-up durations across the studies, another sensitivity analysis was conducted using a Poisson regression model with random intervention effects to calculate the means of inverse-variance weighting of trial-specific log stratified incidence rate ratios. Results were shown as incidence rate ratios, which are exponential coefficients of the regression model.

A meta-regression analysis was conducted using the empirical Bayesian method to estimate the between-study variance tau-squared to assess the effect of colchicine dosage, follow-up duration, percentage of patients with ACS, and percentage of those with diabetes mellitus on treatment effects on the primary endpoint.

Two-tailed P values < .05 were considered statistically significant. Statistical analyses were conducted using the Stata software version 13.1 (StataCorp LP, College Station, United States).

RESULTS

Search results

Figure 1 shows the PRISMA study search and selection process. Out of a total of 1239 unique reports, 12 RCTs5-16 and 1 observational study17 were identified and included in this analysis. The corresponding author of the COOL trial15 was contacted regarding data from a number of patients treated with PCI; 58 out of a total of 80 patients evaluated (72.5%) underwent PCI. The study ultimately met the inclusion criteria and was included in our analysis. The main features of the studies included are shown on table 1. Data on the outcomes, mortality, MI, stroke, and urgent revascularization were reported in 12, 9, 5, and 6 trials, respectively. A total of 3741 and 3673 patients treated with and without colchicine were included (for a total of 7414 patients). Time elapsed from the PCI to the start of colchicine went from immediately before PCI to 13.5 days later as shown on table 1.

Figure 1. Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart of database search results and study selection.

Table 1. Characteristics of trials selected

Trial/Author	Year	Study design	Multicenter	Patients (n)	Population	Colchicine dose and duration	Time elapsed from PCI to start of colchicine	Follow-up
COVERT-MI8	2021	RCT	Yes	192	Adults with a first-time STEMI referred for primary or bailout PCI	2 mg oral loading dose followed by daily oral 0.5 mg twice daily for 5 days	Loading dose immediately before PCI; if not possible, immediately after PCI	3 months
COPE-PCI7	2021	RCT	No	75	Adults with stable angina or NSTEMI undergoing angiography and PCI	1 mg followed by 0.5 mg 1 h later, 6 hrs to 24 hrs pre-PCI	6 hrs to 24 hrs before coronary angiogram	1 day
Colchicine-PCI6	2020	RCT	No	400	Adults with suspected ischemic heart disease or ACS referred for angiography with possible PCI	1.2 mg 1 h to 2 h pre-angiography, 0.6 mg 1 h later or immediately after the procedure if rushed for emergency angiography	1 h to 2 h before coronary angiography	1 month
COPS9	2020	RCT	Yes	795	Adults presenting with ACS and evidence of CAD treated with angiography and managed with PCI or medical therapy	0.5 mg twice daily for 1 month, then 0.5 mg daily for 11 months	Immediately after PCI and randomization	13.2 months
LoDoCo-MI10	2019	RCT	No	237	Adults who sustained a type 1 MI within the past 7 days	0.5 mg daily for 30 days	1.5 days following the index MI	1 month
Talasaz11	2019	RCT	No	196	Adults presenting with STEMI undergoing PCI	NA	NA	1 month
COLCOT I5	2019	RCT	Yes	4745	Adults with MI within the past 30 days who had completed some percutaneous revascularization	0.5 mg once daily for, at least, 2 years	13.5 days	42 months
Vaidya17	2018	Observational	No	80	Adults who presented with ACS < 1 month prior and underwent invasive coronary angiography and revascularization if indicated	0.5 mg once daily for 1 year	NA (< 1 month from ACS per inclusion criteria)	12.6 months
COLIN12	2017	RCT (Open-label)	No	44	Adults admitted for STEMI with occlusion of 1 of the main coronary arteries treated with PCI	1 mg once daily for 1 month	On the first day of the AMI	1 month
Deftereos 201513	2015	RCT (Pilot)	Yes	151	Adults presenting with STEMI of ≤ 12-hour evolution from pain onset treated with PCI	2 mg loading dose, 0.5 mg twice daily for 5 days	Immediately after completion of diagnostic coronary angiography	5 days
Deftereos 201314	2013	RCT	No	222	Adults with diabetes, aged 40-80 treated with PCI with bare metal stent	0.5 mg twice daily for 6 months	Within 24 hrs of index PCI	6 months
COOL15	2012	RCT	No	80	Adults with ACS or acute ischemic stroke	1 mg once daily for 30 days	Immediately after randomization	1 month
O’Keefe16	1992	RCT	No	197	Adults who underwent elective angioplasty (single or multivessel, new or restenosed lesions) for silent, stable or unstable angina; CABG	0.6 mg twice daily for 6 months	Somewhere between 12 hrs before and 24 hrs after balloon angioplasty	6 months
ACS, acute coronary intervention; CABG, coronary artery bypass graft; CAD, coronary artery disease; MI, myocardial infarction; NA, not available; NSTEMI, non-ST-elevation acute myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; STEMI, ST-segment elevation myocardial infarction.

