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

INTRODUCTION

Over the past few years, the term INOCA (ischemia with nonobstructive coronary arteries) has established to define patients with signs or symptoms of ischemic heart disease without angiographically significant obstructive coronary artery disease.1 In these patients, coronary microvascular or epicardial vessel dysfunction could be the pathophysiological mechanism triggering the symptoms and ischemic impairment.2

Currently, the invasive study of microvascular function in patients with INOCA is a recommendation IIa according to the clinical practice guidelines of the European Society of Cardiology.3 What it does is measure the parameters that show its functional or structural status like coronary flow reserve (CFR) or index of microcirculatory resistance (IMR).4

Recently, the possibility of measuring absolute coronary blood flow (Q) and microvascular resistance (R) by continuous thermodilution with the infusion of a physiological saline solution through a specific coronary microcatheter has been described. This technique has potential advantages like its independence from the operator or not needing pharmacologically induced hyperemia.5

The objective of this study is to estimate the prevalence of the different endotypes of patients with INOCA and analyze the correlation between the measurements obtained by continuous thermodilution and the traditional method of intracoronary boluses of physiological saline solutions.

METHODS

This was a prospective and consecutive study of 60 referred patients due to symptoms or signs of myocardial ischemia without angiographically significant coronary artery stenosis on the visual estimate (< 50%) or after functional assessment (resting full-cycle ratio [RFR] > 0.89 or fractional flow reserve [FFR] > 0.80). Severe valvular heart disease, acute coronary syndrome, decompensated heart failure, and any clinical or anatomical condition where the study of microcirculation and vasoreactivity would be considered unnecessary were excluded.

All microcirculation and vasoreactivity studies were scheduled and second-staged. Nitrates and calcium antagonists were withdrawn prior to conducting the tests.

The coronary angiography was performed based on the routine clinical practice via radial access. A spasmolytic cocktail of 200 µg of nitroglycerin was administered. The target artery was the left main coronary artery.

The study was approved by the center ethics research committee and the patients’ written informed consent was obtained.

Vasoreactivity test

First, the vasoreactivity test was performed. Patient monitoring included precordial leads, and baseline angiograms were performed using 2 different projections. The sequential administration of acetylcholine was followed by increasing doses of 2 µg, 20 µg, and 100 µg in intracoronary bolus for 2 min. In the presence of significant bradycardia, the injection was interrupted, and if considered appropriate, it was re-administered at a slower rate. A follow-up angiogram was performed after every dose. In the presence of severe symptoms, changes to the echocardiogram or epicardial spasm 200 µg of intracoronary nitroglycerin were administered.

The test was considered positive based on the criteria established by the COVADIS (Coronary vasomotor disorders international study) group: epicardial spasm in the presence of chest pain, changes to the echocardiogram, and constriction ≥ 90%, and microvascular spasm in the presence of chest pain, and changes to the echocardiogram without epicardial spasm ≥ 90%.6

Indices obtained with continuous thermodilution

After the administration of unfractionated heparin (70 IU/kg), a pressure-temperature sensor guidewire Pressure Wire X (Abbott, United States) was inserted and pressures at the catheter distal border were equalized. The guidewire was advanced until it reached the left anterior descending coronary artery distal segment.

Resting full-cycle ratio was registered to confirm the lack of hemodynamically significant epicardial stenoses (RFR > 0.89).

Afterwards, a specific Rayflow (Hexacath, France) microcatheter for intracoronary infusion was placed in the left anterior descending coronary artery proximal segment. After confirmation that the guidewire sensor was, at least, 3 cm distal to the tip of the microcatheter, the intracoronary infusion of a physiological saline solution at room temperature and at a dose of 20 mL/min was started using an injector pump to induce hyperemia.

Pressure-temperatures curves were registered using Coroventis software (Abbott, United States). When the distal temperature drop was stabilized, the sensor was withdrawn up to the tip of the microcatheter to determine the infusion temperature.

Afterwards, the injection of the physiological saline solution stopped, and Q (L/min) and R (Wood units) values were obtained automatically (figure 1).

Figure 1. Measurements obtained by continuous thermodilution: DP, distal pressure; Q, absolute coronary blood flow; Q_i, infusion flow (mL/min); R, micro­vascular resistance; T, distal temperature; T_i, infusion temperature.

 

Indices obtained with bolus thermodilution of a physiological saline solution

After completion of the continuous thermodilution study, and once the Rayflow microcatheter was removed, the pressure-temperature guidewire was repositioned in its previous location, and thermodilution curves were registered using the Coroventis software after the vigorous manual injection of 3 intracoronary boluses of 3 mL of a physiological saline solution. Measurements were taken at rest and after inducing hyperemia with a peripheral intravenous bolus of regadenoson (400 µg) resulting in the calculation of CFR and IMR.

Statistical analysis

Continuous variables were expressed as mean ± standard deviation or median [interquartile range]. The categorical ones were expressed as absolute value or percentage. ROC (Receiver operating characteristic) curves were used to estimate the optimal cut-off values for the continuous variables Q and R. The cut-off values established as pathological for CFR < 2 and IMR ≥ 25 were used as the reference framework. Once dichotomized, the variables Q and R were compared to the CFR and IMR values using chi-square tests. One-way ANOVA was used to compare the different quantitative variables. The statistical analysis was performed using the SPSS v 20 statistical software package (IBM, United States).P values < .05 were considered statistically significant.

RESULTS

Study patients

Table 1 shows the baseline characteristics of the 60 patients included in the study. Women (55%) were predominant. Also, there was a high prevalence of cardiovascular risk factors. Most showed typical angina-like clinical signs (76%) and had tested positive to an ischemia test performed before the coronary angiography (60%).