 

Baseline characteristics

Main baseline characteristics of the patients included are shown on table 2. Most patients were men with a mean age of 60 years, had ACS, and underwent revascularization with drug-eluting stents.

 

Table 2. Baseline characteristics of patients from each trial

Trial/Author	Mean Age	Men (%)	ACS (%)	DES (%)	HTN (%)	DM2 (%)	HLD (%)	Previous MI (%)	Previous PCI (%)	Previous CABG (%)	Underwent PCI (%)
COVERT-MI8	60	80.3	100	95.7	30.8	13.1	33.1	0	0	0	93
COPE-PCI7	64.7	71.5	58.7	97.0	54.5	22.9	63.5	17.5	16.0	NA	100
Colchicine-PCI6	66.3	93.5	49.5	NA	91.7	57.8	88.8	25.8	37.6	NA	100
COPS9	59.9	79.5	100.0	NA	50.5	19.0	46.0	15.0	13.0	4.5	88
LoDoCo-MI10	61.0	77.0	100.0	NA	47.5	22.0	NA	15.0	11.5	NA	90
Talasaz11	NA	NA	100.0	NA	NA	NA	NA	NA	NA	NA	100
COLCOT I5	60.6	80.9	100.0	NA	51.1	20.2	NA	16.2	16.9	3.2	93
Vaidya17	57.4	77.5	100.0	NA	53.8	31.3	85.0	51.3	63.8	NA	77.5
COLIN12	59.9	79.4	100.0	NA	43.4	13.7	36.5	NA	4.6	2.4	100
Deftereos 201513	58.0	69.0	100.0	NA	39.5	21.5	52.0	0.0	NA	NA	100
Deftereos 201314	63.6	65.5	31.0	0	48.5	100.0	NA	NA	NA	NA	100
COOL15	57.2	88.8	91.3	NA	42.5	16.3	47.5	17.5	0	NA	73
O’Keefe16	60.5	86.0	39.5	0	NA	12.0	NA	NA	NA	25.5	100
ACS, acute coronary syndrome; CABG, coronary artery bypass graft; DES, drug-eluting stent; DM2, diabetes mellitus type 2; HLD, hyperlipidemia; HTN, hypertension; MI, myocardial infarction; NA, not available; PCI, percutaneous intervention.

 

Publication bias and asymmetry

Funnel-plot distributions of pre-specified outcomes indicate absence of publication bias for all the outcomes (figures 1 to 5 of the supplementary data).

Risk of bias assessment

Table 2 and table 3 of the supplementary data summarize the results of the risk of bias assessment. A total of 11 trials were ranked as trials with a low overall risk of bias, 1 presented some concerns while another one was ranked as a trial with a high overall risk of bias.

Outcomes

No differences were seen between patients treated with colchicine and those treated without it or placebo regarding all-cause mortality (OR, 1.06; 95%CI, 0.72-1.55; I² = 0%), cardiovascular mortality (OR, 0.98; 95%CI, 0.42-2.28; I² = 14.2%) or coronary revascularization (OR, 0.64; 95%CI, 0.29-1.42; I² = 49.3%). However, patients treated with colchicine had a lower risk of stroke (OR, 0.38; 95%CI, 0.18-0.81; I² = 0%), and a trend towards a lower risk of MI (OR, 0.84; 95%CI, 0.66-1.07; I² = 0%) (figure 2).

Figure 2. Forrest plot analyses for the main outcomes of death (A), myocardial infarction (B), stroke (C), and revascularization (D). 95%CI, confidence interval; OR, odds ratio.

 

Sensitivity analyses

In the leave-one-out sensitivity analysis, results were consistent with the primary analysis (tables 4 to 8 of the supplementary data). Similarly, in a sensitivity analysis on the use of estimated incidence rate ratios to account for different lengths of follow-up, findings remained unchanged (table 9 of the supplementary data).

When the risk ratios with random-effects models were estimated, findings remained consistent with the main analysis for all endpoints (table 10 of the supplementary data). Random effect meta-regression analyses found no significant impact of colchicine dosage (P = .33), follow-up duration (P = .88), percentage of patients with ACS (P = .37) or percentage of patients with diabetes mellitus (P = .96) on treatment effect regarding the primary endpoint (table 11 of the supplementary data).

DISCUSSION

This meta-analysis included 7414 patients across 12 RCTs and 1 observational study. It showed some clinical benefits on cardiovascular events with the addition of colchicine to standard medical therapy in patients undergoing PCI. Specifically, we found that the addition of colchicine compared to no colchicine or placebo reduced the risk of stroke showing a trend towards a lower risk of MI both with no observed heterogeneity. Additionally, we observed no differences in all-cause mortality, cardiovascular mortality or coronary revascularization. Significantly, colchicine dosage, follow-up duration, percentage of patients with ACS or diabetes mellitus showed no impact on treatment effect (see PRISMA checklist on table 12 of the supplementary data).

Our outcomes regarding all-cause and cardiovascular mortality are consistent with a prior meta-analysis of 5 RCTs conducted by Fu et al.,18 that also found no significant reduction of mortality, MI, serious adverse events, and restenosis. One explanation for the lack of mortality benefit of both trials may be that although mortality rate was generally low and differences were largely not statistically significant in many of these trials, follow-up duration was generally short (< 30 days) in most studies, and it is possible that higher event rates may be seen with longer follow-up data. We should mention that the meta-analysis conducted by Fu et al.18 included 1 RCT of patients treated with CABG, not PCI. It is possible that the inflammatory profiles of this cohort of patients differ from those treated with PCI (eg, multivessel coronary artery disease, longer postoperative recovery, and higher risk of postoperative complications). As a matter of fact, this mixed population may have led to the lack of reduction seen in the overall rate of MI, serious adverse events, and restenosis. Similarly, a prior meta-analysis conducted by Fiolet et al.19 demonstrated that the addition of colchicine to standard medical therapy in patients with acute and chronic coronary syndromes reduced the risk of the primary endpoint significantly (a composite of MI, stroke, and cardiovascular mortality), and the individual endpoint of MI, stroke, and coronary revascularization with no differences whatsoever on all-cause or cardiovascular mortality. Our results demonstrating a lower risk of stroke and a trend towards a lower risk of MI are more consistent with this meta-analysis. A key difference among the different meta-analyses is the population of patients. Fiolet et al.19 included the LoDoCo20 and LoDoCo221 trials whose inclusion criteria were patients with chronic coronary disease and clinical stability for over 6 months. This amounted to > 50% of patients analyzed who were not in the peri-PCI period and likely had a different inflammatory profile at the time of colchicine administration. These 2 trials also had longer follow-ups (36 and 29 months, respectively) potentially allowing for more time to capture outcome differences like MI and urgent revascularization between the different treatment groups. In contrast, our meta-analysis only focused on patients in the peri-PCI as conducted by Fu et al.18 and expanded the total number of studies analyzed to 12 RCTs and 1 observational study. As far as we know, our study is the largest meta-analysis ever conducted to this date to assess the effects of colchicine on the clinical outcomes of patients in the peri-PCI period.