 

Table 1. Clinical and angiographic characteristics (N = 60)

Age (years)	63 ± 10
Women	33 (55%)
Hypertension	39 (65%)
Diabetes	21 (35%)
Dyslipidemia	35 (58%)
Smoking (current or past)	28 (47%)
Previous percutaneous revascularization	4 (7%)
Previous myocardial infarction	3 (5%)
Left ventricular systolic dysfunction	4 (7%)
Ejection fraction (%)	63 ± 8
Clinical presentation
Exertional angina	19 (32%)
Resting angina	13 (22%)
Mixed angina	14 (23%)
Other	14 (24%)
Ischemia test
Ergometry	19 (32%)
Isotopic scintigraphy	18 (30%)
Dobutamine stress echocardiography	3 (5%)
None	20 (33%)
Coronary angiography
Atheromatous disease	22 (37%)
Slow flow	13 (22%)
Data are expressed as no. (%) or mean ± standard deviation.

 

The baseline coronary angiography confirmed that 37% of the patients showed parietal irregularities consistent with atheromatous disease, and 22% had slow coronary flow. The FFR and RFR values were normal in all the cases studied.

Coronary vasoreactivity

As shown on table 2, 60% of the cases (36/60) had a positive response to acetylcholine in the vasoreactivity test. A total of 32% of the cases (19/60) showed severe epicardial vasoconstriction, and 23% (14/60) met the criteria for microvascular spasm. In 3 patients (5%), microvascular spasm was observed concomitantly with the medium dose (20 µg), and epicardial spasm with the high dose (100 µg), which added to the impaired indices of microvascular function was consistent with a mixed endotype.

 

Table 2. Procedural data

Pathological vasoreactivity testing	36 (60%)
Epicardial vasospasm	19 (32%)
Microvascular vasospasm	14 (23%)
Combined vasospasm	3 (5%)
Structural microvascular dysfunction (IMR ≥ 25)	20 (33%)
Isolated	5 (8%)
Associated with epicardial spasm	8 (13%)
Associated with microvascular spasm	4 (7%)
Associated with combined spasm	3 (5%)
CFR < 2	11 (18%)
CFR < 2.5	17 (28%)
RFR	0.93 [0.91-0.94]
FFR	0.90 [0.87-0.93]
Q (mL/min)	170 ([138-219]
R (WU)	496 [381-654]
CFR	3.0 [2.3-4.2]
IMR	20 [12-28]
Data are expressed as no. (%) or median [interquartile range]. CFR, coronary flow reserve; FFR, fractional flow reserve; IMR, index of microvascular resistance; Q, absolute coronary blood flow; R, microvascular resistance; RFR: resting full-cycle ratio.

 

Indices of microvascular function

Both studies—bolus thermodilution and continuous infusion thermodilution—were performed uneventfully in all of the patients. Table 2 shows the values of the measurements of microvascular function obtained with both techniques.

In the continuous infusion study, a median of absolute flow in the left anterior descending coronary artery of 170 mL/min [138-219 mL/min] was described while the median of microvascular resistance was 496 WU [381-654 WU].

A total of 18% of the patients (11/60) had a reduced CFR (CFR < 2) while 33% (20/60) showed elevated resistances (IMR ≥ 25).

The group of patients with microvascular dysfunction due to low CFR with normal IMR (7/60, 12%) with respect to cases with microvascular dysfunction due to high IMR with normal CFR (16/60, 27%) had a clinical profile with a lower mean age (61 ± 11 vs 66 ± 8), and a higher predominance of women (86% vs 58%) although this tendency was not statistically significant.

Table 3 shows the mean transit times (MTT) of bolus thermodilution tests. The cases with low CFR showed significantly shorter baseline MTT (0.48 ± 0.45 vs 1.13 ± 0.70), especially the subgroup of patients with low CFR and high Q (0.31 ± 0.15 vs 0.77 ± 0.68).

 

Table 3. Mean transit times obtained by bolus thermodilution

	Overall (N = 60)	CFR < 2 (N = 11)	CFR < 2 Q > 170 (N = 7)	CFR < 2 Q < 170 (N = 4)
Baseline MTT	1.13 ± 0.70	0.48 ± 0.45*	0.31 ± 0.15*	0.77 ± 0.68
Hyperemic MTT	0.36 ± 0.25	0.35 ± 0.28	0.25 ± 0.14	0.51 ± 0.41
Values (in seconds) are expressed as mean ± standard deviation. CFR, coronary flow reserve; MTT, mean transit time; Q, absolute coronary blood flow. * P < .05 for comparison with the rest of the sample.

 

Figure 2 shows data of coronary flow estimated by MTT measurement divided into 3 groups based on CFR and IMR results. We should mention that patients with low CFR without elevated resistances had significantly high resting flows and hyperemic flows without significant differences compared to the rest while in patients with low CFR and elevated resistances, the opposite phenomenon was described.

Figure 2. Baseline and hyperemic mean flow estimated based on the MTT (1/MTT) and grouped based on the CFR and IMR results. Values are expressed as s^–1. CFR, coronary flow reserve; IMR, index of microvascular resistance; MTT, mean transit time.
* P < .05.

 

Endotypes

Figure 3A shows the percentages of endotypes based on the result of the acetylcholine test and the measurements of CFR and IMR. The most common pattern was microvascular dysfunction (24/60, 40%) followed by the normal study (14/60, 23%). In 20% of the patients (12/60), microvascular dysfunction overlapped with epicardial vasospasm while in 17% of the patients (10/60) isolated epicardial vasospasms were seen.

Figure 3. A: endotype-based classification. Values are expressed as absolute number and percentage.B: mean values of absolute flow and microvascular resistance grouped by endotypes. Q, absolute coronary blood flow; R, microvascular resistance.
* P < .05 with respect to normal study.

 

Table 4 shows how the mechanisms of vasomotor and microvascular dysfunction overlap in many cases.