Alkouli et al.22 reported that the adjusted rate of ischemic stroke increased for patients treated with PCI due to ST-segment elevation myocardial infarction (STEMI) (0.6% to 0.96%), NSTEMI (0.5% to 0.6%), and unstable angina or stable ischemic heart disease (UA/SIHD, 0.3% to 0.72%). In turn, in-hospital mortality was higher (23.5% vs 11.0%, 9.5% vs 2.8%, and 11.5% vs 2.4% for STEMI, NSTEMI, and UA/SIHD cohorts, respectively), and post-PCI stroke was associated with a > 2-fold increase in LoS, a > 3-fold increase in non-home discharges, and a > 60% increase in cost. Given the increasing complexity of patients treated as well as the PCI techniques utilized over the past decade, effective preventive strategies and treatments are needed, and herein lies the opportunity for other anti-inflammatory drugs such as colchicine to further mitigate the morbidity and mortality of patients with post-PCI stroke. In the acute phase of MI, activated inflammasomes mount an intense inflammatory response.23 There is also endothelial damage after PCI, which may result in atherosclerotic plaque destabilization with subsequent thromboembolism causing cerebrovascular events.24 Colchicine may play a role preventing stroke by helping stabilize atherosclerotic plaques in patients undergoing PCI, though this effect may not be robust enough to overcome the direct endothelial injury present at the time of PCI.

Colchicine is a widely available drug with known anti-inflammatory properties. Its mechanism of action is yet to be fully elucidated but has been shown to work partly via the inhibition of NLRP3 (nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing protein 3) inflammasome, which ultimately downregulates interleukin-1B and interleukin-6, 2 known inflammatory mediators.23-27 It also causes microtubule disruption and decreased neutrophil activation and extravasation. Since elevated levels of inflammatory biomarkers are an independent predictor of major adverse cardiovascular events28-31 our results show that colchicine joining the current medical therapy is a potential addition to further attenuate inflammation regarding the secondary prevention of cardiovascular disease in patients undergoing PCI.

Some limitations of our study include the use of aggregate study-level data as opposed to patient-level data. While this limits subgroup analyses, the overall conclusions would remain the same. There was also a small percentage of patients in each of the studies analyzed who did not undergo PCI, which poses some limitations on the overall effects on a PCI population. However, in all studies, the vast majority of patients eventually underwent this procedure. Similarly, the LoDoCo221 trial enrolled patients who underwent PCI but was ultimately excluded from this analysis as patients required a period of clinical stability 6 months after PCI before starting colchicine therapy. A 6-month gap from PCI to colchicine initiation did not fit in with our period of interest (the peri-PCI period). The study conducted by O’keefe16 was completed in an era of balloon angioplasty, and colchicine treatment in this setting may not be comparable to patients who underwent PCI in the era of statins, modern stents, and antiplatelet agents. Additionally, most patients from our study underwent PCI due to the presentation of ACS, yet there were other clinical presentations including stable ischemic heart disease and unstable angina, and yet others that specifically excluded patients with acute MI. Given the different clinical status at presentation for PCI, it’s likely that the inflammatory profile of these different populations of patients also varied resulting in different clinical outcomes. Nevertheless, despite variation in the inclusion and exclusion criteria, outcome definitions, and colchicine dose and duration, this did not introduce heterogeneity into our results.

CONCLUSIONS

In patients undergoing PCI, the addition of colchicine to optimal medical therapy resulted in a significant reduction of strokes, and a trend towards a lower risk of MI. However, this did not result in lower all-cause and cardiovascular mortality rates, and urgent revascularization.

FUNDING

This research did not receive any specific grants from public, private or non-profit sectors.