 

Table 4.Results of the acetylcholine test and bolus thermodilution study (N = 60)

Epicardial spasm	Microvascular spasm	IMR ≥ 25	CFR < 2	Endotype	Cases
−	−	−	−	Normal	14 (23.3%)
+	−	−	−	Epicardial vasospasm	10 (16.7%)
−	+	−	−	Microvascular dysfunction	9 (15.0%)
−	−	+	−	Microvascular dysfunction	5 (8.3%)
−	−	−	+	Microvascular dysfunction	5 (8.3%)
−	+	+	−	Microvascular dysfunction	3 (5.0%)
−	+	−	+	Microvascular dysfunction	1 (1.6%)
−	+	+	+	Microvascular dysfunction	1 (1.6%)
+	−	+	−	Mixed disorder	6 (10.0%)
+	+	+	−	Mixed disorder	2 (3.3%)
+	−	+	+	Mixed disorder	2 (3.3%)
+	−	−	+	Mixed disorder	1 (1.6%)
+	+	+	+	Mixed disorder	1 (1.6%)
Data are expressed as no. (%) CFR, coronary flow reserve; IMR, index of microvascular resistance.

 

The association between epicardial vasospasm and structural microvascular dysfunction (IMR ≥ 25) was the most prevalent combination in cases of mixed disorder (11/12). In turn, this endotype, in continuous thermodilution measurements, showed significant differences compared to the normal pattern, with reduced absolute flow values and elevated resistances (figure 3B) indicative of more serious structural and functional damage.

Concordance among the different indices of microvascular function

The ROC curve analysis of absolute coronary blood flow (Q) with respect to CFR < 2 determined an optimal cut-off value of 170 mL/min (a 64% sensitivity, and a 52% specificity) with an area underthe curve of 0.50 (95% confidence interval [95%CI], 0.33-0.66;P = .97), therefore showing no diagnostic utility.

Given the recent proposal to consider the cut-off value of CFR < 2.57,7 the analysis was performed using this threshold as the reference. In addition, no significant concordance was seen (area under the curve of 0.45 [95%CI, 0.30-0.61;P = .56]).

Regarding R with respect to IMR, an area under the curve of 0.67 (95%CI, 0.51-0.82;P = .04) was obtained, which was indicative of a weak yet significant diagnostic concordance (figure 4). The estimated optimal cut-off value was 435 WU, which was consistent with an 81% sensitivity and a 57% specificity. A total of 66% of cases with IMR ≥ 25 were categorized correctly using this index.

Figure 4. Analysis of the R cut-off value > 435 WU to predict IMR ≥ 25, and scatter plot showing the correlation between IMR and R. IMR, index of microvascular resistance; R, microvascular resistance.

 

The absence of an association between Q and CFR was confirmed in correlation tests (Spearman’s rho correlation coefficient= -0.02; 95%CI, -0.24-0.25;P = .99). However, a weak yet significant correlation was seen between Q and hyperemic MTT (Spearman’s rho= -0.28; 95%CI, -0.01-0.51;P = .04), and between R and IMR (Spearman’s rho= 0.28; 95%CI, 0.04-0.51;P = .03).

Complications

While the vasoreactivity test was being performed, 3 cases of transient bradycardia (5%) without clinical repercussions and 2 episodes of atrial fibrillation (4%) were reported, 1 of them self-limited while the other required sedation and electrical cardioversion. After the administration of regadenoson, most patients experienced some degree of discomfort, which was well-tolerated and reversed with the administration of 100 mg of intravenous theophylline. No other complications or adverse effects were reported.

DISCUSSION

This study confirms that a high percentage of patients with symptoms or signs of INOCA show microvascular dysfunction or vasospasm in invasive functional testing, and that it is feasible and safe to perform (figure 5).

Figure 5. Study design, endotype-based classification, and analysis using the ROC curve. AUC, area under the curve; CFR, coronary flow reserve; IMR, index of microvascular resistance; INOCA, ischemia with nonobstructive coronary artery disease; Q, absolute coronary blood flow; R, microvascular resistance.
* P < .05.

 

The percentage of patients with microcirculation or vasomotility alterations found in our study (77%) is consistent with former studies of patients with angina without obstructive coronary artery disease (64% to 89%8-11).

Vasoreactivity test

Some groups systematically use a dose of 200 µg of intracoronary acetylcholine to perform the vasoreactivity test; in our study, the high dose was established at 100 µg according to the COVADIS group, the CorMicA protocol, and the technical document of the Spanish Society of Cardiology Working Group on Cardiac Catheterization and Interventional Cardiology, which highlights its high sensitivity and specificity rates (90% and 99%, respectively).12 As a matter of fact, the high prevalence of positive results seen in our study in the acetylcholine test (60%) is similar to that reported in other series (57% to 71%13-15). In a recent study of 110 patients, Feenstra et al.11 revealed that 62% of the patients had a pathological acetylcholine test that confirmed the presence of epicardial vasospasm and microvascular spasm (36% and 26%, respectively).

In our study, the complications associated with the vasoreactivity test in our study are not very many: 2 cases of atrial fibrillation (4%), which is consistent with the incidence rate reported by the CorMIcA trial (5%).9

Prevalence of endotypes

The most common endotype in our patients was isolated microvascular dysfunction (40%), but not as much as in the CorMicA trial (52%). These differences could be explained by the discrepancy seen in the percentage of completely normal angiographies (22% in the CorMicA vs 63% in our study) due to the possible association between non-obstructive atheromatous disease and microvascular dysfunction.16,17

The prevalence of the remaining endotypes is similar to that reported in the CorMicA trial: isolated epicardial vasospasm (17% vs 17%), and mixed disorder (20% vs 21%). A recent meta-analysis that included 14 427 patients with INOCA also shows similar percentages.18

Indices of microvascular function obtained through bolus thermodilution

The analysis of the MTT obtained with this technique (figure 2), a parameter that correlates inversely with the direct measurement of coronary flow,19 reveals an interesting finding that is consistent with the data published by Nardone et al.20: patients with low CFR have 2 differentiated phenotypes based on the IMR. On the one hand, cases with reduced CFR and elevated resistances have normal baseline flow and low hyperemic flow, which would be indicative of an insufficient vasodilation response. However, in patients with normal resistances, a reduced CFR would be indicative of an abnormally elevated resting flow with hyperemic flow in the normal range. This phenomenon can also be observed in the analysis of patients with high Q (table 3) in whom a reduced CFR can be attributed to elevated baseline flow instead of an insufficient hyperemic response.