AUTHORS’ CONTRIBUTIONS

M.B. Levine was involved in data curation and research. F. Hayat, and J. Chang were involved in data curation and research, as well as in drafting, editing, and reviewing the early draft of the manuscript. C.E. Soria Jiménez, J. Sanz Sánchez, and H. García-García were involved in project conceptualization, data curation, formal data analysis and investigation, methodology, project administration, resources, validation, visualization, as well as drafting, editing, and reviewing all manuscript drafts and its final version.

CONFLICTS OF INTEREST

H.M. García-García declared institutional grant support from Biotronik, Boston Scientific, Medtronic, Abbott, Neovasc, Shockwave, Phillips, and Corflow. The remaining authors declared no conflicts of interest whatsoever.

REFERENCES

INTRODUCTION

Ischemic heart disease is the leading cause of mortality in developed countries.1 The rate of acute coronary syndrome (ACS), specially non-ST-segment elevation ACS (NSTEACS), has increased over the last few years, in part, due to the ageing of the population.2-3 Given the underlying pathophysiology4 patients receive specific antithrombotic treatment, and invasive approach is used in most of the cases.1-3 The new guidelines published by the European Society of Cardiology (ESC) on the management of NSTEACS1 include changes compared to the guidelines published back in 2016. The most significant ones include antithrombotic treatment, the revascularization strategy, and several controversial innovations.

In the guidelines published in 2020, early cardiac catheterization within the first 24 hours after admission was advised (level of evidence IA) in patients diagnosed with acute myocardial infarction with GRACE scores (Global Registry of Acute Coronary Events) > 140 or dynamic electrocardiographic changes suggestive of ischemia.1 Also, the previous window of recommendation of 0 to 72 hours for moderate risk patients is now gone.4 On the other hand, the systematic use of pretreatment at admission with an P2Y₁₂ inhibitor antiplatelet drug (ticagrelor, prasugrel or clopidogrel) in patients to be treated with an early invasive strategy is now ill-advised.1

The objective of the IMPACT registry (Time of intervention in patients with myocardial infarction with non-ST segment elevation, management and outcomes [IMPACT-TIMING-GO]) is to get the big picture on the current treatment of NSTEACS, in Spain, in association with catheterization times, use of pretreatment in these patients, and describe the possible prognostic implications of the different strategies used in real life.

METHODS

Study design and population

This is an observational, prospective, multicenter, and nationwide registry that will include all consecutive patients admitted with a diagnosis of NSTEACS to the different participant centers, treated with diagnostic coronary angiography, and with unstable or causal atherosclerotic disease regardless of further treatment administered by the heart team. The baseline characteristics of the patients included, and their clinical progression regarding in-hospital events will be studied. Patients will undergo a 1-and-3-year clinical follow-up period.

This registry has been promoted by the Spanish Society of Cardiology Young Cardiologists Working Group with scientific support from the Spanish Society of Cardiology Research Agency. Also, it has been approved by different Research Ethics Committees with drugs from all the participant hospitals. Finally, it has been designed according to the STROBE checklist for observational studies.

The list of centers that will eventually participate in the registry is shown on figure 1. Inclusion and exclusion criteria are shown on table 1. The presence of elevated markers of myocardial damage or electrocardiographic changes is not mandatory. Patients with a clinical diagnosis of unstable angina can be included as long as coronary angiography confirms the clinical diagnosis.

Figure 1. Map with the Spanish participant centers in the IMPACT-TIMING-GO registry.