Therefore, this subgroup probably shows inefficient or dysregulated baseline myocardial flows. This characteristic, of indeterminate cause, could have important therapeutic implications like a lack of response to vasodilator drugs.

Indices of microvascular function obtained by continuous thermodilution

The continuous thermodilution technique has evolved to the point of quantifying Q and R with a microcatheter and specific software in a simple and precise fashion. The main advantages of this method are its independence from an operator, reproducibility, and induction of hyperemia with a physiological saline solution without the need for pharmacological agents.21-24 However, its main limitation is the lack of normal reference values.

In our study, the lack of a correlation between Q and CFR could be justified by the variations described of baseline myocardial flow. Estimating the CFR requires estimating the baseline coronary flow while Q is a measurement that is representative of hyperemic flow.

The weak concordance seen in this study between Q and hyperemic MTT and between R and IMR shows how difficult it is to establish valid cut-off values for patient comparison with these indices.

With an optimal cut-off value of R in our study of 435 WU (an 81% sensitivity, and a 57% specificity), a total of 66% of cases with IMR ≥ 25 were properly categorized with this index. This value is somewhat lower compared to the one shown by Rivero et al.,25 who analyzed 120 patients and found that an R > 500 WU properly categorized 80% of the cases with IMR ≥ 25.Konst et al.26 studied 84 patients with INOCA using both thermodilution techniques only to find no correlation between the Q-R combo and IMR.

The differences seen may be explained by the fact that the quantitative variability of Q and R values among individuals mostly depends on myocardial mass. However, in positron emission tomography studies, considerable ranges were seen even after adjusting for flow and resistance values for myocardial mass. Therefore, it has been speculated that the most plausible hypothesis is the natural variation of hyperemic myocardial perfusion among individuals.27

Therefore, indices like CFR estimated by continuous thermodilution and microvascular resistance reserve are currently in the pipeline. They correlate the absolute values of flow and resistance seen during hyperemia with those obtained at rest. Nonetheless,these new parameters will still need validation in futurestudies.28,29

Limitations

The data presented here should be interpreted while understanding that this is an observational, single-center study with a small sample size. Therefore, results may be biased by confounding factors associated with a study of this nature.

The left anterior anterior descending coronary artery was considered as the pre-specified target vessel. However, in the routine clinical practice, it may be appropriate to assess other arteries in the presence of negative tests and high clinical suspicion.1

The optimal sequence in invasive functional studies has not been established yet.1 In our case, we chose to perform the acetylcholine test first to minimize the instrumentation of the artery and avoid further guidewire-induced vasoreactivity. However, the spasm and symptoms seen during the provocation test, although transient, could interfere with subsequent measurements of microvascular function. The possibility of determining CFR by continuous thermodilution was established at the beginning of our study, and it was assumed that a comparison of the CFRs obtained with both techniques would have been more appropriate.

In most bolus thermodilution studies, intravenous adenosine is used to induce hyperemia. However, we chose regadenoson because it is easy to use, following our previous experience, and because evidence says it is equivalent to adenosine.30,31

Finally, we should not overlook that this is an invasive study so potential risks associated with the examination should be weighed in. To this date, however, conducting this study has not impacted prognosis.

CONCLUSIONS

The invasive study of coronary vasoreactivity and microcirculation is feasible and safe. These studies allow us to easily recognize different endotypes of patients with INOCA and help us optimize their treatment.

The analysis of CFR, IMR, and Q combined can unmask a subtype of microvascular dysfunction characterized by an abnormally high baseline coronary flow.

The new indices obtained by continuous thermodilution show low concordance with respect to the reference indices. Therefore, future studies will be required to determine the utility of this technique.

FUNDING

None whatsoever.

AUTHORS’ CONTRIBUTIONS

All the authors contributed substantially to the study idea, design, and data mining process. In addition, all approved the manuscript final version for publication.

CONFLICTS OF INTEREST

None reported.

REFERENCES

INTRODUCTION

Percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation is the most frequent mode of coronary revascularization.

Calcified coronary lesions pose a challenge to perform successful PCI.1 Coronary calcification impedes PCI by multiple mechanisms like limiting DES lesion crossing, altering the drug elution kinetics, and interfering with optimal stent expansion. In addition, inadequate stent expansion is a powerful predictor of stent thrombosis and restenosis.2-6 Coronary calcification also increases PCI-related procedural complications (dissection, perforation, myocardial infarction), and late adverse clinical outcomes like restenosis, repeat revascularization, stent fracture, and thrombosis.1 The optimal approach for the management of calcified stenosis requires taking into account the characteristics of the lesion, calcium distribution, and the mechanism of action of every plaque-modification device. In this regard, intracoronary imaging techniques such as intravascular ultrasound and optical coherence tomography (OCT) are essential not only to evaluate the severity of calcification and its pattern, but also to optimize stenting.7

Currently, plaque-modification techniques can be categorized into a) balloon-based technologies (cutting/scoring balloons, non-compliant and super high-pressure balloons, and intravascular lithotripsy (IVL), and b) non-balloon-based technologies (rotational atherectomy [RA], orbital atherectomy, and excimer laser coronary angioplasty [ELCA]).8,9

The widespread use of these techniques and devices has been limited due to the risk of complications, the operator’s experience, and the corresponding use of health resources. Over the past few decades, RA has been the therapy of choice for resistant calcified lesions. However, the development of new technologies such as IVL or the improvement of classical therapies such as ELCA has generated uncertainty on the optimal tool to modify calcified plaques as non-randomized comparisons between these techniques have been drawn.

The objective of this randomized trial is to assess the efficacy and safety profile of intensive plaque modification with RA, IVL or ELCA before DES implantation.

METHODS

Patients and study design

The ROLLERCOASTR (Rotational atherectomy, lithotripsy or laser for the treatment of calcified stenosis) is an investigator-initiated, multicenter, prospective, and randomized clinical trial that includes 6 large volume sites. Also, it includes men and women aged ≥ 18 years with a clinical indication for PCI (stable or unstable ischemic heart disease) in vessels with reference diameters ≥ 2.5 and ≤ 4.0 mm and moderate-to-severe calcification estimated by coronary angiography. The main study exclusion criteria are ST-segment elevation acute coronary syndrome as clinical presentation, cardiogenic shock, inability to tolerate dual antiplatelet therapy for, at least, 6 months for those who are not on oral anticoagulation, impossibility to obtain informed consent from the patient or conduct, at least, a 1-year follow-up.

Patients who meet all the inclusion criteria and none of the exclusion ones will be randomized on a 1:1:1 ratio to either lesion preparation with RA, ELCA or IVL. Randomization will on a web-based platform. The complete inclusion and exclusion criteria are shown on table 1 while the study flowchart is described on figure 1.

 

Table 1. Study inclusion and exclusion criteria

Inclusion criteria
≥ 18 years old
Diameter stenosis ≥ 70% or fractional flow reserve < 0.8/non-hyperemic indexes < 0.89
Reference vessel diameter ≥ 2.5 and ≤ 4 mm
Moderate or severe calcification estimated by coronary angiography
Patients with stable coronary artery disease or non-ST-segment elevation acute coronary syndrome
Culprit lesions at native vessels or coronary bypasses
Exclusion criteria
Inability to tolerate a 6-month course of dual antiplatelet therapy in patients naïve to oral anticoagulation
ST-segment elevation acute coronary syndrome
Cardiogenic shock
Impossibility to obtain informed consent from the patient or his legal representative
Impossibility to conduct, at least, a 1-year follow-up

Figure 1. Study flowchart. ELCA, excimer laser coronary angioplasty; EP, endpoint; MACE, major adverse cardiovascular events; OCT, optimal coherence tomography; PCI, percutaneous coronary intervention.

 

Study primary and secondary endpoints

The objective of this study is to evaluate and compare the results of RA, IVL, and ELCA for the management of calcified coronary lesions. This comparison will be made by assessing the angiographic and OCT findings after the implementation of these plaque modification techniques, and DES implantation and optimization.

The primary endpoint is the comparison between RA (reference group) vs ELCA and RA vs IVL in the percentage of stent expansion measured using OCT. As secondary endpoints we’ll be analyzing the device success (successful stent implantation with minimum stent area ≥ 5.5 mm², final TIMI grade-3 flow, and no need for another plaque preparation strategy), procedural success (device success and no severe procedural complications like cardiovascular death, perioperative target vessel myocardial infarction, need for new target lesion revascularization, stent thrombosis, stroke or vessel perforation with extravasation [types II or III]), crossover from the assigned plaque modification technique to a different one, and occurrence of major adverse cardiovascular events at 1-year follow-up (cardiovascular death, target vessel myocardial infarction, target lesion revascularization or stent thrombosis). We’ll also be analyzing device success regarding the type of calcified plaque (concentric, eccentric, calcium nodule). The study primary and secondary endpoints are shown on table 2.

 

Table 2. Study main endpoints

Primary endpoint
Percentage of stent expansion measured by OCT
Key secondary endpoints
Device success (successful stent implantation with minimum stent area ≥ 5.5 mm2, final TIMI grade-3 flow, and no need for another plaque preparation strategy)
Device success depending on the type of the calcific plaque: concentric, eccentric or nodular
Procedural success (device success in the absence of procedural severe complications)
Crossover from the assigned plaque modification technique to a different one
1 year-MACE (CD, TVMI, TLR or ST)
CD, cardiac death; MACE, major adverse cardiovascular events; OCT, optical coherence tomography; ST, stent thrombosis; TLR, target lesion revascularization; TVMI, target vessel myocardial infarction.

 

Devices

• – RA: Rotablator or RotaPro System (Boston Scientific, Unites States).
• – Coronary laser: Coronary laser-emitting device (CVX-300 ELCA System, Spectranetics Inc., United States).
• – Intracoronary lithotripsy: Shockwave System, (Shockwave Medical, United States).
• – OCT system: OCT Imaging system (Abbott Vascular, United States)
• – Stents: new-generation DES are mandatory (those currently being used in participant centers during the inclusion period).

Procedure

The angioplasty will be performed following the recommendations established by the current clinical practice guidelines on the management of coronary revascularization.10 After crossing the lesion with the angioplasty guidewire, a first OCT assessment should be performed. If necessary, balloon dilatation is allowed to cross the OCT catheter. After this first OCT pullback, the use of a plaque modification technique will be required (RA, laser or lithotripsy) on a randomized basis. Afterwards, a second OCT assessment is advised to analyze the effects of the therapy. Finally, the angioplasty will be completed with the implantation of a new-generation DES. Pre or postdilatation will be left to the operator’s criterion. After stenting (in the absence of postdilatation) or after the last postdilatation (if performed), a final OCT pullback will be performed to assess the final stent expansion.

Rotational atherectomy technique

The lesion will be crossed using the RotaWire (Boston Scientific, Unites States) directly or microcatheters or coaxial balloons. The RotaWire type (RotaWire Extra Support and RotaWire Floppy) will be used based on the characteristics of the plaque, the support required, and the operator’s preferences. Afterwards, the rotational atherectomy technique will be used based on the current recommendations.11 A 0.5:0.6 ratio between the burr and the vessel is advised. The rotational speed recommended is between 135 000 rpm and 180 000 rpm. Decelerations > 5000 rpm should be avoided. The burr should be advanced gradually with easy back-and-forth moves. Rotablation time should be < 20 seconds with pauses in between each cycle. Once rotablation has been performed, the burr should be removed with the Dynaglide mode on.