Table 1. Inclusion and exclusion criteria of the IMPACT-TIMING-GO registry

Inclusion criteria
NSTEACS with in-hospital invasive treatment regardless of when it is performed.
Evidence of causal or unstable atherosclerotic disease.
Age ≥ 18 years.
Capacity to give informed consent.
Exclusion criteria
Minors and those who withdraw their consent to be included or followed at any time during the study.
Assessment of myocardial damage markers associated with type 2 myocardial infarction.
Patients without any signs of coronary artery disease including those with myocarditis, Prinzmetal angina, takotsubo syndrome or MINOCA.
Patients diagnosed with spontaneous coronary artery dissection.
Patients with complete left bundle branch block or pacemaker rhythm on the electrocardiogram performed at admission.
Patients with a valve heart disease eligible for surgery.
Patients with a known past medical history of diffuse coronary artery disease noneligible for revascularization.
Patients with known or confirmed allergy to some antiplatelet drug.
IMPACT-TIMING-GO, IMPACT of time of intervention in patients with myocardial infarction with non-ST segment elevation. Management and outcomes; MINOCA, Myocardial infarction with non-obstructive coronary artery disease; NSTEACS, non-ST-segment elevation acute coronary syndrome.

 

Endpoints

The study primary endpoint is to know the degree of compliance of the recommendations included in the clinical practice guide-lines in patients admitted due to NSTEACS treated with coronary angiography, in Spain, describe the use of antithrombotic treatment before cardiac catheterization, and the time elapsed until it is performed in the real-world clinical practice.

The secondary endpoints are:

• – To describe the baseline, clinical, and epidemiological characteristics of the study population.
• – To study the rates of cardiovascular mortality, new revascularization, stent thrombosis, and hospitalizations due to heart failure during admission and at the 1-and-3-year follow-up.
• – To describe major cardiovascular adverse events of all-cause mortality, non-fatal stroke, non-fatal infarction, and the rate of major bleeding grades 3, 4, and 5 according to the BARC scale (Bleeding Academic Research consortium.5) Data will be analyzed during admission and at the 1-and-3-year follow-up.
• – To know the medical treatment at discharge and at follow-up of patients discharged in Spain after NSTEACS.
• – To know the degree of control of the different cardiovascular risk factors associated with the endpoints defined in the ESC guidelines 2021 on prevention of cardiovascular disease in the routine clinical practice.6

Data curation and definitions

Data will be collected prospectively by trained medical investigators from each participant center in a specific standard form. Demographic data, the baseline clinical characteristics, and all analytical, electrocardiographic, and echocardiographic data will be included as well.

Similarly, data on disease progression and the in-hospital stay, indication for coronary angiography and when it is be performed, type of treatment received (conservative, stent implantation or revascularization surgery), and the in-hospital complications occurred (hemorrhages and severity, heart failure or shock, reinfarction, stroke, confusional state, mechanical and arrhythmic complications, infectious complications requiring antibiotic therapy, and mortality causes) will be collected. Finally, the medical treatment at hospital discharge and level of compliance of the current recommendations based on the clinical practice guidelines will be studied too.

The definitions of the variables are shown on table 2.7-8

 

Table 2. Definitions of target variables

Variable	Definition
All-cause mortality	All deaths regardless of their cause.
Cardiovascular death	All deaths of vascular causes both cardiac (heart failure/shock; malignant arrhythmias; myocardial infarction) and non-coronary vascular including cerebrovascular disease, pulmonary embolism, aneurysms/aortic dissections, acute ischemia of lower limbs, etc. All sudden deaths of unknown causes will be adjudicated as cardiovascular death.
Non-cardiac death	All deaths that do not meet the previous definition like deaths due to infections, cancer, pulmonary diseases, accidents, suicide or trauma.
Myocardial infarction	It is defined based on the criteria established in the 4th and current Universal definition.4 Therefore, patients with type 2 infarction, extracardiac causes or without elevated markers of myocardial damage were excluded.
Stroke/Transient ischemic attack	New-onset neurological, focal or global deficit due to ischemia or hemorrhage, and as long as it is part of diagnostic judgement at hospital discharge.
Stent thrombosis	Defined based on the Academic Research Consortium of randomized clinical trials with stents.7
New revascularization	All unscheduled revascularizations performed after hospital discharge, whether surgical or percutaneous, including target vessel failure and target lesion failure.
Admission due to heart failure	Unscheduled hospital admission > 24 hours with a primary diagnosis of heart failure based on the current defintion.8

 

Follow-up

Clinical follow-up to detect events will be conducted by medical investigators through on-site visits, health record reviews or phone calls with the patient, family members or treating physician at 1 and 3 years. Clinical variables, functional class, and additional variables (analytical, electrocardiographic, and echocardiographic, and treatment received) will be included. The overall mortality rate and its causes, need of emergency hospitalization (duration > 24 hours) and its causes, and the rates of non-fatal infarction and stroke will be collected as well. All deaths due to myocardial infarction, sudden death or heart failure will be considered cardiovascular deaths.