Intracoronary lithotripsy technique

The Shockwave balloon (Shockwave Medical, Inc., United States) is a 12 mm-long angioplasty balloon with 2.5 mm to 4 mm diameters. It can be mounted over a 0.014 in guidewire. Mechanical energy is transmitted to the lesion when the Shockwave balloon contacts the artery intima layer and cracks superficial and deep calcium layers. Therefore, the Shockwave balloon/reference vessel diameter ratio should be 1:1.12 Performing an OCT assessment prior to selecting the size of the balloon is also advised. Predilatation with balloons of smaller diameters is allowed to facilitate the passage of the lithotripsy balloon.

Once the Shockwave balloon is on the lesion, it is inflated at a pressure of 4 atm . Up to 80 pulses per balloon can be administrated (8 runs of 10 pulses). After every run (≤ 10 pulses), the Shockwave balloon is inflated at 6 atm and, after deflation, a new cycle can be applied if necessary. A minimum of 20 pulses per lesion is advised.

Laser technique

The size of the ELCA catheter will be selected considering the diameter of the target vessel on a 0.5-0.6 ratio with respect to its diameter.13 However, 0.9 mm catheters will be prioritized because of their greater crossing capabilities and capacity to emit laser energy with greater fluence (80 mJ/mm²) at the maximum pulse repetition rate (80 Hz). Regarding the device settings, it is recommended to start by applying a 60 mJ/mm² fluence and a 60 Hz pulse repetition frequency that can go up to 80 mJ/mm² and 80 Hz based on the operator’s criterion. Energy pulses will be released while the catheter slowly moves forward through the lesion at a rate of 0.5 mm/s, thus allowing proper energy absorption and plaque modification. Retrograde application is also feasible, especially in severe lesions with antegrade resistance. Saline-infusion technique is advised. Both blood and iodinated contrast contain non-aqueous cellular macromolecules like proteins that absorb most of the energy released by the laser creating microbubbles that increase the chances of traumatic dissection.14 On the contrary, the saline solution facilitates the passage of light from the tip of the catheter to the tissue without interferences or microbubbles at that level. Therefore, the saline solution infusion technique is used to safely control the energy that is being released, and minimize the risk of dissection.15 In order to wash out the blood from the catheter-based tissue interface the catheter needs to be properly intubated and the saline solution properly infused during laser application. The application of laser to blood or contrast is allowed in selected cases of uncrossable or undilatable lesions and left to the operator’s criterion.16 At the end of the procedure, parameters like the number of pulses administered, the time of therapy, fluence, and repetition rate will need to be collected.

Crossover

Combination of several plaque modification techniques is permitted as they have shown to be complementary in some cases.17,18 If a different plaque preparation technique is required, the technique should be changed based on why the first technique failed (table 3). This switch is consistent with the routine clinical practice. All the material and techniques used will be registered for further analysis.

 

Table 3. Crossover of plaque modification techniques

Failed early technique	Reason for failure	2nd technique
Rotational atherectomy	Uncrossable lesion with the rotablation olive-shaped burr	ELCA
	Undilatable lesion (suboptimal balloon expansion after rotablation)	Lithotripsy
Lithotripsy	Uncrossable lesion with Shockwave balloon (despite predilatation, if necessary)	Rotational atherectomy
	Undilatable lesion (suboptimal balloon expansion after lithotripsy)	ELCA
ELCA	Uncrossable lesion with ELCA	Rotational atherectomy
	Undilatable lesion (suboptimal balloon expansion after ELCA)	Lithotripsy
ELCA, excimer laser coronary angioplasty.

 

Optical coherence tomography image acquisition and stent optimization protocol

Intravascular OCT is performed using a commercially available system (the ILUMIEN OPTIS, OPTIS Integrated, OPTIS Mobile systems, OPTISIntegrated Next, OPTISMobile Next Abbott Vascular) that incorporates a rapid exchange catheter (Dragonfly OPTIS, Dragonfly OpStar Imaging Catheter; Abbott Vascular) and an integrated pullback system (18-36 mm/s). It acquires images at high axial resolution (~15 μm) with blood displacement. A total of 3 pullbacks are advised before and after using the plaque modification technique (to describe the calcified lesion and the effects of each modality over it, respectively), and optimizing the DES implanted. The automated OCT-angiography co-registration (where available) will be used, and recommendations for PCI guidance with OCT19 will be left to the operator’s criterion. Stent expansion can be estimated using 2 methods (figure 2): 1) dual method: it identifies the stented region and splits it in half. Minimum lumen expansion in the stented area (EXP) is estimated for each half (minimum stent area in each segment divided by the proximal or distal reference area x 100). The center point can be moved by the user (both the minimum stent area and the EXP recalculate automatically); 2) tapered mode: reference lumen profile is estimated based on the distal and proximal reference frame mean diameter and side branch mean diameter in between. The software automatically displays the minimum stent area and identifies the frame with the minimum lumen expansion in the stented area (EXP). A colored expansion indicator automatically pops up when a stent is detected. Automatic detection: minimum stent area frame/Automatic detection of minimum expansion frame (EXP).

Figure 2. Stent expansion estimate by optical coherence tomography. EXP, stented area. MSA, minimum stent area. Modified with permission from Abbott Vascular from User Manual of Ultreon 1.0, and User Instructions of AptiVue Software.

 

With stent lengths > 50 mm, the dual method is preferred. With stent lengths < 50 mm the tapered method is often used. If the dual method is used, the stent expansion percentage of both segments is recorded being considered for analysis the lowest of the 2.

Follow-up and clinical definitions

In-hospital and follow-up outcomes were prespecified in the online database, complied with the requirements set forth by the Spanish Data Protection Act, and were only accessible to participant operators and study coordinators.

After each PCI, electrocardiographic and cardiac biomarker seriation will be performed. Clinical assessment will be conducted 1, 6, 12 months after PCI. Angiographic follow-up will be only clinically driven in patients with new symptoms, ventricular function worsening or new ischemia in non-invasive tests.

Calcification is defined as moderate if radiopacities are noted only during the cardiac cycle before contrast injection, and severe if radiopacities are noted without cardiac motion before contrast injection often compromising both sides of the arterial lumen.

Device success is defined as successful stent implantation with minimum stent areas ≥ 5.5 mm² by OCT, final TIMI grade-3 flow, and no need for another plaque preparation strategy.

Procedural success is defined as device success and no severe procedural complications: cardiovascular death, perioperative target vessel myocardial infarction, need for new target lesion revascularization, stent thrombosis, stroke or vessel perforation with extravasation [types II or III]).

Other procedural complications included ventricular arrhythmias or hemodynamic instability during PCI, major bleeding (bleeding requiring transfusion, vasopressors, surgery or percutaneous intervention), and flow limiting dissection.

Major cardiovascular adverse events include cardiovascular death, target vessel myocardial infarction, stent thrombosis or target lesion revascularization. All deaths were considered cardiac unless other specific causes were documented. Myocardial infarction was defined according to the current recommendations made,20 and only those associated with the targer lesion, perioperative or at follow-up were considered. Target lesion revascularization or stent thrombosis were defined according to the criteria established by the Academic Research Consortium.21

Primary outcome assessment will be conducted in a central core laboratory by looking at the OCT imaging after stenting. All medical data will be codified anonymously and stored, and confidentiality will be protected at any time in observance of the current legislation. Both the clinical events committee and the independent core laboratory will be blinded to the treatment arm.

Secondary outcome assessment will be performed by assessing both the angiography and the OCT in a central core laboratory and through on-site or phone clinical follow-up sessions with the patients.

Statistical considerations

Sample size determination

This is a non-inferiority study. We expect to obtain similar outcomes regarding stent expansion using rotational atherectomy, laser, and intracoronary lithotripsy. The sample size was estimated based on the design of the trial and the results of former studies.22-24 There are no standard criteria to define stent expansion in the routine clinical practice. In a recent expert consensus document, stent expansion > 80%19 was considered appropriate. However, most former studies did not reach this threshold. In the ILUMIEN II trial, the mean stent expansion measured by OCT was 72.8% with a standard deviation of 12.6.24 To calculate the size of the sample, we assume an α error of 0.05 and a β error of 0.2 (80% power), a margin of irrelevance (ε) of 7, and losses of 10% due to measurement difficulty or impossibility to complete the intervention. With these parameters we estimate a sample size of 56 cases per group.

Statistical analysis

The study primary endpoint analysis will be conducted by lesion and intention-to-treat with a 1-sided Student t test and an alpha coefficient of 0.05 between the reference group and the other groups (ELCA, and IVL). An analysis of the primary endpoint per protocol will be conducted and presented for consistency purposes. If the hypothesis of non-inferiority is confirmed, a 2-sided superiority analysis will be conducted. Clinical endpoints will be analyzed by patient.

Quantitative variables following a normal distribution will be expressed as median ± standard deviation. Those not following such distribution will be expressed as median and minimum and maximum values. Qualitative variables will be expressed as absolute values and frequencies.

P values < .05 will be considered statistically significant, and the 95% confidence interval of the study variables will be estimated. The Kolgomorov-Smirnov test will be used to confirm the adjustment of variables to normal distribution. Regarding mean comparisons, the Student t test or the non-parametric Mann-Whitney U test (in case of qualitative dichotomous variables), and the ANOVA test or the non-parametric Kruskal Wallis test (in case of qualitative non-dichotomous variables) will be used. Regarding the bivariate analysis of qualitative variables, the chi-square test or Fisher’s exact test will be used. If necessary, the linear correlation among the different quantitative variables will be performed using Pearson correlation coefficient or Spearman’s correlation.

Regarding the multivariate analysis, the Cox regression analysis with forward, stepwise selection will be used drawing event-free survival curves using the Kaplan-Meier estimator. Variables will be considered potential predictors of risk in the multivariate model in the presence of a statistically significant correlation in the univariate analysis or a trend towards significance. The SPSS statistical software (version 20.0, SPSS Inc) will be used for all the estimates.

Organization and ethical concerns

The study protocol has been approved at each participant center by its internal ethics committee. All patients will have to give their informed written consent prior to their participation. The study is an investigator-initiated trial and follows the good clinical practice guidelines applicable to epidemiological studies. The rights and integrity of participants shall be guaranteed at all time while data confidentiality shall be safeguarded in observance of EU directives, the Declaration of Helsinki, as well as local rules and regulations. The ROLLERCOASTR trial is registered at clinicaltrials.gov wit identifier NCT04181268. The study promoter is Fundación EPIC. The study is supported by unrestricted grants from Fundación EPIC. The steering committee is the trial main decision-making committee and has final word on the medical and scientific approach to the trial. The clinical events committee includes interventional cardiologists who don’t participate in the trial and are blinded to the randomized therapy. The clinical events committee will be responsible for developing specific criteria for the adjudication of the study clinical events and endpoints as per protocol. All members of the clinical events committee will be blinded to the study primary outcomes.

DISCUSSION

At least a third of all coronary lesions requiring PCI show significant calcification.9 As a matter of fact, this is probably one of the greatest challenges interventional cardiologists face to this date. Different tools are available to prepare calcified plaques. These techniques are increasingly used in the routine clinical context based on the operator’s experience or availability25 since there are barely any comparative studies on this regard.