Sample size estimate

Taking the events seen in previous studies with a population of similar characteristics as the reference,9-14 a sample size of 800 patients will be enough to know the baseline characteristics of the study population, and the therapeutic approach currently used in Spain in our routine clinical practice. Patients lost to follow-up will be handled by multiple imputation.

Statistical analysis

Categorical variables will be expressed as number and percentage. Quantitative variables will be expressed as mean ± standard deviation. Quantitative variables with normal distribution will be expressed as median and interquartile range [25%-75%]. The normal distribution of quantitative variables will be assessed using the Kolmogorov-Smirnoff test. Regarding the reference variables, Student t test will be used to compare quantitative variables, and the chi-square test or Fisher’s exact test, if applicable, to compare categorical variables. Statistical analysis will be performed using the SPSS statistical software version 22.0 (IBM Corp., Armonk, United States).

Specific studies on subgroups of special interest will be conducted: feminine sex, patients ≥ 75 years, those with GRACE scores > 140, diabetic patients, those with a past medical history of renal failure, with an indication for chronic oral anticoagulation, with multivessel disease, acute myocardial infarction, ventricular dysfunction according to the current clinical practice guidelines and based on the day of admission (holiday vs working day), and patients who require transfer to tertiary centers to receive a coronary angiography.

Ethical principles

Inclusion in the study will not imply changes to the patients’ treatment. Instead, it will follow the routine clinical practice and the recommendations set forth by the current clinical practice guidelines. Therefore, antithrombotic treatment and additional examinations including the need for a coronary angiography and the time it is performed will all be decided by the heart team based on the routine clinical practice. Coronary angiography, vascular access, antithrombotic treatment during the procedure, and the material and devices used will all be decided by the treating operator in charge of the case. All patients will sign a written informed consent form before being included in the study that will be conducted in full compliance with the Declaration of Helsinki. This study will also observe all legal regulations applicable to this type of studies and follow the good clinical practice rules while being conducted.

DISCUSSION

The IMPACT-TIMING-GO registry will give us information on the current real-world management of patients with NSTEACS with invasive treatment and causal coronary artery disease, which will allow us to assess the degree of implementation of the current recommendations of ESC guidelines 2020 on cardiac catheterizations performed within the first 24 hours and no pretreatment with P2Y₁₂ inhibitors. Similarly, different prognostic differences that early invasive treatment and no pretreatment could have in the real life of patients diagnosed with NSTEACS could be suggested.

Despite the clinical practice guidelines recommendations on the invasive treatment of patients with NSTEACS, the main clinical trials published to this date have been unable to demonstrate any clear benefits from systematic early invasive treatment.9-14 The VERDICT trial,9 published in 2018, randomized 2147 patients with NSTEACS on a 1:1 ratio to receive early (< 12 hours) or delayed (48 to 72 hours) cardiac catheterization. No significant differences were found in the composite endpoint of major cardiovascular events at 4-year follow-up. However, in the subgroup of patients with GRACE scores > 140 statistically significant differences were seen favorable to the early strategy regarding major adverse cardiovascular events (hazard ratio, 0.81; 95% confidence interval, 0.67-1.01; P = .023). Consistent with this, the TIMACS clinical trial10 published in 2008 of 3031 patients with NSTEACS found no differences in the primary endpoint when early invasive strategy (< 24 hours) and delayed approach (> 36 hours) were compared, except for, once again, in patients with GRACE scores > 140. Other randomized clinical trials with fewer patients show contradictory results11-14 some without significant differences.15 Also, in many cases, the results favorable to the early strategy are associated with refractory ischemia, not with hard endpoints like cardiovascular mortality or non-fatal myocardial infarction. In Spain, evidence on the management of NSTEACS is prior to the current clinical practice guidelines,16-17 and the most recent registry is retrospective, which is suggestive of a possible mortality benefit in patients with GRACE scores > 140.18 Over the last 2 decades, in our country, the use of an invasive strategy in patients with NSTEACS has increased significantly from 20% in the MASCARA registry in 200516 up to 80% in the DIOCLES study from 2012.17 However, evidence is scarce on catheterization times, our capacity to adapt to current recommendations (the median time of the DIOCLES trial was 3 days), the possible impact this time reduction can have, and on the consequencies from not starting antiplatelet pretreatment in patients who don’t meet the times recommended.

On the other hand, the current formal recommendation from the clinical practice guidelines of not pretreating systematically with a P2Y₁₂ inhibitor (level of recommendation IIIA1) patients on early invasive treatment is mainly based on 3 clinical trials and their meta-analysis.19 In the ACCOAST trial, pretreatment with prasugrel did not reduce thrombotic events in patients with NSTEMI. However, cardiac surgery-related and potentially fatal hemorrhages increased.20 We should mention that the median time elapsed since the prasugrel loading dose until the coronary angiography was performed was 4 hours. In the ISAR-REACT 5 trial published in 2019, a non-pretreatment strategy with prasugrel in patients with ACS vs pretreatment with ticagrelor proved superior regarding the primary endpoint of thrombotic events with a tendency towards fewer hemorrhagic events.21 We should mention that the intrinsic effect of the drug used should not be obviated or else the fact that the median time elapsed since randomization until the prasugrel loading dose was received in the non-pretreatment group was 60 minutes. Finally, the first study that compared 2 different pretreatment strategies vs the intraoperative administration of ticagrelor did not show any clear benefits regarding thrombosis or a deleterious effect of pretreatment regarding bleeding.22 Once again, the median time elapsed until the cardiac catheterization was performed was < 24 hours since hospital admission (23 hours). Surprisingly, clinical practice guidelines leave the door opened to a weak level of recommendation (IIbC) regarding pretreatment of patients in whom early catheterization < 24 hours is not possible.1

In conclusion, current recommendations on early invasive treatment and no antiplatelet pretreatment in patients with NSTEACS are controversial and can also be difficult to implement in the routine clinical practice in our setting. The ultimate objective of the IMPACT-TIMING-GO registry is to shed light on the current management of NSTEACS in Spain. After the impact that the COVID-19 pandemic has had on the general structure of the healthcare system and the drop in the number of interventional procedures performed in 2020,23 we should expect to see pre-pandemic numbers in 2022 and cath labs and cardiac surgery intensive care units going back to normal. Therefore, moment seems ripe to conduct a real-world registry.

CONCLUSIONS

The IMPACT-TIMING-GO registry is the first prospective study ever conducted in Spain that will be giving us information on the early therapeutic strategies—both pharmacological and interventional—performed in our country in patients with NSTEACS after the publication of the ESC guidelines 2020, and the impact of these and other measures indicated in these patients at follow-up.

FUNDING

This unfunded study has been promoted by the Spanish Society of Cardiology Young Cardiologists Working Group with scientific endorsement from the Spanish Society of Cardiology.

AUTHORS’ CONTRIBUTIONS

Study design, data curation and review, statistical analysis, and manuscript drafting: P. Díez-Villanueva, F. Díez-Delhoyo, and M.T. López-LLuva. All the authors participated in the manuscript review and approval process.

CONFLICTS OF INTEREST

None reported.

ACKNOWLEDGEMENTS

We wish to thank the Spanish Society of Cardiology Young Cardiologists Working Group for their drive to engage the youth in medical research.

REFERENCES