The role of rotational atherectomy is to facilitate stenting in calcified non-dilatable lesions. The technology has evolved for over 20 years now, and lots of patients have been treated with it. The setback is that it has a longer learning curve compared to other plaque modification techniques and requires a specific guidewire. The evidence available on RA in the calcified lesion setting shows higher procedural success rates compared to conventional or modified balloons with almost the same clinical outcomes. However, even the most recent trials have important limitations as a limited use of intracoronary imaging techniques and new-generation DES.22,23

The arrival of laser to treat atherosclerosis goes back to the 1980s to treat lower limb ischemia at the beginning, and then coronary artery disease.26 However, both catheters and the techniques were rudimentary, and complications were a common thing. The early randomized clinical trials that compared ELCA to RA or balloon angioplasty (before the stent era) did not show favorable outcomes.27 The refinement of this technology followed by the introduction of safe laser-based techniques has improved its results. However, no direct comparisons have been drawn over the past few years. Although, traditionally, severe calcification has been a non-favorable scenario for ELCA, this technique has repeatedly obtained good results in settings in which calcium is a common finding: balloon failure (uncrossable or undilatable lesions), in-stent restenosis, underexpanded stents or chronic total coronary occlusions.13 Excimer laser releases energy in the UV range in very short pulses (nanoseconds). Billions of molecules per pulse are broken. Absorption depth is 50 µm, thus reducing the risk of collateral tissue damage (compared to previous infrared lasers). Laser ablates the atherosclerotic material mediated by 3 different mechanisms: photochemical (fracture of molecular bonds): the UV light pulse hits the plaque and is highly absorbed with each photon generated carrying sufficient energy to break molecular bonds; photothermal (tissue vaporization): molecular bonds also vibrate during the absorption process resulting in heat. Intracellular water is vaporized leading to cell rupture and the creation of a vapor bubble, and photokinetic (clearance of byproducts): the rapid expansion and collapse of the vapor bubble further breaks down the plaque, but it also helps clear byproducts of ablation like water, gases, and small particles. Laser effect is amplified especially when it acts directly on blood or a contrast agent. Therefore, to reduce the risk of coronary artery dissection, laser ablation is often performed during the continuous infusion of saline solution.13 One advantage of laser is its short learning curve. It can be used through conventional 0.014 in guidewires in a rapid-exchange fashion and conventional 6-Fr guiding catheters. In addition, most of these particles are small enough to be cleared by the reticuloendothelial system, thus minimizing the risk of distal microembolization (1 more advantage compared to other plaque modification techniques).13

Lithotripsy is the latest technology that has become available to treat heavily calcified lesions. It emits pulsatile mechanical waves through emitters integrated in a semi-compliant balloon that is initially inflated at 4 atm. Afterwards, energy pulses are applied, and the vibrations produced interact with the atherosclerotic plaque breaking down both the superficial and deep calcium deposits.9 This effect on deep calcium deposits is one of the greatest advantages of lithotripsy over other techniques. Also, this technique learning curve is short since it’s based on a well-known coronary balloon technology. The DISRUPT CAD trials12 have demonstrated the safety and efficacy profile of this technique treating heavily calcified lesions and its use has grown exponentially ever since. The main limitation of this technique is that, as it is a balloon-based technology with a smaller diameter of 2.5 mm, extremely tight stenoses can hamper its use as a first-line therapy, thus needing predilatation with lower profile balloons, and even with RA17 or laser18 combined to overcome this problem.

Intracoronary imaging modalities allow more accurate assessments of coronary artery disease compared to conventional angiography and give us essential information for PCI planning. This is particularly relevant during the management of calcified and complex lesions impacting the results of the angioplasty and the patient’s prognosis28 by optimizing DES implantation, thus leading to better stent expansion, vessel wall apposition, and eventually a greater luminal area. The OCT has greater spatial resolution9 compared to the intracoronary ultrasound and has proven useful showing the effect of plaque modification therapies and stent optimization. All these reasons and the lack of use of intracoronary imaging techniques in previous plaque modification techniques has led us to using OCT to assess the study primary endpoint: percentage of stent expansion.

The ROLLERCOASTR trial will compare the 3 strategies most used in the routine clinical practice to treat lesions with moderate-to-severe calcifications. In addition, it will provide us with information on the effect of each of these strategies and the specific settings where they can be more useful. To this end, an intracoronary imaging study with an OCT will be performed to know the specific substrate of calcification and the type of plaque on which the therapy is performed as well as the effects this therapy will have. The study hypothesis is that the 3 modalities complement each other and have different effects depending on the characteristics of the lesion. At manuscript submission, a total of 135 patients have been included.

CONCLUSIONS

The ROLLERCOASTR is a prospective, multicenter, randomized clinical trial designed to compare the safety and efficacy profile of 3 plaque modification techniques in the moderate-to-severe coronary calcification setting: RA, ELCA, and IVL. The study primary endpoint is stent expansion evaluated by OCT. The secondary endpoints are device success, procedural success, crossover rate among techniques, and the occurrence of major adverse cardiovascular events at 1-year follow-up (cardiac death, target vessel myocardial infarction, need for new target lesion revascularization or stent thrombosis). We will also be describing the effects of the 3 imaging modalities in calcified lesions with OCT. Enrollment will end in 2023.

FUNDING

The study is supported by unrestricted grants from Fundación EPIC.

AUTHORS’ CONTRIBUTIONS

A. Jurado-Román: conceptualization, original draft, review, and editing. A. Gómez-Menchero, I.J. Amat-Santos, J. Caballero-Borrego, S. Ojeda, and R. Ocaranza-Sánchez: drafting, review, and editing. S. Jiménez-Valero, G. Galeote, and R. Moreno: conceptualization, drafting, review, and editing.

CONFLICTS OF INTEREST

S. Ojeda and R. Moreno are associate editors of REC: Interventional Cardiology. The journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. S. Ojeda has received consulting fees and participated on Medtronic and Edwards Lifesciences Data Safety Monitoring Board or Advisory Boards, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript drafting or educational events organized by Philips, Biomenco, and World Medica. R. Moreno has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript drafting or educational events organized by Medtronic Inc, Boston scientific, Abbott vascular, Biosensors, Biotronik, Edwards Lifesciences, AMGEN, Astra Zeneca, Daiichi Sankyo New Vascular Therapies, and Biosensors. A. Jurado-Román has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript drafting or educational events organized by Boston Scientific, Shockwave, Philips, Biotronik, Biomenco, Abbott, and Medtronic. A. Gómez-Menchero, J. Caballero-Borrego, R. Ocaranza, G. Galeote, and S. Jiménez-Valero declared no conflicts of interest whatsoever. I. Amat-Santos has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript drafting or educational events organized by Boston Scientific.

REFERENCES

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).

rr

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